Scleroderma renal crisis (SRC) is an infrequent but serious complication of systemic sclerosis (SSc). It is associated with increased vascular permeability, activation of coagulation cascade, and renin secretion, which may lead to the acute renal failure typically associated with accelerated hypertension. The histologic picture of SRC is that of a thrombotic microangiopathy process with prominent small vessel involvement manifesting as myxoid intimal changes, thrombi, onion skin lesions, and/or fibrointimal sclerosis. Renal biopsies play an important role in confirming the clinical diagnosis, excluding overlapping/superimposed diseases that might lead to acute renal failure in SSc patients, helping to predict the clinical outcome and optimizing patient management. Kidney transplantation may be the only treatment option available for a subset of SRC patients who develop end-stage renal failure despite aggressive angiotensin-converting enzyme inhibitor therapy. However, the posttransplant outcome for SSc patients is currently suboptimal compared to the general renal transplant population. 1. Introduction Systemic sclerosis (SSc) is a multisystem autoimmune disorder that can manifest as either the diffuse cutaneous (dc) or the limited cutaneous (lc) variant, distinguished by the degree and the extent of cutaneous sclerosis [1]. Scleroderma renal crisis (SRC) can complicate the course of up to 10% of patients with SSc. Although most frequently seen in dcSSc, SRC can occur in patients with lcSSc [2, 3] and rarely in patients with no significant dermal sclerosis termed systemic sclerosis sine scleroderma (ssSSc) [4]. The etiology of SCR remains incompletely understood, with most models of pathogenesis suggesting an initial trigger of vascular endothelial injury. Alteration in cellular and/or humoral immunity may also play a role in SRC pathogenesis [1, 5, 6]. SSc has been associated with T helper lymphocyte type-2 (TH-2) activation, cytokine production (particularly Il-4, IL-13, and IL-17), and excess collagen accumulation, which could participate in the development of vasculopathy [7]. B cell activation has also been described in SSc patients [7]. The association between the presence of several specific autoantibodies and the development of SRC raises a potential contributing role of autoantibodies in the pathogenesis of SRC [8, 9]. In addition, antiendothelial cell antibodies, which are capable of inducing endothelial cell apoptosis [10] have been detected in up to 85% of SSc patients [11]. Overexpression of endothelin-1, a protein that plays a role in
References
[1]
L. I. Sakkas, “New developments in the pathogenesis of systemic sclerosis,” Autoimmunity, vol. 38, no. 2, pp. 113–116, 2005.
[2]
T. Sugimoto, M. Sanada, and A. Kashiwagi, “Is scleroderma renal crisis with anti-centromere antibody-positive limited cutaneous systemic sclerosis overlooked in patients with hypertension and/or renal dysfunction?” Nephrology, vol. 13, no. 2, pp. 179–180, 2008.
[3]
T. Sugimoto, M. Soumura, and M. Soumura, “Scleroderma renal crisis in a patient with anticentromere antibody-positive limited cutaneous systemic sclerosis,” Modern Rheumatology, vol. 16, no. 5, pp. 309–311, 2006.
[4]
E. A. Gonzalez, E. Schmulbach, and B. Bastani, “Scleroderma renal crisis with minimal skin involvement and no serologic evidence of systemic sclerosis,” American Journal of Kidney Diseases, vol. 23, no. 2, pp. 317–319, 1994.
[5]
C. Chizzolini, “Update on pathophysiology of scleroderma with special reference to immunoinflammatory events,” Annals of Medicine, vol. 39, no. 1, pp. 42–53, 2007.
[6]
S. Sato, M. Fujimoto, M. Hasegawa, K. Takehara, and T. F. Tedder, “Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis,” Molecular Immunology, vol. 41, no. 12, pp. 1123–1133, 2004.
[7]
L. I. Sakkas, I. C. Chikanza, and C. D. Platsoucas, “Mechanisms of disease: the role of immune cells in the pathogenesis of systemic sclerosis,” Nature Clinical Practice Rheumatology, vol. 2, no. 12, pp. 679–685, 2006.
[8]
M. Chang, R. J. Wang, D. T. Yangco, G. C. Sharp, G. R. Komatireddy, and R. W. Hoffman, “Analysis of autoantibodies against RNA polymerases using immunoaffinity-purifed RNA polymerase I, II, and III antigen in an enzyme-linked immunosorbent assay,” Clinical Immunology and Immunopathology, vol. 89, no. 1, pp. 71–78, 1998.
[9]
M. Santiago, M. Baron, M. Hudson, R. W. Burlingame, and M. J. Fritzler, “Antibodies to RNA polymerase III in systemic sclerosis detected by ELISA,” Journal of Rheumatology, vol. 34, no. 7, pp. 1528–1534, 2007.
[10]
M. Worda, R. Sgonc, H. Dietrich, H. Niederegger, R. S. Sundick, M. E. Gershwin, and G. Wick, “In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay,” Arthritis and Rheumatism, vol. 48, no. 9, pp. 2605–2614, 2003.
[11]
C. Mihai and J. W. C. Tervaert, “Anti-endothelial cell antibodies in systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 69, no. 2, pp. 319–324, 2010.
[12]
H. Kobayashi, T. Nishimaki, S. Kaise, T. Suzuki, K. Watanabe, R. Kasukawa, and T. Suzuki, “Immunohistological study of endothelin-1 and endothelin-A and B receptors in two patients with scleroderma renal crisis,” Clinical Rheumatology, vol. 18, no. 5, pp. 425–427, 1999.
[13]
I. Batal, R. T. Domsic, A. Shafer, T. A. Medsger Jr., L. P. Kiss, P. Randhawa, and S. Bastacky, “Renal biopsy findings predicting outcome in scleroderma renal crisis,” Human Pathology, vol. 40, no. 3, pp. 332–340, 2009.
[14]
D. C. Trostle, C. D. Bedetti, V. D. Steen, M. R. Al-Sabbagh, B. Zee, and T. A. Medsger Jr., “Renal vascular histology and morphometry in systemic sclerosis. A case-control autopsy study,” Arthritis and Rheumatism, vol. 31, no. 3, pp. 393–400, 1988.
[15]
D. J. Helfrich, B. Banner, V. D. Steen, and T. A. Medsger Jr., “Normotensive renal failure in systemic sclerosis,” Arthritis and Rheumatism, vol. 32, no. 9, pp. 1128–1134, 1989.
[16]
Y. S. Haviv and R. Safadi, “Normotensive scleroderma renal crisis: case report and review of the literature,” Renal Failure, vol. 20, no. 5, pp. 733–736, 1998.
[17]
B. Lewandowski, I. Domys？awska, P. A. Klimiuk, and S. Sierakowski, “Kidney crisis in systemic sclerosis,” Roczniki Akademii Medycznej w Bialymstoku, vol. 50, pp. 294–296, 2005.
[18]
H. Penn, A. J. Howie, and A. J. Howie, “Scleroderma renal crisis: patient characteristics and long-term outcomes,” QJM, vol. 100, no. 8, pp. 485–494, 2007.
[19]
C. P. Denton, G. Lapadula, L. Mouthon, and U. Müller-Ladner, “Renal complications and scleroderma renal crisis,” Rheumatology, vol. 48, pp. iii32–35, 2009.
[20]
V. D. Steen and T. A. Medsger Jr., “Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis,” Arthritis and Rheumatism, vol. 41, no. 9, pp. 1613–1619, 1998.
[21]
H. Sarwar, L. R. Espinoza, H. McGrath Jr., Z. Yaqub, and E. Cucurull, “Scleroderma renal crisis following widespread application of topical triamcinolone,” Journal of Clinical Rheumatology, vol. 10, no. 5, pp. 275–276, 2004.
[22]
V. D. Steen, “Autoantibodies in systemic sclerosis,” Seminars in Arthritis and Rheumatism, vol. 35, no. 1, pp. 35–42, 2005.
[23]
F. C. Arnett, J. D. Reveille, and J. D. Reveille, “Autoantibodies to fibrillarin in systemic sclerosis (scleroderma): an immunogenetic, serologic, and clinical analysis,” Arthritis and Rheumatism, vol. 39, no. 7, pp. 1151–1160, 1996.
[24]
R. Aggarwal, M. Lucas, N. Fertig, C. V. Oddis, and T. A. Medsger, “Anti-U3 RNP autoantibodies in systemic sclerosis,” Arthritis and Rheumatism, vol. 60, no. 4, pp. 1112–1118, 2009.
[25]
V. D. Steen and T. A. Medsger Jr., “Long-term outcomes of scleroderma renal crisis,” Annals of Internal Medicine, vol. 133, no. 8, pp. 600–603, 2000.
[26]
E. R. Fisher and G. P. Rodnan, “Pathologic observations concerning the kidney in progressive systemic sclerosis,” A. M. A. Archives of Pathology, vol. 65, no. 1, pp. 29–39, 1958.
[27]
L. Mouthon, A. Bérezné, G. Bussone, L.-H. No？l, P. M. Villiger, and L. Guillevin, “Scleroderma renal crisis: a rare but severe complication of systemic sclerosis,” Clinical Reviews in Allergy and Immunology. In press.
[28]
I. Tostivint, B. Mougenot, and B. Mougenot, “Adult haemolytic and uraemic syndrome: causes and prognostic factors in the last decade,” Nephrology Dialysis Transplantation, vol. 17, no. 7, pp. 1228–1234, 2002.
[29]
D. Lapenas, G. P. Rodnan, and T. Cavallo, “Immunopathology of the renal vascular lesion of progressive systemic sclerosis (scleroderma),” American Journal of Pathology, vol. 91, no. 2, pp. 243–258, 1978.
[30]
R. C. McCoy, C. C. Tisher, P. F. Pepe, and L. A. Cleveland, “The kidney in progressive systemic sclerosis. Immunohistochemical and antibody elution studies,” Laboratory Investigation, vol. 35, no. 2, pp. 124–131, 1976.
[31]
A. R. McGiven, W. G. De Boer, and A. J. Barnett, “Renal immune deposits in scleroderma,” Pathology, vol. 3, no. 2, pp. 145–150, 1971.
[32]
F. G. Silva and C. L. Pirani, “Electron microscopic study of medical diseases of the kidney: update—1988,” Modern Pathology, vol. 1, no. 4, pp. 292–315, 1988.
[33]
R. A. Sinclair, T. T. Antonovych, and F. K. Mostofi, “Renal proliferative arteriopathies and associated glomerular changes. A light and electron microscopic study,” Human Pathology, vol. 7, no. 5, pp. 565–588, 1976.
[34]
M. I. Salomon, J. Lamovec, and V. Tcherkoff, “Renal lesions in scleroderma,” Angiology, vol. 29, no. 8, pp. 569–578, 1978.
[35]
R. B. Colvin, “Antibody-mediated renal allograft rejection: diagnosis and pathogenesis,” Journal of the American Society of Nephrology, vol. 18, no. 4, pp. 1046–1056, 2007.
[36]
H. E. Feucht, H. Schneeberger, and H. Schneeberger, “Capillary deposition of C4d complement fragment and early renal graft loss,” Kidney International, vol. 43, no. 6, pp. 1333–1338, 1993.
[37]
I. Batal, A. Girnita, and A. Girnita, “Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney,” Modern Pathology, vol. 21, no. 12, pp. 1490–1498, 2008.
[38]
B. Sis and P. F. Halloran, “Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection,” Current Opinion in Organ Transplantation, vol. 15, no. 1, pp. 42–48, 2010.
[39]
A. Ramaswami, T. Kandaswamy, and T. Kandaswamy, “Scleroderma with crescentic glomerulonephritis: a case report,” Journal of Medical Case Reports, vol. 2, article 151, 2008.
[40]
H. Endo, T. Hosono, and H. Kondo, “Antineutrophil cytoplasmic autoantibodies in 6 patients with renal failure and systemic sclerosis,” Journal of Rheumatology, vol. 21, no. 5, pp. 864–870, 1994.
[41]
D. L. Kamen, F. M. Wigley, and A. N. Brown, “Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis in scleroderma—a different kind of renal crisis,” Journal of Rheumatology, vol. 33, no. 9, pp. 1886–1888, 2006.
[42]
T. Namba, M. Hatanaka, A. Takahashi, M. Takeji, K. Takahara, T. Uzu, and A. Yamauchi, “A case of scleroderma with rapid progressive glomerulonephritis associated with both MPO-ANCA and anti-GBM antibodies,” Nippon Jinzo Gakkai Shi, vol. 50, no. 1, pp. 64–68, 2008.
[43]
M. Kirschstein, U. Helmchen, R. Jensen, R. M. Küster, and H. Lehmann, “Kidney involvement in a 17-year-old boy with eosinophilic fasciitis,” Clinical Nephrology, vol. 52, no. 3, pp. 183–187, 1999.
[44]
R. A. Stone, C. C. Tisher, H. K. Hawkins, and R. R. Robinson, “Juxtaglomerular hyperplasia and hyperreninemia in progressive systemic sclerosis complicated by acute renal failure,” American Journal of Medicine, vol. 56, no. 1, pp. 119–123, 1974.
[45]
P. J. Cannon, M. Hassar, D. B. Case, W. J. Casarella, S. C. Sommers, and E. C. LeRoy, “The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation,” Medicine, vol. 53, no. 1, pp. 1–46, 1974.
[46]
V. Steen, C. P. Denton, J. E. Pope, and M. Matucci-Cerinic, “Digital ulcers: overt vascular disease in systemic sclerosis,” Rheumatology, vol. 48, pp. iii19–24, 2009.
[47]
V. D. Steen, “Renal involvement in systemic sclerosis,” Clinics in Dermatology, vol. 12, no. 2, pp. 253–258, 1994.
[48]
H. Penn, A. J. Howie, R. J. Stratton, et al., “The prognostic value of renal biopsy in scleroderma renal crisis,” Arhtritis and Rheumatism, vol. 56, pp. 53–54, 2007, abstract #3.
[49]
M. G. Hunter, S. Hurwitz, C. O. C. Bellamy, and J. S. Duffield, “Quantitative morphometry of lupus nephritis: the significance of collagen, tubular space, and inflammatory infiltrate,” Kidney International, vol. 67, no. 1, pp. 94–102, 2005.
[50]
D. A. Collins, S. Patel, J. B. Eastwood, and B. E. Bourke, “Favourable outcome of scleroderma renal crisis,” Journal of the Royal Society of Medicine, vol. 89, no. 1, pp. 49–50, 1996.
[51]
V. D. Steen, J. P. Costantino, A. P. Shapiro, and T. A. Medsger Jr., “Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors,” Annals of Internal Medicine, vol. 113, no. 5, pp. 352–357, 1990.
[52]
E. Y. Rhew and W. G. Barr, “Scleroderma renal crisis: new insights and developments,” Current Rheumatology Reports, vol. 6, no. 2, pp. 129–136, 2004.
[53]
E. C. LeRoy and R. M. Fleischmann, “The management of renal scleroderma. Experience with dialysis, nephrectomy and transplantation,” American Journal of Medicine, vol. 64, no. 6, pp. 974–978, 1978.
[54]
A. J. Bleyer, L. A. Donaldson, M. McIntosh, and P. L. Adams, “Relationship between underlying renal disease and renal transplantation outcome,” American Journal of Kidney Diseases, vol. 37, no. 6, pp. 1152–1161, 2001.
[55]
A. R. Nissenson and F. K. Port, “Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders,” Quarterly Journal of Medicine, vol. 74, no. 273, pp. 63–74, 1990.
[56]
I. Batal, S. Bastacky, and P. Randhawa, “The outcome of kidney transplantation in patients with scleroderma,” American Journal of Transplantation, vol. 7, no. 2, pp. 363–363, 2007, abstract 835.
[57]
R. Shapiro, M. L. Jordan, and M. L. Jordan, “A prospective, randomized trial of FK 506/prednisone vs FK 506/azathioprine/prednisone in renal transplant patients,” Transplantation Proceedings, vol. 27, no. 1, pp. 814–817, 1995.
[58]
W. Y. Cheung, I. W. Gibson, D. Rush, J. Jeffery, and M. Karpinski, “Late recurrence of scleroderma renal crisis in a renal transplant recipient despite angiotensin II blockade,” American Journal of Kidney Diseases, vol. 45, no. 5, pp. 930–934, 2005.
[59]
P.-T. T. Pham, P.-C. T. Pham, and P.-C. T. Pham, “Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature,” American Journal of Transplantation, vol. 5, no. 10, pp. 2565–2569, 2005.
[60]
P. Liptak and B. Ivanyi, “Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts,” Nature Clinical Practice Nephrology, vol. 2, no. 7, pp. 398–404, 2006.
