Clin Exp Nephrol (2010) 14:487–491 DOI 10.1007/s10157-010-0300-5
Rapidly progressive lupus nephritis and concomitant thrombotic microangiopathy Chems Gharbi • Edward Bourry • Philippe Rouvier Sabria Hacini • Ahmed Letaief • Alain Baumelou • Hassane Izzedine
Received: 12 January 2010 / Accepted: 14 May 2010 / Published online: 11 June 2010 Ó Japanese Society of Nephrology 2010
Abstract Although uncommon, thrombotic microangiopathy (TMA) is one of the most serious complications in patients with systemic lupus erythematosus. A 30-year-old black woman admitted to our hospital because of fever, fatigue, ‘dark’ urine and rapidly progressive renal failure was found to have systemic lupus erythematous and atypical hemolytic uremic syndrome. Kidney biopsy showed WHO class IV lupus nephritis with crescents and TMA. Hemodialysis was initiated for worsening renal failure. The patient was treated with corticosteroids, monthly pulse intravenous Cyclophosphamide, plasmapheresis and Rituximab on a weekly basis for 4 weeks. The patient’s blood pressure was aggressively controlled using antihypertensive agents. Despite this extensive therapy, she remained dialysis dependent although hematological parameters returned to normal values.
Keywords Lupus nephritis Thrombotic microangiopathy Dialysis Plasmapheresis Rituximab
C. Gharbi E. Bourry S. Hacini A. Baumelou H. Izzedine Department of Nephrology, Pitie´-Salpeˆtriere Hospital, Paris, France P. Rouvier Department of Pathology, Pitie´-Salpeˆtriere Hospital, Paris, France A. Letaief Department of Nephrology, Foch Hospital, Suresnes, France H. Izzedine (&) Assistance Publique-Hoˆpitaux de Paris, La Pitie´-Salpeˆtrie`re Hospital, Pierre et Marie Curie University, 47-80 Boulevard de l’Hoˆpital, 75013 Paris, France e-mail: [email protected]
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a life-threatening clinical condition characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, acute renal impairment and/or neurological impairment. TTP-HUS in systemic lupus erythematosus (SLE) has been reported mainly in isolated case reports. The prevalence and pathogenesis of patients with TTP-HUS in lupus nephritis are unclear. However, long-term outcome seems to be worse in patients with both TTP-HUS and lupus nephritis than in patients with lupus nephritis alone. We report a patient with TTP-HUS who unfortunately remained dialysis dependent despite extensive treatment.
A previously healthy 30-year-old black woman was admitted with a 3-week history of fever, fatigue, ‘dark’ urine and rapidly progressive renal failure (serum creatinine concentration of 9.66 mg/dl or 850 lmol/l). She denied a history of diarrhea, arthritis, photosensitivity or skin rash. Her family history was negative for anemia or thrombotic manifestations. Physical exam was remarkable for generalized edema, moderate ascities, lower extremity bruising and hypertension. No oral ulcers were found. Laboratory results are summarized in Table 1. Bilateral renal ultrasound demonstrated 12-cm long kidneys with no hydronephrosis. There were no pericardial or pleural effusions on chest X-ray. The association of acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia implied a working diagnosis of atypical hemolytic uremic syndrome. The CT scan and MRI brain scan
Clin Exp Nephrol (2010) 14:487–491
Table 1 Clinical and biological parameters
Follow-up (4 months later)
Renal parameters Blood pressure Proteinuria
\0.15 g/24 h
3 g/24 h
\5 9 103/ml
2.8 9 104
Total serum proteins
Hematological parameters Hemoglobin
Haptoglobin Partial thromboplastin time
0.55–1.70 g/l 35/35 s
Anti-Ds DNA Abs.
C3 Complement fraction
C4 Complement fraction
Complement regulatory proteins factors (H, I, CD46): normal levels without mutations
Anti-b2 glycoprotein 1 Abs.
showed no focal abnormalities. A diagnosis of HUS/TTP in the setting of SLE was considered. Renal pathology examination showed diffuse, proliferative, necrotizing glomerulonephritis and thrombotic microangiopathy. Material for light microscopy contained 30 glomeruli, 60% of which were globally sclerotic; 40% contained crescents (cellular and fibrous), necrosis or both. Several glomeruli presented double contour appearances without endothelial cell swelling. There was moderate chronic tubulointerstitial damage characterized by tubular atrophy, interstitial fibrosis and mononuclear inflammatory cell infiltration. The small arteries and arterioles showed fibrin thrombi (Fig. 1). Immunofluorescence revealed mesangial areas staining with IgG, C3 and Clq, with arteriolar staining positive for fibrinogen. Electron microscopy was not performed. A diagnosis of class IV lupus nephritis (ISN/ RPS 2003 classification) with crescents and thrombotic
microangiopathy was made. Hemodialysis was initiated for worsening renal failure. In addition, the patient was given three daily infusions of Methylprednisolone 1 g, monthly pulse intravenous Cyclophosphamide (IV CTC) 500 mg and Rituximab 375 mg/m2 on a weekly basis for 4 weeks. The patient’s blood pressure was aggressively controlled. However, since she remained anuric, plasmapheresis therapy was initiated 1 week later (eight daily plasma exchange sessions). After this, the hemoglobin rose to 12.9 g/dl and platelets to 198 9 109/l. Corticosteroids were slowly tapered to prednisone 0.5 mg/kg daily over the following 4 weeks. Four weeks later, prednisone dosages were tapered by 2.5 mg every 2 weeks. The patient received six fortnightly IV CYC pulses at a fixed dose of 500 mg. Despite this treatment, she remained dialysis dependent probably because of established extensive glomerular fibrosis.
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Fig. 1 Transjugular renal biopsy specimen showing a multiple thrombi occluding glomerular capillaries, b a large fibrin thrombus obstructing the afferent arteriole and c glomerulus compressed by a large fibrocellular crescent (Masson trichrome, 9400)
Discussion Rapidly progressive glomerulonephritis with simultaneous TMA is an unusual association of SLE. Schistocytes along with the Coombs-negative anemia and thrombocytopenia
are not seen in a significant number of patients with SLE unless associated with malignant hypertension. The association favored a diagnosis of atypical HUS/TTP. Renal histopathology provide solid evidence of both TMA and lupus nephritis. Possible explanations for TMA in a patient with SLE include malignant hypertension, APS, HUS/TTP and SLE exacerbation with hemolytic anemia, diffuse small-vessel vasculitis and nephritis. Differentiation of these clinical syndromes is challenging, if not impossible, given their many overlapping clinical and laboratory characteristics (Tables 2, 3) [1, 2]. Careful evaluation of the peripheral smear and direct Coombs’ test results can help to distinguish among these conditions. Although a secondary antiphospholipid antibody syndrome may be seen in patients with SLE and may mimic a microangiopathic process , the lack of radiological or histological evidence of vascular thrombosis coupled with the absence of anti-cardiolipin antibodies and the lupus anticoagulant  rules out this possibility in our patient. In addition to glomerulonephritis, physicians should pay more attention to vascular diseases, such as TMA, because its presence can adversely affect prognosis [5–7]. Up to 100 isolated cases of SLE/TMA association were reported in the literature [1, 2, 8–20]. However, an exact frequency cannot be calculated because patients with SLE and HUS/TTP share very similar clinical features [2, 21]. In literature reviews, the incidence of HUS/TTP occurring in the setting of SLE varied from 0.5 to 3% [22, 23] and could be proved in only 2.0% (7/353) of patients with biopsyproven lupus nephritis [3, 24–26]. Patients with both lupus nephritis and HUS/TTP have a significantly higher CI score, which may explain the worse long-term renal outcome . Such patients have glomerular hypercellularity in addition to the changes of TMA; however, they may also have glomerular capillary loop deposits, just like patients with proliferative lupus nephritis without TMA [28, 29]. It is probable that the glomerulonephritis in our patient was the result of the combined effects of TMA and the autoimmune disease of SLE. Systemic lupus erythematosus precedes TTP in a majority of cases, although TTP can antedate or occur simultaneously with it [16, 30]. Activity of SLE and onset of TTP run a parallel course in some of these patients, which also remains true in these case series [16, 30]. In a review that included 40 adult patients with SLE and TTP, SLE preceded the diagnosis of TTP in 73% of patients, whereas simultaneous (12%) or later diagnosis of SLE (15%) was less common . Although there are no established guidelines for the treatment of TTP-HUS in patients with lupus nephritis, most authors advised plasma exchange and immunosuppressive therapy [13, 31]. Vasoo et al.  suggested that
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Table 2 Clinical features of renal vasculopathies in SLE (adapted from ) Frequency
Vascular immune deposits
All, mostly III, IV
Noninflammatory necrotizing vasculopathy
True renal vasculitis
Table 3 Differential diagnosis of renal thrombotic processes during SLE (adapted from ) Characteristics
Direct Coombs’ test Thrombocytopenia
Positive or negative Immune-mediated
Positive or negative Immune-mediated
TMA and nephritis
Fibrous intimal hyperplasia, organizing thrombosis
Arteriolar fibrinoid necrosis, onion skin lesions
SLE systemic lupus erythematous, HUS/TTP hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, APL antiphospholipid, HT hypertension, TMA thrombotic microangiopathy
cytotoxic agents may also have an important role. While plasmapheresis has not been shown to improve survival in patients with fulminant SLE glomerulonephritis, it is clearly indicated in the management of TTP [32, 33]. The mortality rate of patients with co-existing TTP and SLE treated with plasmapheresis or plasma exchange is reported to be as high as 25–34% [2, 30]. It was suggested that the combination of the two diseases may have a worse prognosis than SLE or idiopathic TTP-HUS alone [20, 34]. In conclusion, hematological abnormalities in patients with active SLE should not necessarily be attributed to auto-antibodies directed against red blood cell and platelet antigens. SLE-associated TMAHA, such as HUS or TTP, should also be considered, especially in the presence of schistocytes in the peripheral blood. Renal biopsy is an important guide to therapy. Prompt institution of aggressive blood pressure control, plasma exchange, corticosteroids and possibly cytotoxic agents might yield a survival benefit. Conflict of interest statement
References 1. Shah AA, Higgins JP, Chakravarty EF. Thrombotic microangiopathic hemolytic anemia in a patient with SLE: diagnostic difficulties. Nat Clin Pract Rheumatol. 2007;3:357–62. 2. Musio F, Bohen EM, Yuan CM, Welch PG. Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus. Semin Arthritis Rheum. 1998;28:1–19.
3. Daugas E, Nochy D, Huong DLT, Duhaut P, Beaufils H, Caudwell V, Bariety J, Piette JC, Hill G. Antiphospholipid syndrome nephropathy in systemic lupus erythematosus. J Am Soc Nephrol. 2002;13:42–52. 4. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum. 1999;42:1309–11. 5. Cervera R, Abarca-Costalago M, Abramovicz D, et al. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the ‘Euro-Lupus Project’. Autoimmun Rev. 2006;5: 180–6. 6. Cervera R, Font J, Shoenfeld Y. European working party on systemic lupus erythematosus: a 15-year report. Autoimmun Rev. 2006;5:549–53. 7. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol. 1994;4: 1499–515. 8. Ichiki Y, Kitajima Y. Thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus. Eur J Dermatol. 2007;17:548–9. 9. Yuen LK, Lai WM, Tong PC, Poon WT, Tse KC, Chiu MC. Recurrent thrombotic thrombocytopenic purpura in a young boy with systemic lupus erythematosus. J Clin Rheumatol. 2007;13: 224–8. 10. Majithia V, Harisdangkul V. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: a frequent and severe consequence of active disease. Rheumatology (Oxford). 2006;45: 1170–1. 11. Aleem A, Al-Sugair S. Thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus. Acta Haematol. 2006;115:68–73. 12. Dold S, Singh R, Sarwar H, Menon Y, Candia L, Espinoza LR. Frequency of microangiopathic hemolytic anemia in patients with systemic lupus erythematosus exacerbation: distinction from thrombotic thrombocytopenic purpura, prognosis, and outcome. Arthritis Rheum. 2005;53:982–5.
Clin Exp Nephrol (2010) 14:487–491 13. Starck M, Abedinpour F, Dendorfer U, Wagner-Czekalla J, Pachmann M, Mann JF, Nerl C. Acquired thrombotic thrombocytopenic purpura as the presenting symptom of systemic lupus erythematosus. Successful treatment with plasma exchange and immunosuppression—report of two cases. Eur J Haematol. 2005; 75:436–40. 14. Singh R, Saunders B, Scopelitis E. Pancreatitis leading to thrombotic thrombocytopenic purpura in systemic lupus erythematosus: a case report and review of literature. Lupus. 2003;12:136–9. 15. Manadan AM, Harris C, Schwartz MM, Block JA. The frequency of thrombotic thrombocytopenic purpura in patients with systemic lupus erythematosus undergoing kidney biopsy. J Rheumatol. 2003;30:1227–30. 16. Vasoo S, Thumboo J, Fong KY. hrombotic thrombocytopenic purpura in systemic lupus erythematosus: disease activity and the use of cytotoxic drugs. Lupus. 2002;11:443–50. 17. Sakarcan A, Stallworth J. Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case and review. Pediatr Nephrol. 2001;16:672–4. 18. Charney DA, Nassar G, Truong L, Nadasdy T. ‘Pauci-Immune’ proliferative and necrotizing glomerulonephritis with thrombotic microangiopathy in patients with systemic lupus erythematosus and lupus-like syndrome. Am J Kidney Dis. 2000;35:1193–206. 19. Brunner HI, Freedman M, Silverman ED. Close relationship between systemic lupus erythematosus and thrombotic thrombocytopenic purpura in childhood. Arthritis Rheum. 1999;42: 2346–55. 20. Nast C, Appel G. A case of lupus nephritis. Clin J Am Soc Nephrol. 2008;3:297–306. 21. Hunt L, Li XN, Judith J, et al. Thrombotic thrombocytopenic purpura and systemic lupus erythematosus: distinct but potentially overlapping syndromes. Blood. 2004;104:245a. 22. Bray VJ, West SG, Kristo DA. Simultaneous presentation of thrombotic thrombocytopenic purpura and systemic lupus erythematosus. S Med J. 1994;87:827–30. 23. Nesher G, Hanna VE, Moore TL, Hersh M, Osborn TG. Thrombotic microangiographic hemolytic anemia in systemic lupus erythematosus. Semin Arthritis Rheum. 1994;24:165–72.
491 24. Banfi G, Bertani T, Boeri V, Faraggiana T, Mazzucco G, Monga G, Sacchi G. Renal vascular lesions as a marker of poor prognosis in patients with lupus nephritis. Am J Kidney Dis. 1991;18:240–8. 25. Tsumagari T, Fukumoto S, Kinjo M, Tanaka K. Incidence and significance of intrarenal vasculopathies in patients with systemic lupus erythematosus. Hum Pathol. 1985;16:43–9. 26. Descombes E, Droz D, Drouet L, Gru¨nfeld JP, Lesavre P. Renal vascular lesions in lupus nephritis. Medicine (Baltimore). 1997; 76:355–68. 27. Yu F, Tan Y, Zhao MH. Lupus nephritis combined with renal injury due to thrombotic thrombocytopaenic purpura-haemolytic uraemic syndrome. Nephrol Dial Transplant. 2010;25:145–52. 28. Kant KS, Pollak VE, Weiss ME, Glueck HI, Miller MA, Hess EV. Glomerular thrombosis in systemic lupus erythematosus: prevalence and significance. Medicine. 1981;60:71–86. 29. Hughson MD, Nadasdy T, McCarty GA, Sholer C, Min KW, Silva F. Renal thrombotic microangiopathy in patients with systemic lupus erythematosus and the antiphospholipid syndrome. Am J Kidney Dis. 1992;2:150–8. 30. Hamasaki K, Mimura T, Kanda H, Kubo K. Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case report and literature review. Clin Rheumatol. 2003;22:355–8. 31. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA. Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991; 325:393–7. 32. Levine SP. TTP and other forms of nonimmunologic platelet destruction. In: Lee G, Foerster J, Lukens J, Paraskevas F, Rodgers G, editors. Wintrobe’s clinical hematology. Baltimore: Lippincott Williams & Wilkins; 1999. p. 1612–22. 33. Wallace DJ. Apheresis for lupus erythematosus. Lupus. 1999;8: 174–80. 34. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004;103:4043–9.