Anaemia is present in the great majority of patients with chronic renal failure. Several factors have been implicated:
ERYTHROPOIETIN DEFICIENCY is the most important BONE MARROW TOXINS such as polyamines, aluminium, arsenic, copper, lead BONE MARROW FIBROSIS secondary to hyperparathyroidism HAEMATINIC DEFICIENCy-iron, vitamin B12′ folate INCREASED RED CELL DESTRUCTION due to mechanical, oxidant and thermal damage during haemodialysis ABNORMAL RED CELL MEMBRANES causing increased osmotic fragility
INCREASED BLOOD Loss-occult gastrointestinal bleeding, blood sampling, blood loss during haemodialysis or due to platelet dysfunction
ACE inhibitors may cause anaemia in chronic renal failure, probably by interfering with the control of endogenous erythropoietin release.
RENAL OSTEODYSTROPHY. The term renal osteodystrophy embraces the various forms of bone disease that develop in chronic renal failure, i.e. osteomalacia and osteoporosis, secondary and tertiary hyperparathyroidism and osteosclerosis (Fig. 9.32). Covert renal osteodystrophy is present in most patients with severe renal failure. Phosphate retention results in hyperphosphataemia, which lowers the concentration of ionized serum calcium. Other effects include decreased renal production of 1,25(OH)2D3′ which leads to decreased calcium absorption and a fall in serum calcium. This in turn stimulates the release of PTH, which may already be increased due to the loss of the normal inhibitory effect of 1,25(OH)2D3
OSTEOMALACIA AND OSTEOPOROSIS
HYPERPARATHYROIDISM. Poor absorption of dietary calcium and phosphate retention lowers the serum calcium. PTH is released in response to hypocalcaemia and promotes resorption of calcium from bone and increased proximal tubular reabsorption of calcium in the kidney in an attempt to correct the low serum calcium. Over months or years, this ‘secondary’ hyperparathyroidism can lead to severe decalcification of the skeleton associated with the classical radiological appearances listed in Fig. 9.32.
A common, but not inevitable, sequel to long-standing secondary hyperparathyroidism is hyperplasia of the glands, leading to autonomous or ‘tertiary’ hyperparathyroidism. In this condition PTH is released inappropriately, resulting in hypercalcaemia and severe bone disease. Hyperparathyroidism causes bone and joint pains and a high serum alkaline phosphatase. Histologically there is
increased osteoclastic activity, cyst formation and bone marrow fibrosis (osteitis fibrosa cystica or von Recklinghausen’s disease of bone).
OSTEOSCLEROSIS. This literally means ‘hardening of bone’ and may be a direct result of excess PTH. Alternate bands of sclerotic and porotic bone in the vertebrae produce the characteristic ‘rugger-jersey spine’ X-ray appearance.
Itching is a common and frequently intractable problem in dialysis patients. The cause is multifactorial and includes:
• Elevated calcium x phosphate product-the most important remediable cause
• Hyperparathyroidism (even if calcium and phosphate levels are well controlled)
• Iron deficiency
• Inadequate dialysis
• Dry skin-simple aqueous creams are helpful Chronic renal failure may also cause pseudoporphyria, a blistering photosensitive skin rash. The pseudoporphyria is due to suppression of hepatic uroporphyrin decarboxylase combined with a decreased clearance of porphyrins in the urine or by dialysis.
DECREASED GASTRIC EMPTYING and increased risk of reflux oesophagi tis.
INCREASED RISK OF PEPTIC ULCERATION.
INCREASED RISK OF ACUTE PANCREATITIS-particularly in continuous ambulatory peritoneal dialysis (CAPD) (see p.488). However, elevations of serum amylase of up to three times normal may be found in chronic renal failure without any evidence of pancreatic disease, due to retention of high-molecular-weight forms of amylase normally excreted in the urine. In patients on CAPD, presence of amylase in the peritoneal effluent is diagnostic of pancreatitis.
CONSTIPATION-particularly in patients on CAPD.
GOUT. Urate retention is a common feature of chronic renal failure, particularly in renal vascular disease. Treatment of asymptomatic hyperuricaemia does not (as once thought) protect against further deterioration in renal function. Treatment of clinical gout is complicated by the nephrotoxic potential of NSAIDs. Colchicine is useful in treatment of the acute attack, and allopurinol should be introduced later under colchicine cover to prevent further attacks. The dose of allopurinol should be reduced in renal impairment.
INSULIN RESISTANCE is a feature of advanced renal impairment, and may contribute to hypertension and lipid abnormalities, but rarely causes clinically significant hyperglycaemia.
Pathogenesis and radiological features of renal osteodystrophy.
LIPID METABOLISM ABNORMALITIES are common In renal failure and include:
• Impaired clearance of triglyceride-rich particles
• Hypercholesterolaemia (particularly in advanced renal failure)
The situation is further complicated in end-stage renal cisease, excessive glucose absorption (in CAPD) and immunosuppressive drugs (in transplantation) may all contribute to lipid abnormalities.
HYPERPROLACTINAEMIA, which may present with galactorrhoea in men as well as women.
INCREASED LUTEINIZING HORMONE (LH) LEVELS in both sexes, and abnormal pulsatility of LH release.
DECREASED SERUM TESTOSTERONE LEVELS (only rarely below the normal levels). Impotence and decreased spermatogenesis are common.
ABSENCE OF NORMAL CYCLICAL CHANGES IN FEMALE SEX HORMONES, resulting in oligomenorrhoea or amenorrhoea.
COMPLEX ABNORMALITIES OF GROWTH HORMONE SECRETION AND ACTION, resulting in impaired growth in uraemic children. Pharmacological treatment with recombinant growth hormone and insulinlike growth factor is being studied.
ABNORMAL THYROID HORMONE LEVELS, partly due to altered protein binding. Sensitive assays for thyroidstimulating hormone are the best way to assess thyroid function. True hypothyroidism occurs with increased frequency in renal failure. Function of the posterior pituitary is normal in renal failure.
Uraemia appears to interfere with muscle energy metabolism, but the mechanism for this interference is uncertain. Decreased physical fitness (cardiovascular deconditioning) also contributes; exercise training programmes are of benefit in uraemic patients.
CENTRAL. Severe uraemia causes an unusual combination of depressed cerebral function and decreased seizure threshold. However, convulsions in a uraemic patient are much more commonly due to other causes such as accelerated hypertension, TTP, or drug accumulation.
Asterixis, tremor and myoclonus are also features of severe uraemia.
Rapid correction of severe uraemia by haemodialysis leads to ‘dialysis disequilibrium’ due to osmotic cerebral swelling; this can be avoided by correcting uraemia by short, repeated haemodialysis or by the use of peritoneal dialysis.
‘Dialysis dementia’ is a syndrome of progressive intellectual deterioration, speech disturbances, myoclonus and fits which is now known to be due to aluminium intoxication; it may be accompanied by aluminium bone disease and by microcytic anaemia. Low-grade aluminium exposure may also cause more subtle, subclinical deterioration in intellectual function.
AUTONOMIC. Reversible autonomic dysfunction is common in renal impairment. Findings include:
• Increased circulating catecholamine levels associated with down-regulation of a-receptors
• Impaired baroreceptor sensitivity
• Impaired efferent vagal function
All of these abnormalities improve to some extent after institution of regular dialysis and resolve completely after successful renal transplantation.
PERIPHERAL. Median nerve compression in the carpal tunnel is common, and usually due to J32-microglobulinrelated amyloidosis .
Restless legs syndrome is common in uraemia. Patients complain of an irresistible need to move their legs, often interfering with sleep. The syndrome is difficult to treat.
Iron deficiency should be treated if present. Attention should be paid to adequacy of dialysis. Symptoms may improve with the correction of anaemia by erythropoietin.
Clonazepam and codeine phosphate are sometimes useful. Renal transplantation cures the problem. A polyneuropathy occurs in patients who are inadequately dialysed.
Life expectancy remains severely reduced compared to the normal population due to a greatly increased incidence of cardiovascular disease, particularly myocardial infarction, cardiac failure, sudden cardiac death and stroke.
Hypertension is a frequent complication of renal failure.
Cardiac hypertrophy is common, even in patients without hypertension. Causative factors include anaemia, causing increased cardiac work, hyperparathyroidism, hypertension, sympathetic overactivity, recurrent volume overload and possibly uraemia per se.
Systolic and diastolic dysfunction are also common. Diastolic dysfunction is largely attributable to left ventricular hypertrophy and contributes to hypotension during fluid removal on haemodialysis. Systolic dysfunction may be due to:
• Myocardial fibrosis
• Abnormal myocyte function due to uraemia
• Calcium overload and hyperparathyroidism
• Carnitine and selenium deficiency
Successful renal transplantation improves some, but not all, of these abnormalities. Left ventricular hypertrophy is a risk marker for early death in renal failure, as in the general population, but it is not yet known whether treatments which result in regression of left ventricular hypertrophy reduce mortality. Systolic dysfunction is also an important marker for early death in renal failure. Vascular calcification is frequent in all sizes of vessel in renal failure. In addition to the classical risk factors for atherosclerosis, a raised calcium x phosphate product causes medial calcification. Hyperparathyroidism may also contribute independently to the pathogenesis by increasing intracellular calcium. Diffuse calcification of the myocardium is also common; the causes are similar.
There is no good evidence that dialysis per se results in accelerated atherosclerosis; the excess risk of cardiovascular death is highest in the predialysis phase of chronic renal failure.
Pericarditis is common and occurs in two clinical settings:
URAEMIC PERICARDITIS is a feature of severe, preterminal uraemia or of underdialysis. Haemorrhagic pericardial effusion and atrial arrhythmias are often associated. There is a danger of pericardial tamponade and anticoagulants should be used with caution. Pericarditis usually resolves with intensive dialysis.
DIALYSIS PERICARDITIS occurs as a result of an intercurrent illness or surgery in a patient receiving apparently adequate dialysis.