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Dialysis. Transplantation. Case Report. Hepatitis-C-virus-associated cryoglobulinaemic membranoproliferative glomerulonephritis in patients infected by HIV.
Nephrol Dial Transplant ( 1997) 12: 1980–1984

Nephrology Dialysis Transplantation

Case Report

Hepatitis-C-virus-associated cryoglobulinaemic membranoproliferative glomerulonephritis in patients infected by HIV E. Morales, R. Alegre, J. C. Herrero, J. M. Morales, T. Ortun˜o and M. Praga Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain

Key words: Hepatitis C virus; membranoproliferative glomerulonephritis; cryoglobulinaemia; HIV infection

Introduction In recent years it has been clearly established that hepatitis C virus ( HCV ) is a major cause of mixed cryoglobulinaemia [1,2]. Some patients with HCVassociated cryoglobulinaemia develop a glomerular disease characterized by proteinuria, haematuria and variable degrees of renal insuciency [3,4]. The most commonly found histological lesion is a membranoproliferative glomerulonephritis (MPGN ) although other forms of glomerular involvement have also been described (mesangioproliferative and membranous glomerulonephritis) [5,6 ]. On the other hand, some patients infected by HCV have showed glomerular diseases without evidence of concomitant cryoglobulinaemia [7 ]. Although the coexistence of human immunodeficiency virus (HIV ) and HCV infections in the same patient is a common clinical problem [8,9], HCVassociated cryoglobulinaemic MPGN has been very rarely reported in patients coinfected by HIV. Here we report on three HIV-positive patients who developed this complication.

Case reports Case no. 1 (Figure 1) A 40-year-old white woman was admitted to our hospital because of oedema and arterial hypertension. Two years before she has tested positive for HIV; her husband was an intravenous drug abuser, and also positive for HIV. She had noted dark urine and maleolar oedema in the 2 months prior to admission. Physical examination disclosed a blood pressure of

190/120 mmHg, oedema in both legs, and skin lesions suggestive of livedo reticularis. Laboratory evaluation showed the following results: haematocrit, 32%; haemoglobin, 9.7 g/dl; white blood cell count, 8170/mm3; total CD4 lymphocyte count, 429/mm3 (33%); platelet count, 295 000/mm3; serum creatinine, 1.5 mg/dl; creatinine clearance, 55 ml/min; serum total proteins, 6.2 g/dl; serum albumin, 2.1 g/dl; IgG, 2050 mg/dl; IgA, 113 mg/dl; IgM, 205 mg/dl; C3, 80 mg/dl, and C4, 20 mg/dl; bilirubin and serum transaminases were normal; test for serum cryoglobulins was positive and antinuclear antibodies, anti-DNA, and ANCA negative; the urine sediment contained 20 red cells and 15 white cells per high-power field. Proteinuria was 9.7 g/day. Tests for HIV were positive by ELISA and Westernblot analysis. HCV antibodies were positive by ELISA; infection by HCV was confirmed by PCR (genotype 1b ). A skin biopsy showed lesions of leukocytoclastic vasculitis. A percutaneous renal byopsy was performed: mesangial hypercellularity and mesangial expansion with duplication of basement membranes, characteristics of MPGN were evident. On immunofluorescencemicroscopy, deposits of C3 and IgG were observed. The material submitted to electron-microscopy contained no glomeruli. Treatment with zidovudine was started. Throughout the following 2 years the patient continued with nephrotic proteinuria and deteriorating renal function. Bouts of skin purpura and livedo reticularis were reported. A second renal biopsy was obtained: images of MPGN persisted but nearly 70% of the glomeruli showed advanced glomerulosclerosis; in addition, severe interstitial fibrosis was evident. Serum creatinine was 6.3 mg/dl and creatinine clearance 15 ml/min. Three boluses of intravenous methylprednisolone (250 mg/day) were administered, followed by oral prednisone (1 mg/kg/day) for 3 weeks. However, renal function continued to deteriorate and the patient started chronic dialysis 2 months later. Case no. 2 (Figure 2)

Correspondence and oprint requests to: Manuel Praga MD, Servicio de Nefrologı´a, Hospital 12 de Octubre, Ctra Andalucı´a km 5,400, 28041 Madrid, Spain.

A 37-year-old white man, ex-intravenous drug addict and known to be HIV positive, had been diagnosed of

© 1997 European Renal Association–European Dialysis and Transplant Association

HCV-associated glomerulonephritis in HIV patients

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Fig. 1. Clinical course of patient no. 1.

tuberculous cervical adenitis 6 months before admission. Treatment with isoniazid, rifampicin and pyrazinamide was started; serum creatinine and creatinine clearance were normal. In the month prior to admission, the patient noted progressive oedema and decrease of urine output. On physical examination, anasarca was evident, with pleural eusion, ascites, and generalized oedema. Blood pressure was 140/70 mmHg. Laboratory data showed the following: haematocrit, 27%; haemoglobin, 8.9 g/dl; white blood cell count, 3790/mm3; CD4 lymphocyte count, 194/mm3 (29%); platelet count, 156 000; serum creatinine, 2.7 mg/dl creatinine clearance, 22 ml/min; serum total proteins, 7.4 g/dl; serum albumin, 2 g/dl; IgG, 3450 mg/dl; IgA, 119 mg/dl; IgM, 413 mg/dl; C3, 76 mg/dl; C4, 26 mg/dl; serum bilirubin, 0.1 mg/dl; serum aspartate aminotransferase, 61 U/l, serum alanine aminotransferase 41 u/l, gamma GT 29 U/l. Proteinuria was 10 g/day and gross haematuria was present. Antinuclear antibodies, anti-DNA, and ANCA were negative. Test for serum cryoglobulins was positive. Antibodies to HCV were detected by ELISA, and HCV RNA was later detected by PCR (genotype 1b). A percutaneous renal biopsy showed the characteristic images of MPGN. On immunofluorescence, deposits of IgG, IgM and C3 were observed. On electron-microscopy, increase in matrix and cells in the

mesangium, with interposition between the capillary basement membrane and endothelial cell, was observed. Electron-dense deposits in subendothelial locations were identified. Intensive diuretic therapy was started but renal function showed a progressive derangement. Four boluses of i.v. methylprednisolone (250 mg/day), were administered and oral prednisone (1 mg/kg/day) was maintained for 4 weeks. A progressive recovery of renal function, together with proteinuria decrease, was observed. At the end of steroid treatment, renal function was normal (serum creatinine 1.3 mg/dl, creatinine clearance 90 ml/min), and proteinuria had decreased to 2.4 g/day. Three months later proteinuria was 2 g/day and renal function remained normal. Case no. 3 A 36-year-old white man with a history of intravenous drug abuse and known to be HIV positive was admitted because of arterial hypertension. He reported frequent headaches in the 2 months prior admission. On physical examination blood pressure was 200/130 mmHg, the remainder of the examination was unremarkable. Laboratory findings were as follows: haematocrit, 42%; haemoglobin, 14 g/dl; white blood cells count, 5200/mm3; CD4 lymphocyte count, 193.6/mm3 (11%);

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Fig. 2. Clinical course of patient no. 2.

platelet count, 206 000/mm3; serum creatinine, 1 mg/dl; creatinine clearance, 108 ml/min; serum total proteins, 7.8 g/dl; serum albumin, 3.9 g/dl; serum bilirubin, 0.34 mg/dl; serum aspartate aminotransferase, 18 U/l, serum alanine aminotransferase 38 U/l and gamma glutamyl transpeptidase 143 U/l; C3, 65 mg/dl; C4, 26 mg/dl; IgG, 1860 mg/dl, IgA, 105 mg/dl; IgM, 507 mg/dl; antinuclear antibodies, anti-DNA, and ANCA were negative. Proteinuria was 2 g/day; urine sediment contained 60 red blood cell and 10 leukocytes per high-power field. Serum cryoglobulins were detected, with a cryocrit of 2%. HIV infection was confirmed by Western blot. Antibodies to HVC were detected by ELISA and HCV RNA by PCR (genotype 1b ). A percutaneous renal biopsy showed a typical MPGN; on immunofluorescence, deposits of IgG and C3 were identified. On electron-microscopy, characteristic images of MPGN were observed: increase and extension of mesangial matrix and cells, with interposition of mesangium along capillary walls. Electrondense deposits in both subendothelial and epimembranous locations were observed (type III MPGN ). Blood pressure was controlled with an angiotensinconverting enzyme inhibitor. After 6 months of followup the patient is asymptomatic, with normal renal function, normal blood pressure, and proteinuria ranging between 0.2 and 1 g/day.

Discussion Renal disease is a frequent complication in the course of HIV infection. Its most common presentation is the so-called HIV-associated nephropathy (HIVAN ), characterized clinically by a nephrotic syndrome with rapid progression towards end-stage renal failure, and histologically by a focal and segmental glomerulosclerosis with severe tubulointerstitial inflammation [10–12 ]. Remarkably, almost 90% of the cases of HIVAN occur in blacks; the reasons for this racial predilection remain unknown. In addition to HIVAN, patients with HIV infection are also at risk of developing many other forms of renal disease. Concerning glomerular diseases, several types of immune-complex glomerulonephritis have been described: membranous, membranoproliferative, endocapillary proliferative, and IgA glomerulonephritis among others [13–15]. Nevertheless, although the coexistence of HIV and HCV infection is a common clinical observation [8,16 ], very few HIV-positive patients showing HCV-associated renal diseases have been reported so far. The predominant form of HCV-associated glomerular diseases is an MPGN, associated with circulating cryoglobulins in a majority of cases [6,17,18]. Skin manifestations of cutaneous vasculitis, arthritis, peripheral neuropathy, and other non-renal symptoms

HCV-associated glomerulonephritis in HIV patients

associated with cryoglobulinaemia can be present [19,20]. Decreases of serum C3 and C4 complement factors and positivity of rheumatoid factor are also commonly observed. In addition, the severity of hepatic involvement by HCV varies from minor histological changes without clinical repercusion to advanced liver failure. Our three patients showed concomitant infection by both HIV and HCV. Two patients (cases 1 and 2 ) had no clinical or biochemical evidence of hepatic dysfunction, whereas in case 3 a mild increase of serum hepatic enzymes was observed. HCV-genotype 1b was detected in the three patients. With the exception of case 1, that showed a cutaneous vasculitis, no other extrarenal symptoms attributable to cryoglobulinaemia were reported. The manifestations of renal involvement were rapidly progressive in our cases 1 and 2 (see Figures 1 and 2 ), with a nephrotic syndrome and a rapid derangement of renal function that might resemble the characteristic evolution of HIVAN. However, their renal biopsies revealed a MPGN type I. In the other patient (case 3 ) clinical presentation was less aggressive (arterial hypertension, microhaematuria, nonnephrotic proteinuria, and preserved normal renal function). This patient’s renal biopsy showed a type III MPGN (electron-dense deposits in both sides of the basement membrane). As far as we know, only five cases of HCV-associated glomerular disorders in HIV-positive patients have been published so far, in abstract form [21]. Renal biopsies showed MPGN in four patients and membranous GN in one patient. Some other cases of MPGN in HIV-positive patients have been published [15,22]. However, no information about concomitant HCV infection or presence of cryoglobulinaemia was given. Treatment of patients with HCV-related glomerular disorders remains debatable. Some studies have shown that interferon therapy has beneficial eects, although its long-term ecacy remains undetermined [6,21,23,24 ]. On the other hand it has been suggested that in HCV patients with more aggressive forms of glomerulonephritis (rapidly deteriorating renal function) treatment with steroids and immunosuppressive agents could be preferable to interferon [6,25]. The existence of a concomitant HIV infection, as in our patients, makes the therapeutic approach more dicult. However, the evolution of our patients oers some interesting data. Patient 1 was initially treated with zidovudine, on the assumption that HIV could be playing a pathogenic role in the glomerular lesion (by the time of her first renal biopsy the entity of HCV-associated cryoglobulinaemic MPGN was not yet well characterized ). Evolution was unfavourable ( Figure 1). Later, when renal insuciency was very advanced and severe sclerosis has been observed in a second renal biopsy, she received a cycle of high-dose steroids. No beneficial influence was detected and the patient started chronic dialysis. However, patient 2 was treated with a short cycle of high-dose steroids, shortly after his renal

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biopsy, in which no fibrosis was detected. He showed a dramatic improvement, with recovery of normal renal function and sharp proteinuria decrease (Figure 2 ). Patient 3, with normal renal function and non-nephrotic proteinuria did not receive specific treatments other than antihypertensive drugs. The five patients with HCV-associated glomerular disease and coinfection by HIV reported by Cheng et al. [21 ] showed a rapidly progressive renal insuciency and a poor clinical outcome. Two patients were treated with interferon, with no appreciable beneficial eects on renal function. In summary, coinfection by HCV should be ruled out in HIV patients who develop glomerular disease; the detection of cryoglobulinaemia or the finding of MPGN on renal biopsy should reinforce the suspicion of concomitant HCV infection. High-dose steroids, when administered precociously, could halt the rapid evolution towards end-stage renal disease in HIVpositive patients with aggressive forms of HCV-associated MPGN.

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E. Morales et al. 21. Cheng JT, Anderson H, D’Agati V, Herbert L. Clinical course of hepatitis C virus associated glomerular disease in patients co-infected with HIV. J Am Soc Nephrol 1996; 7: 1330 22. Kimmel PL, Phillips TM, Ferreira-Centeno A, Farkas Szallasi T, Abraham AA, Garret CT. HIV-associated immune-mediated renal disease. Kidney Int 1993; 44: 1327–1339 23. Johnson RJ, Gretch DR, Couser WG et al. Hepatitis C virusassociated glomerulonephritis. Eect of alpha-interferon therapy. Kidney Int 1994; 46: 1700–1704 24. Boyer N, Marcellin P, Degott C et al. Recombinant interferon alfa for chronic hepatitis C in patients positive for antibody to human immunodeficiency virus. J Infect Dis 1992; 165: 723–726 25. D’Amico G, Colasanti G, Ferrario F, Sinico RA. Renal involvement in essential mixed cryoglobulinaemia. Kidney Int 1989; 35: 1000–1004 Received for publication: 16.4.97 Accepted: 21.4.97