Renal Transplantation in a Patient With Hypocomplementemic Urticarial Vasculitis Syndrome

Renal Transplantation in a Patient With Hypocomplementemic Urticarial Vasculitis Syndrome Philippe Grimbert, MD, Klaus Schulte, MD, Claude Buisson, MD, Dominique Desvaux, MD, Christophe Baron, MD, Myriam Pastural, MD, Djamel Dhamane, MD, Philippe Remy, MD, Bertrand Weil, MD, and Philippe Lang, MD • We describe a 36-year-old man who presented with hypocomplementemic urticarial vasculitis syndrome (HUVS) with severe renal involvement. Despite steroid therapy, the patient developed end-stage renal disease (ESRD) leading to chronic hemodialysis therapy. Renal transplantation was performed after hemodialysis therapy (secondary), and the patient developed a typical HUVS relapse 9 months after transplantation despite conventional immunosuppressive therapy that was successfully treated with plasma exchange. This case shows for the first time that HUVS can induce severe renal involvement responsible for ESRD and that HUVS can relapse after renal transplantation. It also suggests that plasma exchange therapy may be of value for rapidly controlling the clinical symptoms. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Hypocomplementemic urticarial vasculitis syndrome (HUVS); systemic lupus erythematosus (SLE); glomerulonephritis; renal transplantation; recurrence.

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YPOCOMPLEMENTEMIC urticarial vasculitis syndrome (HUVS), also known as McDuffie syndrome, is an uncommon disorder reminiscent of systemic lupus erythematosus (SLE). It is defined as recurrent urticaria and hypocomplementemia combined with at least two of the following: dermal vasculitis on biopsy, arthralgia or arthritis, uveitis or episcleritis, recurrent abdominal pain, glomerulonephritis, and/or a decrease in Clq level with a positive Clq precipitating test result. Renal involvement in HUVS consists primarily of moderate to heavy proteinuria and usually mild renal failure. Histologically, mesangioproliferative and membranoproliferative glomerulonephritis are the predominant abnormalities. 24 Severe renal involvement has been reported in some patients, but renal function stabilization was usually achieved with immunosuppressive therapy. 5,6 We describe the first reported case of HUVS with end-stage renal disease (ESRD) treated by dialysis and kidney transplantation. From the Department of Nephrology and Transplantation, Henri Mondor Teaching Hospital, Cr#teil, France. Received April 4, 2000: accepted in revised form July 7, 2000. Address reprint requests to Philippe Lang, MD, PhD, Service de Ndphrologie, H~pital Henri Mondor, 51 avenue du Mar&'hal de Lattre Tassigny, 94010 Crdteil, France. E-maih [email protected]~-l~arisfr © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3701-001953.00/0 doi : 10.1053/ajkd.2001.20605 144

CASE REPORT

Starting in 1971 (Fig 1), a 36-year-old white man developed recurrent, 4-day-long episodes of symptoms that included urticaria, polyarthritis, fever, and gross hematuria at intervals of 4 to 6 weeks. He was admitted to our unit in 1978 for hematuria and oliguria. Routine laboratory tests showed marked evidence of inflammation (erythrocyte sedimentation rate, 150 ram/h, and leukocytosis, up to 30,000/ /xL). Creatinine clearance was 15 mL/min, and proteinuria was 6 g/d of protein. Total hemolytic activity (CHs0) was markedly diminished (10.5 U/mL; normal, 35 to 50 U/mL), as were serum complement fractions C4 (0.11 g/L; normal, 0.14 to 0.42 g/L) and C3 (0.25 g/L; normal, 0.53 to 1.15 g/L). Serum Clq level was decreased (<2 mg/dL; normal, 10 to 16 mg/dL), and immunoglobulin G (IgG) antibody to C lq was detectable (20 standard deviation units [SDU]/50 ttL). Test results were negative for antinuclear antibodies, antibodies to double-stranded DNA, and ribonucleoprotein, rheumatoid factors, and cryoglobulinemia. C3 nephritic factor was absent. Laboratory findings were normal between the attacks. Membranoproliferative glomerulonephritis was found on renal biopsy. Immunofluorescence (Fig 2) showed coarse granular deposits of IgG, Clq, and C3 along the glomerular capillary walls and within the mesangium. The bouts of symptoms were treated by either oral prednisone (50 rag/d) or intravenous methylprednisolone pulses (1 g/d for 3 days). Six episodes of recurrent HUVS were managed by steroid therapy between 1978 and 1984. However. the glomerular disease persisted between the attacks, progressing to chronic renal failure. Additional laboratory investigations confirmed that all serological test results for SLE were still negative. Tests were also negative for antineutrophil cytoplasmic antibodies and hepatitis C virus serological markers. Chronic hemodialysis therapy was used from 1985 to 1987. Throughout this period, the patient remained free of HUVS attacks. Renal transplantation was performed in 1987. The immediate postoperative course was uneventful. Immunosuppressive therapy was with cyclosporine (4 mg/kg/d), azathio-

American Joumal of Kidney Diseases, Vo137, No 1 (January), 2001 : pp 144-148

RENAL TRANSPLANTATION FOR HUVS serum creatinine

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Fig 1. Clinical course of a patient with recurrent HUVS. Abbreviations: S, steroid therapy; PE, plasmatic exchange; o, clinical recurrence of HUVS.

prine (75 mg/d), and prednisone (10 mg/d). No episodes of acute rejection occurred. Serum creatinine level was stable at 140/xm/L. Nine months after transplantation, the patient developed a typical HUVS relapse with urticaria, severely disabling arthritis, fever, hematuria, bilateral palpebral angioedema, and stupor. Findings were normal from an electroencephalogram, a cerebral computed tomographic scan, and cerebrospihal fluid cell counts and cultures. Serum creatinine level was up to 450/zm/L, proteinuria was 2.5 g/d of protein, and C3 and C4 levels were very low (0.21 and 0.10 g/L, respectively). Serum Clq level was less than 2 mg/dL, and IgG antibody to Clq was detectable (60 SDU/50 htL). Test results were again negative for SLE, cryoglobulinemia, and the full range of antitissue antibodies. Circulating immune complexes were detected at a level of 3.0 g/L (normal < 1.5 g/L). Renal biopsy (Fig 3) showed diffuse membranoproliferative glomerulonephritis without evidence of acute or chronic rejection, lmmunofluorescence showed extramembranous granular deposits of Clq and basement membrane granular deposits of Clq, C3, and IgM. Skin biopsy showed dermal capillary congestion and a sparse lymphohistiocytic infiltrate, without signs of vasculitis. Because the original episode were poorly controlled by steroid therapy, and posttransplantation immunosuppressive therapy failed to protect our patient from typical HUVS recurrences, three sessions of plasma exchange therapy were administered. A dramatic remission occurred within 24 hours of the last session, with resolution

of the fever, urticaria, neurological symptoms, and angioedema. Serum creatinine level decreased from 450 to 180 ~tm/L. C3 and C4 levels returned to normal, and the proteinuria resolved after termination of the clinical attack. Four similar relapses occurred during the next 3 years, and all were successfully treated with plasma exchange. Nevertheless, chronic renal failure developed gradually. In 1991, serum creatinine level was 250 ~m/L, and chronic glomerulopathy was present. A percutaneous renal biopsy showed mesangial hypercellularity, basement membrane thickening with double contours, and diffuse interstitial fibrosis. Immunofluorescence showed intern mesangial deposits of IgM, IgG, C3, and C I q. The patient died suddenly in 1992 of myocardial infarction. DISCUSSION

T h i s c a s e o f H U V S is i n s t r u c t i v e for s e v e r a l r e a s o n s . First, it s h o w s that renal i n v o l v e m e n t in H U V S can b e s e v e r e . In m o s t p u b l i s h e d cases, renal i n v o l v e m e n t c o n s i s t e d o f b e n i g n g l o m e r u lar alterations, and renal f u n c t i o n i m p a i r m e n t has b e e n e x c e e d i n g l y rare. 6,7 M o r e o v e r , in s e v e r a l reports, 5-8 the renal a b n o r m a l i t i e s r e s p o n d e d fav o r a b l y to steroid a n d / o r i m m u n o s u p p r e s s i v e t h e r a p y ( a z a t h i o p r i n e , c y c l o p h o s p h a m i d e , or c y -

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Fig 2. Immunofluorescence showing coarse granular deposits of IgG along the glomerular capillary walls. (Original magnification x300.)

closporine). Our case is the first instance of HUVS with ESRD. It suggests that in some patients, steroid therapy alone may be insufficient to halt the progression of renal damage. Second, no extrarenal attacks of HUVS occurred while our patient was undergoing hemodialysis. A similar effect of hemodialysis has been reported in patients with SLE and most other vasculitides. 9 A likely hypothesis is that the immunodeficiency associated with uremia and chronic hemodialysis may attenuate immune complex-mediated injury in HUVS and other diseases.

Fig 3. Light microscopy showing diffuse membranoproliferative glomerulonephritis (Trichrome; original magnification x400.)

Third, our report is the first to provide outcome data after renal transplantation for ESRD secondary to HUVS. In patients with SLE treated with renal transplantation, the incidence of recurrent disease has been extremely low (1% to 3%). ~0This has been ascribed primarily to continued immunosuppressive therapy after renal transplantation, the immune modulation afforded by pretransplantation blood transfusions, and the immunosuppressive effect of uremia during the pretransplantation period. HUVS shares many characteristics with SLE. It has been suggested that HUVS may not be a

RENAL TRANSPLANTATION FOR HUVS

distinct clinical entity, but rather a syndrome that can occur in a spectrum of diseases ranging from SLE to HUVS. ~ However, although HUVS and SLE probably share pathogenic mechanisms common to immune complex-mediated diseases, they differ by a number of clinical and serological features. In particular, recurrent angioedema and urticaria, as described in this report, are apparently common in HUVS but rare in SLE. Our patient also had positive anti-Clq antibody and a persistent absence of anti-DNA and other antibodies to nuclear constituents considered specific for SLE. Our patient experienced no HUVS attacks during his 2 years on hemodialysis therapy. He was administered three random blood transfusions before transplantation, then a combination of cyclosporine, azathioprine, and prednisone after transplantation. A favorable response of dermal HUVS symptoms to combined steroid and azathioprine therapy has been reported, 6 as well as improved or more slowly progressive renal involvement with the same combination or cyclosporine therapy. 5 However, posttransplantation immunosuppressive therapy failed to protect our patient from typical HUVS recurrences, with renal involvement starting 9 months after transplantation. Recurrent membranoproliferative glomerulonephritis was clearly related to HUVS: the initial renal biopsy showed no evidence of acute or chronic rejection and no signs of chronic cyclosporine toxicity. This suggests that immunosuppressive therapy may not be able to prevent HUVS recurrences in some patients. The steroidresistant course of the disease indicated an unusual and severe form of HUVS that would perhaps have required more aggressive posttransplantation treatment to prevent recurrence. Because the posttransplantation recurrence was fairly late (after 9 months), at a time when dosages of immunosuppressive agents had been reduced, the possibility remains that a more potent immunosuppressive regimen might have prevented the recurrence. Recurrent SLE with renal transplant loss has also been reported.12 Fourth, plasma exchange therapy in our patient induced a dramatic remission of clinical HUVS symptoms and also partly improved the renal manifestations. To our knowledge, this is

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the first reported case successfully treated with plasma exchange. The efficacy of this approach is further evidence that HUVS may be an immune complex-mediated condition, and also opens up the possibility that plasma exchange may be a valuable therapeutic alternative for patients with HUVS who fail to respond to conventional immunosuppressive therapy. Our patient underwent only three plasma exchanges after each HUVS attack. That he developed chronic glomerular disease suggests that prolonged plasma exchange therapy may be warranted. In conclusion, HUVS is an uncommon disorder that can induce severe renal involvement responsible for ESRD. Our case report shows that HUVS can relapse after renal transplantation and suggests that plasma exchange therapy may be of value for rapidly controlling the clinical symptoms. Prolonged plasma exchange may be required to achieve long-term control of the renal disease. REFERENCES

1. Schwartz HR, McDuffieFC, Black LF, SchroeterAL, Conn DL: Hypocomplementemicurticarial vasculitis: Association with chronic obstructive pulmonary disease. Mayo Clin Proc 57:231-238, 1982 2. Ludivico CL, Myers AR, Maurer AR, Maurer K: Hypocomplementemicurticarial vasculitis with glomerulonephritis and pseudotumorcerebri.ArthritisRheum 22:10241028, 1979 3. Wiesnieski JJ, Baer AN, Christensen J, Christensen J, Cupps TR, Flagg DN, Jones JV, KatzensteinPL, McFadden ER, McMillen J J, Pick MA: Hypocomplementemicurticarial vasculitis syndrome.Clinical and serologicfindings in 18 patients. Medicine74:24-41, 1995 4. Moorthy AV, Pringle D: Urticaria, vasculitis, hypocomplementemiaand immune-complexglomerulonephritis. Arch Pathol Lab Med 106:68-70, 1982 5. Soma J, Sato H, Ito S, Saito T: Nephrotic syndrome associated with hypocomplementaemicurticarial vasculitis syndrome: Successful treatment with cyclosporinA. Nephrol Dial Transplant 14:1753-1757, 1999 6. Ramirez G, Saba SR, Espinoza L: Hypocomplementemicvasculitisand renal involvement.Nephron45:147150, 1987 7. Feig PU, Soter NA, Yager HM, Caplan L, Rosen S: Vasculitis with urticaria, hypocomplementemiaand multiple system involvement.JAMA 263:2065-2068, 1976 8. Werder M, Truniger B: Hypocomplementaemicurticarial vasculitis. Nephrol Dial Transplant 12:1278-1279, 1997 9. Nossent HC, Swaak TJG, Berden JHM: Systemic lupus erythematosus: Analysis of disease activity in 55

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patients with end-stage renal failure treated with hemodialysis or CAPD. Am J Med 89:169-174, 1990 10. Mathew TH: Recurrence of disease following renal transplantation. Am J Kidney Dis 12:85-96, 1988 11. Schultz DR, Perez GO, Volanakis JE, Pardo V, Moss SH: Glomerular disease in two patients with urticaria, cuta-

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neous vasculitis and hypocomplementemia. Am J Kidney Dis 1:157-165, 1981 12. Nyberg D, Blohm6 I, Persson H, Olausson M, Svalander C: Recurrence of SLE in transplanted kidneys: A follow-up transplant biopsy study. Nephrol Dial Transplant 7:1116-1123, 1992