sign in sign up
<<
Home , Scleroderma

Case report Scleroderma renal crisis as an initial presentation of systemic sclerosis: a case report and review of the literature K.M. Logee, S. Lakshminarayanan

Division of , University ABSTRACT precipitously. An evaluation for hae- of Connecticut Health Center, Farmington, Scleroderma renal crisis (SRC) is a life- molysis revealed an elevated serum lac- Connecticut, USA. threatening complication of systemic tate dehydrogenase which rose to 1155 Kristin M. Logee, DO sclerosis (SSc) that is characterised U/L and an undetectably low hapto- Santhanam Lakshminarayanan, MD by new-onset malignant globin. Peripheral smear showed schis- Please address correspondence and progressive acute renal failure, of- tocytes with evidence of microangio- and reprint requests to: ten with associated microangiopathic pathic haemolytic anaemia (MAHA). Dr Kristin M. Logee, haemolytic anaemia and thrombocy- Division of Rheumatology, The patient was thought to have throm- University of Connecticut Health Center, topenia. SRC was at one time almost botic (TTP) 263 Farmington Avenue, uniformly fatal, with death often occur- with MAHA and treated with methyl- Farmington, ring within a few weeks. With the de- prednisolone 1g IV daily for 3 days and Connecticut 06030, USA. velopment of angiotensin-converting- plasmapheresis. ADAMTS13 level was E-mail: [email protected] enzyme inhibitors (ACE-I), survival ordered. Received on March 21, 2014; accepted in has improved dramatically, but death Over the next several days, despite revised form on November 24, 2014. rates still remain unacceptably high. treatment for TTP, the patient’s condi- Clin Exp Rheumatol 2015; 33 (Suppl. 91): About 20% of SRC cases occur prior to tion continued to worsen. Her platelet S171-S174. making a diagnosis of SSc and, in some count fell to 43 k/uL and her haemo- © Copyright Clinical and cases, there is no evidence of skin scle- globin dropped to 6.2 g/dL, her creati- Experimental Rheumatology 2015. rosis at the time that SRC develops. In nine rose to 4.1 mg/dL and she devel- this report, we present a case in which oped pulmonary oedema. At that point Key words: systemic sclerosis, a patient developed SRC prior to being she was started on haemodialysis. Her renal crisis, literature review diagnosed with scleroderma. Addition- ADAMTS13 activity level was 43%, ally, we review the pathogenesis, pre- which, in combination with her intact senting signs and symptoms, manage- mental status and lack of improvement ment and prognosis of SRC. with treatment, brought the diagnosis of TTP into question. Given her history of Case report Sjögren’s syndrome and cutaneous vas- A 60-year-old Hispanic female with a culitis, as well as her clinical picture of long-standing history of Sjögren’s syn- hypertension, acute renal failure, throm- drome and cutaneous , charac- bocytopenia and MAHA, the diagnosis terised by tender, erythematous, ulcerat- of scleroderma renal crisis (SRC) was ing nodules involving the extremities, considered and a rheumatology con- initially presented to the Emergency sultation was requested. The patient Room with a 3-week history of epigas- was noted to have 3+ and tric pain, nausea, vomiting and diar- loss of digital pulp. Serologic studies rhoea. As an outpatient, she had been revealed a positive ANA (speckled pat- taking 15 mg of prednisone daily for her tern, titer 1:5120) and a positive scl-70 vasculitis and lisinopril 2.5 mg daily. at 90 U/mL. Anti-glomerular Upon presentation, her blood pressure basement membrane, anti-neutrophil was 178/85 mmHg, her creatinine was cytoplasmic and anti-RNA III polymer- 1.4 mg/dL (increased from her baseline ase were negative. of 0.7 mg/dL) and her platelet count was Based on these findings, the patient 143K/ul. She was admitted for further was started on treatment for SRC with evaluation. captopril. After 3 days of treatment, her Over the next two days, the patient re- blood pressure remained uncontrolled mained persistently hypertensive and and valsartan was added. Over the next her creatinine continued to rise. Her week, her blood pressure, anaemia and Competing interests: none declared. platelet count and haemoglobin dropped thrombocytopenia gradually improved.

S-171 CASE REPORT Scleroderma renal crisis: a literature review / K.M. Logee & S. Lakshminarayanan

Her platelet count increased to 105 k/ Risk factors arteries of SRC patients. In the future, uL and she was able to safely undergo Certain risk factors for SRC have been ET-1 receptor blockade may serve as an a renal biopsy to clarify her diagno- identified. Patients with early, diffuse alternative therapy for SRC (17, 18). sis. Light microscopy showed marked SSc (disease duration <4 years) have Corticosteroid use has been associated edematous intimal expansion of the been found to be at greatest risk of de- with SRC in multiple studies (8, 10, interlobular arteries with skeins of fi- veloping SRC (11). A retrospective case 19-21). One retrospective study of 50 brinoid material and interstitial fibro- series of 110 patients with SRC showed SRC patients demonstrated that 60% sis. The glomeruli were normocellular that only 2% with lcSSc versus 12% had been exposed to but appeared ischaemic and markedly with dcSSc developed SRC. Also, 66% prior to SRC onset, with an odds ratio congested. The diagnosis reported was developed renal crisis within the first of 24.1 for developing SRC associated “thrombotic microangiopathy consist- year of SSc diagnosis. In fact, in 22% of with exposure in the pre- ent with scleroderma renal crisis.” the patients¸ renal crisis was the initial ceding 3-month period (19). Steen et al. The patient’s hypertension remained presenting feature, occurring before the report a case-controlled study of 110 controlled with captopril and valsartan diagnosis of SSc was made (5). Addi- SSc patients in which 36% of SSc pa- and her thrombocytopenia and MAHA tional risk factors include: rapidly pro- tients receiving steroids (at least 15 mg resolved. She was then discharged from gressive skin thickening, new cardiac of prednisone/day) developed SRC ver- the hospital but has remained dialysis- events such as pericardial effusions and sus 12% not receiving steroids (10). A dependent over the following 3 years. congestive , new anaemia recent systematic review also supported (9), presence of anti-RNA polymerase the association between the use of me- Literature review antibodies and use of corticosteroid dium and high dose corticosteroids and Introduction therapy (>15 mg prednisone/day) (10). the development of SRC (21). Howev- Systemic sclerosis (SSc) is a multisys- er, this relationship was not found in the tem disease charac- Pathogenesis review of 110 SRC patients by Penn et terised by immune system activation, Although incompletely understood, the al. (5). A systematic review by Iudici et microvascular injury and widespread pathogenesis of SRC appears to result al. found that a beneficial role of low to of skin and internal organs from an initial trigger of vascular en- medium dose corticosteroids in SSc is (1). It primarily affects the skin, heart, dothelial injury resulting in increased limited, although they could be used in lungs, kidneys and gastrointestinal permeability and intimal oedema. This certain situations (i.e. for treatment of tract and exists in both diffuse (dcSSc) results in a cascade of events as the sub- interstitial lung disease, diffuse cutane- and limited forms (lcSSc). endothelial connective tissue is exposed ous disease or ) (22). Immuno- Scleroderma renal crisis (SRC) is a life- to circulating elements in the blood, suppressive agents such as methotrex- threatening complication of SSc that causing activation of the coagulation ate, or was first characterised by Moore and cascade and thrombosis. Additionally, may be used to minimise corticosteroid Sheehan in 1952 as malignant hyperten- the connective tissue reacts to the in- exposure (10). When corticosteroids are sion and acute renal failure (2), often jury, resulting in fibroblastic and nonfi- needed, the lowest possible dose should with associated thrombotic microangi- broblastic stromal proliferation. These be used and patients should be closely opathy. While SRC remains a very seri- events (oedema, thrombosis and stromal monitored with regular blood pressure ous complication of SSc, it was at one proliferation) result in narrowing of re- checks and serum creatinine levels to time almost uniformly fatal, with death nal arterial vessels and decreased renal allow for early detection of SRC (23). often occurring within a few weeks. perfusion with subsequent hyperplasia With the development and usage of an- of the juxtaglomerular apparatus and Presentation giotensin-converting-enzyme inhibitors increased renin release. The increase in SRC typically presents as a new onset (ACE-I) in the late 1970s, 1-year sur- renin causes accelerated hypertension of significant systemic hypertension vival from SRC improved dramatically, and further renal injury (12-16). SRC and acute renal failure. Approximately from 18% to 76% (3). However, early patients often have markedly elevated 10% of patients may be normotensive diagnosis and treatment remain critical renin levels, and hypertension has been but almost invariable have an increase to improving outcome. shown to improve dramatically after ne- in blood pressure above their baseline phrectomy, likely because of the result- (6, 19). Additionally, about 60% of pa- Epidemiology ant fall in renin production (16). tients will also present with MAHA and SSc has an estimated prevalence of Over-expression of -1 (ET-1) 50% with thrombocytopenia. Symp- 276 cases per million persons in the and its receptor, endothelin-B, has also toms may include hypertensive enceph- US (4), and SRC has been found to af- been implicated in the pathogenesis of alopathy with confusion, fatigue, leth- fect 3–13% of all SSc patients (5-8). SRC. ET-1 is produced by endothelial argy, headache, visual changes and sei- Studies have shown that SRC primar- and smooth muscle cells and acts as a zures. Severe cases can lead to cerebral ily affects Caucasians (92–94%) and potent vasoconstrictor. Increased expres- haemorrhage, coma and death. Patients females (75–80%), with a mean age of sion of ET-1 and its receptors has been may also suffer from congestive heart 50 years at the onset (9-11). demonstrated in the renal arterioles and failure, pericardial effusions, pericardi-

S-172 Scleroderma renal crisis: a literature review / K.M. Logee & S. Lakshminarayanan CASE REPORT tis, arrhythmias and pulmonary haem- of 252 SSc patients found that 24% CCBs had a greatly reduced risk of de- orrhage (5, 6). In some cases, there with this antibody developed SRC (30). veloping SRC. This suggests that CCBs is no evidence of skin sclerosis when RNA polymerase antibodies have been may be useful as a “background” thera- SRC develops (known as systemic reported in 25–59% of SRC patients (5, py for SSc, although further studies are sclerosis sine scleroderma). However, 31-33). Anti-centromere, anti-topoi- needed (7). Possible future therapies in- skin thickening often develops within somerase I and anti-U3 RNP autoanti- clude continuous low-dose prostacyclin, the next few months with eventual pro- bodies have not been found to correlate direct renin inhibitors and endothelin gression to diffuse SSc (24-26). with SRC development (5, 32-34). receptor antagonists. Case reports and a Although uncommon, there have been recent pilot study have shown some suc- several reports of systemic vasculitis Biopsy findings cess with endothelin receptor blockade; (including antineutrophil cytoplasmic Although biopsy is not always neces- however, formal trials are needed (18, antibodies (ANCA)-associated vasculi- sary, findings are specific to SRC and 36, 39, 40). tis (AAV) and mixed cryoglobulinemia can be used to confirm the diagnosis. Despite maximal medical therapy, di- vasculitis) developing in patients with Microscopic examination reveals a pic- alysis is required in up to half of SRC SSc. It is important to be aware of this ture of a thrombotic microangiopathic patients (11). Fifty percent of those potential overlap as renal vasculitis may process affecting small vessels (12, 24, patients initially requiring dialysis are be confused with SRC and proper diag- 35). Larger arteries are often normal. able to be weaned off within 2 years. nosis is critical to allow for appropriate Early changes include accumulation of For patients requiring dialysis beyond and timely treatment. Vasculitis should mucin in the arcuate and interlobular 2 years, renal transplant should be con- be considered in SSc patients with acute arteries with mucoid intimal thickening sidered, as this has shown to improve renal failure, especially with features not and fibrinoid necrosis of the arterioles long-term outcomes (5). Unfortunately, typical of SRC. Such features include: (14). Later changes include hyperten- graft survival is typically lower in SSc renal failure late in disease (mean of 8–9 sive vascular damage, glomerular is- patients than in transplant patients in years after SSc develops), normotensive chemia and thrombosis with vascular the general population (41). This re- renal failure, absence of MAHA and occlusion and fibrosis. The classic “on- duced graft survival may be secondary thrombocytopenia, presence of signifi- ion skin lesion” results from prolifera- to recurrence of SRC and the systemic cant hematuria and/or proteinuria and tion of the vascular intimal cells which nature of SSc. positive testing for perinuclear ANCA causes narrowing of the vessel lumen. and anti-myeloperoxidase antibodies. Chronic changes including glomeru- Prognosis Anti-Scl-70 antibodies have also been losclerosis and ischaemic glomerular While prognosis for SRC was at one time found to occur much more commonly collapse can occur. Additionally, hyper- dismal, with the advent of ACE-I, it im- in patients with AAV-SSc overlap than plasia of the juxtaglomerular apparatus proved dramatically. However, despite those with SSc alone (27-29). from increased renin production has maximal therapy with ACE-I, other anti- been found in 12% of cases (13). In ad- hypertensive and dialysis, Laboratory findings vanced stages of the disease, histologic the mortality rate remains high. Studies Typical laboratory abnormalities found findings may be non-specific (12). have found that 36–38% of patients re- in patients with SRC include: elevated covered without dialysis, 23% required serum creatinine (present in 90–96% of Treatment temporary dialysis and 39–41% had poor cases), hyperreninaemia, and MAHA The mainstay of treatment for SRC is outcomes (death or permanent dialysis) (45–60% of cases) with associated with ACE-Is. ACE-I therapy should be (5, 11). 1- and 5-year survival rates have thrombocytopenia, schistocytes in pe- started as soon as possible and contin- been reported to be between 78–82% and ripheral smear, elevated serum LDH ued even if serum creatinine continues 59–69%, respectively (5, 19). and decreased haptoglobin (5, 11). The to rise. Prompt, aggressive treatment Certain factors have been identified degree of thrombocytopenia is usually greatly reduces the need for dialysis as poor prognostic indicators in multi- moderate (>50,000/mm3) and platelet (11). Use of ACE-I prophylactically ple studies. Normal or mildly elevated counts return to baseline once blood has not been found to prevent develop- blood pressure at presentation is associ- pressure is controlled (24). Urinalysis ment of SRC (5, 19, 20). Angiotensin- ated with a higher mortality (5, 6, 19). may show evidence of mild proteinuria receptor blockers theoretically should This may be a result of delayed diagno- and haematuria with granular casts on also be beneficial, but currently clinical sis with ongoing subclinical kidney in- microscopy (5, 15, 24). experiences have been inconsistent (24, jury. Additionally, it may be that normo- Antinuclear antibodies (ANAs) have 36, 37). Additionally, calcium-channel tensive patients have a less renin-angio- been found in virtually all patients with blockers (CCBs), alpha-blockers (36, tensin-aldosterone system-dependent SSc. An ANA speckled pattern has been 38) and nitrates can be used when blood process occurring and therefore, may be found in 60% of SRC patients and is as- pressure remains uncontrolled despite less responsive to ACE-Is (5). Addition- sociated with development of SRC (5). maximal ACE-I therapy. A recently re- al factors associated with a poorer out- Anti-RNA polymerase III antibodies ported retrospective case series of 410 come include: male sex, older age (>55 are also strongly associated. One study SSc patients found that those taking years old), higher initial serum creati-

S-173 CASE REPORT Scleroderma renal crisis: a literature review / K.M. Logee & S. Lakshminarayanan nine (greater than 3.0 mg/dL), MAHA the prevention and development of scleroder- 25. GONZALEZ EA, SCHMULBACH E, BASTANI and thrombocytopenia (5, 11, 19). ma renal crisis in an Italian case series. Clin B: Scleroderma renal crisis with minimal skin Exp Rheumatol 2013; 31 (Suppl. 76): S135-9. involvement and no serologic evidence of Biopsy findings have been studied to 8. DeMARCO PJ, WEISMAN MH, SEIBOLD JR et systemic sclerosis. Am J Kidney Dis 1994; 23: determine whether they could provide al.: Predictors and outcomes of scleroderma 317-9. further information regarding patient renal crisis: the high-dose versus low-dose D- 26. MOLINA JF, ANAYA JM, CABRERA GE, HOFF- in early diffuse systemic scle- MAN E, ESPINOZA LR: Systemic sclerosis prognosis. Acute vascular changes and rosis trial. Arthritis Rheum 2002; 46: 2983-9. sine scleroderma: an unusual presentation in the extent of vascular injury were found 9. STEEN VD, MEDSGER TA, OSIAL TA, ZIE- scleroderma renal crisis. J Rheumatol 1995; to be most indicative of a poor outcome GLER GL, SHAPIRO AP, RODNAN GP: Factors 22: 557-60. predicting development of renal involvement 27. ARAD U, BALBIR-GURMAN A, DOENYAS- (5, 13). in progressive systemic sclerosis. Am J Med BARAK K, AMIT-VAZINA M, CASPI D, ELKAY- 1984; 76: 779-86. AM O: Anti-neutrophil antibody associated Discussion 10. STEEN VD, MEDSGER TA: Case-control study vasculitis in systemic sclerosis. Semin Arthri- In the case described in this report, the of corticosteroids and other drugs that either tis Rheum 2011; 41: 223-9. precipitate or protect from the development 28. OMAIR MA, MOHAMED N, JOHNSON SR, AH- patient developed SRC prior to being of scleroderma renal crisis. Arthritis Rheum MAD Z, LEE P: ANCA-associated vasculitis in diagnosed with scleroderma. Because 1998; 41: 1613-9. systemic sclerosis report of 3 cases. Rheuma- she did not have known SSc when she 11. STEEN VD, MEDSGER TA: Long-term out- tol Int 2013; 33: 139-43. comes of scleroderma renal crisis. Ann Intern 29. QUEMENEUR T, MOUTHON L, CACOUB P et presented with renal failure and MAHA, Med 2000; 133: 600-3. al.: Systemic vasculitis during the course of there was a delay in the diagnosis and 12. BATAL I, DOMSIC RT, MEDSGER TA, BAS- systemic sclerosis: report of 12 cases and re- treatment of her SRC. While the patient TACKY S: Scleroderma renal crisis: a pathol- view of the literature. Medicine 2013; 92: 1-9. ogy perspective. Int J Rheumatol 2010; 2010: 30. OKANO Y, STEEN VD, MEDSGER TA: Auto- was fortunate to survive her illness, 543704. antibody reactive with RNA Polymerase III she unfortunately remained dialysis- 13. BATAL I, DOMSIC RT, SHAFER A et al.: Renal in systemic sclerosis. Ann Intern Med 1993; dependent. Initiation of an ACE-I ear- biopsy findings predicting outcome in sclero- 119: 1005-13. lier in her disease course may have im- derma renal crisis. Human Pathology 2009; 31. NIKPOUR M, HISSARIA P, BYRON J et al.: 40: 332-40. Prevalence, correlates and clinical usefulness proved her outcome. This case serves as 14. TROSTLE DC, BEDETTI CD, STEEN VD, AL- of antibodies to RNA polymerase III in sys- an important reminder to clinicians that SABBAGH MR, ZEE B, MEDSGER TA: Renal temic sclerosis: a cross-sectional analysis of SRC can develop in patients with little vascular histology and morphometry in sys- data from and Australian cohort. Arthritis Res temic sclerosis: a case-control autopsy study. Ther 2011; 13: R211. to no skin involvement and may be the Arthritis Rheum 1988; 31: 393-400. 32. HESSELSTRAND R, SCHEJA A, WUTTGE DM: initial presenting feature of the disease. 15. DENTON CP, LAPADULA G, MOUTHON L, Scleroderma renal crisis in a Swedish system- In patients with new onset refractory MULLER-LADNER U: Renal complications ic sclerosis cohort: survival, renal outcome, and scleroderma renal crisis. Rheumatology and RNA polymerase III antibodies as a risk hypertension, renal failure and MAHA, 2009; 48: iii32-iii35. factor. Scand J Rheumatol 2012; 41: 39-43. it is important to perform a thorough 16. SHAPIRO CB, LERNER NE, ACKAD AS, 33. NGUYEN B, SHERVIS A, ARNETT FC, MAYES physical examination as subtle findings ABRAMSON RG, STEIN RM: Malignant hy- MD: Association of RNA polymerase III anti- pertension and uremia in scleroderma: effi- bodies with scleroderma renal crisis. J Rheu- (i.e. early sclerodactyly) may provide cacy of nephrectomy and hemodialysis. Clin matol 2010; 37: 1068-9. clues that scleroderma is the underlying Nephrol 1977; 8: 321-3. 34. AGGARWAL R, LUCAS M, FERTIG N, ODDIS aetiology. Early detection and treatment 17. MOUTON L, MEHRENBERGER M, TEIXEIRA L CV, MEDSGER TA: Anti-U3 RNP autoanti- of this disease is critical for renal recov- et al.: Endothelin-1 expression in scleroderma bodies in systemic sclerosis. Arthritis Rheum renal crisis. Hum Pathol 2011; 42: 95-102. 2009; 60: 1112-8. ery and patient survival. 18. PENN H, QUILLINAN N, KHAN K et al.: 35. FISHER ER, RODNAN GP: Pathologic obser- Targeting the endothelin axis in scleroderma vations concerning the kidney in progressive References renal crisis: rationale and feasibility. Q J Med systemic sclerosis. AMA Arch Pathol 1958; 1. LAZAROS IS: New developments in the 2013; 106: 839-48. 65: 29-39. pathogenesis of systemic sclerosis. Autoim- 19. TEIXEIRA L, MOUTHON L, MAHR A et al.: 36. DENTON CP, BLACK CM: Scleroderma – clin- munity 2005; 38: 113-6. Mortality and risk factors of scleroderma re- ical and pathological advances. Best Pract 2. MOORE HC, SHEEHAN HL: The kidney of nal crisis: a French retrospective study of 50 Res Clin Rheumatol 2004; 18: 271-90. scleroderma. Lancet 1952; 1: 68-70. patients. Ann Rheum Dis 2008; 67: 110-6. 37. CASKEY FJ, THACKER EJ, JOHNSTON PA, 3. STEEN VD, CONSTANTINO JP, SHAPIRO AP, 20. GUILLEVIN L, BEREZNE A, SEROR R et al.: BARNES JN: Failure of losartan to control MEDSGER TA: Outcome of renal crisis in Scleroderma renal crisis: a retrospective mul- blood pressure in scleroderma renal crisis. systemic sclerosis: relation to availability of ticentre study on 91 patients and 427 controls. Lancet 1997; 349: 620. angiotensin converting enzyme inhibitors. Rheumatology 2012; 51: 460-7. 38. WALKER K, POPE J: Treatment of systemic Ann Intern Med 1990; 113: 352-7. 21. TRANG G, STEELE R, BARON M, HUDSON M: sclerosis complications: what to use when 4. MAYES MD, LACEY JV, BEEBE-DIMMER J et Corticosteroids and the risk of scleroderma first-line treatment fails – a consensus of sys- al.: Prevalence, incidence, survival, and dis- renal crisis: a systematic review. Rheumatol temic sclerosis experts. Semin Arthritis Rheum ease characteristic of systemic sclerosis in a Int 2012; 32: 645-53. 2012; 42: 42-55. large US population. Arthritis Rheum 2003; 22. IUDICI M, van der GOES MC, VALENTINI G, 39. DHAUN N, MacINTYRE IM, BELLAMY C, 48: 2246-55. BIJLSMA JWJ: Glucocorticoids in systemic KLUTH DC: Endothelin receptor antagonism 5. PENN H, HOWIE AJ, KINGDON EJ et al.: Scle- sclerosis: weighing up the benefits and risks and renin inhibition as treatment options for roderma renal crisis: patient characteristics – a systematic review. Clin Exp Rheumatol scleroderma kidney. Am J Kidney Dis 2009; and long-term outcomes. Q J Med 2007; 100: 2013; 31 (Suppl. 76): S157-S165. 54: 726-31. 485-94. 23. PENN H, DENTON CP: Diagnosis, manage- 40. IZZEDINE H, ROUVIER P, DERAY G: Endothe- 6. HELFRICH DJ, BANNER B, STEEN VD, ment and prevention of scleroderma renal dis- lin receptor antagonism-based treatment for MEDSGER TA: Normotensive renal failure in ease. Curr Opin Rheumatol 2008; 20: 692-6. scleroderma renal crisis. Am J Kidney Dis systemic sclerosis. Arthritis Rheum 1989; 32: 24. MOUTHON L, BEREZNE A, BUSSONE G, 2013; 62: 394-5. 1128-34. NOEL LH, VILLIGER PM, GUILLEVIN L: 41. BLEYER AJ, DONALDSON LA, MCINTOSH M, 7. MONTANELLI G, BERETTA A, SANTANIELLO Scleroderma renal crisis: a rare but severe ADAMS PL: Relationship between underlying R, SCORZA R: Effect of dihydropyridine cal- complication of systemic sclerosis. Clinic renal disease and renal transplantation out- cium channel blockers and glucocorticoids on Rev Allergy Immunol 2011; 40: 84-91. come. Am J Kidney Dis 2001; 37: 1152-61.

S-174