Renal manifestations of systemic autoimmune disease: diagnosis and therapy

Best Practice & Research Clinical Rheumatology Vol. 18, No. 3, pp. 411–427, 2004 doi:10.1016/j.berh.2004.03.002 available online at http://www.sciencedirect.com

9 Renal manifestations of systemic autoimmune disease: diagnosis and therapy C.A. O’Callaghan*

BM, BCh, MA, D Phil, MRCP

MRC Senior Clinical Fellow and Honorary Consultant Nephrologist Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK

Renal involvement is relatively common in certain systemic autoimmune diseases, but can be clinically silent. Active surveillance is, therefore, essential because the early recognition of renal involvement may influence the extent of renal recovery. Blood pressure control is also essential, regardless of the underlying disease. In systemic lupus erythematosus, therapy usually depends on the renal biopsy findings as not all forms of renal involvement respond in the same way. Typically, for aggressive disease, therapy is with steroids and a cytotoxic agent, usually cyclophosphamide initially and then azathioprine. In systemic vasculitis with renal involvement, a similar approach is adopted, therapy including steroids and cyclophosphamide initially and then steroids and azathioprine. With severe fulminant disease, plasma exchange or pulsed intravenous methylprednisolone is added initially. Scleroderma renal crises are managed by blood pressure control using angiotensin-converting enzyme inhibitors and other agents as required. Dialysis and transplantation can be successful in these conditions. Key words: kidney; glomerulonephritis; systemic lupus erythematosus; systemic vasculitis; scleroderma; immunosuppression.

The kidney can be affected by systemic autoimmune diseases, with important consequences. Renal involvement may be clinically silent but can cause serious and permanent damage with profound implications for the patient. For this reason, it is important to be vigilant for renal involvement in the presence of any systemic disease that may affect the kidney. This chapter will outline our current understanding of the renal problems associated with key systemic autoimmune diseases and how to detect and manage them. As many patients with systemic autoimmune diseases are seen at the same or different points in their lives by renal, rheumatological and other teams, it is essential that there is good communication between all those involved in caring for these patients. The major systemic autoimmune diseases that commonly affect the kidney are systemic lupus erythematosus and systemic vasculitis. However, a range of other conditions, including scleroderma and rheumatoid arthritis, can also be associated with * Tel.: þ 44-1865-221333/221351; Fax: þ44-1865-222901. E-mail address: [email protected] (C.A. O’Callaghan). 1521-6942/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

412 C. A. O’Callaghan

renal pathology. Although renal involvement does occur in rheumatoid arthritis, this is not a common problem, and most renal problems in this condition are consequences of the treatments used or the result of amyloidiosis caused by the persistent acute-phase response. In particular, the role of non-steroidal anti-inflammatory drugs in renal dysfunction is increasingly being recognized. A severe vasculitis involving the kidneys can occur in rheumatoid arthritis and is treated in the same way as primary vasculitis with renal involvement. This review will focus on systemic lupus erythematosus, systemic vasculitis and scleroderma.

SYSTEMIC LUPUS ERYTHEMATOSUS The aetiology of systemic lupus erythematosus is unclear, but the disease is characterized by polyclonal B-cell activation and the presence of autoantibodies. Antibodies and complement components are usually found in the kidneys of patients with renal involvement. In a review of approximately 1000 patients with systemic lupus erythematosus in a rheumatology clinic, 16% had renal involvement at presentation, this number rising to 50% during follow-up.1 Many groups have reviewed the number of lupus patients who develop renal disease, and overall estimates vary from 25% to 65%.2 In most cases, renal disease develops within the first 3 years following diagnosis with systemic disease. Diagnostic classification The nature of the renal disease caused by systemic lupus erythematosus is highly variable from patient to patient and can result from several disease processes. These include those causing a minimal change nephropathy, a proliferative glomerulonephritis, a membranous glomerulonephritis, tubulo-interstitial damage and in some cases renal vascular thrombosis. The most commonly used classification system is the histopathological one developed by the World Health Organization (Table 1). The changes are in part classified according to the degree of cellular proliferation. In type 1 disease there is no obvious cellular proliferation, whereas in type 2 disease there is only mesangial cell proliferation. In type 3 disease there is focal proliferation (cellular proliferation that is present in only a proportion of the glomeruli). In type 4 disease there is diffuse proliferation (cellular proliferation that is present in all the glomeruli). Crescents may occur in types 3 and 4, and are caused by the proliferation of monocytes in Bowman’s capsule. Type 5 disease is a membranous nephropathy. Although the World Health Organization classification is useful, different types may be present to different extents, simultaneously or consecutively, in any patient, Table 1. World Health Organization classification of renal involvement in systemic lupus erythematosus. Type 1 Type 2a Type 2b Type 3 Type 4 Type 5

Normal Mesangial deposits Mesangial hypercellularity Focal segmental profierative glomerulonephritis Diffuse proliferative glomerulonephritis Membranous glomerulonephritis

Renal manifestations of systemic autoimmune disease 413

Table 2. National Institutes of Health activity/chronicity index. Activity index Glomerular abnormalities 1. Cellular proliferation 2. Fibrinoid necrosis, karyorrhexis 3. Cellular crescents 4. Hyaline thrombi, wire loops 5. Leukocyte infiltration Tubulointerstitial abnormalities 1. Mononuclear cell infiltrates

Chronicity index

1. Glomerular sclerosis 2. Fibrous crescents

1. Interstitial fibrosis 2. Tubular atrophy

and the classification focuses only on the predominant abnormalities. Other scoring systems, which quantitate the degree of chronic fibrosis, especially that involving the tubules and interstitium, correlate more usefully with long-term renal prognosis. The US National Institutes of Health activity/ chronicity index (Table 2) provides measures of the degrees of current disease activity and of chronic irreversible damage.3 This can be useful in assessing the extent to which the renal lesion is likely to be reversible and therefore likely to benefit from immunosuppression. About 60 –70% of all patients biopsied have tubulo-interstitial changes. Proliferative disease The most common histopathological picture is of a proliferative glomerulonephritis. The proliferation ranges from mesangial proliferation to focal or diffuse proliferation with crescents. There is usually renal immunoglobulin and complement deposition, which may be causally related to the renal damage. Membranous disease A membranous nephropathy can arise with some localization of immune deposits within the glomeruli, which may promote an inflammatory response. The usual appearance is of sub-epithelial deposits of immunoglobulin and complement with little cellular infiltration or proliferation. Tubulo-interstitial disease Any renal inflammation, whether glomerular or otherwise, can result in inflammatory and then fibrotic changes in the renal tubules and interstitium. This can damage the tubules and the interstitial supporting tissues around the tubules and the glomeruli. In systemic lupus erythematosus, there are often immune complexes and an inflammatory infiltrate in the interstitium. Renal vascular thrombosis Renal vascular thrombosis in systemic lupus erythematosus is associated with the presence of anti-phospholipid antibodies. Renal artery or renal vein thrombosis can

414 C. A. O’Callaghan

occur. Small-vessel thrombosis can cause a non-inflammatory microangiopathy. Thrombotic occlusion or narrowing of the renal arterioles causes glomerular ischaemia, which triggers renin secretion and angiotensin II production, thus causing severe hypertension. The effect is similar to that seen with malignant hypertension. Intraglomerular thrombosis can cause a steady loss of glomerular filtration and function without obvious proteinuria or other urinary abnormalities. Some intraglomerular thrombosis often co-exists with focal and diffuse proliferative glomerulonephritis in the presence of systemic lupus erythematosus. With small-vessel thrombosis, there may be no detectable anti-phospholipid antibodies, but there may be a low platelet count and there is usually glomerular complement and immune complex deposition. Clinical presentations of renal disease Renal involvement in systemic lupus erythematosus can cause a wide range of abnormalities, from asymptomatic proteinuria or microscopic haematuria with normal renal function, to severe nephrotic syndrome or acute renal failure. Mild changes may be intermittent. Several patterns of clinical presentations are recognizable. First, mild asymptomatic renal involvement is usually detectable as mild proteinuria or microscopic haematuria. Clinically silent renal involvement is well documented, and diffuse proliferative glomerular changes have been reported in up to 45% of such patients who have been biopsied.4 The renal involvement typically fluctuates along with other systemic manifestations of the disease and can become more severe at any time. Second, the nephrotic syndrome can occur, with hypertension, significant and relatively rapid-onset renal impairment and haematuria. Typically, there is substantial extra-renal disease activity, and the course is one of relapses and remissions of both the renal and extra-renal disease. Without treatment, such patients often reach end-stage renal disease or die within about 2 years. Third, the nephrotic syndrome can occur with just mild renal impairment, microscopic haematuria and sometimes hypertension. Such disease is usually slowly progressive and associated with mild systemic disease. Around half of these patients will eventually develop end-stage renal disease over many years. Fourth, a small group of patients present with severe fulminant disease and rapidly develop end-stage renal disease, usually despite aggressive therapy. There is usually severe extra-renal disease, severe hypertension and often encephalopathy with papilloedema. There may be widespread capillary thrombi on a renal biopsy and sometimes crescents. Rarely, an acute anuric state arises as a result of intrinsic disease activity or the administration of non-steroidal anti-inflammatory drugs. Such patients can develop a thrombotic, thrombocytopenic purpura-like disease with a microangiopathic haemolytic anaemia, seizures and acute renal failure. This can happen particularly in pregnancy and in patients with a lupus anticoagulant. Finally, a distal renal tubular acidosis can occur with systemic lupus erythematosus but is usually of minimal clinical significance, although nephrocalcinosis and stone formation sometimes occur. Treatment It is difficult to formulate a management plan for renal involvement without a renal biopsy. However, if aggressive therapy such as cyclophsophamide or plasmapheresis is to be used for severe extra-renal disease anyway, a renal biopsy is unlikely to alter management and carries its own risks.

Renal manifestations of systemic autoimmune disease 415

Mild renal changes If the blood pressure is normal, renal function is normal, the urine sediment does not contain red cell casts and proteinuria is less than 1 g/day, no specific therapy is required for minimal or mesangial changes. Non-steroidal anti-inflammatory drugs should be used with caution as they can reduce the glomerular filtration rate. Moderate renal changes Focal proliferative glomerular changes do not necessarily require treatment, although the use of low doses of steroids and cytotoxic agents has been advocated.5 If there is severe segmental proliferation, substantial proteinuria, renal impairment and nephritic syndrome, it is usual to treat the patients as if they have a diffuse proliferative glomerulonephritis. Membranous nephropathy Patients with membranous nephropathy, asymptomatic haematuria and stable renal function are not usually given any specific therapy. Steroids do not appear to control the proteinuria, and the role of cytotoxic agents is unclear. If there is a sudden deterioration in renal function, a new biopsy is necessary to exclude a more aggressive pattern of disease. A small study of ciclosporin in membranous nephropathy in systemic lupus erythematosus showed a substantial reduction of proteinuria in all patients treated.6 Severe proliferative changes Diffuse proliferative and severe focal proliferative glomerulonephritis are usually treated aggressively if there is nephrotic syndrome, an active urinary sediment or renal impairment. The disease is, however, highly variable from patient to patient, so rigid adherence to protocols derived from clinical trials may expose patients with mild or highly responsive disease to excessive immunosuppression. Steroids are effective, but the morbidity from high-dose therapy is substantial. Oral prednisolone has usually been used at 1– 2 mg/kg/day, although a maximum dose of around 60 mg is now more common. Pulsed intravenous methylprednisolone regimens (0.5 – 1 g/day for 3 days) may reduce the steroid-related side-effects in the longer term and are effective.7,8 Following these pulses, prednisolone is usually maintained until the disease is in remission and then gradually tapered. It is usual to add a cytotoxic agent, based in large part on the results of an National Institutes of Health study9 that randomized patients with renal involvement to one of five regimens: high-dose prednisolone (1 mg/kg/day initially), azathioprine (up to 4 mg/ kg/day), oral cyclophosphamide (up to 4 mg/kg/day), combined oral cyclophosphamide and azathioprine (up to 1 mg/kg/day) or intravenous cyclophosphamide (0.75 g/m2 every 3 months, rising to 1 g/m2 if the nadir white cell count was not below 4.0 £ 109/l). Low-dose prednisolone (0.5 mg/kg/day) was given with all the cytotoxic regimens. The risk of developing renal failure was greater in those treated only with steroids than in all other groups. However, only the comparison between intravenous pulsed cylcophosphamide and high-dose prednisolone reached statistical significance. In those given cytotoxics, the incidence of malignancy was lowest in the pulsed cyclophosphamide group. The highest risk of infection occurred in the high-dose steroid group. Haemorrhagic cystitis, bone marrow depression and gonadal toxicity occurred only with oral cyclophosphamide.

416 C. A. O’Callaghan

Intravenous methylprednisolone monthly for 6 months has been compared with intravenous cyclophosphamide monthly for 6 months and with intravenous cyclophosphamide monthly for 6 months and then every 3 months for a further 2 years.10 The only significant advantage in the progression of renal disease occurred in the last group, and the addition of the quarterly doses of cyclophsophamide reduced the frequency of relapse from 50% to 10% over 5 years. The risks of such long-term cytotoxic therapy are, however, substantial. Other groups have obtained good results using methylprednisolone induction therapy followed by oral prednisolone and oral cytotoxic therapy.11,12 A study of 65 patients with severe diffuse proliferative disease achieved remission in 29% of patients receiving monthly intravenous pulses of methyl prednisolone, in 65% of those receiving monthly cyclophosphamide and in 85% of those receiving a combination of the two.13 Although there are no large-scale studies with controlled data demonstrating that cyclophosphamide is superior to azathioprine, the consensus view is that this is the case. There seems a marginal advantage to the use of intravenous over oral cyclophosphamide. Relapsing lupus nephritis and long term-monitoring Patients who have had renal disease should be monitored for life with checks of blood pressure, serum creatinine or creatinine clearance and dipstick urinalysis every 3 –6 months. If renal impairment, significant proteinuria or haematuria occurs, a renal biopsy should be considered and a nephrologist consulted. The relapse of treated lupus nephritis is common, and if the clinical features have changed or a significant period of time has elapsed since the previous renal biopsy, this should be repeated. If there is active disease without overwhelming chronic damage, it is usual to treat the patient with immunosuppression again, as described above. In some patients, relapses are rapid and frequent, and in these patients it may be worth a trial of a less-validated alternative agent, such as mycophenolate. Other agents Reports suggest that mycophenolate can reduce proteinuria and improve renal function.14,15 In a series of 13 individuals who had failed to respond to conventional therapy or had relapsed, mycophenolate was associated with a significant fall in creatinine and proteinuria, and a normalization of the urinary sediment.16 In a small study, 42 patients with diffuse proliferative disease were randomized to prednisolone and mycophenolate for 12 months or prednisolone and cyclophosphamide for 6 months, then prednisolone and azathioprine for 6 months.17 The response to treatment was similar in both groups. However, the trial excluded patients with a serum creatinine greater than 300 mmol/l, those with other life-threatening problems such as cerebral involvement, those with a history of poor compliance, those who had received cyclophosphamide within the previous 6 months and those who had taken moderate doses of oral prednisolone for more than 2 weeks. A recent paper reported complete or partial remission in 12 patients with proliferative disease treated with mycophenolate.18 However, only two out of six patients with membranous lupus nephritis showed any response, and the mean follow-up was only 15.3 months. Mycophenolate is extensively used in renal transplantation and a relatively standard dose would be 1 g twice daily for a 70 kg individual. The drug is well tolerated, and drug levels are not routinely monitored. Ciclosporin at 5 mg/kg/day in addition to steroids has been associated with an improvement in renal function.19 Plasma exchange has not been shown to have any

Renal manifestations of systemic autoimmune disease 417

significant benefit in severe diffuse proliferative lupus glomerulonephritis.20 A small series suggested some benefit from intravenous immunoglobulin in treatment-resistant membranous or membrano-proliferative lupus nephritis.21 In 14 randomized patients, monthly intravenous immunoglobulin was of comparable efficacy to intravenous cyclophosphamide as maintenance therapy, but all the patients had previously been treated with cyclophosphamide to induce remission.22 Typically, severe diffuse proliferative glomerulonephritis in the context of systemic lupus erythematosus is treated as follows. Steroids are given as 0.5 – 1 g/day of intravenous methyl prednisolone for 3 days, followed by 0.5 – 1 g/kg/day oral prednisolone tapered to the lowest possible dose and ideally stopped. Cyclophosphamide is usually added at a dose of 1– 2 mg/kg/day for 2 – 6 months followed by azathioprine 1– 2 mg/kg/day. Intravenous cyclophosphamide pulses may also be used in some cases. In some patients with contraindications to the above regimens, or in those who do not respond, ciclosporin may be tried at 5 mg/kg/day. A recent meta-analysis concluded that cyclophosphamide combined with steroids remains the best option to preserve renal function in patients with diffuse proliferative lupus glomerulonephritis.23

End-stage renal disease Patients who lose renal function require renal replacement therapy. Patients with severe progressive renal impairment need regular nephrological review to plan for renal replacement therapy. Those who have had a slowly progressive disease usually have relatively inactive disease while on dialysis. However, those patients who have had aggressive, fulminant disease may remain unwell, with active disease. Although a significant number of these patients die shortly after they have commenced dialysis, 10 – 28% may recover renal function and stop dialysis.24 Patients with lupus anticoagulant activity may have problems with thrombosis of dialysis fistulae. Transplantation is often postponed for a year after the commencement of dialysis to allow for any possible renal recovery and in some cases to allow the patient to recover from previous immunosuppression. Lupus nephritis recurs in around 3 – 4% of transplanted patients.25

General aspects of treatment Patients with lupus nephritis may be affected by the many problems that can affect all patients with renal disease. Hypertension can promote further renal damage and is a cardiovascular risk factor, which may require multiple drugs to control it. In black patients, calcium channel blockers or diuretics may be required. Diuretics are usually appropriate in any hypertensive patients with salt and water retention, especially nephrotic patients. In patients without salt and water retention, the usual first choice is an angiotensin-converting enzyme inhibitor, which may reduce proteinuria. In the presence of very poor renal function, blood pressure may be difficult to control until dialysis or haemofiltration is instituted. All patients with chronic renal disease have an elevated risk of vascular disease and are often hyperlipidaemic, so lipid-lowering therapy might be expected to be beneficial. Unfortuantely, as renal patients have generally been excluded from trials of lipidlowering therapy, there is no reliable randomized evidence of benefit in this group. Nevertheless, it is standard practice to monitor lipids and treat with an appropriate statin if the total or low-density lipoprotein – cholesterol level is elevated.

418 C. A. O’Callaghan

Future prospects The B-cell tolerogen LJP 394 (abetimus sodium) is a synthetic compound that binds to anti-double-stranded (ds) DNA antibodies on B-cells and in solution. It acutely reduces circulating anti-dsDNA antibody levels, presumably by forming soluble complexes that do not seem to result in significant complement activation. In rodents, LJP 394 induces B-cell tolerance by cross-linking anti-dsDNA immunoglobulin on the B-cell surface and triggering B-cell anergy or apoptosis.26 In a randomized controlled trial, treatment with LJP 394 in patients with high-affinity antibodies to its DNA epitope prolonged the time to renal flare, decreased the number of renal flares and required fewer episodes of conventional treatment compared with placebo.27 The drug was well tolerated, but, on an overall intention-to-treat analysis, the time to renal flare and the number of renal flares did not differ between the placebo and treatment groups. In organ transplantation, the potent immunosuppressive agent CTLA4-Ig is at an experimental stage. It binds to CD80 and CD86 and is thought to interrupt costimulatory signals to T-cells; it has been shown to have some efficacy in animal models of lupus nephritis.28,29

SYSTEMIC VASCULITIS Estimates of the incidence of primary vasculitic disease are around 7– 15 new cases per million per year; the small-vessel vasculitic diseases are the most common.30 In one report, Wegener’s granulomatosis and microscopic polyangiitis accounted for 0.5% of patients on renal replacement therapy in Europe.31 Most patients are white Caucasians, and the peak incidence seems to be in the fifth and sixth decades. In a recent review, the cumulative survival of patients with systemic vasculitides and renal involvement was 82% at 1 year and 76% at 5 years.32 End-stage renal disease occurred in 28% and at least one relapse occurred in 34% at a median of 13 months following diagnosis. The most frequently classification system for vasculitic disease is the Chapel Hill consensus classification, which is based on the smallest vessels involved (Table 3).33 The term ‘renal limited vasculitis’ refers to isolated focal necrotizing glomerulonephritis resulting from a small-vessel vasculitis restricted to the kidney. Secondary causes of vasculitis and glomerulonephritis include rheumatoid arthritis and systemic lupus erythematosus.

Table 3. Classification of vasculitic disorders. Small-vessel vasculitis

Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Henoch Scho¨nlein purpura Essential cyroglobulinaemic vasculitis Cutaneous leucocytoclastic angiitis

Medium-vessel vasculitis

Polyarteritis nodosa Kawasaki disease

Large-vessel vasculitis

Giant cell (temporal) arteritis Takayasu’s arteritis

Renal manifestations of systemic autoimmune disease 419

Clinical features of the small-vessel vasculitic disorders According to the Chapel Hill consensus, Wegener’s granulomatosis is a granulomatous inflammation involving the respiratory tract with a necrotizing vasculitis in vessels of small to medium size. Microscopic polyangiititis is a necrotizing vasculitis affecting small vessels without granulomatous inflammation and with few or no immune deposits. All the features of microscopic polyangiitis can occur in Wegener’s granulomatosis, but the reverse is not true.

Renal involvement in small-vessel vasculitic disorders Renal involvement is variable and rarely gives rise to prominent presenting symptoms. There may rarely be macroscopic haematuria or heavy proteinuria causing frothy urine. Hypertension is not a major feature and is present in around half or fewer of all patients. When there is a clinical suspicion of vasculitis, renal function should be checked and urine examined by dipstick analysis for blood and protein and by microscopy for granular or red cell casts. Imaging the kidneys is seldom helpful other than to establish the anatomy prior to biopsy, although it may show increased renal echogenicity.

Renal biopsy If renal disease is suspected, it is usual to confirm this by renal biopsy unless treatment has already been mandated by other findings, especially histological findings from other parts of the body. The key renal appearance is usually of a focal segmental necrotizing glomerulonephritis. In patients with advanced aggressive disease, the lesions may become diffuse, affecting every glomerulus sampled. Furthermore, in such patients, there may be extracapillary proliferation and the formation of crescents in the Bowman’s capsules. Lesions of different chronicity may be seen, with fresh inflammatory changes as well as chronic damage. In addition, there is sometimes an interstitial inflammatory infiltration. Immunofluorescence is typically negative for immunoglobulins and complement, although small amounts are occasionally seen.

Anti-neutrophil cytoplasmic antibodies Two major clinically useful patterns of anti-neutrophil cytoplasmic antibody (ANCA) specificity have been identified. ANCA with a cytoplasmic immunofluorescence distribution is termed c-ANCA, and such antibodies are usually directed against the neutrophil granule enzyme proteinase 3. Typically, such antibodies are found in patients with Wegener’s granulomatosis. The other principal type of ANCA has a perinuclear immunofluorescence distribution, is termed p-ANCA and is usually directed against the granule enzyme myeloperoxidase. This type of ANCA is typically associated with microscopic polyangiitis, renal limited vasculitis and Churg-Strauss disease. The relapse rate is about fourfold higher for patients with c-ANCAs than for those with p-ANCAs.34 Antibodies with a p-ANCA pattern but without specificity for myeloperoxidase occur in many different disorders, such as inflammatory bowel disease and infective endocarditis. A p-ANCA without specificity for myeloperoxidase is a test of low specificity for vasculitis.

420 C. A. O’Callaghan

Making a diagnosis A definitive diagnosis is usually made from histology of the affected tissue. A renal biopsy showing a focal necrotizing glomerulonephritis in the right clinical setting and the presence of ANCAs is certainly sufficient evidence to commence therapy. Vasculitis is occasionally seen on a renal biopsy, but this is often not the case. In the right clinical setting, ANCA assays will often be sufficient evidence for the commencement of therapy, especially if it is not possible to perform a biopsy for clinical reasons. Various other investigations may support the diagnosis. These include a normochromic, normocytic anaemia (or hypochromic microcytic anaemia if there is haemorrhage), a raised white cell count, a raised platelet count and a raised erythrocyte sedimentation rate or C-reactive protein level. There may also be a fall in albumin and a rise in alkaline phosphatase as part of the acute-phase response. Immunoglobulins may be raised. Complement levels are usually normal, but positive rheumatoid factors may occur. If there is renal dysfunction, serum urea and creatinine values may be raised, and there may be microscopic haematuria or proteinuria with red cell and granular casts in the urine. Diagnostic imaging may be helpful, especially in the lungs using high-resolution computed tomography. Important differential diagnoses are anti-glomerular basement membrane disease, cryoglobulinaemia, Henoch-Scho¨nlein purpura and systemic lupus erythematosus. In all these cases, there is usually clear evidence of immune deposits on renal biopsy. Treatment A National Institutes of Health study demonstrated clear benefit from the combined use of cyclophosphamide and steroids in Wegener’s granulomatosis.35 However, this study used high doses of cyclophosphamide for at least a year after remission and high doses of steroids, resulting in substantial complication rates.36 Diabetes arose in 8%, cataracts in 21%, hair loss in 17%, significant infections in 46%, haemorrhagic cystitis in 43% (with bladder cancer in 2.5%) and avascular bone necrosis in 3% of patients. After 1 year of cylcophosphamide, 57% of women of reproductive age had biochemical ovarian failure or amenorrhoea, or were unable to conceive. In addition, there was a significant increase in the number of haematological malignancies. The regimen developed at the Hammersmith Hospital in the UK has been shown to reduce the complication rate but retain efficacy (Table 4).37 This regimen uses cyclophosphamide only in the early stages of treatment and uses adjunctive therapy in severe fulminant disease. Cyclophosphamide is used for 3 months, and then the patient is converted to azathioprine. The dose of cyclophosphamide is reduced in older patients who are especially vulnerable to its side-effects. Fulminant disease is also treated with plasma exchange or pulsed intravenous methyl prednisolone. After induction therapy, maintenance therapy is usually with azathioprine, typically at a maximum dose of 1 mg/kg/day. Steroids are weaned down to around 5 mg/day and then slowly withdrawn if possible. In the presence of a relapse, cyclophosphamide is recommenced. Cyclophosphamide can be given as intravenous pulses, which reduces the total dose and allows the co-administration of Mesna, to protect against haemorrhagic cystitis. In a randomized, controlled, multicentre study of patients with renal involvement, the cumulative cyclophosphamide dose was reduced by 57% in those treated with intravenous pulses compared with oral therapy.38 The patient survival, remission rate, relapse rate and renal outcome did not differ between the two groups, but the incidence of severe leucopenia, severe infection and gonadal toxicity was reduced in

Renal manifestations of systemic autoimmune disease 421

Table 4. Treatment protocol for vasculitis. Induction Prednisolone 60 mg/day Cyclophosphamide Adjunctive therapy for fulminant disease Plasma exchange OR Methyl prednisolone Maintenance therapy Prednisolone Azathioprine

3 mg/kg/day if ,55 years 2 mg/kg/day if .55 years 4l/day for albumin for 5–10 days 0.5 g intravenously for 3 days Taper dose and stop 1–2 mg/kg/day from 3 months after diagnosis to 1 year after remission

the intravenous therapy group. Pulsed administration may, however, be less good at controlling disease, especially granulomatous disease.37 Cyclophosphamide seems superior to azathioprine in Wegener’s granulomatosis, but in microscopic polyangiitis this has not been established with certainty. However, some patients do not respond adequately to azathioprine.39 After 3 months of induction therapy, the European vasculitis study group randomized patients to maintenance with either cyclophosphamide (1.5 mg/day) or azathioprine (2 mg/kg/day).40 The relapse rate was the same in both groups at around 15% over 18 months. Adjunctive treatment in severe disease Plasma exchange has been used with good results in patients with focal necrotizing glomerulonephritis. In patients with disease severe enough to merit haemodialysis, 10 of 11 patients treated with plasma exchange were able to stop haemodialysis, compared with only 3 of 8 patients who were not given plasma exchange.41 There was no benefit in patients with less severe renal disease. Pulsed intravenous methylprednisolone has also been shown to be of adjunctive benefit: 16 of 23 patients treated with methylprednisolone were able to stop dialysis, compared with 0 of 9 who did not receive the drug.42 Plasma exchange has the disadvantage that it is expensive, can cause bleeding and allergic reactions, and requires central vascular access. Methylprednisolone may, however, be associated with a greater infection risk and increases the probability of diabetes mellitus, avascular bone necrosis, cataracts and hypertension. Other approaches to therapy Methotrexate at a dose of 0.3 mg/kg/week has been associated with a 75% response rate.43 Co-trimoxazole use conveys some benefit in limited Wegener’s granulomatosis, but there is no good evidence to support its use in renal disease.44 Ciclosporin does not seem to be of much use, although there are anecdotal reports of its adjunctive use. However, intravenous immunoglobulin at a dose of 0.5 g/kg/day over 5 days produced good results without major problems when used in combination with steroids and cytotoxic agents.45 In a randomized trial, intravenous immunoglobulin was compared with placebo in previously treated patients with vasculitis for whom there was an

422 C. A. O’Callaghan

intention to escalate therapy.46 The course of immunoglobulin reduced disease activity compared with placebo, but this effect was not maintained at 3 months. In extremely severe, refractory disease, antibodies against immune cells such as anti-CD52 or antiCD4 have been shown to be helpful, as have anti-thymocyte polyclonal antibodies.47,48 End-stage renal disease Patients with systemic vasculitis who reach end-stage renal disease require renal replacement therapy. Both haemodialysis and peritoneal dialysis are generally well tolerated. Renal transplantation is considered if the disease has been in remission for at least 6 months, but recurrence can occur and can affect the graft. There is no good evidence for altering standard transplantation immunosuppression regimens for patients who have systemic vasculitis.

SCLERODERMA Renal involvement in scleroderma can be acute and life-threatening or insidious and benign. The most dramatic presentation is with an acute renal crisis, and surveillance for this condition should be an important part of the routine follow-up of patients with scleroderma. Many patients display minor renal abnormalities, which are usually of minimal clinical significance. In a series from the UK, major renal disease occurred with an overall incidence of 5.3%.49 The incidence was, however, 1.6% with limited cutaneous scleroderma and 12.4% with diffuse scleroderma. A major risk factor seems to be diffuse skin involvement. Other risk factors include African ethnicity, pregnancy and a rapid progression of skin disease. In one series, the incidence of scleroderma renal crisis was 21% in patients of African ethnicity and 7% in white Caucasians.50 A scleroderma renal crisis in the third trimester can be mistaken for pre-eclampsia. However, unlike pre-eclampsia, a scleroderma renal crisis can also occur in the postpartum period. Renal crisis are more common in the winter and usually occur within 5 years of diagnosis. Pathophysiology of scleroderma renal crisis The cause of scleroderma is unknown, but pathological changes include connective tissue proliferation and vascular abnormalities, which can impair tissue perfusion and lead to organ dysfunction (Figure 1). Vascular changes in the kidney can include intimal hyperplasia and fibrinoid necrosis. and plasma renin levels are high. Vascular narrowing, which may be due to structural and vasoconstrictive changes, reduces renal blood flow. This promotes renin production from the juxtaglomerular apparatus in each nephron. Renin promotes the formation of the vasoconstrictor angiotensin II, which causes further renal vasoconstriction and so worsens the renal ischaemia. A vicious circle is established that rapidly reduces renal blood flow and glomerular filtration rate, and causes hypertension. Angiotensin II acts directly on receptors in the proximal tubule to promote sodium reabsorption and acts on the adrenal cortex to promote aldosterone production, which increases distal tubular sodium reabsorption. Sodium retention and concomitant water retention further exacerbate hypertension and can contribute to the formation of pulmonary oedema.

Renal manifestations of systemic autoimmune disease 423

Vasoconstriction

Trigger? eg.cold, infection?

Renal vessel Narrowing

Structural vascular change

Hypertension

Renal ischaemia

Renin

Systemic vasoconstriction

Angiotensin II

Sodium retention Water retention

Aldosterone

Figure 1. The pathophysiological basis of the scleroderma renal crisis. The effects of the underlying disease process can be structural vascular change and vasoconstriction, and these changes allow a positively reinforcing cycle of events to occur that causes the renal crisis and hypertension.

Minor renal disease Minor insidious disease may be more common than is generally appreciated. In autopsy series, vascular abnormalities have been found in 60 – 80% of cases.51,52 Renal disease is, however, a major cause of death in hospital, and such patients are more likely to have autopsies performed on them. Radio-isotope studies have shown that reduced renal blood flow can be present in the absence of any other evidence of renal involvement.51 This study also demonstrated that 36% of patients with scleroderma had at least 1 þ proteinuria, 24% had a blood pressure above 140/90mmHg and 19% had an elevated blood urea nitrogen level. Presumably, these changes reflect the autopsy findings and are not usually sufficient reason for a renal biopsy in the context of scleroderma. Major renal disease: the acute scleroderma renal crisis A major renal crisis can occur with severe hypertension of sudden onset and an acute deterioration in renal function. Clinical presentations reflect the severe hypertension and include headaches, visual disturbances and seizures. On examination, blood pressure is raised and there are usually acute retinal changes. Proteinuria is usually present but is not generally in the nephrotic range and may precede the acute presentation. Microscopic haematuria can be present, along with granular casts. If the hypertension is severe and there is marked sodium and water retention, pulmonary oedema can occur. Blood tests show renal impairment with elevated urea and creatinine levels. A blood film may suggest a microangiopathic haemolytic process if the hypertension is severe. Patients may have positive anti-nuclear antibodies, anti-scl-70 antibodies, anti-centromere antibodies and anti-RNA-polymerase antibodies, but there is no specific serological marker of renal involvement.

424 C. A. O’Callaghan

Renal biopsy Renal biopsies are usually performed to rule out other possible diagnoses such as acute glomerulonephritis. The blood pressure must be well controlled before a biopsy to reduce the risk of bleeding. A biopsy is useful if renal replacement therapy is planned because it excludes other possible causes and may influence later decisions about transplantation. Slow, but surprisingly useful, renal recovery can follow an acute scleroderma renal crisis, so renal transplantation is usually delayed for at least 2 years following the crisis. There are several well-recognized biopsy findings in a scleroderma renal crisis. Intimal proliferation can arise in the renal arterial walls; when severe, the appearance is termed ‘onion skinning’. This is prominent in the arcuate and interlobular arteries and may result in narrowing of the vessel lumen with consequent renal ischaemia. There may also be an accumulation of glycoproteins and mucopolysaccharides in the vessel walls. Fibrinoid necrosis occurs in the small arteries and arterioles. There may be focal or diffuse glomerular basement membrane thickening, glomerular thrombosis and ultimately glomerular sclerosis. Tubulo-interstitial changes eventually occur.

Management A key aspect of management in scleroderma is the surveillance for and prevention of a renal crisis. Black and Denton recommend that all patients with diffuse disease have monthly monitoring of their blood pressure, with 3– 6 monthly estimations of creatinine clearance and urine testing for proteinuria.49 This monitoring should continue for the first 5 years and can then be less frequent if there are no worrying changes. Patients with limited disease are less likely to have a renal crisis and may be monitored less frequently from the start, with annual glomerular filtration rate estimations. If patients have any evidence of renal disease or hypertension, they should be treated with angiotensin-converting enzyme inhibitors. It has been suggested that angiotensin-converting enzyme inhibitors may help to prevent the development of renal crises.53 Generally, anti-hypertensive therapy is also likely to be useful for Raynaud’s symptoms. There have been suggestions that high-dose steroid therapy and ciclosporin may predispose to renal crises. In a renal crisis, the key aspect of treatment is aggressive control of the blood pressure with angiotensin-converting enzyme inhibitors. Patients are usually admitted to hospital, and the blood pressure is reduced by about 10 – 15mmHg per day until it is in the range 120– 130/70– 80mmHg. If the blood pressure is reduced too rapidly, further severe renal ischaemia will occur, which is not desirable. Calcium channel blockers and other drugs may also be used. Low-dose prostacyclin may be used, although there is no clear evidence that it is beneficial; it may help to reduce blood pressure and has potentially useful effects on renal blood flow.54 Renal function should be monitored daily. In addition, regular monitoring of the full blood count, blood film, clotting and fibrin degradation products are important to look for signs of a microscopic angiopathic haemolytic anaemia. Nephrotoxic agents, such as nonsteroidal anti-inflammatories and contrast dyes, should be avoided. When blood pressure is controlled and clotting is normal, a renal biopsy may be performed to confirm the diagnosis.

Renal manifestations of systemic autoimmune disease 425

End-stage renal disease Dialysis may be required if renal damage is severe, but transplantation should be withheld for up to 2 years to allow time for any renal recovery. Angiotensinconverting enzyme inhibitors should be continued during this period and blood pressure tightly controlled to optimize the chances of renal recovery. Scleroderma patients have a significantly worse survival than other patients with end-stage renal disease.55

SUMMARY There are different reasons for the development of renal disease in the conditions discussed, but common themes emerge. Whatever the diagnosis, control of the blood pressure is essential and can influence the outcome. Renal disease can be silent so active surveillance is essential in patients with conditions that may involve the kidneys. If renal involvement is identified and treated early, this may allow more salvage of useful renal function than would be possible if the disease is allowed to progress. For some clinical situations, well-validated treatment regimens are available, but the optimal immunosuppression regimens for some clinical situations are not yet apparent. Immunosuppression may need tailoring to the patient’s age and general health, and to the response or otherwise of the disease. The diversity of clinical presentations and the small number of patients with some patterns of systemic autoimmune disease makes large-scale clinical trials difficult to undertake, but progress is being made.

Practice points † renal disease can be silent so active surveillance is essential in patients with conditions that may involve the kidneys † if the renal involvement is identified and treated early, this may allow more salvage of useful renal function than would be possible if the disease is allowed to progress † whatever the diagnosis, blood pressure control is essential and can influence the outcome

Research agenda † the role of mycophenolate in renal autoimmune disease merits further largerscale investigations † clinical studies to define the optimum cytotoxic regimens for older people with vasculitis are required

426 C. A. O’Callaghan

REFERENCES 1. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1993; 72: 113 –124. 2. CameronJ. Rheumatologyandthekidney. InDavisonA,CameronJS,GrunfeldJP, KerrDNS,RitzE &Winearls CG (eds) Oxford Textbook of Clinical Nephrology, 2nd edn. Oxford: Oxford University Press, 1997, pp 2709–2716. 3. Austin III HA, Muenz LR, Joyce KM, et al. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney International 1984; 25: 689–695. 4. Mahajan SK, Ordonez NG, Feitelson PJ, et al. Lupus nephropathy without clinical renal involvement. Medicine (Baltimore) 1977; 56: 493–501. 5. Lee HS, Mujais SK, Kasinath BS, et al. Course of renal pathology in patients with systemic lupus erythematosus. American Journal of Medicine 1984; 77: 612–620. 6. Radhakrishnan J, Kunis CL, D’Agati V & Appel GB. Cyclosporine treatment of lupus membranous nephropathy. Clinical Nephrology 1994; 42: 147–154. 7. Kimberly RP. Pulse methylprednisolone in SLE. Clinics in Rheumatic Disease 1982; 8: 261– 278. 8. Ponticelli C, Zucchelli P, Moroni G, et al. Long-term prognosis of diffuse lupus nephritis. Clinical Nephrology 1987; 28: 263–271. 9. Austin III HA, Klippel JH, Balow JE, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. New England Journal of Medicine 1986; 314: 614– 619. * 10. Boumpas DT, Austin III HA, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992; 340: 741–745. 11. Ponticelli C. Current treatment recommendations for lupus nephritis. Drugs 1990; 40: 19–30. 12. Pollak VE, Kant KS & Hariharan S. Diffuse and focal proliferative lupus nephritis: treatment approaches and results. Nephron 1991; 59: 177 –193. * 13. Gourley MF, Austin III HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled tria. Annals of Internal Medicine 1996; 125: 549 –557. 14. Briggs WA, Choi MJ & Scheel Jr. PJ. Successful mycophenolate mofetil treatment of glomerular disease. American Journal of Kidney Disease 1998; 31: 213–217. 15. Glicklich D & Acharya A. Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide. American Journal of Kidney Disease 1998; 32: 318– 322. 16. Dooley MA, Cosio FG, Nachman PH, et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. Journal of the American Society of Nephrology 1999; 10: 833 –839. * 17. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. New England Journal of Medicine 2000; 343: 1156–1162. 18. Kapitsinou PP, Boletis JN, Skopouli FN, et al. Lupus nephritis: treatment with mycophenolate mofetil. Rheumatology (Oxford) 2004; 43: 377–380. 19. Favre H, Miescher PA, Huang YP, et al. Cyclosporin in the treatment of lupus nephritis. American Journal of Nephrology 1989; 9(supplement 1): 57 –60. 20. Lewis EJ, Hunsicker LG, Lan SP, et al. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. New England Journal of Medicine 1992; 326: 1373–1379. 21. Levy Y, Sherer Y, George J, et al. Intravenous immunoglobulin treatment of lupus nephritis. Seminars in Arthritis and Rheumatism 2000; 29: 321–327. 22. Boletis JN, Ioannidis JP, Boki KA & Moutsopoulos HM. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999; 354: 569– 570. 23. Flanc RS, Roberts MA, Strippoli GF, et al. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. American Journal of Kidney Disease 2004; 43: 197–208. 24. Cheigh JS & Stenzel KH. End-stage renal disease in systemic lupus erythematosus. American Journal of Kidney Disease 1993; 21: 2–8. 25. Mojcik CF & Klippel JH. End-stage renal disease and systemic lupus erythematosus. American Journal of Medicine 1996; 101: 100– 107. 26. Coutts SM, Plunkett ML, Iverson GM, et al. Pharmacological intervention in antibody mediated disease. Lupus 1996; 5: 158–159. 27. Alarcon-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism 2003; 48: 442–454. 28. Finck BK, Linsley PS & Wofsy D. Treatment of murine lupus with CTLA4Ig. Science 1994; 265: 1225–1227.

Renal manifestations of systemic autoimmune disease 427

* *

* * *

*

29. Schiffer L, Sinha J, Wang X, et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. Journal of Immunology 2003; 171: 489– 497. 30. Watts RA, Carruthers DM & Scott DG. Epidemiology of systemic vasculitis: changing incidence or definition? Seminars in Arthritis and Rheumatism 1995; 25: 28– 34. 31. Geerlings W, Tufveson G, Ehrich JH, et al. Report on management of renal failure in Europe, XXIII. Nephrology, Dialysis and Transplantation 1994; 9(supplement 1): 6–25. 32. Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. American Journal of Kidney Disease 2003; 41: 776 –784. 33. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis and Rheumatism 1994; 37: 187– 192. 34. Gaskin G & Pusey CD. ANCA-associated renal disease. Quarterly Journal of Medicine 1993; 86: 138– 139. 35. Fauci AS, Haynes BF, Katz P & Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Annals of Internal Medicine 1983; 98: 76–85. 36. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Annals of Internal Medicine 1992; 116: 488–498. 37. Gaskin GAP & Denton CD. Systemic vasculitis. In Davison A, Cameron JS, Grunfeld JP, Kerr DNS, Ritz E & Winearls CG (eds) Oxford Textbook of Clinical Nephrology, 2nd edn. Oxford: Oxford University Press, 1997, pp 877 –910. 38. Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis and Rheumatism 1998; 41: 1835–1844. 39. Fauci AS, Katz P, Haynes BF & Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. New England Journal of Medicine 1979; 301: 235–238. 40. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. New England Journal of Medicine 2003; 349: 36–44. 41. Pusey CD, Rees AJ, Evans DJ, et al. Plasma exchange in focal necrotizing glomerulonephritis without antiGBM antibodies. Kidney International 1991; 40: 757–763. 42. Bolton WK & Sturgill BC. Methylprednisolone therapy for acute crescentic rapidly progressive glomerulonephritis. American Journal of Nephrology 1989; 9: 368– 375. 43. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis and Rheumatism 1995; 38: 608 –613. 44. Reinhold-Keller E, De Groot K, Rudert H, et al. Response to trimethoprim/sulfamethoxazole in Wegener’s granulomatosis depends on the phase of disease. Quarterly Journal of Medicine 1996; 89: 15– 23. 45. Jayne DR, Davies MJ, Fox CJ, et al. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991; 337: 1137– 1139. 46. Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. Quarterly Journal of Medicine 2000; 93: 433 –439. 47. Lockwood CM, Thiru S, Isaacs JD, et al. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993; 341: 1620–1622. 48. Hagen EC, de Keizer RJ, Andrassy K, et al. Compassionate treatment of Wegener’s granulomatosis with rabbit anti-thymocyte globulin. Clinical Nephrology 1995; 43: 351– 359. 49. Black CD & Denton CP. The patient with scleroderma-systemic sclerosis. In Davison A, Cameron JS, Grunfeld JP, Kerr DNS & Ritz E (eds) Oxford Textbook of Clinical Nephrology, 2nd edn. Oxford: Oxford University Press, 1997, pp 961–974. 50. Traub YM, Shapiro AP, Rodnan GP, et al. Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases. Medicine (Baltimore) 1983; 62: 335–352. 51. Cannon PJ, Hassar M, Case DB, et al. The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine (Baltimore) 1974; 53: 1–46. 52. D’Angelo WA, Fries JF, Masi AT & Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. American Journal of Medicine 1969; 46: 428– 440. 53. Steen VD, Costantino JP, Shapiro AP & Medsger Jr. TA. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Annals of Internal Medicine 1990; 113: 352 –357. 54. Scorza R, Rivolta R, Mascagni B, et al. Effect of iloprost infusion on the resistance index of renal vessels of patients with systemic sclerosis. Journal of Rheumatology 1997; 24: 1944–1948. 55. Abbott KC, Trespalacios FC, Welch PG & Agodoa LY. Scleroderma at end stage renal disease in the United States: patient characteristics and survival. Journal of Nephrology 2002; 15: 236 –240.