The kidneys are two organs that filter the blood and excrete waste products and excess water as urine. The kidneys are situated at the back of the abdominal cavity, on either side of the spine.
Each kidney is surrounded by a fibrous capsule and is made up of an outer layer (cortex) and an inner layer (medulla).The cortex contains specialized capillaries (tiny blood vessels) called glomeruli; these vessels, together with a series of tubules, make up the nephrons, the filtering units of the kidney. Urine, the waste product from filtering, passes through tubules to the medulla, collects in an area called the renal pelvis, then travels through tubes called ureters to the bladder.
The nephrons filter blood under pressure and then selectively reabsorb water and certain other substances into the blood. Urine is formed from substances that are not reabsorbed. The kidneys also regulate the body’s fluid balance. To do this, they excrete excess water, and when water is lost from the body (for example, as a result of sweating), they conserve it. In addition, they control the body’s acid–base balance by adjusting urine acidity. Lastly, the kidneys produce hormones involved in the regulation of red blood cell production and blood pressure.
The kidneys’ main function is to filter the blood. This activity is essential in regulating the body’s fluid balance and acid-base balance. Each kidney has about 1 million nephrons, where the filtering takes place. A nephron consists of a knot of capillaries, which is called a glomerulus, and a tubule, where urine is formed. Urine drains out of the kidney via the ureter; the normal daily output is 1 to 2 litres.
The kidneys are susceptible to a wide range of disorders. Only one normal kidney is needed for good health, however, so disease is rarely life-threatening unless it affects both kidneys and is at an advanced stage.
Hypertension (high blood pressure) can be both a cause and an effect of kidney damage. Other effects of serious damage include nephrotic syndrome and kidney failure.
Congenital and genetic disorders
Congenital abnormalities, such as duplex kidney (in which a kidney is partially duplicated) and horseshoe kidney (in which the two kidneys are joined at their base), are fairly common and usually harmless. Serious inherited disorders include polycystic kidney disease , in which multiple cysts develop on both kidneys; and Fanconi’s syndrome and renal tubular acidosis,in which the kidney tubules function abnormally so that certain substances are inappropriately lost in the urine.
Impaired blood supply
Various conditions may cause damage to, or lead to blockage of, the blood vessels within the kidneys, impairing blood flow. Such conditions include shock, haemolytic–uraemic syndrome, poly-arteritis nodosa, diabetes mellitus, and systemic lupus erythematosus. Impaired blood flow through the kidneys can lead to tissue damage, hypertension, and kidney failure.
Glomerulonephritis includes a group of autoimmune disorders (in which the immune system attacks the body’ s own tissues) that cause the filtering units of the kidneys to become inflamed and unable to function normally.
Allergic reactions to drugs, prolonged treatment with analgesic drugs (pain-killers), and some antibiotics can damage kidney tubules.
Noncancerous kidney tumours are rare; kidney cancer is uncommon.
A cancerous tumour of the kidney. Most kidney cancers originate in the kidney itself, but in rare cases cancer spreads to the kidney from another organ.
There are three main types of cancer that affect the kidney: renal cell carcinoma, nephroblastoma, and transitional cell carcinoma.
Renal cell carcinoma
Also known as hypernephroma or adenocarcinoma, this is the most common type of kidney cancer. It usually occurs in people over the age of 40 and affects twice as many men as women. A common symptom is blood in the urine. There may also be pain in the back, a lump in the abdomen, fever, or weight loss. The cancer often spreads to the lungs, bones, liver, and brain.
Nephroblastoma (also called Wilms’ tumour) is a fast-growing tumour that mainly affects children under five years old. Nephroblastoma sometimes runs in families, but its cause is unknown. Symptoms may include swelling of the abdomen, abdominal pain or discomfort, and, occasionally, blood in the urine. Nephroblastoma may spread to the lungs, liver, and brain.
Transitional cell carcinoma
This type of kidney cancer arises from cells lining the renal pelvis (the urine-collecting system within the kidney); it is most common in smokers or in people who have taken certain analgesic drugs for a long time. Blood in the urine is a common symptom; hydronephrosis (distension of the kidney with urine) may occur due to blockage of the ureter.
Diagnosis, Treatment and Outlook of Kidney Cancer
The doctor will conduct a physical examination and test a urine sample for the presence of blood. Diagnosis can be confirmed by ultrasound scanning, CT scanning, MRI, or intravenous urography. All types of kidney cancer require surgical removal of the affected kidney and sometimes also of the ureter.Any remaining cancerous cells are destroyed using radiotherapy and/or treatment with anticancer drugs (for example, interleukin or medroxyprogesterone are given to treat some cases of renal cell carcinoma). Survival rates vary, depending on the type of cancer and how early treatment is commenced. In the case of nephroblastoma, about four in every five affected children survive; cure rates for this form of kidney cancer are relatively high even if it has spread by the time diagnosis is made.
Diabetes mellitus is the commonest cause of kidney failure in developed countries. Other metabolic disorders, such as hyperuricaemia, may cause kidney stones to form (see calculus, urinary tract).
Infection of the kidney is called pyelo-nephritis and can be a complication of cystitis. A predisposing factor to infection is obstruction of urine flow through the urinary tract due to a kidney or ureteral stone, tumour, or congenital defect.
Hydronephrosis (a kidney swollen with urine) is caused by obstruction of the urinary tract. Crush syndrome is a condition in which kidney function is disrupted by proteins released into the blood from damaged muscle.
Kidney disorders are investigated by kidney imaging techniques such as ultrasound scanning, urography, angiography, and CT scanning or MRI; by kidney biopsy (removal of a small amount of tissue for analysis; by blood tests; and by kidney function tests such as urinalysis.
Kidney Function Tests
Tests that are performed to investigate kidney disorders. Urinalysis is a simple test in which a urine sample is examined under a microscope for blood cells, pus cells, and casts (cells and mucous material that accumulate in the tubules of the kidneys and pass into the urine). Urinalysis is used to test for substances, such as proteins, that leak into the urine when the kidneys are damaged. Kidney function can be assessed by measuring the concentration in the blood of substances that the kidneys normally excrete, such as urea and creatinine; by creatinine clearance, in which levels of creatinine in the blood are compared with creatinine excreted in urine over 24 hours; and by kidney imaging with radioisotope.
Techniques for visualizing the kidneys, usually performed for diagnosis. Ultrasound scanning is often the first investigation and can be used to identify kidney enlargement, a cyst or tumour, and the site of any blockage. Conventional X-rays show the outline of the kidneys and most kidney stones, while intravenous urography shows the internal anatomy of the kidney and ureters. Angiography is used to image blood circulation through the kidneys. CT scanning and MRI provide detailed cross-sectional images of kidney tissue and the urine-collecting system, and can show abscesses or tumours. Two types of radionuclide scanning areused: DMSA and DTPA scanning. DMSA is given by intravenous injection and binds to cells in the kidney tubules, giving a single, static picture of the kidneys. DTPA, also given intravenously, is filtered in the kidneys and passes out in the urine. Pictures taken at intervals record its clearance by the kidney, providing an indicator of kidney function The various kidney imaging techniques can provide different types of information to help doctors investigate and diagnose kidney disorders.
MRI and CT scanning
These techniques produce cross-sectional images of body tissues, displayed as computer-generated pictures. They clearly show structural abnormalities such as tumours and cysts.
IVU (Intravenous urography)
This is a type of X-ray in which fluid containing a contrast medium (a substance opaque to X-rays) is introduced into the urinary system, then X-rays are taken. The images show how the fluid moves through the kidneys, ureters, and bladder, and can show up any obstructions, such as stones in the urinary tract.
This is a quick technique, which provides clear images of the structure of the kidney. It can reveal fluid-filled structures such as cysts, which can be clearly differentiated from the kidney tissue surrounding them.
This produces coloured images to show the functioning of the kidneys. (This scan is taken from the back.) Areas that are brighter than normal show overactive cells, as in a tumour; colours that are less intense than normal show underactivity, as in kidney failure.
A procedure in which a small sample of kidney tissue is removed and examined under a microscope. Kidney biopsy is performed to investigate and diagnose serious disorders such as glomerulonephritis, proteinuria, nephrotic syndrome, and acute kidney failure, or to assess the kidneys’ response to treatment. There are two basic techniques: percutaneous needle biopsy, in which a hollow needle is passed through the skin into the kidney under local anaesthesia; and open surgery under general anaesthesia
A reduction in the function of the kidneys. Kidney failure causes waste products such as urea and excess fluid to accumulate in the body, and also produces other chemical imbalances in the blood and body tissues.
Kidney failure can be acute or chronic. In the acute form, kidney function often returns to normal once the underlying cause has been discovered and treated. In chronic kidney failure, however, kidney tissue is progressively damaged over several months or years. This condition may develop into end-stage kidney failure, a life-threatening condition in which kidney function is usually irreversibly lost.
Causes of acute kidney failure include a severe reduction in blood flow to the kidneys, as occurs in shock; an obstruction to urine flow, for example due to a bladder tumour; or certain rapidly developing types of kidney disease, such as glomerulonephritis. Chronic kidney failure can be the result of a disease that causes progressive damage to the kidneys, such as polycystic kidney disease, diabetes mellitus, and hypertension (high blood pressure), or from longstanding obstruction to urine flow.
The most obvious symptom of acute kidney failure is oliguria (a reduced volume of urine). Urea and other waste products build up in the blood and tissues causing drowsiness, nausea, and breathlessness. Symptoms of chronic kidney failure develop more gradually, and may include nausea, loss of appetite, and weakness. The kidney damage leads to conditions such as anaemia and hyperparathyroidism.
Diagnosis and Treatment
A person with suspected kidney failure will initially need blood and urine tests. Other tests, such as kidney biopsy (examination of a tissue sample) and intravenous urography (taking X-rays of the urinary tract), may be carried out to identify the cause of the kidney failure if this is not already obvious.
If acute kidney failure is due to a sudden reduction in blood flow, blood volume and pressure can be normalized by saline intravenous infusion or blood transfusion.If there is an obstruction in the urinary tract, surgery may be needed.
Acute kidney disease may be treated with corticosteroid drugs. Treatment may also involve diuretic drugs and temporary dialysis (artificial purification of the blood). A high-carbohydrate, low-protein diet with controlled fluid and salt intake is important in the treatment of acute and chronic kidney failure, because this reduces the workload on the kidneys. For end-stage kidney failure, long-term dialysis or a kidney transplant is the only effective treatment.
- The Clinical Presentation of Kidney Disease in detail
- Acute kidney injury (acute renal failure)
- Kidney disease in the tropics
- Disorders of renal calcium handling, urinary stones, and nephrocalcinosis
- Kidney cancer
Chronic Kidney Disease - summary - technical
Definition—chronic kidney disease (CKD) is defined as kidney damage lasting for more than 3 months characterized by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR).
Staging—CKD has been subdivided into five stages depending on the estimated GFR (eGFR), but in brief: CKD 1 is eGFR greater than 90 ml/min (per 1.73 m2) with other evidence of renal disease; CKD stage 2 is eGFR 60 to 89 ml/min, with other evidence of renal disease; CKD stage 3 is eGFR 30 to 59 ml/min CKD stage 4 is eGFR 15 to 29 ml/min and CKD stage 5 is eGFR less than 15 ml/min. CKD 3 can be divided into 3A (eGFR 45–59) and 3B (eGFR 30–44), and the suffix ‘p’ can be added to any stage to denote proteinuria (ACR >30mg/mmol, PCR >50mg/mmol).
Epidemiology—mild CKD is common, with about 10% of the population of the United States of America having CKD 1, 2, or 3 (combined), but advanced CKD is relatively rare (about 0.2% are receiving renal replacement therapy). Patients with CKD 1, 2, or 3 are at relatively low risk of progressing to require renal replacement therapy, but are at high risk of death from cardiovascular disease.
Aetiology—the causes of chronic renal failure recorded in various national registries are diabetes mellitus (22–45%), glomerulonephritis (10–23%), hypertension (5–25%), chronic pyelonephritis (0.5 to 7%), adult polycystic kidney disease (2–7%), renal vascular disease (2–7%), other recognized conditions (13–15%), and unknown causes (4–26%). However, these data are flawed for many reasons: diagnoses are often allocated as ‘best guesses’ by clinicians, there is no universal agreement on the meaning of terms such as ‘pyelonephritis’, glomerulonephritis may be diagnosed without histological proof, and hypertension is often cited when it may be no more than a consequence of whatever caused the renal failure.
Compensatory mechanisms and their consequences—as kidney function gradually fails, these generally maintain acceptable health until the GFR is about 10 to 15 ml/min, and patients will not usually die of renal failure until the GFR is less than 5 ml/min. Despite a widened range of single-nephron GFR in damaged or diseased kidneys, glomerular and tubular function remains closely integrated in all individual nephrons (the ‘intact nephron hypothesis’). However, the functional adaptations required to maintain overall homeostasis come at a price (the ‘trade-off hypothesis’), with the ‘hyperfiltration hypothesis’ most clearly articulating how these adaptive changes lead, in the long run, to glomerulosclerosis and tubulointerstitial fibrosis and progressive decrease in GFR.
Pathophysiological changes—these include impairment in: (1) concentration and/or dilution of the urine; (2) excretion and/or conservation of sodium; (3) excretion of potassium, with hyperkalaemia often the immediate life-threatening consideration in the management of patients with renal failure; (4) excretion of acid; (5) calcium/phosphate/vitamin D/bone homeostasis; (6) erythropoietin production, leading to renal anaemia; (7) excretion of many substances and metabolites that act as ‘uraemic toxins’; and (8) a wide range of endocrine functions.
Prevention of progression
Specific and general measures—in some patients, measures to conserve renal function may be specific to the cause of renal impairment, e.g. relief of obstruction, but it is probable that all patients will benefit from good blood pressure control and (when relevant) measures to reduce proteinuria, which is not only a marker but a promoter of progression of CKD.
Blood pressure and proteinuria—there is limited information on the target blood pressure to be achieved in patients with chronic kidney disease, but the consensus is that the lower the blood pressure, the better—as long as this can be achieved without unacceptable side effects. The European Society of Hypertension/European Society of Cardiology guidelines recommend a target of less than 130/80 mmHg, and even lower if there is significant proteinuria, which should be lowered as much as possible, preferably to less than 1 g/24 h (roughly equivalent to an albumin:creatinine ratio (ACR) of less than 60 mg/mmol or a protein:creatinine ratio (PCR) of less than 100 mg/mmol). Combination therapy with several antihypertensive agents (including loop diuretics) is usually required, but there is good evidence that the regimen should contain an angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker, which have antiproteinuric effects, if these can be tolerated (hyperkalaemia being the most common reason why they cannot be used in this context).
Medical management of the consequences of CKD
Diet—only patients with oliguric endstage renal failure need to restrict their fluid intake precisely. It is sensible to recommend modest dietary sodium restriction (100 mmol/day) in most cases. Patients with a tendency to hyperkalaemia should be offered advice regarding a low-potassium diet (with particular care taken if they are given medications that induce hyperkalaemia). Chronic acidosis will benefit from treatment with alkali. Malnutrition is common in advanced CKD, can be detected by serial monitoring of body weight and serum albumin concentration, and is best treated by initiating renal replacement therapy.
Chronic kidney disease mineral and bone disorders (MBD)—these including osteitis fibrosa, osteomalacia, adynamic bone disease, and osteopenia, the impact of which extends beyond the bones to cardiovascular structure and function, with increased mortality. Pathogenesis is complex but includes phosphate retention, deficiency of active forms of vitamin D, hypocalcaemia, and the development of hyperparathyroidism. Secondary hyperparathyroidism can be prevented by giving: (1) cholecalciferol 1000 U/day if serum 25-(OH)D3 is low; (2) calcium carbonate 0.5 to 1.0 g with each meal if plasma calcium is decreased and/or plasma phosphate is increased; (3) calcium-free phosphate binder, e.g. sevelamer or lanthanum carbonate, if serum phosphate is increased and plasma calcium is normal or high; or (4) calcitriol 0.125 to 0.25 µg/day, or equivalent doses of alfacalcidol or other active vitamin D analogues, if serum intact parathyroid hormone (PTH) is consistently above target ranges and serum calcium/phosphate is normal (spontaneously or after intervention).
Advanced hyperparathyroidism can be treated by: (1) normalizing serum calcium and phosphate levels if serum intact PTH is constantly above target range; (2) reducing serum phosphate, if this is elevated, by using phosphate binders, dietary restriction, and increased dialysis; (3) reducing serum calcium if this is elevated by reducing/withdrawing calcium-containing phosphate binders and active vitamin D sterols, and by reducing dialysate calcium concentration; (4) if serum calcium and phosphate have been normalized and elevated intact PTH persists, by increasing dose or frequency of calcitriol or other active vitamin D sterols (e.g. alfacalcidol, paricalcitol, doxercalciferol), or alternatively administering the calcimimetic cinacalcet, which renders the calcium receptor more sensitive to calcium; and (5) if serum intact PTH fails to decrease and/or hypercalcaemia/hyperphosphataemia develop or persist, then consider cinacalcet or surgical parathyroidectomy.
Anaemia—this is common in chronic kidney disease and is particularly marked in patients with diabetes. Partial correction of such anaemia by use of erythropoiesis-stimulating agents (ESAs) improves patients’ physiological and clinical status, as well as quality of life. If a patient with chronic kidney disease has haemoglobin of less than 11 g/dl and symptoms that might be attributable to anaemia, then treatment to restore haemoglobin to the range 11 to 12 g/dl is warranted, but it has been convincingly shown in randomized studies that correction to a higher level (‘normal or near normal’) is associated with poorer outcomes and should be prevented. Treatment involves: (1) exclusion of other causes of anaemia; (2) optimization of iron status, which usually requires administration of intravenous iron; and (3) initiation and adjustment of dosage/frequency of administration of ESAs, with regular monitoring to achieve haemoglobin in the target range 11 to 12 g/dl.
Preparation for renal replacement therapy or conservative (palliative) management of terminal uraemia
Once endstage renal failure is inevitable, the patient must be prepared physically and psychologically for renal replacement therapy. In many cases it is possible to predict approximately when the endstage will be reached from consideration of the rate of renal deterioration, most easily demonstrated by plotting the reciprocal of the serum creatinine against time.
There are patients for whom dialysis is inappropriate, or who either choose not to start or to discontinue treatment. In frail patients, usually elderly and with multiple comorbidities, it is not likely that dialysis will greatly prolong life, although it can certainly lower the quality of it. The ethical and legal issues are complex and require that the patient makes the decision not to start or to discontinue treatment when fully informed and able to do so. They must be given a realistic account of what dialysis can achieve, what it cannot achieve, and at what cost—access, travel, restrictions, and complications. These conversations can be difficult and cannot be hurried, it being critically important that the patient (and their relatives/friends) does not get the entirely erroneous impression that dialysis means that ‘the doctors care and I’ll live for ever’, whereas no dialysis means that ‘the doctors don’t care and I’ll die soon’. Properly managed, death from uraemia is peaceful and free of suffering.
Chronic Kidney Disease (CKD) in detail - technical article
According to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, chronic kidney disease (CKD) is defined as kidney damage lasting for more than 3 months characterized by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR). CKD has been subdivided into five stages (Table 1.)
- ◆ CKD stage 1—where there are pathological abnormalities or markers of kidney damage such as urinary abnormalities (albuminuria, proteinuria, abnormal urine sediment) or abnormal imaging tests of the kidney, in the presence or absence of arterial hypertension, and GFR is above 90 ml/min per 1.73 m2.
- ◆ CKD stage 2—defined by the presence of pathological abnormalities or markers of kidney damage, with or without high blood pressure, and GFR is in the range between 60 and 89 ml/min per 1.73 m2. Note that CKD stage 2 is not defined just on the basis of GFR.
- ◆ CKD higher stages—defined by GFR below 60 ml/min per 1.73 m2 for more than 3 months. Note that the serum concentration of creatinine can be elevated or, because of the limited sensitivity of serum creatinine, normal. Progressive decrease in GFR may be associated with a variety of biochemical abnormalities and with abnormal imaging tests.
|Table 1 Classification of chronic kidney disease (CKD)|
|CKD stage a||eGFR (ml/min per 1.73 m2 body surface area)|
|1||>90, with other evidence of renal disease|
|2||60–89, with other evidence of renal disease|
|5||<15, or receiving renal replacement therapy|
Patients with CKD stages 3A, 3B, 4, and 5 may or may not have any other evidence of renal disease.
a The suffix (p) can be used to denote the presence of proteinuria as defined by a spot urinary albumin:creatinine ratio (ACR) of ≥30 mg/mmol, which is approximately equivalent to a protein:creatinine ratio (PCR) of ≥50 mg/mmol (≥0.5 g/24 h).
Table 1 summarizes the five stages of CKD suggested by the committee of the K/DOQI guidelines.
The issue of impaired renal function immediately raises the problem of which functional parameters are the most appropriate to define impairment. Currently the most frequently used index is the estimated GFR (eGFR), based on an update of the formula used in the Modification of Diet in Renal Disease (MDRD) study. This is based on standardized measurement of serum creatinine (a method which is easily disturbed by numerous confounders) and considers, in addition to serum creatinine, the age, gender, and ethnicity of the patient. The formula has acceptable accuracy only for eGFR below 60 ml/min per 1.73 m2, and in the early stages of CKD it is inadequate as an estimate for follow-up examinations when particular precision is required, as documented in patients with diabetic nephropathy. A better indicator of decreased GFR is the serum concentration of the microprotein cystatin C, which is also a more accurate predictor of cardiovascular events than serum creatinine or eGFR, but the high cost of its measurement currently prevents its widespread use.
In addition to eGFR, information on urinary albumin/protein excretion is indispensable for the full assessment of renal dysfunction. At any given serum creatinine, the excretion in the urine of even small amounts of albumin (microalbuminuria) is indicative of a higher renal and cardiovascular risk. The renal risk is particularly elevated at protein excretion rates above 300 mg/day and increases progressively with increasing severity of proteinuria (for details, see below).
Prevalence and incidence of CKD
The enormous frequency of impaired renal function in the general population has been recognized only recently. Particularly at risk are prediabetic patients with metabolic syndrome, patients with diabetes mellitus, and individuals with many other conditions, e.g. advanced age, female sex, smokers, or patients receiving potentially nephrotoxic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs).
Based on data of the National Health and Nutrition Examination Survey (NHANES) reported in 2003, it has become apparent that—in contrast to the relatively modest number of patients on renal replacement therapy (RRT) in the United States of America (300 000, i.e. less than 1% of the population of 175 million) —the estimated number of adults with CKD stages 1, 2, and 3 (combined) was 18.8 millions, i.e. 10–11% of the population. This observation is not only of academic interest, but also of major public health importance. The reason is shown in Table 2: in individuals with CKD stage 2 the risk of them living long enough to require RRT is 20 times lower than their risk of dying from cardiovascular causes. Even patients in the more advanced stage 4 of CKD are twice as likely to die from cardiovascular causes as they are to end up on RRT. From a public health perspective, there is therefore a great need to recognize CKD early to allow opportunity for therapeutic interventions, in particular to improve cardiovascular prognosis.
|Table 2 Risk (percentage chance over 5 years) of death from CKD progression towards endstage renal disease (defined as need for renal replacement therapy, RRT) and risk of death from cardiovascular disease in 27 998 American patients with glomerular filtration rate (GFR) below 90 ml/min per 1.73 m2 (for the period 1996–2001)|
|GFR (ml/min per 1.73 m2)||Risk over 5 years (%)|
|CKD stage 2 (60–89)||1.1||19.5|
|CKD stage 3 (30–59)||1.3||24.3|
|CKD stage 4 (15–29)||19.9||45.7|
(From Keith DS, et al. (2004). Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med, 164, 659–63, with permission.)
The prevalence and incidence of endstage renal disease is shown in Table 3, which gives the total number of patients on RRT worldwide at the end of 2004, i.e. 1.8 million, of whom 1.4 million were treated by haemodialysis or continuous ambulatory peritoneal dialysis (or other modalities of peritoneal dialysis) and 412 000 were alive with a functioning renal transplant. In Europe, an estimated total of 324 000 patients were on RRT and 149 000 were alive with a functioning renal graft. This gives a prevalence of 400 per million population for patients on dialysis (haemodialysis and peritoneal dialysis combined) and of 185 per million population for kidney transplant recipients.
|Table 3 Global and regional overview of endstage renal disease (ESRD), dialysis, and transplant patient numbers, and prevalence values at year-end 2004 (numbers rounded)|
|Region||Patient numbers||Prevalence values (per million population)|
|ESRD||Dialysis (HD + PD)||Transplant||ESRD||Dialysis (HD + PD)||Transplant|
|Global||1 783 000||1 371 000||412 000||280||215||65|
|North America||492 000||337 000||154 000||1505||1030||470|
|Europe||473 000||324 000||149 000||585||400||185|
|(thereof EU)||(387 000)||(252 000)||(135 000)||(850)||(550)||(295)|
|Japan||261 000||248 000||13 000||2045||1945||100|
|Asia (excluding Japan)||237 000||196 000||41 000||70||60||10|
|Latin America||205 000||170 000||35 000||380||320||65|
|Africa||61 000||57 000||5000||70||65||5|
|Middle East||54 000||39 000||15 000||190||140||55|
HD, haemodialysis; PD, peritoneal dialysis.
(From Grassmann A, et al. (2005). ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends. Nephrol Dial Transplant, 20, 2587–93, with permission.)
Between 1990 and 1999 there was a dramatic increase in the adjusted incidence of RRT in Europe, rising from 73 per million population (range 58–101 per million population) in 1990–1991 to 117 per million population (range 92–145 per million population) in 1998–1999, i.e. by 4.8% per year (range 3.1–6.4%). The increase was greater in men than in women and did not flatten out at the end of the decade, except in the Netherlands. It is of note, however, that the incidence of end stage renal disease due to diabetic nephropathy (the commonest single cause of requiring RRT) has begun to flatten out in the general population of the United States of America. It has also done so in Pima Indians, in whom the cardiovascular risk is less than in whites, which excludes the possibility that failure to observe more diabetic patients reaching endstage renal disease was due to their more frequent death from cardiovascular causes before reaching endstage renal disease. A similar trend with regard to diabetic nephropathy as a cause of endstage renal failure has also been observed in Denmark, but there have been large differences in overall incidence and prevalence of RRT between European countries. Specifically, in the United Kingdom, the annual acceptance rate for RRT increased from 20 per million population in 1982 to 101 per million population in 2002, largely owing to higher acceptance rates of patients over 65 years of age and of those with comorbidities.
It has long been known that endstage renal disease is much more frequent in older people than in young people. Based on European Renal Association/European Dialysis and Transplant Association (ERA/EDTA) Registry data, Jager et al. found a four- to fivefold increase in the incidence and prevalence of RRT over the period 1985 to 1999, and in 1999 no fewer than 48% of new patients were above age 65 years, leading to their referring to RRT as an epidemic of ageing. In this context, it is also of interest that the long-term function of kidney grafts obtained from elderly donors, irrespective of whether they were live donors or cadaveric, is inferior to the function of kidney grafts from younger donors. As typical signs of senescence, telomere length is reduced, repair capacity is curtailed, and the kidneys of older people are generally hypoperfused as a consequence of vascular sclerosis.
It is of interest that the incidence of new patients requiring RRT does not parallel the prevalence of CKD stages 3 and 4. Despite similar prevalences of CKD stages 3 and 4, the incidence of CKD patients requiring RRT in Norway is significantly lower than in white patients in the United States of America. This is explained not by high mortality prior to endstage renal disease, but by more effective intervention with progression of CKD to stage 5, an observation that illustrates the great benefit of dedicated nephrological care for patients with advanced CKD.
Causes of Chronic Kidney Disease (CKD)
The usual sources for descriptions of the causes of CKD are endstage renal failure databases. These are flawed for many reasons: diagnoses are often allocated as ‘best guesses’ by clinicians; there is no universal agreement on the meaning of terms such as ‘pyelonephritis’; glomerulonephritis may be diagnosed without histological proof; hypertension is often cited when it may be no more than a consequence of whatever caused the renal failure. With these important caveats in mind, Table 4 lists the given causes of endstage renal failure in recent reports from the United Kingdom Renal Registry, the Australia and New Zealand Dialysis and Transplant Registry, and the US Renal Data Systems. Less common causes of chronic renal failure are given in Bullet list 1. Note that some causes of chronic renal failure that are uncommon from a global perspective, e.g. Balkan nephropathy and HIV nephropathy, may be very common in some populations.
- Cystinosis, cystinuria (stones), oxalosis, nephrocalcinosis, urate nephropathy.
- Alport’s syndrome, Fabry’s disease, tuberous sclerosis, sickle cell disease, medullary cystic disease (and the metabolic conditions listed above).
- Vasculitides and other multisystem disorders
- Wegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa, Henoch–Schönlein purpura, systemic lupus erythematosus, scleroderma, sarcoidosis.
- Renal cell cancer, von Hippel–Lindau disease, lymphoma.
- Myeloma, primary (AL) and secondary (AA) amyloid, cryoglobulinaemia.
- Cystic disease other than autosomal dominant polycystic kidney disease, congenital and acquired abnormalities of the lower urinary tract, tuberculosis and schistosomiasis, Balkan nephropathy, Chinese herb nephropathy, analgesic nephropathy, nephrotoxic metals, radiation nephropathy.
- Haemolytic uraemic syndrome, postpartum renal failure, acute cortical necrosis, accelerated (‘malignant’) hypertension, HIV nephropathy.
|Table 4 Percentage distribution of primary renal diagnosis in patients starting on renal replacement therapy|
|Diagnosis||UKRR a||ANZDATA b||USRDS c|
|Glomerulonephritis||10.4 f||23 g||8.5|
|Chronic pyelonephritis h||7.2||4||0.5|
|Renal vascular disease||6.8||Not specified||1.9 i|
|Adult polycystic kidney disease||6.7||6||2.2|
ANZDATA, Australia and New Zealand Dialysis and Transplant Registry (2007 report); UKRR, United Kingdom Renal Registry (December 2007 report); USRDS, United States Renal Data Systems (2005 report).
a Data from 5343 patients beginning dialysis in United Kingdom renal units in 2006 for whom a primary renal diagnosis was reported.
b Data from all 2378 patients beginning dialysis in Australian renal units in 2006.
c Data from 484 998 incident patients from 1999 to 2003.
d Also includes “glomerulonephritis not proven by biopsy”.
e It can be impossible to know whether diabetes is a cause of endstage renal failure or merely an association.
f 100% biopsy proven.
g 76% biopsy proven.
h Patients diagnosed as having “reflux nephropathy” are included under this heading.
i Classified as a subgroup of “hypertension”.
j Reporting practices varied widely and variation in attribution of hypertension as a cause almost certainly does not reflect real differences in causation of endstage renal failure.
k Includes urinary obstruction.
As stated above, in most countries diabetic nephropathy has become the single most frequent cause of endstage renal disease. In contrast to previous years, the relative contribution of glomerulonephritis has substantially decreased, and the diagnosis of ‘pyelonephritis’, i.e. the concept that chronic bacterial colonization of the kidney and of the urinary tract causes chronic loss of renal function even in the absence of malformation or urological disease, has increasingly been abandoned on the basis of follow-up studies in cohorts of subjects with uncomplicated chronic urinary tract infection who failed to develop CKD in the absence of additional pathologies. It is of note, however, that in aboriginal populations the spectrum of renal disease is strikingly different, and this is also true for immigrant populations, including in the United Kingdom, who have an excess of diabetic nephropathy and a variety of renal diseases which are less frequently or rarely seen in white patients, e.g. renal tuberculosis, sickle cell anaemia nephropathy, and HIV nephropathy.
Pathophysiology of CKD
As kidney function gradually fails, compensatory mechanisms generally maintain acceptable health until the GFR is about 10 to 15 ml/min, and patients will not usually die of renal failure until the GFR is less than 5 ml/min. The remarkable capacity of renal function to adapt to maintain overall homeostasis in the face of such dramatic reduction in glomerular filtration is best understood on the basis of the ‘intact nephron’ hypothesis and the ‘trade-off’ hypothesis.
The intact nephron hypothesis, first articulated by Bricker, states that despite a widened range of single-nephron GFR in damaged or diseased kidneys, glomerular and tubular function remains closely integrated in all individual nephrons, both normal and damaged. As the GFR of the whole kidney falls, those nephrons that are still functioning produce an increased volume of filtrate (hyperfiltration), and their tubules respond appropriately for overall homeostasis by excreting fluid and solutes in amounts that maintain external balance, although the capacity for adaptation is variable. For sodium and potassium, compensation can occur down to GFR as low as 5 ml/min, but this cannot be achieved for phosphate and urate, plasma concentrations of which may be elevated when the GFR falls below 20 ml/min in some patients.
The trade-off hypothesis recognizes that the functional adaptations required to maintain overall homeostasis come at a price and that they contribute to changes characteristic of the syndrome of uraemia. The best example of such a trade-off is the generation of hyperparathyroidism. As GFR falls, leading (if there were no compensation) to a reduction in phosphate excretion and a rise in serum phosphate, the serum parathyroid hormone concentration rises and serves to maintain homeostasis by reducing tubular reabsorption of phosphate. However, a consequence is secondary (and sometimes tertiary) hyperparathyroidism, with adverse effects on blood vessels and bones.
Electrolyte, water, and acid–base homeostasis
An inability to concentrate the urine in the face of dehydration is sometimes the first symptom of chronic renal failure, manifesting as polyuria, nocturia and thirst. This is particularly likely in conditions that predominantly affect the renal medulla, e.g. obstructive uropathy, interstitial nephritides, medullary cystic disease. By contrast, urinary diluting capacity is preserved until renal failure is advanced, at which time urinary osmolality becomes fixed at around 300 mOsm/kg (roughly isotonic with plasma) and there is obligatory polyuria. It should be noted, however, that although urinary diluting capacity is maintained until late in chronic renal failure, large water loads are excreted more slowly than in normal subjects and excessive intake (by drinking or ill-advised iatrogenic infusion of dextrose-containing solutions) can lead to symptomatic hyponatraemia.
As renal function decreases, sodium balance and extracellular fluid volume are maintained until GFR is less than about 10 ml/min by an increase in the fractional excretion of sodium (the amount excreted in the urine as a fraction of that filtered at the glomerulus) from 1% (normal) to 30%. This capacity for adaptation is overwhelmed in advanced chronic renal failure, with sodium retention manifest as hypertension and/or oedema (peripheral and/or pulmonary). Such patients can also be at increased risk of sodium depletion as they are unable to restrict sodium excretion promptly in response to stimuli that would normally be expected to lead to such restriction, e.g. diarrhoea, vomiting. A few patients with modest impairment of GFR (e.g. CKD stage 3), usually with diseases affecting the medulla, may present with low blood pressure (often with a postural drop) due to sodium depletion caused by a urinary sodium leak: sodium supplements may be required.
Most patients maintain normal external potassium balance until their GFR is less than 5 ml/min, but their capacity to excrete potassium is limited and severe hyperkalaemia may follow a sudden reduction in GFR such as might be caused by intercurrent illness, excess dietary intake, or prescription of drugs that impair potassium excretion (ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics). Some patients, particularly those with diabetes mellitus and/or interstitial nephritis, may develop hyperkalaemia due to hyporeninaemic hypoaldosteronism at levels of GFR that would not otherwise be expected to cause problems with potassium homeostasis. Hyperkalaemia is often the immediate life-threatening consideration in the management of patients with renal failure. See Chapters 21.2.2 and 21.5 for further discussion.
The kidney normally maintains acid–base homeostasis by reabsorbing filtered bicarbonate, acidifying urinary buffers, and excreting ammonia. Increasing acidosis tends to occur at a GFR of less than 10 ml/min, and is more likely to be an early feature in diseases that primarily affect the tubules and interstitium (aside from the renal tubular acidoses, where there are specific defects in acid–base homeostasis.
Abnormalities of calcium and phosphate homeostasis are discussed later in this article.
In CKD, hormone concentrations may be elevated as a result of reduced degradation (e.g. insulin) or increased secretion in response to metabolic changes (e.g. parathyroid hormone), or reduced by impaired production (e.g. 1,25-dihydroxyvitamin D, erythropoietin, oestrogen, testosterone). Reductions in hormone-binding proteins, e.g. through protein losses in patients with nephrotic syndrome or on peritoneal dialysis, are common and may affect levels of free hormones circulating in the blood. Effects on vitamin D and erythropoietin are discussed later in this chapter.
Total thyroxine (T4) and T3 (tri-iodothyronine) may be low, with impaired peripheral deiodination of T4 to T3 and preferential diversion to inactive metabolites. However, patients are not clinically hypothyroid, and levels of thyroid-stimulating hormone (TSH) are generally normal and can be used in the usual way as a diagnostic test for hypothyroidism.
The kidney is the main site of growth hormone degradation and plasma levels of growth hormone are abnormally high in patients with renal failure because of this, and also because of alterations in hypothalamic–pituitary control. It is not clear whether or not this has any clinical impact in adults with renal failure, but in children with renal failure and growth restriction the impaired production of insulin-like growth factor 1 can be overcome by treatment with supraphysiological doses of recombinant growth hormone.
Decreased insulin clearances seems to be balanced by increased peripheral resistance to the effects of insulin, hence patients with renal failure are not prone to hypoglycaemia or diabetes, but there is a reduced requirement for exogenous insulin in people with diabetes as renal function declines.
Prolactin levels are high in renal failure and may contribute to gynaecomastia and sexual dysfunction in men and to infertility in women. Men with CKD may also have testosterone levels that are low to normal, with raised gonadotropins implying that testicular failure is the cause. The pituitary–ovarian access is disturbed in advanced renal failure, with many cycles anovulatory, causing oestrogen deficiency.
Middle molecules and the uraemic syndrome
Many of the clinical manifestations that are seen with progressive decline in renal function are attributable to derangements in fluid balance, electrolyte handling, and endocrine function as described above. However, these derangements do not provide adequate explanation for all clinical features, and it is assumed that those which are unexplained are due to retention of substances and metabolites that the failing kidney is unable to excrete. The nature of these ‘uraemic toxins’ is uncertain. Accumulation of urea itself has modest effects, and failure to excrete a variety of small water-soluble compounds, protein-bound compounds, and ‘middle molecules’ (meaning those whose molecular weight in the range 500–12 000 Da) is held responsible, although incriminating specific toxins has proved difficult. Among the small water-soluble compounds, those thought to have a role in the uraemic syndrome include various guanidine compounds, oxalate, phosphates and polyamines; and among the protein-bound compounds, p-cresol and p-cresylsulphate, homocysteine, various indoles, and furanproprionic acid. The best-characterized example of a uraemic middle molecule is β2-microglobulin, which is normally excreted by the kidneys, reaches a blood concentration 30 times higher than normal in dialysis patients, and accumulates as β2-microglobulin amyloid in joints and bone. Many of the other middle molecules that have been incriminated have a proinflammatory effect, including a variety of advanced glycosylation endproducts that are probably attributable to increased concentrations of small carbonyl precursors in uraemia (and not to hyperglycaemia).
Progression of Chronic Kidney Disease
Brenner advanced the concept that the adaptive changes (described above) aimed at increasing the excretory capacity of the kidney are maladaptive in the long run, causing deterioration of renal function mainly as a result of glomerulosclerosis and tubulointerstitial fibrosis, the final result being endstage renal disease. The adaptive changes leading to single-nephron hyperfiltration, which sustains whole-kidney GFR in the short term, are mediated by a reduction of the resistance of the afferent preglomerular arterioles and an increase of the angiotensin-II-dependent resistance of the postglomerular efferent arterioles, which combine to raise intraglomerular capillary pressure (glomerular hypertension). Over time, however, GFR will decrease, driven by several pathogenic mechanisms, including proteinuria and oxidative stress.
This hypothesis led not only to the introduction of remarkably effective therapeutic and preventive approaches aimed at interfering with progression (see below), it also had repercussions concerning the relation between GFR and metabolic abnormalities in CKD. The Mild and Moderate Kidney Disease (MMKD) study found an increase in the plasma concentration of asymmetric dimethyl L-arginine (ADMA), even when whole-kidney GFR was still normal. The same was true for apolipoprotein abnormalities and sympathetic overactivity. A plausible explanation for these findings, despite normal whole-kidney GFR, is loss of nephrons with associated loss of metabolic capacity while whole-kidney GFR is still normal because of single-nephron hyperfiltration, hence having a normal GFR does not exclude functional renal abnormalities.
The rate of progression of CKD varies considerably depending on age, gender, type of underlying renal disease, genetics (family history of renal disease and cardiovascular disease), and many other factors. For a given primary kidney disease, the risk of progression is lower in premenopausal women than in men. Such gender difference is not found in children or postmenopausal women. This finding points to the role of sex hormones, which has also been documented in experimental studies. Testosterone aggravates renal disease, possibly by raising blood pressure and activating the renin–angiotensin system, whereas oestrogens ameliorate the evolution of renal disease.
Some types of renal disease tend to progress slowly and others rapidly: adult polycystic kidney disease, renal dysplasia, IgA-glomerulonephritis, and membranous glomerulonephritis usually progress slowly; rapid progression is anticipated in antiglomerular basement membrane glomerulonephritis and vasculitis; and intermediate rates of progression are typical in diabetic nephropathy.
Ethnicity also determines the renal risk for currently poorly understood reasons: in Australian aboriginals, Maoris, American Indians, and particularly individuals of African descent, the frequency of CKD and the rate of its progression are substantially higher than in white people. This has been particularly well documented in the immigrant population from south Asia living in the United Kingdom. A powerful predictor of the renal risk is a positive family history, not only of CKD but also of cardiovascular events in first-degree relatives, which is associated with a substantial increase in the risk of developing progressive kidney disease.
A relatively new insight is that a history of pre-eclampsia is associated with a dramatic increase in the risk of developing overt kidney disease later in life. Similarly, faulty prenatal programming in utero plays a role in the onset and progression of CKD. This is part and parcel of the Barker hypothesis, according to which interference with organogenesis in the prenatal period predisposes an individual at adult age to CKD, hypertension and the metabolic syndrome.
Although such non modifiable predictors are of some interest, more important clinically are modifiable predictors associated with a higher rate of progression (Bullet list 2). It has been well documented that blood pressure has an adverse effect on progression of CKD, and this is true even for values below the former definition of hypertension (above 140/90 mmHg). This finding has greatly increased the ability to interfere with progression, and the same is true for measures to interfere with the activation of the renin–angiotensin system to reduce proteinuria.
Bullet list 2 Modifiable and nonmodifiable predictors of the rate of progression of CKD
- ◆ Age
- ◆ Gender
- ◆ History of pre-eclampsia
- ◆ Ethnicity
- ◆ Genetics (family history—renal and cardiovascular)
- ◆ Type of renal disease
- ◆ Prenatal programming (e.g. maternal hyperglycaemia, malnutrition, pre-eclampsia, low birthweight)
- ◆ Elevated (systolic) blood pressure (particularly during the night)
- ◆ Activation of renin–angiotensin system
- ◆ Proteinuria
- ◆ Smoking
- ◆ Salt intake
- ◆ Obesity/metabolic syndrome
- ◆ Protein intake?
Of major clinical importance is the fact that while renal function tends to deteriorate progressively in many (but not all) patients with CKD, almost exclusively this is true only in patients with albuminuria/proteinuria. The increased risk of cardiovascular events and cardiovascular death in patients with albuminuria/proteinuria has already been emphasized (Table 2- above).
The various presentations of renal disease are discussed in this article:
but in brief the clinical presentation of CKD depends on the degree of renal dysfunction at the time that the condition is recognized.
At one extreme are patients with no symptoms whatsoever in whom an abnormal eGFR and/or proteinuria are detected on routine examination, such as an insurance medical. Such patients may be shocked when hearing for the first time that they have lost what might be a substantial amount of their kidney function. Counselling and persuading them to comply with follow-up and to take medications occasionally proves difficult. Illnesses known to cause CKD, such as autosomal dominant polycystic kidney disease, other hereditary kidney diseases, or diabetic nephropathy, are generally easier to manage because these patients are more likely to understand the progressive nature of CKD and the benefit of treatment to prevent or slow progression.
Patients with associated disease
The presence of CKD may be diagnosed in many medical contexts in the absence of any symptoms pointing to the kidneys, e.g. outpatient clinics for hypertension, diabetes, cardiac disorders, or urological diseases.
In relatively few patients is the diagnosis of CKD made on the basis of symptoms or signs pointing to kidney disease, such as nocturia, foaming of the urine, facial or pedal oedema, or haematuria. Symptoms or signs pointing to advanced CKD include (among others) lethargy, personality change, changes in mentation, loss of appetite, nausea (often in the morning), and vomiting. These may or may not be accompanied by evidence of hypervolaemia, such as dyspnoea on exertion or at rest, swollen ankles/legs, elevated venous pressure, cardiomegaly, or basal crackles, and often only fluid removal can decide whether such manifestations are the result of fluid retention caused by renal failure, or by cardiac disease, and not infrequently they are the result of both. The final stage of uraemia is heralded by bleeding tendency, pericarditis, obtundation, and coma.
A relatively common clinical challenge to renal services is patients who present as an acute emergency requiring urgent RRT. This is not infrequently due to late referral, but it is not uncommon for there to be an acute deterioration of renal function in patients with pre-existing CKD as a result of intercurrent illness or medical interventions, e.g. cardiac decompensation from myocardial infarction or arrhythmia, hypovolaemia, exposure to radiocontrast media, or prescription of particular drugs. Regarding the latter, common culprits would be the new prescription of ACE inhibitors or angiotensin-II receptor blockers, particularly in patients with advanced CKD in the presence of hypovolaemia, heart failure, or other conditions activating the renin–angiotensin system. NSAIDs are also commonly incriminated, with other possibilities being nephrotoxic antibiotics (e.g aminoglycosides) and cis-platinum.
When a patient arrives in hospital as an ‘acute uraemic emergency’ it is important to determine whether the problem is acute kidney injury (acute renal failure, which may be entirely reversible), acute-on-chronic kidney failure (when recovery to previous baseline renal function may be possible), or the endstage of progressive chronic kidney failure (which by definition is not reversible). The only infallible method of determining whether a patient has CKD is to find documentation of previously reduced GFR indicated by past measurement of serum creatinine. When this is not available it is sometimes simply not possible to be sure of the situation at the time of presentation, although ultrasonography with documentation of small kidneys is often of great help in indicating chronicity.
Features that suggest the presence of chronic renal failure are shown in Bullet list 3, and causes of acute deterioration of chronic renal failure are shown in Bullet list 4
Bullet list 3 Indications of chronic renal failure
More than 6 months’ ill health, long-standing hypertension, proteinuria, nocturia for more than 6 months, sexual dysfunction, abnormalities previously detected during routine medicals and/or pregnancies, recurrent illness during childhood
Pallor, pigmentation, pruritus, brown nails, evidence of long-standing hypertension; the patient often appears ‘well’ for their very abnormal biochemistry
Normochromic anaemia, small kidneys on ultrasound (except in diabetes, amyloid, myeloma, or adult polycystic kidney disease), renal osteodystrophy on radiography (this is rarely found but is conclusive evidence if present).
Bullet list 4 Causes of acute deterioration in patients with chronic renal failure.
◆ Renal hypoperfusion:
- • Dehydration—diarrhoea, vomiting, excessive diuretics, inadequate fluid replacement (e.g. postsurgical)
- • Cardiac failure
- • Drugs—especially ACE inhibitors, angiotensin receptor blockers, NSAIDs
- • systemic infection
- • Renal vascular disease
- • Pericardial tamponade (rare)
◆ Obstruction and infection of the urinary tract:
- • Benign prostatic hypertrophy
- • Urinary stones
- • Cancer—particularly of prostate or bladder
- • Clot in the ureter
- • Papillary necrosis and sloughing—to be considered in patients with diabetes, sickle cell disease, and analgaesic nephropathy.
- • Polycystic cysts (rare)
◆ Metabolic and toxic:
- • Hypercalcaemia
- • Hyperuricaemia
- • Contrast media—especially in diabetes
- • Drugs—especially aminoglycosides
◆ Progression/relapse of underlying diseases:
- • Various nephritides and autoimmune/vasculitic conditions—look for an active urinary sediment with proteinuria, haematuria, and cellular casts, and also for serological evidence of disease activity
- ◆ Development of accelerated-phase hypertension
- ◆ Renal vein thrombosis—usually in severely nephrotic patients
- • At the end of the pregnancy or after delivery, e.g. in patients with reflux nephropathy.
When taking the personal history, it is important to ask about nocturia (which may be the first, although nonspecific, sign of renal disease), foaming of the urine, past or present periorbital or pedal oedema, episodes of macroscopic haematuria, and whether or not urinary abnormalities (proteinuria, haematuria) have been detected previously, e.g. in medical examinations performed before military service or for occupational or insurance purposes. The information that the patient was told that they had ‘a bit of protein/blood in the urine’ many years ago (and almost certainly ‘not to worry about it’) clearly indicates long-standing renal pathology in the context of a patient presenting with renal impairment.
In women, information on proteinuria in pregnancy or pre-eclampsia is important. A history of pre-eclampsia greatly increases the risk of CKD later in life, and pregnancy often leads to the first manifestation or aggravation of pre-existing renal disease.
In elderly men, a history of prostatic disease or related lower urinary tract symptoms (problems with bladder emptying, dribbling, etc.) should raise the suspicion of obstructive nephropathy.
Also important when evaluating a patient with CKD are episodes of urinary tract infection before and after puberty, as well as a history of urolithiasis. A history of urinary stones may point to a urological cause of renal failure, and may also very occasionally be an indication of hyperparathyroidism.
In proteinuric patients with CKD of unknown origin, one should enquire for a history of chronic bacterial infection, e.g. bronchiectasis or osteomyelitis, and for a history of rheumatoid arthritis, all of which are potential causes of secondary amyloidosis. Particularly in older people with CKD of unknown origin, it is also important to ask regarding symptoms that might indicate multiple myeloma, which can cause renal impairment via a number of mechanisms.
The patient should be asked about the use of potentially nephrotoxic drugs, such as NSAIDs, analgesics (if taken regularly in high dose for prolonged periods, particularly compound preparations or those containing phenacetin, which has now been banned in many countries), nephrotoxic antibiotics (e.g. aminoglycosides), antineoplastic agents (cis-platinum), and herbal/alternative/homeopathic treatments (e.g. Chinese herbs). Covert drug intake, including laxatives and diuretics with or without surreptitious vomiting, may also cause chronic kidney disease. Since many drugs are excreted via the kidney, it is also important to ask patients with chronic kidney disease for a history of drug side effects.
Women with CKD may have menorrhagia or (in advanced CKD) amenorrhoea, and men with CKD not infrequently have erectile failure/impotence, but few will volunteer this information and it will only be discovered by the physician who asks directly.
Symptoms of advanced renal failure (uraemia)
With advancing renal failure to CKD stage 5, patients may develop anaemia and fluid retention manifested as breathlessness on exercise or even at rest, particularly at night-time, and they may notice swelling of their ankles and legs. The first symptoms pointing to the uraemic syndrome are anorexia with attendant loss of body weight and nausea and vomiting, frequently in the morning when brushing the teeth.
Further symptoms are superimposed if a patient enters the preterminal phase of uraemia, including severe dyspnoea as the combined result of metabolic acidosis and pulmonary congestion, pericarditic and pleuritic chest pains, bleeding tendency (bleeding mouth ulcers, gastrointestinal haemorrhage), numbness of the feet (polyneuropathy), and insomnia, headache, myoclonic jerks, and impairment of consciousness/coma.
It is important to ask for a family history of renal disease, the most common causes of familial nephropathy being autosomal dominant polycystic kidney disease and reflux nephropathy. If the patient has a history of hypertension, then concomitant proteinuria or diabetes should be sought, because very often these will be undiagnosed. Patients with type 2 diabetes who have a family history of diabetic nephropathy are at higher risk of nephropathy themselves.
A patient’s risk of progressive kidney disease is greater if a first-degree relative has had any kind of CKD, even if this was not caused by the same kidney disease as that in the patient, suggesting that hereditary mechanisms are involved in the genesis of progression. Furthermore, the renal risk is higher if a first-degree relative has had essential hypertension or cardiovascular events.
Except in areas of world with very poor access to medical services, or in individuals who are severely neglected, the physician will rarely see the desperate case of terminal uraemia with coma, blindness from retinopathy, pericardial rub from uraemic pericarditis, massive gastrointestinal ulceration and bleeding, and urea frost covering the face. Patients with CKD stage 5 who are typically seen in Western countries may be pale (anaemic), have severe hypertension, and have fluid retention manifested as peripheral oedema and crackles/effusions in the lungs. As uraemia progresses, patients usually develop progressive hyperpigmentation of the skin, pruritus with excoriations and prurigo, xerosis, brown nails, and evidence of peripheral polyneuropathy.
Further signs are superimposed if a patient enters the preterminal phase of uraemia, including severe tachypnoea (before terminal cessation of breathing) with an acidotic sighing respiratory pattern and/or widespread crackles of pulmonary oedema, jerking movements (metabolic asterixis/flap/twitching), pericarditic and/or pleuritic rubs, impairment of consciousness/coma, red eyes, and evidence of bleeding (from mouth or rectum).
In routine outpatient practice, all patients presenting with CKD require a thorough general physical examination with particular attention to the features described in Table 5. Rarely there will be manifestations of systemic or genetic disorders associated with renal disease.
|Table 5 Features to look for on physical examination of patients with CKD|
|General||Pallor||Anaemia is a common feature of advanced CKD|
|Pigmentation, scratch marks, brown nails||Indicate long-standing CKD|
|Cardiovascular/respiratory||Blood pressure||Hypertension is a common association (but uncommon cause) of CKD|
|Elevated jugular venous pressure, enlarged heart, gallop rhythm, mitral regurgitant murmur, pulmonary crackles, peripheral oedema||Manifestations of fluid overload caused by CKD and/or cardiac failure associated with hypertension or ‘uraemia’|
|Aortic systolic murmur||Valvular calcification is more common in CKD|
|Peripheral pulses, vascular bruits||Absence of pulses and/or presence of bruits increase the likelihood of renovascular disease as the cause of CKD|
|Abdominal||Palpable kidneys||Likely to indicate adult polycystic kidney disease in this context|
|Palpable bladder, malignant-feeling prostate on digital examination||Consider urinary obstruction as cause of CKD|
|Hernias||Require repair if peritoneal dialysis otherwise preferred as RRT|
|Neurological||Peripheral neuropathy||Indicates long-standing CKD|
|Proximal myopathy||Indicates long-standing CKD|
||Gout and pseudogout are associated with CKD|
|Ocular fundi||Features of hypertension|
CKD, chronic kidney disease; RRT, renal replacement therapy.
Investigations required in the assessment of patients with CKD are shown in Table 6.
|Table 6 Investigations required in the assessment of patients with CKD|
|Type of investigation/test||Comment|
|Dipstick||Screening for proteinuria, haematuria, glycosuria, nitrite, pyuria. Heavy proteinuria suggests glomerular disease|
|Microscopy||If abnormality on stick testing to detect bacteriuria, quantitate pyuria, look for cellular casts (indicative of renal inflammatory process)|
|Albumin:creatinine ratio (ACR)||To quantitate proteinuria|
|Culture||To detect urinary tract infection. For tuberculosis if clinically indicated (sterile pyuria)|
|Creatinine||To quantitate level of renal function by eGFR|
|Electrolytes||Hyperkalaemia is the obvious concern|
|Urea||Elevated out of proportion to creatinine in dehydration and catabolism|
|Glucose||Exclusion of diabetes mellitus|
|Lipids||Assessment of cardiovascular risk|
|Full blood count||To detect anaemia|
|Liver and bone profile||Routine screen|
|ECG||Look for changes of ischaemia and/or left ventricular hypertrophy. Changes in morphology due to hyperkalaemia indicate the level of risk of cardiac arrhythmia and dictate treatment|
|Chest radiograph||Assessment of heart size and evidence of fluid overload (pulmonary oedema, pleural effusion)|
|Ultrasonography of urinary tract||Expect to find two small and echogenic kidneys in CKD; exclude urinary obstruction; diagnose presence of renal cysts|
|In selected patients to diagnose particular causes of CKD|
|Bence Jones proteinuria||To detect myeloma when clinically appropriate|
|Serum protein electrophoresis||To detect myeloma when clinically appropriate|
|Autoimmune/vasculitis screen—ANA, complement, ANCA, anti-GBM, cryoglobulins||To detect autoimmune (systemic lupus erythematosus) and vasculitic (Wegener’s granulomatosis, microscopic polyangiitis) conditions, also Goodpasture’s disease and cryoglobulinaemia, when clinically relevant|
|Plain abdominal film (KUB)||To look for urinary stones and/or renal calcification|
|CT scan||To determine cause of urinary obstruction|
|Renal angiography||If renal artery stenosis is likely|
|DMSA/MAG3 scan||To detect renal scarring|
|Renal biopsy||To be performed only in cases where there is diagnostic doubt and there is a reasonable likelihood that the result will affect the management of the particular patient. Should not be done otherwise|
|In patients with significantly impaired renal function (CKD stages 3B, 4, or 5) to look for complications of renal impairment and/or guide management|
|PTH||To diagnose hyperparathyroidism and monitor response to treatment|
|Bicarbonate||To detect acidosis and monitor response to treatment|
|Uric acid||In patients with gout associated with CKD|
|Haematinics—iron studies, vitamin B12, folate||In patients with anaemia. Optimal response to erythropoietin (see later) requires plentiful iron stores (high normal/high ferritin)|
|Virology—screen for hepatitis C, hepatitis B, HIV||Relevant to RRT with dialysis or by transplantation|
|Virology—screen for CMV, HSV, HZV, EBV||Relevant to RRT by transplantation|
|Blood group||Relevant to RRT by transplantation|
|Type of investigation/test||Comment|
|Echocardiogram||To assess left ventricular function. To exclude pericardial effusion when clinically appropriate|
|Tests for coronary heart disease—exercise tolerance test, radionuclide stress test, coronary angiography||If symptomatic. To assess risk of and fitness for renal transplantation|
|Radiographs of hands||To look for changes of renal osteodystrophy|
ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; anti-GBM, antiglomerular basement membrane antibody; CKD, chronic kidney disease; CMV, cytomegalovirus; DMSA, dimercaptosuccinic acid; EBV, Epstein–Barr virus; ECG, electrocardiogram; HSV, herpes simplex virus; HZV, herpes zoster virus; KUB, kidneys, ureter, and bladder; MAG3, mercaptoacetyltriglycine; PTH, parathyroid hormone; RRT, renal replacement therapy.
Management to prevent progression of CKD
In some patients, measures to conserve renal function may be specific to the cause of renal impairment, e.g. relief of obstruction, cessation of nephrotoxic drugs (e.g. lithium, ciclosporin, NSAIDs), relief of renal artery stenosis, and treatment of active autoimmune/vasculitic disorders. However, the mechanisms of progression described briefly above are common to all forms of CKD, and insight into them has provided effective strategies aimed at slowing or—when started early—even halting progression of CKD. Since not all patients with primary kidney disease inevitably progress to endstage renal disease, it is important to identify factors predisposing to an adverse renal outcome in individual patients—the main ones being high blood pressure (particularly at night-time), proteinuria, and reduced baseline eGFR—and to direct particular attention towards to such cases.
It is recommended that all patients with CKD stages 4 and 5 (also those with CKD stage 3 whose GFR is deterioratingrapidly—meaning by more than 5 ml/min per year—or who have significant proteinuria/haematuria), excepting those who are terminally ill or for whom it would otherwise be inappropriate, are referred to and managed by or in conjunction with a nephrologist. This is important because appropriate timely intervention can reduce the rate of progression and also because the results of eventual dialysis and/or transplantation are better if the patient has been properly prepared (including blood pressure normalization, correction of anaemia, hepatitis B vaccination, creation of vascular access, and the search for a living kidney donor that might render pre-emptive transplantation possible).
Interventions to prevent progression of CKD should be initiated as early as possible, which justifies efforts to diagnose renal disease sooner rather than later. The best evidence comes from studies of patients with diabetes. Controlled trials in advanced diabetic nephropathy achieved reduction of progression by no more than about 30%. By contrast, in diabetic patients with early nephropathy, mostly at the stage of microalbuminuria, the DETAIL study had achieved by its fifth year a rate of loss of GFR that was virtually indistinguishable from that seen with advancing age. Even if progression is not completely halted, but only attenuated, the gain in years free of RRT is substantially greater if treatment is started early rather than late.
Blood pressure control
Although the adverse effects of high blood pressure on progression of renal disease had been recognized for many years, the first solid documentation of the importance of achieved blood pressure on progression was provided only in 1989, when a study of patients of the Kaiser Permanente cohort in the United States of America who had normal baseline urinary findings found that even within the range of normotensive values the risk of reaching endstage renal disease increased progressively with progressively higher blood pressure values at baseline (more so in patients with than without diabetes).
There is limited information on the optimal target blood pressure and the role of different antihypertensive agents. One recent high quality study in African American patients with hypertensive kidney disease found no benefit of intensive (mean 130/78mmHg) compared to standard (mean 141/86mmHg) blood pressure control in preventing decline of renal function, excepting in those who had significant proteinuria. Nevertheless, the consensus remains that the lower the blood pressure, the better, as long as this can be achieved without unacceptable side effects. The guidelines of the European Society of Hypertension/European Society of Cardiology on treatment of hypertension state:
Protection against progression of renal dysfunction has two major requirements: strict blood pressure control (<130/80 mmHg), and even lower if proteinuria is >1 g/day, and lowering of proteinuria to values as near to normal as possible. To achieve the blood pressure goal, combination therapy of several antihypertensive agents (including loop diuretics) is usually required. To reduce proteinuria, an angiotensin receptor blocker, and ACE inhibitor, or a combination of both are required.
It obviously needs to be considered whether such aggressive blood pressure lowering is safe. No excess of cardiovascular events or of mortality has been reported in nondiabetic patients and patients without coronary disease, although in older people limited tolerance and safety (orthostatic hypotension, falls) of intensive blood pressure lowering have to be taken into account. By contrast, higher mortality in patients with advanced diabetic nephropathy has been found with an achieved systolic blood pressure below 120 mmHg, and in nonrenal patients with coronary heart disease the rate of myocardial infarction has been reported to be increased if diastolic blood pressure is lowered to below 70 mm/Hg, hence some caution is indicated in populations at high cardiovascular risk, including those with CKD.
The most important predictor of progressive loss of renal function is the systolic blood pressure, not the mean or the diastolic blood pressure. Of particular concern in renal patients is the tendency for an attenuated decrease of blood pressure—or even a paradoxical increase—at night-time, recognition of which requires the use of ambulatory blood pressure measurements. Because of the complexity of blood pressure analysis and the limited accuracy of office blood pressure measurements, it is bad advice to stick only to fixed blood pressure targets—particularly since almost all studies have shown that the proportion of renal patients reaching target blood pressure values is disappointingly low, despite the use of multidrug regimens.
Selection of antihypertensive agents
There is good evidence from experimental studies that activation of the renin–angiotensin system (RAS) and of the sympathetic nervous system play a major causal role in the genesis of progression. There has been some controversy over whether the effect of antihypertensive agents interfering with the activity of the RAS is exclusively explained by lowering of blood pressure. Considering controlled intervention trials where similar blood pressure lowering was achieved with antihypertensive agents that did and did not block the RAS, it is obvious that a definite but limited contribution to the slowing of progression is achieved by RAS blockade. An example of the finding of such a trial is: Pohl MA, et al. (2005). Independent and additive impact of blood pressure control and angiotensin-II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am Soc Nephrol, 16, 3027–37.
A head-to-head comparison, although somewhat underpowered, suggested that the effect of ACE inhibition and angiotensin receptor blockade is comparable in magnitude with respect to halting progression of renal disease. The blockade of the RAS is effective and safe, if properly supervised, but the risk of hyperkalaemia has to be taken into consideration, which is caused most frequently by excessive potassium intake and prescription of other drugs interfering with potassium excretion (β-blockers, potassium-sparing diuretics).
Patients with CKD are at high cardiovascular risk and, aside from renal benefit, ACE inhibition (if tolerated) has been shown in some trials to reduce cardiovascular mortality more effectively in those with impaired than in those with normal renal function.
Reduction of proteinuria
Proteinuria is not only a marker, but also an extremely important promoter of CKD progression, and it has therefore become an important additional treatment target. In patients with primary renal disease, the higher the baseline proteinuria, the greater the subsequent decline in GFR, and also the greater the risk of cardiovascular events. Even very modest increase in proteinuria within the normal range is associated with increased mortality. A recent meta-analysis of data collected over more than 700,000 patient years reported that compared with ACR 0.6mg/mmol (low normal range), an ACR of 1.1mg/mmol was associated with a mortality hazard ratio of 1.20, and an ACR of 3.4mg/mmol (upper limit of normal range for men) with a mortality hazard ratio of 1.63.
Current guidelines recommend that proteinuria should be lowered as much as possible, preferably to less than 1 g/24 h (roughly equivalent to ACR <60 mg/mmol or PCR <100 mg/mmol). When this goal is not achieved, it is wise to check whether modifiable factors explain the limited efficacy of blood pressure lowering with RAS blockers, such as patient noncompliance, high sodium intake (which abrogates the antiproteinuric action of RAS blockade), high protein intake (which increases proteinuria), smoking, and poor glycaemic control in people with diabetes. If these factors have been excluded, there remain three strategies. First, one can attempt dose escalation of the ACE inhibitor or angiotensin receptor blocker above the dose licensed for blood pressure lowering. This strategy has been shown to be effective in slowing the progression of CKD, with angiotensin receptor blockers often preferred in this situation because of their better side effect profile. Second, postulating that ACE inhibitors and angiotensin receptor blockers might interfere with progression via different pathways, consider a combination of ACE inhibitor and angiotensin receptor blocker, but data in support of this strategy are somewhat less solid. Third, consider blockade of the mineralocorticoid receptor: aldosterone levels decrease immediately after the start of RAS blockade, but in many patients they subsequently rise again, a phenomenon known as ‘aldosterone escape’, which can be accompanied by failure to restrain proteinuria. Several studies have shown that, without further lowering of blood pressure, blockade of the mineralocorticoid receptor by low doses of spironolactone (25 mg/day) or eplerenone can prevent such relapse. There is, however, a danger of precipitating hyperkalaemia, a risk that is justifiable only in patients who have received and accept appropriate dietary education and agree to close follow-up.
Dietary protein restriction
Reducing dietary protein intake may protect against progression of CKD by haemodynamically mediated reduction in intraglomerular pressure, by changes in cytokine profile, and/or by changes in matrix synthesis in the renal interstitium. It has been shown to be effective in attenuating progression of renal failure in several well-conducted animal studies. In clinical trials, numerous uncontrolled studies have also shown an apparently beneficial effect of low dietary protein intake on CKD progression, but the only major controlled prospective trial (the MDRD study) failed to document a significant effect. Although subsequent post hoc analyses were consistent with some benefit from dietary protein restriction, its magnitude does not compare with what can be achieved by lowering blood pressure and RAS blockade, and it is important to recognize that drastic lowering of protein intake carries the risk of malnutrition. In routine practice, most nephrologists do no more than to advise against high-protein diets, recommending limitation of protein (but not energy) intake only in CKD patients who have a gross excess of protein intake, e.g. more than 2 g/kg body weight per day, documented by urinary urea measurements. Those of a more interventionist persuasion may recommend a daily protein intake of 0.8 to 1 g/kg per day (and some even 0.7 g/kg per day), with careful monitoring to ensure that protein malnutrition does not develop and that there is adequate intake of calories.
Other dietary and lifestyle measures
As shown in Box 2 - above, other modifiable progression promoters are smoking, high salt intake, obesity, and the metabolic syndrome. In diabetic patients, the risk of onset of microalbuminuria, and the progression from microalbuminuria to overt diabetic nephropathy, is higher in smokers, as is the rate of loss of GFR in smokers with advanced diabetic nephropathy. At least in diabetic patients, some evidence suggests that cessation of smoking slows the progression of CKD. Thus, in addition to the aim of reducing cardiovascular risk, this finding is another strong reason for patients with renal disease to stop smoking. Recent evidence even indicates that passive smoking increases albuminuria and is injurious to the kidney.
There is scant evidence in humans, in contrast to convincing evidence in animals, for an adverse effect of high salt intake on the progression of primary renal diseases. It is, however, important to recognize that high salt intake militates against control of hypertension and interferes with the antiproteinuric action of ACE inhibition, hence it seems sensible—in line with general recommendations accepted for the treatment of hypertension—to advise reduction in sodium intake from the usual (in developed countries) 150 to 200 mmol/day to 100 mmol/day (6 g of sodium chloride). In practice, this means the patient reducing the amount of processed food that they consume.
A further risk factor for the onset and promotion of CKD progression is visceral obesity and the metabolic syndrome. The worse the metabolic syndrome, the greater the prevalence of CKD and of microalbuminuria in the general (American) population, and the degree of obesity at which renal risk increases is surprisingly low. Overweight patients with early CKD should therefore try to reduce their body weight, since this has proven to be effective in several studies. However, in more advanced stages of CKD—namely at an eGFR of approximately 30 to 50 ml/min—the situation is more complex, with higher body weight (even in the range of morbid obesity) lowering the risk of death for unknown reasons.
Other pharmacological interventions
Other interventions on top of ACE inhibition and/or angiotensin receptor blockade to attenuate CKD progression that are under evaluation include renin inhibitors, endothelin I blockers, glycosaminoglycans (increasing the electronegativity of the charge of the glomerular basement membrane), erythropoietin (effective in experimental studies), NSAIDs (potentially dangerous because of overshooting reduction of GFR), vitamin D analogues, and statins.
Medical management of the consequences of CKD
Water, electrolytes, acidosis, and nutrition
Only patients with oliguric endstage renal failure need to restrict their fluid intake precisely, when the usual recommendation (seldom complied with) is that the patient’s daily intake should be a volume equal to their daily urinary output plus 500 ml for insensible losses. Most patients with CKD pass a normal volume of urine, but they need to avoid binge drinking because their ability to excrete free water is impaired, and also to be aware of the fact that they will need to drink more if they have other significant fluid losses, e.g. vomiting, diarrhoea, or excessive sweating, because their kidneys will not be able to elaborate appropriately concentrated urine.
As stated above, it is sensible to recommend modest dietary sodium restriction (100 mmol/day) to patients with CKD. Reduction of sodium intake to around 60 mmol/day can be helpful in patients with fluid retention in the context of advanced CKD, but many patients find this unacceptable and the use of loop diuretics to encourage sodium excretion is more effective in most cases.
Hyperkalaemia is most commonly seen in the context of renal failure (acute or chronic) and can be life threatening. An important aim of medical management of patients with CKD is to avoid such excitement. Monitoring of the serum potassium must be routine whenever the creatinine is checked, and especially after introduction of drugs that are known to cause hyperkalaemia (including ACE inhibitors, angiotensin receptor blockers, and potassium-sparing diuretics). The patient should be offered dietary advice if serum potassium is found to be in the range 5.5 to 6.5 mmol/litre, and the measurement should be repeated a few days later (unless they are known to have a stable potassium in this range). Dietary advice combined with stopping of all medications that might precipitate hyperkalaemia is appropriate if potassium is in the range 6.5 to 7 mmol/litre, again with repeated measurement a few days later. If the potassium is above 7 mmol/litre, the patient should be reviewed in hospital, with checking of the ECG for hyperkalaemic manifestations being an immediate priority, followed by consideration of possible precipitants, which include dietary indiscretion (fruit, chocolate, coffee) and gastrointestinal haemorrhage as well as more obvious intercurrent illness.
Chronic acidosis with serum bicarbonate in the range 12 to 20 mmol/litre is most common in patients with interstitial renal disease and will aggravate hyperkalaemia, inhibit protein anabolism, and accelerate calcium and phosphate loss from bone. Treatment with alkali to maintain the serum bicarbonate above 22 mmol/litre is recommended. Sodium bicarbonate (0.6–1.8 g three times a day) is the first-line treatment, with sodium citrate an alternative for those who cannot tolerate bicarbonate (usually because of abdominal bloating) as long as they are not taking aluminium-containing antacids (citrate enhances aluminium absorption).
Malnutrition is common in advanced chronic renal failure because of anorexia, impaired gut function, and acidosis. The most practical ways of detecting its insidious development is by serial monitoring of body weight and serum albumin concentration. Standard advice is that patients with CKD should have a diet containing about 30 to 35 kcal/kg body weight per day. Dietary supplements may be helpful in achieving this, but they are not a cure for the problem: a patient that is becoming malnourished needs to start RRT sooner rather than later.
Mineral and bone disorder
The mineral and bone disorder (MBD) associated with CKD is a major cause of disability in patients with endstage renal failure. It is mainly, but not exclusively, the consequence of abnormalities of the metabolism of calcium, phosphorus, parathyroid hormone (PTH), and vitamin D, and presumably also the novel phosphaturic hormones FGF23 and Klotho.
CKD-MBD is complex. Osteomalacia was first recognized as a major feature of bone disease in uraemic patients, and in the 1970s and 1980s aluminium-induced bone disease—secondary to high aluminium concentrations in the dialysate or ingestion of aluminium-containing phosphate binders—played an important role, but this iatrogenic complication has now virtually disappeared. Secondary hyperparathyroidism then became considered the major component of CKD-MBD, but with more efficient prevention and treatment of parathyroid overactivity, patients with advanced stages of CKD started to develop low bone turnover with increasing frequency, characterized by frequent episodes of hypercalcaemia, more or less permanent hyperphosphataemia, a high incidence of vascular calcification, and histologically by adynamic bone disease.
Clinicians have become increasingly aware of the potential impact of CKD-MBD on cardiovascular structure and function, as well as on parathyroid glands and bone. It is associated with an increased risk of arterial and valvular calcification, and increased cardiovascular and all-cause mortality, with the impact of severe renal secondary hyperparathyroidism on all-cause mortality best illustrated by the observation that actuarial survival is improved after parathyroidectomy. This adds a new dimension to the importance of CKD-MBD and its prevention or treatment in patients with impaired kidney function, and it is for this reason that weprefer the term CKD-MBD to renal osteodystrophy, which we restrict to usage in the context of the histological aspects of the various forms of renal bone disease.
In early stages of CKD, the plasma phosphate concentration remains normal or may be even low, which is achieved at the price of increased fractional clearance of phosphate. Hyperphosphataemia develops once the GFR has decreased to between 60 and 30 ml/min (CKD stage 3). Hyperphosphataemia aggravates secondary hyperparathyroidism by indirect mechanisms, such as inhibition of the synthesis of the active vitamin D metabolite 1,25-(OH)2vitamin D3 (1,25-(OH)2D3 or calcitriol) in tubular epithelial cells, and possibly also by inducing a tendency for hypocalcaemia. It has also been shown that phosphate directly stimulates PTH synthesis and secretion as well as parathyroid cell proliferation, independent of low serum 1,25-(OH)2D3 and hypocalcaemia. Increased PTH secretion reduces tubular phosphate reabsorption. In parallel, plasma FGF23 increases in CKD as a result of phosphate retention, and this in concert with Klotho also decreases renal phosphate reabsorption. The relative roles of PTH and FGF23 in the control of phosphate reabsorption are currently unclear.
The hepatic vitamin D metabolite 25-(OH)vitamin D3 (25-(OH)D3) is transformed, mainly in renal tubular epithelial cells, to the most active vitamin D metabolite, 1,25-(OH)2D3, which acts as a circulating hormone (apart from paracrine actions of locally synthesized 1,25-(OH)2D3 in tissues such as activated macrophages, vascular cells, and others). Its synthesis is stimulated by PTH but inhibited by phosphate and FGF23, and even in early stages of CKD there is a tendency for 1,25-(OH)2D3 concentration to decrease, although it remains mostly within the normal range because such decrease is counteracted by increases in PTH. The average concentration of 1,25-(OH)2D3 falls progressively as CKD advances.
One specific problem is that circulating vitamin D metabolites bound to vitamin D-binding protein may be lost in the urine of patients with heavy proteinuria, so that deficiency of vitamin D metabolites, such as 25-(OH)D3 and 1,25-(OH)2D3, may ensue. The renal 1α-hydroxylase reaction is normally substrate independent, but with progression of CKD it becomes increasingly dependent on the availability of the substrate 25-(OH)D3, with deficiency of this form of vitamin D further aggravating the impairment of synthesis of 1,25-(OH)2D3.
Average serum levels of so-called intact PTH increase progressively as average serum 1,25-(OH)2D3 levels decrease with decreasing GFR in patients with various stages of CKD.
On average, plasma (total and ionized) calcium concentrations are maintained in the normal range until CKD stage 5. Nevertheless, for several reasons there is a permanent tendency towards hypocalcaemia, mainly because of reduced active intestinal calcium absorption as a result of insufficient active vitamin D generation and diminished release of calcium (skeletal resistance) in response to PTH and 1,25-(OH)2D3.
Skeletal resistance may well play an important role in the pathogenesis of secondary hyperparathyroidism, with another mechanism being impaired inhibition by extracellular Ca2+ of the parathyroid gland, which senses this cation via the calcium-sensing receptor (CaR), expression of which is decreased in CKD-MBD in parathyroid tissue. Some reports have showed abnormal Ca2+ sensing even in early stages of CKD. CaR down-regulation in the parathyroid can be reversed by low phosphate diet, calcimimetics, and other compounds.
Types of bone mineral disorder in CKD
The bone lesions discussed below, collectively known under the term renal osteodystrophy, are found in the skeleton of patients with CKD, in isolation or in combination (Bullet list 5
Bullet list 5 Bone lesions in patients with CKD (renal osteodystrophy)
- ◆ Osteitis fibrosa
- ◆ Osteomalacia
- ◆ Mixed lesions
- ◆ Adynamic bone disease—overtreatment with calcium and/or vitamin D; rarely (today) from aluminium overload
- ◆ β2-Microglobulin-related amyloidosis
- ◆ Sequelae of preceding corticosteroid therapy—fractures, osteonecrosis
- ◆ Osteopenia, particularly in postmenopausal patients
- ◆ Reflex sympathetic dystrophy
- ◆ Bony problems caused by primary disease leading to CKD—e.g. oxalosis
This is characterized histologically by an increase in both osteoclastic bone resorption and osteoblastic bone apposition rates with (1) consecutive intense remodelling of bone trabeculae in the spongiosa, and (2) rarefaction and tunnelization of cortical and cancellous bone, with or without deposition of fibrous tissue (endosteal fibrosis).
Osteomalacia is characterized by a disparity between the rate of bone matrix synthesis and bone matrix mineralization, leading to widening of the seam of unmineralized bone matrix (osteoid), usually associated with signs of diminished numbers and activities of cells at the bone surface. Pure osteomalacia is rarely seen nowadays: 30 years ago it was mainly due to aluminium intoxication, and before that to overt vitamin D (cholecalciferol) deficiency.
In many patients with advanced stages of CKD, a combination of osteitis fibrosa and osteomalacia is present, which is commonly called mixed lesions or mixed renal osteodystrophy.
Adynamic bone disease
In patients with low or normal serum intact PTH concentrations, the number and activity of cells on the bone surface is strikingly reduced, as is bone turnover. This condition is most common in patients with CKD due to diabetes, those with poor nutritional status, and those who have been overtreated with active vitamin D and/or calcium-containing phosphate binders. It predisposes to hypercalcaemia, hyperphosphataemia, and soft tissue calcification because the capacity of the skeleton to sequester calcium and phosphate is reduced. There is some evidence that adynamic bone may contribute to skeletal fractures in patients on dialysis, but it is not known whether there are more far-reaching clinical implications.
The term osteopenia is preferred to osteoporosis because the pathophysiology of bone disease in CKD is strikingly different from that in idiopathic osteoporosis. Diminished bone mass (osteopenia), superimposed on uraemia-specific bony abnormalities, is very common in patients with advanced CKD. The most frequent causes are a history of treatment with steroids and (premature) menopause. It is not known whether the risk is aggravated by smoking and low calcium diets, or whether it can be prevented by substitution of oestrogens/gestagens or selective oestrogen receptor modulators.
Other bone-related pathologies
In patients with CKD, several bone pathologies unrelated to calcium metabolism may coexist with CKD-MBD (Bullet list 5). Specifically, a dialysis-associated type of amyloidosis with preferential osteoarticular involvement, called β2-microglobulin-related amyloidosis, must be considered in the differential diagnosis of bone pain and osteoarticular destruction.
MBD in CKD is usually asymptomatic. Bone pain is not common, even in advanced osteitis fibrosa, although bones subjected to mechanical stress (spine, calcaneus, foot) may be painful. While fractures are uncommon, skeletal deformity, facial leontiasis, and avulsion of the patella may occur. By contrast, osteomalacia, particularly that secondary to aluminium intoxication, may be very painful, especially when Looser’s zones (fatigue fractures) are present. Again, it is important to exclude alternative causes of bone pain, particularly myeloma and metastases (Bullet list 6
Bullet list 6 Differential diagnosis of bone pain in patients with advanced CKD or on dialysis
- ◆ Osteitis fibrosa—pain relatively rare
- ◆ Osteomalacia—secondary to vitamin D deficiency, or exceptionally aluminium accumulation
- ◆ β2-Amyloidosis
- ◆ Skeletal metastases, myeloma
- ◆ Osteomyelitis, mostly spondylodiscitis—may be related to infected vascular access
- ◆ Neuromelic pain after creation of arteriovenous fistula
- ◆ Bone infarction, osteonecrosis—related to corticosteroid treatment, sickle cell anaemia
- ◆ Osteopenia-associated infarctions and fractures
Severe extraosseous calcifications, specifically periarticular, bursal, and visceral calcifications, are usually the consequence of severe hyperphosphataemia and high-normal serum calcium, with either high or low serum intact PTH concentrations. Tumoural tissue calcification is often triggered by trauma with haematoma formation and favoured by low bone turnover, which diminishes the capacity of the bone to sequester calcium and phosphate from the extracellular space.
Slowly progressing arterial and valvular calcifications may be associated with clinical evidence of cardiovascular disease, indeed cardiovascular mortality in dialysis patients is strongly predicted by the presence of coronary artery calcification detected by electron beam CT scanning.
Calciphylaxis, also called calcific uraemic arteriolopathy, is a rare medical emergency characterized by ischaemic eschars of the skin secondary to calcification of cutaneous arterial vessels. Predisposing factors, apart from secondary hyperparathyroidism, include diabetes, obesity, female gender, and (probably) treatment with warfarin. It can produce gangrene and may be fatal. It may respond to parathyroidectomy if serum PTH levels are elevated.
While patients with advanced stages of CKD left untreated usually have hypocalcaemia and hyperphosphataemia, patients with advanced secondary hyperparathyroidism are characterized by hypercalcaemia and hyperphosphataemia associated with an increase in serum total alkaline phosphatases and its bone-specific isoenzyme. The findings on serum biochemistry in patients with CKD-MBD are shown in Table 7, with the findings in the two main contrasting forms of MBD compared in Table 8. In patients with hypercalcaemia it is important to consider causes other than secondary hyperparathyroidism which necessitate specific treatment, as listed in Bullet list 7
Bullet list 7 Differential diagnosis of hypercalcaemia in patients with advanced CKD or on dialysis
- ◆ Severe hyperparathyroidism
- ◆ Intoxication with vitamin D sterols—cholecalciferol, ergocalciferol, calcidiol, calcitriol, or active vitamin D derivatives
- ◆ Excessive dose of calcium-containing phosphate binders
- ◆ Inappropriately high dialysate calcium concentration
- ◆ Immobilization
- ◆ Cancer with bone metastases
- ◆ Myeloma
- ◆ Granulomatous disease—e.g. sarcoidosis, tuberculosis
- ◆ Other rare causes of hypercalcaemia
- ◆ Pseudohypercalcaemia—elevated total protein concentration
|Table 7 Serum biochemistry in the evaluation of CKD-MBD|
|Calcium||Low, normal, or elevated (elevated in severe HPT, vitamin D excess, therapy with calcium-containing phosphate binders, inappropriately high dialysate calcium, immobilization)||2.2–2.6 mmol/litre or 8.8–10.4 mg/dl|
|Phosphate||Elevated in advanced CKD (GFR <30 ml/min)||0.8–1.4 mmol/litre or 2.4–4.2 mg/dl|
|Intact PTH||Elevated in HPT; can be normal or even low (mostly in cases of aluminium intoxication, adynamic bone disease, overtreatment with calcitriol, after parathyroidectomy); beware of interassay variations of intact PTH measurements||1–7 pmol/litre or 10–65 pg/ml|
|25-(OH)D3 (calcidiol)||Often low because of reduced sun exposure or low dietary intake; seasonal variation; if increased, check for exogenous source||50–200 nmol/litre or 20–80 ng/ml a|
|1,25-(OH)2D3 (calcitriol)||Usually low (if increased, check for calcitriol ingestion; rarely endogenous overproduction (granulomatous disease))||50–120 pmol/litre or 25–50 pg/ml a|
|Total alkaline phosphatases (AP)||Normal or increased; elevated in severe HPT (exclude concomitant liver disease by determination of γ-GT or bone-specific AP isoenzyme)||60–170 IU/litre|
|Osteocalcin||Diagnostic information analogous to AP; fragments accumulate in advanced CKD; probably no extra information in addition to intact PTH and bone isoenzyme of AP||c.3–8 µg/litre b (may depend on assay)|
|Magnesium||Normal or elevated (decreased renal excretion)||0.8–1.3 mmol/litre|
|Aluminium||Normal; elevated if aluminium-containing phosphate binders are taken or if dialysate is aluminium contaminated||<10 µg/litre|
AP, alkaline phosphatase; CKD, chronic kidney disease; GFR, glomerular filtration rate; γ-GT, γ-glutamyl transferase; HPT, hyperparathyroidism; MBD, mineral and bone disorder; PTH, parathyroid hormone.
a Normal range varies depending on season (consult local laboratory guidance).
b In individual with normal renal function.
|Table 8 Typical serum biochemistry in the two main contrasting forms of renal bone disease|
|Analyte||Osteitis fibrosa||Adynamic bone disease|
|Calcium||Variable, high normal or elevated in advanced secondary hyperparathyroidism||Tendency to hypercalcaemia|
|Phosphate||Marked increase (dissolution of bone mineral)||No typical pattern, often elevated|
|Intact parathyroid hormone||Markedly elevated||Normal or low|
|Total alkaline phosphatases||Usually elevated||Tend to be low|
Prophylaxis and management of secondary hyperparathyroidism
Secondary hyperparathyroidism is the combined result of failing excretory function of the kidney (leading to phosphate retention) and failing endocrine function of the kidney (leading to calcitriol deficiency). Appropriate management requires prevention (whenever possible) and treatment of both abnormalities.
Approach to serum phosphate control
It is usually recommended that phosphate-lowering interventions should begin once plasma phosphate concentrations exceed the upper limit of the normal range, i.e. 1.45 mmol/litre. This is generally the case when GFR has decreased to about 30 ml/min and persists even when patients with CKD are on dialysis, which cannot (on a conventional thrice-weekly haemodialysis regimen, or by peritoneal dialysis) clear the amount consumed in a standard Western diet (50–100 mmol/day, of which 50–70% is absorbed).
The risk of soft tissue precipitation of calcium phosphate is particularly high if hyperphosphataemia is accompanied by hypercalcaemia and a high calcium × phosphate product (desirable target below 5.6 mmol2/litre2). The K/DOQI guidelines propose an upper limit of serum phosphorus of 1.8 mmol/litre in dialysis patients.
Phosphate is present in virtually all foods, hence reduction of dietary intake is difficult without incurring the risk of malnutrition. Patients should be advised to avoid food items with very high phosphate content, e.g. some dairy products, and those to which phosphate is added, such as sausages and phosphate-rich soft drinks. A protein-restricted diet will reduce phosphate intake, but the merit or otherwise of protein restriction is debatable (see previous discussion). However, given that sufficient dietary restriction of phosphate is usually not feasible, patients with advanced CKD remain in positive phosphate balance unless oral phosphate binders are administered.
All oral phosphate binders trap phosphate in the intestinal lumen by forming insoluble complexes with it, hence they must be taken together with meals, after which the phosphate concentration in the gut is highest. The agents most commonly used in the recent past as phosphate binders were calcium carbonate and calcium acetate with magnesium hydroxide and magnesium carbonate sometimes employed, but usually avoided because of their propensity to cause diarrhoea and the possibility of inducing hypermagnesaemia. Although very effective in controlling serum phosphate, the prescription of aluminium-containing compounds has been abandoned by most nephrologists because of the risk of aluminium intoxication, excepting for short term use. However, calcium-containing phosphate binders cause positive calcium balance and perhaps promote vascular calcification. Recently, the calcium-free and aluminium-free phosphate binders sevelamer (an anion-exchange resin) and lanthanum carbonate have been introduced into clinical practice. These allow similar control of plasma phosphate, while avoiding calcium and aluminium overload. Use of sevelamer may cause less progression of coronary artery calcification than calcium containing phosphate binders. However, no randomized trial has shown that selecting a particular phosphate binder improves any clinically relevant outcome.
If hyperphosphataemia does not respond to medical intervention, then issues to consider include noncompliance, increased phosphate release from the skeleton (e.g. in severe osteitis fibrosa) and/or stimulation of intestinal phosphate absorption by excessive amounts of active vitamin D sterols, and (in patients on RRT) inadequate dialysis.
Approach to serum calcium control
The target range for serum total calcium (corrected for albumin) is 2.20 to 2.38 mmol/litre (8.8–9.5 mg/dl). If the corrected total serum calcium level exceeds 2.55 mmol/litre (10.2 mg/dl), then therapies that cause a rise in serum calcium should be adjusted and other potential causes of hypercalcaemia should be considered, in particular an inappropriately high dialysate calcium concentration and immobilization (see Bullet list 7).
Reversal of deficiency of native vitamin D3
Deficiency of the parent compound vitamin D3 (cholecalciferol) is common among patients with CKD as a result of altered lifestyle, with insufficient sun exposure, hyperpigmentation of the skin, and loss of protein-bound vitamin D (metabolites) into proteinuric urine or peritoneal dialysis fluid. Vitamin D deficiency can be diagnosed, according to some authorities, when plasma 25-(OH)D3 concentrations are below 40 nmol/litre (16 ng/ml), and vitamin D insufficiency when they are between 40 and 80 nmol/litre (16–32 ng/ml). The latter values are higher than recommended in the past, and are based on the recognition that still higher levels, although not providing further benefit in terms of calcium metabolism, may be necessary to achieve the recently recognized pleiotropic effects of vitamin D, e.g. on infection control, vascular biology, insulin sensitivity, and control of renin secretion.
In CKD, the synthesis of 1,25-(OH)2D3 depends on the concentration of the precursor substance 25-(OH)D3. This explains why administration of at least 1000 IU vitamin D per day, possibly 2000 IU per day (which is 2–3 times the average daily intake with vitamin D fortified food), leads to an increase of serum calcitriol and a decrease of serum intact PTH in many patients with CKD. Serum 25-(OH)D3 levels can usually be raised to a target of at least 75 nmol/litre (30 ng/ml) by supplementation with cholecalciferol or (less reliably) by sufficient sun exposure. Note, however, that treatment with pharmacological doses of native vitamin D is not appropriate in CKD: these are much less effective than its hydroxylated, more active metabolites (see below) and, if they do raise serum calcium and phosphate concentration, carry a substantial risk of inducing prolonged increases in serum calcium × phosphate product and soft tissue calcification.
Administration of active vitamin D sterols
If serum 25-(OH)D3 levels are more than 75 nmol/litre (30 ng/ml) and intact PTH levels remain elevated, treatment with low doses of active vitamin D sterols (calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) should be considered. In patients with CKD stage 5, whether on dialysis or not, complete return of intact PTH concentrations to normal is not desirable: in this condition, normal bone turnover requires that measured intact PTH concentrations be above the normal range. It is uncertain whether this reflects mainly PTH resistance of the skeleton, or problems with the second-generation intact PTH assay, which also measures inactive fragments of PTH. However, in reflection of these concerns, the K/DOQI guidelines advise variable target ranges for PTH dependent on the stage of renal failure: 35 to 70 pg/ml (3.8–7.6 pmol/litre) in CKD stage 3; 70 to 110 pg/ml (7.6–11.8 pmol/litre) in CKD stage 4; and 150 to 300 pg/ml (16–32 pmol/litre) in CKD stage 5.
Bullet list 8 provides an algorithm for the prophylaxis of secondary hyperparathyroidism. In experimental studies, continuous (daily) administration of calcitriol or alfacalcidol lowers intact PTH concentration and prevents parathyroid hyperplasia less effectively than intermittent (pulse) administration given at longer intervals, but there is no good evidence that this effect is of clinical importance.
Bullet list 8 Algorithm for prophylaxis of secondary hyperparathyroidism
- ◆ calcium, albumin, phosphate, intact parathyroid hormone (PTH), 25-(OH)D3, aluminium
If serum 25-(OH)D3 is low, i.e. below 75 nmol/litre (30 ng/ml)
→ give cholecalciferol 1000 U/day
If plasma calcium is decreased and/or plasma phosphate is increased
→ give calcium carbonate 0.5–1.0 g with each meal
If serum phosphate is increased and plasma calcium is normal or high
→ consider calcium-free phosphate binder, e.g. sevelamer or lanthanum carbonate
If serum intact PTH is consistently above target ranges (see text) and serum calcium/phosphate is normal (spontaneously or after intervention)
→ give calcitriol 0.125–0.25 µg/day or equivalent doses of alfacalcidol or other active vitamin D analogues.
Medical management of advanced hyperparathyroidism
The main side effects of treatment with active vitamin D sterols are hypercalcaemia and hyperphosphataemia. There has therefore been an intense search for new vitamin D analogues that suppress the parathyroid gland while causing less hypercalcaemia and hyperphosphataemia. Some of these—including paricalcitol (19-nor-1-α,25-(OH)2D2) and doxercalciferol—are available in some countries, but there is no firm evidence from clinical trials that they are clinically better than the parent compound, calcitriol, although observational studies in large dialysis patient cohorts suggest that treatment with active vitamin D compounds is associated with better outcome than no vitamin D treatment, and that treatment with novel active vitamin D derivatives may lead to better patient outcome than treatment with calcitriol.
Another method of affecting calcium balance in patients on dialysis is to manipulate the concentration of calcium in the dialysate. In the past, a dialysate calcium concentration of 1.75 mmol/litre (7 mg/100 ml) was recommended, such that net uptake of calcium occurred during the dialysis session to compensate for convective loss of calcium via ultrafiltration during, and negative intestinal calcium balance between, dialysis sessions. However, if calcium-containing phosphate binders or active vitamin D sterols are administered, then intestinal uptake of calcium is increased and patients may develop positive calcium balance, with or without hypercalcaemia. Lowering the dialysate calcium concentration to 1.5 mmol/litre (6 mg/100 ml) (and temporarily even to 1.25 mmol/litre (5 mg/100 ml)) counteracts this tendency, but it is essential to make absolutely sure that patients take their medication in this circumstance: if calcium carbonate and/or active vitamin D derivatives are omitted, then a negative calcium balance ensues with exacerbation of secondary hyperparathyroidism.
Another effective treatment for hyperparathyroidism is to use a calcimimetic, only one of which—cinacalcet—is in clinical use at present. This renders the CaR more sensitive to extracellular Ca2+ and has been shown to reduce both elevated serum intact PTH concentrations and the calcium × phosphorus product in dialysis patients with moderate or severe hyperparathyroidism. Its beneficial effect on serum biochemistry is maintained over prolonged time periods, but it is not licensed for use in patients with CKD who are not on dialysis, and some experts—including the KDIGO working group—do not recommend its use in such cases because of lack of data on long term efficacy and safety in this population.
Tumour-like parathyroid growth and parathyroidectomy
Severe secondary hyperparathyroidism is a process that bears similarities to tumour growth. Nodular hyperplasia is usually found in patients whose estimated parathyroid mass exceeds 1 to 1.5 g, with the nodules exhibiting clonal growth, with microsatellite analysis showing loss of heterozygosity for many alleles, including putative tumour suppressor genes. The parathyroid tissue within these nodules is also characterized by reduced expression of vitamin D receptors (VDR) and CaR, which could explain—at least in part—the frequent lack of response to medical management. It appears that continuous stimulation of the parathyroid gland selectively favours cells with higher proliferative potential, so that the gland progressively escapes from growth-inhibitory control mechanisms. This is illustrated by the fact that regrowth, including locally invasive regrowth, occurs in many patients after subtotal parathyroidectomy or autotransplantation of parathyroid tissue.
Before the introduction of cinacalcet treatment, there was a tendency to consider parathyroidectomy in patients with marked elevation of serum intact PTH (>c.50 pmol/litre or 500 pg/ml) who failed to respond to medical treatment within 4 to 8 weeks, particularly in those with massive parathyroid enlargement on imaging procedures (estimated mass >1–1.5 g). Cinacalcet, when available, is now the treatment of first choice.
An absolute indication for parathyroidectomy is calciphylaxis (also called calcific uraemic arteriolopathy), namely ischaemic skin necrosis secondary to calcification of skin arteries, but only if associated with elevated serum intact PTH levels. Other indications are severe hypercalcaemia refractory to medical treatment, progressive and debilitating hyperparathyroid bone disease, and intractable pruritus or otherwise unexplained symptomatic myopathy associated with high intact PTH.
There has been a long-standing debate as to whether total parathyroidectomy or subtotal parathyroidectomy should be preferred, the latter with a remnant left in situ or autotransplanted into the subcutaneous abdominal fat or forearm musculature. There are no trial data to inform decision making. Leaving parathyroid tissue behind is associated with a relatively high risk of local recurrence, presumably because of the increased growth potential of parathyroid cells, although the risk can be reduced if only nonnodular parts of the gland are autotransplanted. Alcohol injection into the enlarged parathyroids under ultrasonographic guidance has been tried as an alternative to surgery, but this procedure has not found wide application except in Japan.
Bullet list 9 summarizes the approach to the management of patients with advanced renal secondary hyperparathyroidism.
Bullet list 9 Treatment of advanced hyperparathyroidism
→ normalize serum calcium and phosphate levels.
If serum phosphate is elevated
→ give calcium carbonate, calcium acetate, or calcium-free phosphate binders with meals.
→ reduce excessive intake of dietary phosphate.
→ increase efficacy of dialysis (higher blood flow, longer dialysis sessions, more frequent dialysis sessions)
If serum calcium is elevated
→ reduce dialysate calcium to 1.5 mmol/litre (6 mg/dl) or—transiently—to 1.25 mmol/litre (5 mg/dl)
→ reduce or withdraw calcium-containing oral phosphate binders or active vitamin D sterols
If serum calcium and phosphate have been normalized and elevated intact PTH persists
→ increase dose of calcitriol (0.5–3 µg) or alternative active vitamin D sterols (e.g. alfacalcidol, paricalcitol, doxercalciferol)—these can be given one to three times per week, or daily, with dose and time interval depending on degree of elevation of serum intact PTH; alternatively, administer cinacalcet (initial dose 30 mg/day)
→ monitor serum calcium, phosphate, intact PTH, and total alkaline phosphatases
If serum intact PTH decreases below approximately 16.5 pmol/litre (150 pg/ml)
→ interrupt administration of calcitriol, measure intact PTH again, and decide whether low-dose long-term prophylaxis is necessary
If serum intact PTH fails to decrease and/or hypercalcaemia/hyperphosphataemia develop or persist
→ monitor parathyroid gland size (ultrasonography; MIBI scan before surgery to localize ectopic glands)
→ consider cinacalcet (initial dose 30 mg/day) or surgical parathyroidectomy
Note: active vitamin D sterols are contraindicated as long as plasma phosphate is elevated.
Note: active vitamin D sterols are contraindicated as long as serum calcium is elevated.
The maintenance of a normal red-cell mass requires a rate of red-cell production by the bone marrow, with no substrate limitations and under the influence of an adequate amount of erythropoietin, which is sufficient to balance red-cell loss and destruction. All elements are disturbed in uraemia, and anaemia is one of the most obvious manifestations of the uraemic syndrome. Red-cell lifespan is shortened by accelerated destruction. Erythropoietin secretion is enhanced, but not to a sufficient level.
Epidemiology and clinical significance
Anaemia (defined as a haemoglobin concentration <13 g/dl in adult men and postmenopausal women, and <12 g/dl in premenopausal women) is common in CKD, particularly in those with diabetes, but affects nearly 90% of all with CKD stages 4 and 5, many of whom will have haemoglobin below 10 g/dl. Renal anaemia, which is normochromic and normocytic, accounts for many of the symptoms that previously were attributed to uraemia, including lethargy, cold intolerance, and general fatigue. Population studies and registry data generally report higher mortality for dialysis patients with haematocrit 30 to 33% compared with those with haematocrit 33 to 36%, or for haemoglobin levels less than 11 g/dl or 11.5 g/dl than above.
As a result of many trials of erythropoietin and other erythropoiesis-stimulating agents (ESAs), there is now general agreement that partial correction of anaemia in patients with CKD improves physiological and clinical status, as well as quality of life. This agreement has manifested itself in a plethora of clinical practice guidelines, including those produced by the National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) in the United States of America, the European Renal Association/European Dialysis and Transplant Association (ERA/EDTA), the Canadian Society of Nephrology, and the Japanese Society for Dialysis Therapy. There are minor differences between the particular guidelines, but they are all essentially very similar.
There is no particular haemoglobin concentration at which symptoms become manifest in all patients, hence the decision to start treatment in a particular patient is always a matter of judgement. As a rule of thumb, if a patient with CKD has haemoglobin below 11 g/dl and symptoms that might be attributable to anaemia, then treatment to restore haemoglobin to the range 11 to 12 g/dl is warranted if available, but it has been convincingly shown in randomized studies that correction to a higher level (‘normal or near normal’) is associated with poorer outcomes and should be prevented.
Before starting treatment with ESAs it is important to exclude other causes of anaemia: serum vitamin B12, red-cell folate, and indices of iron status should be assessed in all patients, with other tests on the basis of clinical suspicion, e.g. an elderly patient presenting with renal impairment and marked anaemia may have myeloma. If a patient is significantly iron deficient, then standard clinical methods of history and examination followed by appropriate investigation may be required to determine the cause, but otherwise it is important to recognize that optimal response to ESAs requires plentiful iron, not simply a level that is not deficient. It is also important to ensure that blood pressure is reasonably controlled before ESAs are given. In the early days of erythropoietin treatment, rapid increases in haemoglobin concentration in combination with poorly controlled blood pressure precipitated hypertensive encephalopathy in some patients. The standard advice is thus that ESAs should not be started (or doses omitted) if blood pressure is above 160/100 mmHg.
Bullet list 10 shows an algorithm whereby the patient’s iron status is optimized before ESAs are administered. A range of ESAs are available: all are clinically effective, many can be administered intravenously or subcutaneously, patients may prefer one rather than another because of the particular method of delivery and frequency of administration (variable from once or twice a week to monthly), and those paying may wish to choose the cheapest. If the haemoglobin fails to respond, or falls after initially responding, then causes given in Table 9 need to be considered.
Bullet list 10 Treatment of renal anaemia
Is anaemia due to CKD?
→ consider other causes.
Determine iron status
→ iron deficiency is defined by serum ferritin <100 µg/litre a .
→ functional iron deficiency is defined by serum ferritin >100 µg/litre with hypochromic red cells b >6% or transferrin saturation <20%
Optimize iron status
→ aim to maintain serum ferritin >200 µg/litre with hypochromic red cells <6% (unless ferritin >800 µg/litre) or transferrin saturation >20% (unless ferritin >800 µg/litre).
→ it is likely that this will require intravenous iron (usually 600–1000 mg for adults)
Initiate erythropoiesis-stimulating agents (ESAs) and adjust dose and frequency
→ to maintain stable Hb in range 10.5–12.5 g/dl (to achieve the maximum number of patients within target range of 11–12 g/dl).
→ to keep the rate of increase of Hb between 1 and 2 g/dl per month
Maintain adequate iron levels
→ keep serum ferritin in the range 200–500 µg/litre with hypochromic red cells <6% (unless ferritin >800 µg/litre) or transferrin saturation >20% (unless ferritin >800 µg/litre).
→ it is likely that this will require regular but infrequent intravenous iron
→ Hb every 2–4 weeks (induction phase, or after ESA dosage change) or every 1–3 months (maintenance phase).
→ iron status every 1–3 months (but not within a week of receiving intravenous iron)
→ patient’s clinical response
→ if there is any unexpected change in Hb level
a The ‘normal’ range for ferritin is usually quoted as 15–200 µg/litre
b Percentage of hypochromic red cells directly reflects the number of red cells with suboptimal haemoglobin content and may be determined by some automated analysers: <2.5% is normal and >10% indicates definite iron deficiency
|Table 9 Causes of failure to respond to erythropoiesis-stimulating agents (ESAs)|
|Is the patient receiving the injections?|
|Absolute or functional iron deficiency||Check serum ferritin and hypochromic red cells or transferrin saturation|
|Acute or chronic inflammatory states||These reduce the efficacy of ESAs|
|Other haematological conditions||Consider myeloma, other malignant diseases affecting the bone marrow, thalassaemia, vitamin B12 or folate deficiency|
|Chloramine in dialysis water||Can cause haemolysis presenting as apparent resistance to ESAs|
|Antierythropoietin antibodies||Rare, but a significant concern with one ESA preparation that led to its temporary withdrawal|
Complications of chronic renal failure
Chronic renal failure affects all parts of the body. Many of its complications have been discussed in this chapter, but a more complete—although not exhaustive—list is given in Table 10.
|Table 10 Complications of chronic renal failure|
|Hypertension||Discussed in text|
|Left ventricular hypertrophy||Found in 75% of dialysis patients|
|Coronary atherosclerosis||Cardiovascular disease is responsible for about 50% of deaths of patients receiving RRT. High risk of acute myocardial infarction, but sudden arrhythmic death is the most common fatal cardiac event|
|Pericarditis||A feature of neglected uraemia, including inadequate dialysis; can lead to tamponade and death|
|Calcific valvular disease||Mitral valve calcification found in one-third of dialysis patients. Calcific aortic stenosis can progress very rapidly|
|Pulmonary oedema||Feature of fluid retention|
|Pleural effusion||Feature of fluid retention|
|Anorexia, nausea and vomiting|
|Poor oral hygiene|
|Haemorrhage||Due to nonspecific gastric ulceration and/or angiodysplasia anywhere in the gastrointestinal tract; CKD renders normal bone marrow compensatory mechanisms less effective|
|Pancreatitis||Can be provoked by hypercalcaemia; long-term dialysis patients develop pancreatic fibrosis, but this does not seem to affect pancreatic function|
|Encephalopathy||Typically presents with confusion, myoclonic muscular twitching, and impairment of consciousness; seizures are rare unless there is accelerated hypertension|
|Sensorimotor peripheral polyneuropathy||Presents as dysaesthesias, restless legs, eventually weakness with foot drop; dialysis leads to slow improvement, but patients are often left with motor disability|
|Autonomic neuropathy||Manifests as abnormal cardiovascular reflexes, particularly on dialysis|
|Carpal tunnel compression||Caused by β2-microglobulin amyloid deposition; a feature in almost all patients who have been on dialysis for more than 10 years|
|Dialysis dementia||Presents as gradual deterioration in intellectual performance, progressing to dementia with abnormal movements. Due to aluminium intoxication. Should be of historical interest only|
|Mineral and bone disorder||Discussed in text|
|Crystal arthropathy||Gout and pseudogout (pyrophosphate arthropathy) are common. Management of gout can be difficult: NSAIDs are best avoided if possible in patients with advanced CKD who are not on dialysis, although very short-term use is acceptable; diarrhoea caused by colchicine can lead to acute deterioration of CKD; a short course of oral prednisolone (20 mg/day) may be the best treatment for an acute attack; reduced dose of allopurinol required|
|Pruritis||Can be a cause of significant distress. Associated with dry skin (xerosis), and worse when the skin is warm. Cause is uncertain—raised calcium × phosphate product, histamine sensitivity, and ‘uraemia’ have been blamed. Scratching can lead to infection and nodular prurigo. Treatments include starting/increasing dialysis, emollient lotions/creams, controlling plasma phosphate, keeping cool, antihistamines (e.g. chlorphenamine 4 mg at night), naltrexone, and ultraviolet phototherapy|
|Calciphylaxis||Discussed in text|
|Bullous eruptions||Pseudoporphyria, affecting sun-exposed areas. Thought to be due to accumulation of porphyrins in high-molecular-weight protein-bound complexes that are not removed by haemodialysis. Treatment is by avoidance of sun exposure, phlebotomy (for patients who are not anaemic and who have increased iron stores) and ESAs (which remove iron from stores by enhancing production of red blood cells)|
|Men||Loss of libido and erectile impotence are common and of multifactorial cause. Sperm counts may be low leading to reduced fertility. Priapism is a rare complication of haemodialysis treatment|
|Women||Most women with severe CKD develop irregular periods or amenorrhoea and are infertile, with rare pregnancies almost always ending in miscarriage. For general discussion of pregnancy in women with kidney disease.|
|Anxiety and depression are predictable and understandable consequences of loss of health, control, and pleasure. They tend to be most prominent in young patients. The best treatment is by sympathetic support of the dialysis multidisciplinary team. Psychotherapy/counselling can be helpful, but psychiatrists and/or medication have little to offer unless there is a specific mental illness|
|Glucose intolerance||CKD causes resistance to insulin-mediated glucose uptake in skeletal muscle|
|Complex effects on lipids||Increased very-low-density lipoproteins (VLDL); increased high density lipoproteins (HDL)|
|Enhanced protein catabolism||Risk of malnutrition discussed in text|
|Anaemia||Discussed in text|
|Impaired platelet function||Platelet numbers are normal, but function impaired at the level of endothelial contact|
|Impaired T-cell immunity||Mechanism uncertain, but puts patients with advanced CKD at higher risk of reactivation of tuberculosis and herpes zoster, of failure to clear some viral infections (e.g. hepatitis B), and of failure to generate normal responses to immunization (e.g. hepatitis B vaccine)|
|Impaired neutrophil function||Mechanism uncertain, but may in part explain high incidence and severity of bacterial infections|
|Blood-borne viruses||Dialysis is a risk factor for hepatitis C, hepatitis B and HIV|
|Methicillin-resistant Staphylococcus aureus (MRSA)||Dialysis patients are at high risk of acquiring MRSA because of their frequent contact with medical services, common requirement for invasive procedures/indwelling lines, and (perhaps) susceptibility to infection|
|Clostridium difficile infection||A problem on many renal units|
|Endocarditis||Bacteraemias in dialysis patients are often attributable to infection of vascular access sites, which, combined with high prevalence of calcific valvular disease, creates high risk of endocarditis, usually (70%) due to S. aureus|
CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; NSAID, nonsteroidal anti-inflammatory drug; RRT, renal replacement therapy.
Preparation for renal replacement therapy
A point of seemingly minor but in fact crucial importance in any patient with advanced CKD who is likely to progress to endstage renal failure is to preserve superficial veins of the forearm for vascular access. Whenever possible, blood should only be drawn from the veins on the dorsal surface of the hand, or—if veins in the forearm or elbow must be punctured or cannulated—the nondominant arm must be kept free from assault for later formation of an arteriovenous dialysis fistula.
Once endstage renal failure is inevitable, the patient must be prepared physically and psychologically for RRT. In many patients it is possible to predict approximately when the endstage will be reached from consideration of the rate of renal deterioration, most easily demonstrated by plotting the reciprocal of the serum creatinine against time. This information is useful for the patient and those planning care, providing a guide for the timing of the creation of permanent vascular access (thereby avoiding the perils of temporary lines), placement of peritoneal dialysis catheters, or activating the patient on to a transplant waiting list. The temptation to delay starting dialysis for as long as possible should be avoided: severe uraemia puts the patient at risk of life-threatening complications, but there is no evidence that starting dialysis early in an asymptomatic patient (eGFR 10-14ml/min) is better than starting when they begin to develop their first uraemic symptoms.
The absolute indications for dialysis, other than in patients for whom such treatment would be inappropriate, are the development of complications that cannot be treated by conservative and pharmacological means. These are hyperkalaemia, fluid overload, severe hypertension, pericarditis, encephalopathy, and neuropathy. To wait for these is bad practice, but nephrologists generally do wait until the patient has some uraemic symptoms such as anorexia, lassitude and pruritus, if only because their relief reinforces the need to adjust to regular dialysis. Apart from the serum potassium concentration and the degree of acidosis, blood tests such as urea and creatinine do not provide a safe guide as to when to start. Nevertheless, it is advisable to start dialysis, even in the absence of symptoms, when GFR falls below about 10 ml/min. In small patients with little muscle bulk the urea concentration is often between 30 and 40 mmol/litre and the creatinine concentration between 650 and 800 µmol/litre; in larger subjects the blood urea concentration is typically 45 to 50 mmol/litre and that of creatinine above 1000 µmol/litre. Initiation of dialysis at lower blood levels of urea and creatinine is recommended in diabetic patients.
The choice of modality—haemodialysis, continuous ambulatory peritoneal dialysis, or renal transplantation—depends on many factors, not least their availability and the patient’s preference. If transplantation is appropriate, there is no reason not to perform it before dialysis is required. If haemodialysis is chosen, vascular access should be created 4 to 6 months before it is needed. If continuous ambulatory peritoneal dialysis is to be used, the Tenckhoff catheter should be placed 2 to 3 weeks before dialysis needs to be started to allow it to seal.
Conservative management of terminal uraemia
There are patients for whom dialysis is inappropriate, or who choose either not to start treatment or to discontinue it. Because, intuitively, one would predict that instituting dialysis in a patient with renal failure and other comorbid conditions should result in some improvement by ameliorating at least one element of their clinical condition, many nephrologists find it very hard not to start. Some—often those who visit the floor of the dialysis unit relatively infrequently—argue that there is no harm done by starting because treatment can always be stopped, or the patient will die despite dialysis. However, haemodialysis is usually the only treatment modality possible in such circumstances, and the business of establishing access by (inevitably) insertion of central venous lines, the complications of such lines, the requirement for thrice-weekly transport to dialysis facilities for treatment that the frail body may find difficult if not impossible to tolerate, recovering only in time for the next dialysis session, can be truly miserable for the patient and all others concerned. Furthermore, in frail patients, usually elderly and with multiple comorbidities, it is not likely that dialysis will greatly prolong life, although it can certainly lower the quality of it. There have been no trials that have randomized such patients to treatment with RRT or to conservative (palliative) management, but one study reported the outcome of 63 patients who were recommended to receive palliative care after multidisciplinary assessment and counselling about treatment options. Ten of these patients opted for and received dialysis treatment, but their median survival after initiation of dialysis (8.3 months) was not significantly longer than survival beyond the putative date of dialysis initiation in the palliatively treated patients (6.3 months), and 65% of those treated with dialysis died in hospital, compared with 27% of those receiving palliative care. A study of 3702 nursing home residents in the United States who started on dialysis treatment between June 1998 and October 2000 revealed that 12 months later most (58%) had died and only 13% had maintained their predialysis functional state.
Withdrawing dialysis or dying while on treatment is often traumatic for the patient, the patient’s family and friends, and staff, but at least 10% of deaths in dialysis programmes follow withdrawal of treatment.
If one takes the view that dialysis is a treatment offered to allow a patient to continue living with a reasonable quality of life, as opposed to delaying death in the short term, then it will not be offered to patients with other immediately life-limiting conditions. One could argue that it should not be started when survival beyond 3 months outside hospital is unlikely. However, the ethical and legal issues are complex and require that the patient makes the decision not to start or to discontinue treatment when fully informed and able to do so. If possible, the physician should discuss with the patient the option of not starting before dialysis is actually needed. The patient needs to be given a realistic account of what dialysis can achieve, what it cannot achieve, and at what cost—access, travel, restrictions, and complications. These conversations can be difficult and cannot be hurried. They can often be helped by offering arrangements for the patient (and relative/friend) to visit the dialysis unit, and it is critically important that the patient (and their relatives/friends) does not get the entirely erroneous impression that dialysis means that ‘the doctors care and I’ll live for ever’, whereas “no dialysis means that ‘the doctors don’t care and I’ll die soon’.
Properly managed, death from uraemia is peaceful and free of suffering. It is important to ensure so far as is possible that the patient has peace of mind, that they are comfortable with their decision, and that their family members are understanding and supportive. They will be comforted to know that their doctor respects their decision. Several distressing symptoms may need to be controlled. Breathlessness from pulmonary oedema and acidosis is best controlled with a morphine infusion. Nausea and anorexia can be helped with regular chlorpromazine 25 mg four times daily, and ondansetron 8 mg twice daily can also be effective. Food and fluid should be offered in small, palatable helpings, with no pressure to eat or drink exerted on the patient. The mouth can become dry and crusted from mouth breathing and will smell foul from uraemic saliva, for which regular mouth washes and gum care will help. Pruritus is managed by keeping the skin cool, and soft with emollients. The patient may not be aware of myoclonic jerks, but these may distress the family: benzodiazepines, such as clonazepam, can be prescribed if needed.