- Email: [email protected]
Renal Osteodystrophy
CHRONIC RENAL FAILURE
women), unexplained declining renal function, haematuria or proteinuria. Renal biopsy is usually indicated to diagnose non-urological causes of persistent microscopic haematuria, particularly if accompanied by raised blood pressure, proteinuria (from > 0.5 g/ 24 hours to nephrotic-range) or renal functional impairment. These last two factors are indications for biopsy in their own right. Biopsy is not routinely performed in patients with diabetes if the clinical and nephrological course is consistent with the natural history of diabetic nephropathy. However, discussion with a nephrologist is warranted in patients with renal impairment disproportionate to or antedating proteinuria, and, particularly, in type 1 diabetes patients with no retinopathy and neuropathy but with proteinuria. Coagulation defects must be corrected, blood pressure controlled and urinary sepsis and obstruction dealt with before biopsy is undertaken, and this should be performed only in centres fully equipped for renal histopathology. Other invasive investigations (e.g. renal angiography) may be needed in specific cases. A major reason for timely referral of patients with declining renal function is to facilitate an orderly start of renal replacement therapy. In this setting, important aims are to: • reduce the rate of renal functional decline to a minimum • reverse/prevent complications of renal disease at this stage (e.g. renal bone disease, anaemia, acidosis, left ventricular hypertrophy) • obtain dialysis access (e.g. arteriovenous fistula) in good time • educate the patient and carers about renal disease and its implications and treatments. There is no precise creatinine level or GFR at which dialysis must be started. With careful attention, many patients function well with a GFR of less than 10 ml/minute. In some cases, fluid overload or hyperkalaemia mandates a sudden start. In others, loss of appetite, nausea or decreasing albumin or body weight is a sign that dialysis should be started. u
Renal Osteodystrophy Michael J D Cassidy
Both high and low bone turnover states may develop in chronic renal failure (CRF). The term ‘renal osteodystrophy’ generally encompasses the four major histological types of bone disease: • secondary hyperparathyroidism • osteomalacia • mixed renal osteodystrophy • adynamic bone disease. Other skeletal complications of renal failure include osteoporosis, dialysis-associated amyloid and metastatic calcification. There is a strong association between the development and severity of renal osteodystrophy and disorders of divalent metabolism, and the degree of renal failure. Problems can develop early and patients with a glomerular filtration rate (GFR) of 60 ml/minute/1.73m2 are at risk and should be evaluated for bone disease (National Kidney Foundation).
Pathogenesis Hormonal control of bone metabolism is discussed in MEDICINE 29:12.
What’s new ? • It is recognized that bone disease occurs early in the course of CRF • There is interest in vascular calcification (particularly of the coronary artery) and its relationship to calcium phosphate product and mortality • New non-calcium, non-aluminium phosphate binders have been developed • Osteoporosis is a significant bone disease emerging in post-transplantation patients
REFERENCES Jafar T H, Schmid C H, Landa M et al. Angiotensin-converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease. A Meta-analysis of Patient-level Data. Ann Intern Med 2001; 135: 73–87. Klag M J, Whelton P K, Randall B L et al. Blood Pressure and End-stage Renal Disease in Men. N Engl J Med 1996; 334: 13–18. Lazarus J M, Bourgoignie J J, Buckalew V M et al. Achievement and Safety of a Low Blood Pressure Goal in Chronic Renal Disease. Hypertension 1997; 29: 641–50. Lewis E J, Hunsicker L G, Clarke W R et al. Renoprotective Effect of the Angiotensin-receptor Antagonist Irbesartan in Patients with Nephropathy due to Type 2 Diabetes. N Engl J Med 2001; 345: 851–60.
Michael J D Cassidy is Clinical Director of the Nottingham City Hospital Renal and Transplant Unit, Nottingham, UK. He qualified from St Bartholomew’s Hospital, London, and trained in general medicine and nephrology at the University of Cape Town, South Africa and in Newcastle upon Tyne, UK. He was senior lecturer at the University of Cape Town and Groote Schuur Hospital, Cape Town. His research interests include renal bone disease and metastatic calcification.
FURTHER READING Johnson R J, Feehally J. Comprehensive Clinical Nephrology. London: Harcourt, 1998.
MEDICINE
56
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
• In late renal failure, both the number of calcitriol receptors on parathyroid gland cells and their capacity to bind calcitriol are inhibited, further worsening the situation. • Skeletal resistance to the hypercalcaemic action of PTH aggravates the hyperparathyroidism with advancing uraemia, partly as a result of the decreased calcitriol levels. In addition, high circulating levels of non-1–84 PTH, some with effects antagonistic to the intact hormone, accumulate in CRF (Slatopolsky E et al.) Over time, stimulation of parathyroid tissue leads to nodular hyperplasia and monoclonal expansion of adenomatous cells. Autonomous parathyroid production can lead to hypercalcaemia (tertiary hyperparathyroidism). This is uncommon in predialysis patients. ‘Osteitis fibrosa cystica’ is the term used to describe the effect of secondary hyperparathyroidism on trabecular bone. The effect on cortical bone is generalized thinning and reduction of bone mass. The main pathological hallmarks of the condition (Figure 2) include fibrosis of the bone marrow and accelerated bone turnover; proliferation of active osteoblasts (driven by PTH) leads to rapid deposition of osteoid, and proliferation of osteoclasts (driven by cytokines such as interleukin-6 and interleukin-11) leads to rapid resorption of bone. In severe cases, proliferation of osteoclasts results in cyst formation within bone (Brown cysts).
Secondary hyperparathyroidism A degree of secondary hyperparathyroidism is found in almost all patients with advanced CRF and in those on dialysis. Several mechanisms, which are not mutually exclusive, are responsible. • In early renal impairment, a slight increase in serum phosphate is associated with a slight decrease in serum calcium (Figure 1). Hypocalcaemia triggers release of parathyroid hormone (PTH), a single-chain polypeptide of 84 amino acids that redresses the balance (i.e. secondary hyperparathyroidism). Serum calcium and phosphate levels are returned to normal by this chronic parathyroid gland stimulation. In animal models, high serum phosphate stimulates PTH secretion directly. Phosphate retention is the usual consequence of reduced nephron mass when GFR declines to less than 30 ml/minute/1.73 m2. Serum phosphate levels are not consistently elevated in early renal failure, however, and there must be other reasons for the development of secondary hyperparathyroidism. • Decreased 1,25-dihydroxycholecalciferol (calcitriol) production by the kidney results in reduced calcium absorption by the gut and hypocalcaemia. Calcitriol is also an important regulator of parathyroid gene expression; reduced levels increase PTH production directly, independent of ionized calcium. End-organ (bone and gut) resistance to the effect of calcitriol also occurs in some patients with early renal insufficiency. It is unlikely that the reduction in calcitriol production seen in early renal insufficiency is caused by a reduction of renal mass, and it has been suggested that increased intracellular phosphate concentration in tubular cells inhibits calcitriol production. • As renal failure advances, secondary hyperparathyroidism progresses. In addition, the sensitivity of the parathyroid gland to ionized calcium in uraemia is altered and higher ionized calcium levels are required to inhibit hormone secretion (increased ‘set-point’ for PTH suppression).
Osteomalacia The biochemical and radiological characteristics of osteomalacia are listed in Figure 1, and osteomalacia is discussed further in MEDICINE 29:12, 74. A defect of mineralization sufficient to cause clinical osteomalacia is uncommon. Relative hypophosphataemia, hypocalcaemia, aluminium toxicity and chronic acidosis increase the risk of osteomalacia. Osteomalacic renal osteodystrophy may be associated with proximal myopathy. In young children, the complications of bone disease may be severe and resemble late
Characteristic biochemical disturbances and radiological features of renal bone disease Type of bone disease Hyperparathyroid
Biochemical features • Early – low-normal calcium, high-normal phosphate, raised calcium phosphate product • PTH more than three times normal • Serum phosphate, alkaline phosphatase and PTH rising with increasing severity • Hypercalcaemia with tertiary hyperparathyroidism
Radiological characteristics • Osteopenia and areas of sclerosis (‘rugger-jersey spine’, ‘pepper-pot skull’) • Subperiosteal erosions first seen in phalanges • Metastatic calcification • Reduced bone mineral density on DXA
Osteomalacia
• Tendency to lower serum phosphate levels, more severe acidosis, lower serum calcitriol levels, low or only slightly elevated PTH • Elevated serum aluminium may be the cause
• Osteopenia, Looser’s zones (particularly in ribs, scapulae and pelvis), skeletal deformity, vertebral compression • Reduced bone mineral density on DXA
Adynamic bone disease
• Tendency to hypercalcaemia, particularly in patients given calcitriol or calcium-containing phosphate binders • Normal serum alkaline phosphatase • Low PTH
• Osteopenia • Reduced bone mineral density on DXA
PTH, intact parathyroid hormone; DXA, dual-energy X-ray absorptiometry
1
MEDICINE
57
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
a
b
2 Trabecular bone histology. a Relatively normal bone with healthy trabeculae (green, calcified trabeculae). b Biopsy from a patient with severe secondary hyperparathyroidism, showing increased osteoid (red), increased bone resorption and marked fibrosis of the marrow space. (Masson’s trichrome stain.)
rickets (though they may be caused by severe secondary hyperparathyroidism rather than by osteomalacia). Mineralization of trabecular bone involves incorporation of calcium hydroxyapatite crystals into the collagen matrix (osteoid) produced by osteoblasts lining the surface of bony trabeculae; this occurs in an well-ordered manner along a mineralization front. In pure osteomalacia, osteoid is deposited at normal rates but does not calcify normally. Aluminium toxicity – the worst cases of osteomalacia in patients with CRF were seen in the 1970s, in haemodialysis units in areas where the water supply contained high levels of aluminium. On bone biopsy, staining revealed aluminium at the mineralization front, which prevented calcification.
bone disease of CRF. Osteoporosis is increasingly recognized as a problem following renal transplantation. The most dramatic loss of bone density occurs in the first 12 months after transplantation.
Clinical features The bony complications of chronic renal insufficiency develop over time. Patients most at risk include those with tubulo-interstitial diseases and those with a long history of uraemia. Growth and skeletal maturation are usually stunted in children. Osteomalacia is often associated with bone pain, skeletal deformity, proximal myopathy and a waddling gait. Reduced bone mineral density occurs in both high-turnover and low-turnover bone states and the incidence of fractures is increased, particularly following transplantation. Patients with secondary hyperparathyroidism may be relatively asymptomatic; however, increased levels of calcium phosphate product are commonly associated and can lead to cutaneous manifestations including pruritus, conjunctival inflammation (‘red eye’ syndrome of uraemia) and, rarely, calciphylaxis (Figure 3). In addition, strong epidemiological evidence indicates an association between hyperphosphataemia and increased calcium phosphate product, and coronary artery calcification and death.
Mixed renal osteodystrophy Tetracycline is incorporated in the mineralization front in a manner similar to aluminium. Mineralization time can be measured accurately by giving patients tetracycline before bone biopsy. Increased osteoid may be caused by increased production (in hyperparathyroidism) or reduced mineralization (osteomalacia); mixed renal osteodystrophy is said to occur when both abnormalities are found on bone biopsy. Clinical osteomalacia is uncommon; however, defects in mineralization, in association with hyperparathyroidism and detected using time-spaced tetracycline markers, are present in more than 50% of patients with advanced renal failure.
Management The mainstay of prevention and treatment of renal osteodystrophy is the maintenance of normal blood divalent ion concentration (particularly phosphorus). Biochemical and radiological monitoring is essential; bone biopsy may be required in difficult cases (Figure 4). It is best to start treatment early, when creatinine clearance declines to about 40 ml/minute; at this stage, dietary reduction of phosphate with an adequate calcium intake may be effective. Patient education and support is essential to improve compliance, which is a major problem with both the diet and the taking of phosphate binders.
Adynamic bone disease Adynamic bone disease is characterized by reduced trabecular bone formation and resorption. The surfaces of bone trabeculae are devoid of cellular activity and the trabeculae become progressively thinner. Mineralization of the little osteoid that is produced is not impaired unless aluminium is responsible. This condition is increasingly recognized; aetiological factors in addition to aluminium include diabetes mellitus and use of calcitriol to suppress PTH. Patients on continuous ambulatory peritoneal dialysis also appear to be more susceptible.
Phosphate binders: as renal failure advances, dietary efforts do not usually suffice. The next step is the introduction of oral phosphate binders; these must be taken with meals and the dose should be adjusted to cater for the anticipated phosphate load of
Osteoporosis Osteoporosis, particularly in the elderly and in patients treated with corticosteroids for prolonged periods of time, may complicate the
MEDICINE
58
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
3 Two patients with calciphylaxis. a Relatively extensive livedo reticularis can be seen below the area of skin necrosis on the medial aspect of the upper thigh. b This illustration shows how extensive and catastrophic the skin necrosis can be.
b
a
the meal. Calcium carbonate or calcium acetate (the latter may be more effective), 2–8 g/day, is currently the binder of choice. This also slightly improves metabolic acidosis. More than 30% of the calcium load is absorbed, however, which may result in hypercalcaemia and increased calcium phosphate product. As discussed above, data suggest that this increases the risk of metastatic calcification and its complications, including death from cardiovascular disease. Calcium citrate should not be used because it augments aluminium absorption. In some patients, serum phosphate is not controlled by calcium carbonate, and aluminium phosphate binders (at the lowest effec-
tive dose) must be used. Aluminium binders should not be used in children, and should be used for only limited periods in adults, with regular monitoring of serum aluminium levels. Magnesium carbonate and magnesium sulphate have also been used in dialysis patients; the amount of magnesium in the dialysate must be reduced to prevent toxicity. These agents should not be used in predialysis patients. Sevelamer hydrochloride (RenaGel – a non-absorbable polymeric phosphate binder) is a promising new agent. It is calciumfree and binds phosphate through ion exchange and hydrogen binding. Studies have shown it to be as effective as calcium carbon-
Methods of monitoring bone disease in chronic renal failure Test • Serum calcium, phosphate, albumin, alkaline phosphatase
Frequency in patients on dialysis Monthly
Comments Detects rises in phosphate quickly Calculate corrected calcium, calculate calcium phosphate product; if raised, check alkaline phosphatase is from bone and use in conjunction with tests below
• Parathyroid hormone
6-monthly
Physicians should ensure which assay is used; intact parathyroid hormone and N-terminal parathyroid hormone assays are required C-terminal assays do not reflect parathyroid gland activity accurately in renal failure
• Serum aluminium
Annually
Beware contamination; trace amounts of aluminium are found throughout the environment
• Desferrioxamine test
Used to confirm body tissue levels when the clinical suspicion of aluminium bone disease is high
• Radiography of hands
The earliest subperiosteal erosions are found in the phalanges
• Skeletal survey
Detects osteopenia, Looser’s zones and other fractures, metastatic calcification and subperiosteal erosions
• Dual-energy X-ray absorptiometry
Detects reduced bone mineral density, but does not give the cause
• Bone biopsy
Reserve for difficult cases; it diagnoses adynamic bone disease, and confirms aluminium bone disease definitively
4
MEDICINE
59
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
ate and acetate in lowering phosphate and controlling calcium phosphate product, with fewer episodes of hypercalcaemia. Suppression of PTH is achieved, but not to the same extent as with calcium binders, which may reduce the risk of low-turnover bone disease (see below). Coronary artery calcification does not progress to the same extent as in patients treated with calcium-containing binders; the effect of this on cardiovascular mortality is not yet known. Currently, this drug is licensed in the UK for haemodialysis patients only. It is well tolerated and has an advantageous sideeffect of lowering blood cholesterol by about 10%. Lanthanum carbonate (Fosrenol) is a new non-calcium, nonaluminium phosphate binder that is effective and has a good safety profile. It is currently undergoing approval in Europe and the USA.
at the time of transplantation may reduce bone loss. Currently, most manufacturers of bisphosphonates advise against their use in patients with a GFR of less than 30 ml/minute. There are also theoretical reasons why they should not be used in patients with adynamic bone disease. A significant proportion of renal transplant patients have low-turnover bone disease and may also have a GFR of less than 30 ml/minute, so use of bisphosphonates in post-transplantation patients with reduced bone mineral density is not straightforward. In the author’s unit, a significant number of transplant patients are vitamin D-deficient and are therefore treated with Calcichew D3 Forte. At present, there are no guidelines available for the management of post-transplant bone disease because there is no evidence base for treatment. u
Suppression of PTH: over-enthusiastic suppression of PTH in advanced renal failure should be avoided because it results in adynamic bone disease. PTH is necessary for normal bone turnover, and in uraemia the ‘skeletal resistance’ to PTH necessitates higher levels. The aim should be to maintain levels at 1.5–3 times normal. Treatment with oral calcitriol can be titrated according to PTH levels; the dose usually ranges from 0.25 µg on alternate days to 1 µg/day. Calcitriol ‘pulse therapy’, in which higher doses (2–4 µg) are given three times weekly orally or intravenously, has also been effective in treating established hyperparathyroidism. Combined use of calcium salts and calcitriol increases the risk of hypercalcaemia, and regular blood monitoring is therefore required. In dialysis patients, hypercalcaemia can be controlled using a low-calcium dialysate. Although new vitamin D metabolites (e.g. 22-oxacalcitriol, paracalcitriol (19-nor-1,25-dihydroxyvitamin D2), doxercalciferol) are available, their benefits over conventional calcitriol and alfacalcidol remain to be established (Cunningham).
REFERENCES Cueto-Manzano A M, Konel S, Hutchinson A J et al. Bone Loss in Long-term Renal Transplantation: Histopathology and Densitometry Analysis. Kidney Int 1999; 55: 2021–9. Cunningham J. What is the Optimal Regimen for Vitamin D? Kidney Int 1999; 56: S59–64. Musci I, Hercz G. Adynamic Bone Disease: Pathogenesis, Diagnosis and Clinical Relevance. Curr Opin Nephrol Hypertens 1997; 6: 356–61. National Kidney Foundation. K/DOQI Clinical Guidelines for Chronic Kidney Disease: Executive Summary. New York: National Kidney Foundation, 2002. Slatopolsky E, Finch J, Clay P et al. A Novel Mechanism for Skeletal Resistance in Uremia. Kidney Int 2000; 58: 753–61. FURTHER READING Davison A M, Cameron J S, Grünfeld J-P et al., eds. Oxford Textbook of Clinical Nephrology. Vol. 3. 2nd ed. Oxford: Oxford University Press, 1998. (A good textbook account of the management of renal bone disease.) Drüeke T B, Salusky I, eds. The Spectrum of Renal Osteodystrophy. 1st ed. Oxford: Oxford University Press, 2001 (Outstanding exposition on the whole subject.) Hruska K. New Concepts in Renal Osteodystrophy. Nephrol Dial Transplant 1998; 13: 2755–60. (Detailed description of current thought on the pathogenesis of renal bone disease.) Parfitt A M. A Structural Approach to Renal Bone Disease. J Bone Miner Res 1998; 13: 1213–20. (Excellent overview of the pathology of renal bone disease.) Roe S, Cassidy M J D. Diagnosis and Monitoring of Renal Osteodystrophy. Curr Opin Nephrol Hypertens 2000, 9: 675–81. (A practical approach to diagnosing and following patients with renal bone disease.)
Parathyroidectomy (partial or total) is occasionally required. In most patients, PTH concentration is more than 1000 ng/litre before parathyroidectomy is undertaken, though there is no absolute level. Indications for parathyroidectomy include tertiary hyperparathyroidism, uncontrollable pruritus with raised calcium phosphate product and PTH, and metastatic calcification (including calciphylaxis, skin necrosis caused by calcification of the small vessels of the skin). Control of aluminium: in all dialysis units, water is treated to remove aluminium; this has led to a dramatic decrease in fracturing osteodystrophy in units where this was a problem. Gut absorption of aluminium can cause problems, and aluminium-containing phosphate-binding gels should be avoided if possible. Development of hypercalcaemia with small doses of calcitriol should alert the physician to the possibility of aluminium toxicity or adynamic bone disease. Serum aluminium levels should be checked periodically and should be less than 50 µg/litre. Desferrioxamine can be used in provocative tests to determine the body burden of aluminium, and in treatment to remove aluminium by chelation.
Practice points • Both high and low bone turnover states exist in CRF • Bone disease can occur early in renal failure (GFR 60 ml/minute) • The mainstay of management is control of serum phosphate • Raised serum phosphate and raised calcium phosphate product are both associated with increased mortality in dialysis patients
Following transplantation (Cueto-Manzano et al.), the risk of osteoporosis can be minimized by life-style adjustments, hormone replacement therapy in post-menopausal women and testosterone in hypogonadal men. There is evidence that pamidronate given
MEDICINE
60
© 2003 The Medicine Publishing Company Ltd
women), unexplained declining renal function, haematuria or proteinuria. Renal biopsy is usually indicated to diagnose non-urological causes of persistent microscopic haematuria, particularly if accompanied by raised blood pressure, proteinuria (from > 0.5 g/ 24 hours to nephrotic-range) or renal functional impairment. These last two factors are indications for biopsy in their own right. Biopsy is not routinely performed in patients with diabetes if the clinical and nephrological course is consistent with the natural history of diabetic nephropathy. However, discussion with a nephrologist is warranted in patients with renal impairment disproportionate to or antedating proteinuria, and, particularly, in type 1 diabetes patients with no retinopathy and neuropathy but with proteinuria. Coagulation defects must be corrected, blood pressure controlled and urinary sepsis and obstruction dealt with before biopsy is undertaken, and this should be performed only in centres fully equipped for renal histopathology. Other invasive investigations (e.g. renal angiography) may be needed in specific cases. A major reason for timely referral of patients with declining renal function is to facilitate an orderly start of renal replacement therapy. In this setting, important aims are to: • reduce the rate of renal functional decline to a minimum • reverse/prevent complications of renal disease at this stage (e.g. renal bone disease, anaemia, acidosis, left ventricular hypertrophy) • obtain dialysis access (e.g. arteriovenous fistula) in good time • educate the patient and carers about renal disease and its implications and treatments. There is no precise creatinine level or GFR at which dialysis must be started. With careful attention, many patients function well with a GFR of less than 10 ml/minute. In some cases, fluid overload or hyperkalaemia mandates a sudden start. In others, loss of appetite, nausea or decreasing albumin or body weight is a sign that dialysis should be started. u
Renal Osteodystrophy Michael J D Cassidy
Both high and low bone turnover states may develop in chronic renal failure (CRF). The term ‘renal osteodystrophy’ generally encompasses the four major histological types of bone disease: • secondary hyperparathyroidism • osteomalacia • mixed renal osteodystrophy • adynamic bone disease. Other skeletal complications of renal failure include osteoporosis, dialysis-associated amyloid and metastatic calcification. There is a strong association between the development and severity of renal osteodystrophy and disorders of divalent metabolism, and the degree of renal failure. Problems can develop early and patients with a glomerular filtration rate (GFR) of 60 ml/minute/1.73m2 are at risk and should be evaluated for bone disease (National Kidney Foundation).
Pathogenesis Hormonal control of bone metabolism is discussed in MEDICINE 29:12.
What’s new ? • It is recognized that bone disease occurs early in the course of CRF • There is interest in vascular calcification (particularly of the coronary artery) and its relationship to calcium phosphate product and mortality • New non-calcium, non-aluminium phosphate binders have been developed • Osteoporosis is a significant bone disease emerging in post-transplantation patients
REFERENCES Jafar T H, Schmid C H, Landa M et al. Angiotensin-converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease. A Meta-analysis of Patient-level Data. Ann Intern Med 2001; 135: 73–87. Klag M J, Whelton P K, Randall B L et al. Blood Pressure and End-stage Renal Disease in Men. N Engl J Med 1996; 334: 13–18. Lazarus J M, Bourgoignie J J, Buckalew V M et al. Achievement and Safety of a Low Blood Pressure Goal in Chronic Renal Disease. Hypertension 1997; 29: 641–50. Lewis E J, Hunsicker L G, Clarke W R et al. Renoprotective Effect of the Angiotensin-receptor Antagonist Irbesartan in Patients with Nephropathy due to Type 2 Diabetes. N Engl J Med 2001; 345: 851–60.
Michael J D Cassidy is Clinical Director of the Nottingham City Hospital Renal and Transplant Unit, Nottingham, UK. He qualified from St Bartholomew’s Hospital, London, and trained in general medicine and nephrology at the University of Cape Town, South Africa and in Newcastle upon Tyne, UK. He was senior lecturer at the University of Cape Town and Groote Schuur Hospital, Cape Town. His research interests include renal bone disease and metastatic calcification.
FURTHER READING Johnson R J, Feehally J. Comprehensive Clinical Nephrology. London: Harcourt, 1998.
MEDICINE
56
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
• In late renal failure, both the number of calcitriol receptors on parathyroid gland cells and their capacity to bind calcitriol are inhibited, further worsening the situation. • Skeletal resistance to the hypercalcaemic action of PTH aggravates the hyperparathyroidism with advancing uraemia, partly as a result of the decreased calcitriol levels. In addition, high circulating levels of non-1–84 PTH, some with effects antagonistic to the intact hormone, accumulate in CRF (Slatopolsky E et al.) Over time, stimulation of parathyroid tissue leads to nodular hyperplasia and monoclonal expansion of adenomatous cells. Autonomous parathyroid production can lead to hypercalcaemia (tertiary hyperparathyroidism). This is uncommon in predialysis patients. ‘Osteitis fibrosa cystica’ is the term used to describe the effect of secondary hyperparathyroidism on trabecular bone. The effect on cortical bone is generalized thinning and reduction of bone mass. The main pathological hallmarks of the condition (Figure 2) include fibrosis of the bone marrow and accelerated bone turnover; proliferation of active osteoblasts (driven by PTH) leads to rapid deposition of osteoid, and proliferation of osteoclasts (driven by cytokines such as interleukin-6 and interleukin-11) leads to rapid resorption of bone. In severe cases, proliferation of osteoclasts results in cyst formation within bone (Brown cysts).
Secondary hyperparathyroidism A degree of secondary hyperparathyroidism is found in almost all patients with advanced CRF and in those on dialysis. Several mechanisms, which are not mutually exclusive, are responsible. • In early renal impairment, a slight increase in serum phosphate is associated with a slight decrease in serum calcium (Figure 1). Hypocalcaemia triggers release of parathyroid hormone (PTH), a single-chain polypeptide of 84 amino acids that redresses the balance (i.e. secondary hyperparathyroidism). Serum calcium and phosphate levels are returned to normal by this chronic parathyroid gland stimulation. In animal models, high serum phosphate stimulates PTH secretion directly. Phosphate retention is the usual consequence of reduced nephron mass when GFR declines to less than 30 ml/minute/1.73 m2. Serum phosphate levels are not consistently elevated in early renal failure, however, and there must be other reasons for the development of secondary hyperparathyroidism. • Decreased 1,25-dihydroxycholecalciferol (calcitriol) production by the kidney results in reduced calcium absorption by the gut and hypocalcaemia. Calcitriol is also an important regulator of parathyroid gene expression; reduced levels increase PTH production directly, independent of ionized calcium. End-organ (bone and gut) resistance to the effect of calcitriol also occurs in some patients with early renal insufficiency. It is unlikely that the reduction in calcitriol production seen in early renal insufficiency is caused by a reduction of renal mass, and it has been suggested that increased intracellular phosphate concentration in tubular cells inhibits calcitriol production. • As renal failure advances, secondary hyperparathyroidism progresses. In addition, the sensitivity of the parathyroid gland to ionized calcium in uraemia is altered and higher ionized calcium levels are required to inhibit hormone secretion (increased ‘set-point’ for PTH suppression).
Osteomalacia The biochemical and radiological characteristics of osteomalacia are listed in Figure 1, and osteomalacia is discussed further in MEDICINE 29:12, 74. A defect of mineralization sufficient to cause clinical osteomalacia is uncommon. Relative hypophosphataemia, hypocalcaemia, aluminium toxicity and chronic acidosis increase the risk of osteomalacia. Osteomalacic renal osteodystrophy may be associated with proximal myopathy. In young children, the complications of bone disease may be severe and resemble late
Characteristic biochemical disturbances and radiological features of renal bone disease Type of bone disease Hyperparathyroid
Biochemical features • Early – low-normal calcium, high-normal phosphate, raised calcium phosphate product • PTH more than three times normal • Serum phosphate, alkaline phosphatase and PTH rising with increasing severity • Hypercalcaemia with tertiary hyperparathyroidism
Radiological characteristics • Osteopenia and areas of sclerosis (‘rugger-jersey spine’, ‘pepper-pot skull’) • Subperiosteal erosions first seen in phalanges • Metastatic calcification • Reduced bone mineral density on DXA
Osteomalacia
• Tendency to lower serum phosphate levels, more severe acidosis, lower serum calcitriol levels, low or only slightly elevated PTH • Elevated serum aluminium may be the cause
• Osteopenia, Looser’s zones (particularly in ribs, scapulae and pelvis), skeletal deformity, vertebral compression • Reduced bone mineral density on DXA
Adynamic bone disease
• Tendency to hypercalcaemia, particularly in patients given calcitriol or calcium-containing phosphate binders • Normal serum alkaline phosphatase • Low PTH
• Osteopenia • Reduced bone mineral density on DXA
PTH, intact parathyroid hormone; DXA, dual-energy X-ray absorptiometry
1
MEDICINE
57
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
a
b
2 Trabecular bone histology. a Relatively normal bone with healthy trabeculae (green, calcified trabeculae). b Biopsy from a patient with severe secondary hyperparathyroidism, showing increased osteoid (red), increased bone resorption and marked fibrosis of the marrow space. (Masson’s trichrome stain.)
rickets (though they may be caused by severe secondary hyperparathyroidism rather than by osteomalacia). Mineralization of trabecular bone involves incorporation of calcium hydroxyapatite crystals into the collagen matrix (osteoid) produced by osteoblasts lining the surface of bony trabeculae; this occurs in an well-ordered manner along a mineralization front. In pure osteomalacia, osteoid is deposited at normal rates but does not calcify normally. Aluminium toxicity – the worst cases of osteomalacia in patients with CRF were seen in the 1970s, in haemodialysis units in areas where the water supply contained high levels of aluminium. On bone biopsy, staining revealed aluminium at the mineralization front, which prevented calcification.
bone disease of CRF. Osteoporosis is increasingly recognized as a problem following renal transplantation. The most dramatic loss of bone density occurs in the first 12 months after transplantation.
Clinical features The bony complications of chronic renal insufficiency develop over time. Patients most at risk include those with tubulo-interstitial diseases and those with a long history of uraemia. Growth and skeletal maturation are usually stunted in children. Osteomalacia is often associated with bone pain, skeletal deformity, proximal myopathy and a waddling gait. Reduced bone mineral density occurs in both high-turnover and low-turnover bone states and the incidence of fractures is increased, particularly following transplantation. Patients with secondary hyperparathyroidism may be relatively asymptomatic; however, increased levels of calcium phosphate product are commonly associated and can lead to cutaneous manifestations including pruritus, conjunctival inflammation (‘red eye’ syndrome of uraemia) and, rarely, calciphylaxis (Figure 3). In addition, strong epidemiological evidence indicates an association between hyperphosphataemia and increased calcium phosphate product, and coronary artery calcification and death.
Mixed renal osteodystrophy Tetracycline is incorporated in the mineralization front in a manner similar to aluminium. Mineralization time can be measured accurately by giving patients tetracycline before bone biopsy. Increased osteoid may be caused by increased production (in hyperparathyroidism) or reduced mineralization (osteomalacia); mixed renal osteodystrophy is said to occur when both abnormalities are found on bone biopsy. Clinical osteomalacia is uncommon; however, defects in mineralization, in association with hyperparathyroidism and detected using time-spaced tetracycline markers, are present in more than 50% of patients with advanced renal failure.
Management The mainstay of prevention and treatment of renal osteodystrophy is the maintenance of normal blood divalent ion concentration (particularly phosphorus). Biochemical and radiological monitoring is essential; bone biopsy may be required in difficult cases (Figure 4). It is best to start treatment early, when creatinine clearance declines to about 40 ml/minute; at this stage, dietary reduction of phosphate with an adequate calcium intake may be effective. Patient education and support is essential to improve compliance, which is a major problem with both the diet and the taking of phosphate binders.
Adynamic bone disease Adynamic bone disease is characterized by reduced trabecular bone formation and resorption. The surfaces of bone trabeculae are devoid of cellular activity and the trabeculae become progressively thinner. Mineralization of the little osteoid that is produced is not impaired unless aluminium is responsible. This condition is increasingly recognized; aetiological factors in addition to aluminium include diabetes mellitus and use of calcitriol to suppress PTH. Patients on continuous ambulatory peritoneal dialysis also appear to be more susceptible.
Phosphate binders: as renal failure advances, dietary efforts do not usually suffice. The next step is the introduction of oral phosphate binders; these must be taken with meals and the dose should be adjusted to cater for the anticipated phosphate load of
Osteoporosis Osteoporosis, particularly in the elderly and in patients treated with corticosteroids for prolonged periods of time, may complicate the
MEDICINE
58
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
3 Two patients with calciphylaxis. a Relatively extensive livedo reticularis can be seen below the area of skin necrosis on the medial aspect of the upper thigh. b This illustration shows how extensive and catastrophic the skin necrosis can be.
b
a
the meal. Calcium carbonate or calcium acetate (the latter may be more effective), 2–8 g/day, is currently the binder of choice. This also slightly improves metabolic acidosis. More than 30% of the calcium load is absorbed, however, which may result in hypercalcaemia and increased calcium phosphate product. As discussed above, data suggest that this increases the risk of metastatic calcification and its complications, including death from cardiovascular disease. Calcium citrate should not be used because it augments aluminium absorption. In some patients, serum phosphate is not controlled by calcium carbonate, and aluminium phosphate binders (at the lowest effec-
tive dose) must be used. Aluminium binders should not be used in children, and should be used for only limited periods in adults, with regular monitoring of serum aluminium levels. Magnesium carbonate and magnesium sulphate have also been used in dialysis patients; the amount of magnesium in the dialysate must be reduced to prevent toxicity. These agents should not be used in predialysis patients. Sevelamer hydrochloride (RenaGel – a non-absorbable polymeric phosphate binder) is a promising new agent. It is calciumfree and binds phosphate through ion exchange and hydrogen binding. Studies have shown it to be as effective as calcium carbon-
Methods of monitoring bone disease in chronic renal failure Test • Serum calcium, phosphate, albumin, alkaline phosphatase
Frequency in patients on dialysis Monthly
Comments Detects rises in phosphate quickly Calculate corrected calcium, calculate calcium phosphate product; if raised, check alkaline phosphatase is from bone and use in conjunction with tests below
• Parathyroid hormone
6-monthly
Physicians should ensure which assay is used; intact parathyroid hormone and N-terminal parathyroid hormone assays are required C-terminal assays do not reflect parathyroid gland activity accurately in renal failure
• Serum aluminium
Annually
Beware contamination; trace amounts of aluminium are found throughout the environment
• Desferrioxamine test
Used to confirm body tissue levels when the clinical suspicion of aluminium bone disease is high
• Radiography of hands
The earliest subperiosteal erosions are found in the phalanges
• Skeletal survey
Detects osteopenia, Looser’s zones and other fractures, metastatic calcification and subperiosteal erosions
• Dual-energy X-ray absorptiometry
Detects reduced bone mineral density, but does not give the cause
• Bone biopsy
Reserve for difficult cases; it diagnoses adynamic bone disease, and confirms aluminium bone disease definitively
4
MEDICINE
59
© 2003 The Medicine Publishing Company Ltd
CHRONIC RENAL FAILURE
ate and acetate in lowering phosphate and controlling calcium phosphate product, with fewer episodes of hypercalcaemia. Suppression of PTH is achieved, but not to the same extent as with calcium binders, which may reduce the risk of low-turnover bone disease (see below). Coronary artery calcification does not progress to the same extent as in patients treated with calcium-containing binders; the effect of this on cardiovascular mortality is not yet known. Currently, this drug is licensed in the UK for haemodialysis patients only. It is well tolerated and has an advantageous sideeffect of lowering blood cholesterol by about 10%. Lanthanum carbonate (Fosrenol) is a new non-calcium, nonaluminium phosphate binder that is effective and has a good safety profile. It is currently undergoing approval in Europe and the USA.
at the time of transplantation may reduce bone loss. Currently, most manufacturers of bisphosphonates advise against their use in patients with a GFR of less than 30 ml/minute. There are also theoretical reasons why they should not be used in patients with adynamic bone disease. A significant proportion of renal transplant patients have low-turnover bone disease and may also have a GFR of less than 30 ml/minute, so use of bisphosphonates in post-transplantation patients with reduced bone mineral density is not straightforward. In the author’s unit, a significant number of transplant patients are vitamin D-deficient and are therefore treated with Calcichew D3 Forte. At present, there are no guidelines available for the management of post-transplant bone disease because there is no evidence base for treatment. u
Suppression of PTH: over-enthusiastic suppression of PTH in advanced renal failure should be avoided because it results in adynamic bone disease. PTH is necessary for normal bone turnover, and in uraemia the ‘skeletal resistance’ to PTH necessitates higher levels. The aim should be to maintain levels at 1.5–3 times normal. Treatment with oral calcitriol can be titrated according to PTH levels; the dose usually ranges from 0.25 µg on alternate days to 1 µg/day. Calcitriol ‘pulse therapy’, in which higher doses (2–4 µg) are given three times weekly orally or intravenously, has also been effective in treating established hyperparathyroidism. Combined use of calcium salts and calcitriol increases the risk of hypercalcaemia, and regular blood monitoring is therefore required. In dialysis patients, hypercalcaemia can be controlled using a low-calcium dialysate. Although new vitamin D metabolites (e.g. 22-oxacalcitriol, paracalcitriol (19-nor-1,25-dihydroxyvitamin D2), doxercalciferol) are available, their benefits over conventional calcitriol and alfacalcidol remain to be established (Cunningham).
REFERENCES Cueto-Manzano A M, Konel S, Hutchinson A J et al. Bone Loss in Long-term Renal Transplantation: Histopathology and Densitometry Analysis. Kidney Int 1999; 55: 2021–9. Cunningham J. What is the Optimal Regimen for Vitamin D? Kidney Int 1999; 56: S59–64. Musci I, Hercz G. Adynamic Bone Disease: Pathogenesis, Diagnosis and Clinical Relevance. Curr Opin Nephrol Hypertens 1997; 6: 356–61. National Kidney Foundation. K/DOQI Clinical Guidelines for Chronic Kidney Disease: Executive Summary. New York: National Kidney Foundation, 2002. Slatopolsky E, Finch J, Clay P et al. A Novel Mechanism for Skeletal Resistance in Uremia. Kidney Int 2000; 58: 753–61. FURTHER READING Davison A M, Cameron J S, Grünfeld J-P et al., eds. Oxford Textbook of Clinical Nephrology. Vol. 3. 2nd ed. Oxford: Oxford University Press, 1998. (A good textbook account of the management of renal bone disease.) Drüeke T B, Salusky I, eds. The Spectrum of Renal Osteodystrophy. 1st ed. Oxford: Oxford University Press, 2001 (Outstanding exposition on the whole subject.) Hruska K. New Concepts in Renal Osteodystrophy. Nephrol Dial Transplant 1998; 13: 2755–60. (Detailed description of current thought on the pathogenesis of renal bone disease.) Parfitt A M. A Structural Approach to Renal Bone Disease. J Bone Miner Res 1998; 13: 1213–20. (Excellent overview of the pathology of renal bone disease.) Roe S, Cassidy M J D. Diagnosis and Monitoring of Renal Osteodystrophy. Curr Opin Nephrol Hypertens 2000, 9: 675–81. (A practical approach to diagnosing and following patients with renal bone disease.)
Parathyroidectomy (partial or total) is occasionally required. In most patients, PTH concentration is more than 1000 ng/litre before parathyroidectomy is undertaken, though there is no absolute level. Indications for parathyroidectomy include tertiary hyperparathyroidism, uncontrollable pruritus with raised calcium phosphate product and PTH, and metastatic calcification (including calciphylaxis, skin necrosis caused by calcification of the small vessels of the skin). Control of aluminium: in all dialysis units, water is treated to remove aluminium; this has led to a dramatic decrease in fracturing osteodystrophy in units where this was a problem. Gut absorption of aluminium can cause problems, and aluminium-containing phosphate-binding gels should be avoided if possible. Development of hypercalcaemia with small doses of calcitriol should alert the physician to the possibility of aluminium toxicity or adynamic bone disease. Serum aluminium levels should be checked periodically and should be less than 50 µg/litre. Desferrioxamine can be used in provocative tests to determine the body burden of aluminium, and in treatment to remove aluminium by chelation.
Practice points • Both high and low bone turnover states exist in CRF • Bone disease can occur early in renal failure (GFR 60 ml/minute) • The mainstay of management is control of serum phosphate • Raised serum phosphate and raised calcium phosphate product are both associated with increased mortality in dialysis patients
Following transplantation (Cueto-Manzano et al.), the risk of osteoporosis can be minimized by life-style adjustments, hormone replacement therapy in post-menopausal women and testosterone in hypogonadal men. There is evidence that pamidronate given
MEDICINE
60
© 2003 The Medicine Publishing Company Ltd