Ignatius K.P. Cheng

A prospective study of hepatitis C virus infection among renal transplant recipients

BACKGROUND Chronic non-A, non-B hepatitis is a major cause of liver disease in renal transplant recipients. METHODS One hundred eight-five renal allograft recipients, including 151 who had been prospectively followed up for 24 months, were studied to determine the prevalence and course of hepatitis C virus (HCV) infection. Antibody to HCV (anti-HCV) was measured by enzyme immunoassay, and HCV RNA was measured by nested polymerase chain reaction assay. RESULTS Twenty-three (12.4%) patients were positive for anti-HCV and/or HCV RNA: 19 (10.3%) were anti-HCV positive; and HCV RNA was detected in 18 (94.7%) anti-HCV-positive and 4 (2.4%) anti-HCV-negative patients. Markers of HCV infection persisted in all HCV-positive patients over the 2-year period. Most HCV-positive patients acquired HCV infection before or at the time of transplantation. The incidence of new infection after transplantation was 0.45% per patient-year. Anti-HCV and/or HCV RNA was detected in 75% of patients with biochemical chronic non-A, non-B hepatitis, but transaminase levels were persistently normal in 30.4% of HCV-positive individuals. CONCLUSIONS HCV infection is common among renal transplant recipients. Testing for HCV RNA is important because some patients might not produce anti-HCV. Transaminase levels cannot be used as a surrogate marker of HCV infection in these patients.

Sequential Therapy for Diffuse Proliferative and Membranous Lupus Nephritis: Cyclophosphamide and Prednisolone Followed by Azathioprine and Prednisolone

A retrospective single-center cohort study was conducted on 35 patients with diffuse proliferative (WHO type IV) and/or membranous (type V) lupus nephritis (22 with type IV, 6 with type V, and 7 with type IV plus V) who had been treated with a sequential regimen comprising prednisolone and cyclophosphamide during active disease, followed by low-dose prednisolone and azathioprine maintenance. The follow-up period was 33.2 +/- 4.5 months. At presentation, 32 (91.4%) patients were nephrotic, and an abnormal serum creatinine level was noted in 14 (48.3%) patients with type IV changes. Cyclophosphamide was given for 26.8 +/- 2.8 weeks. 33 (94.3%) patients achieved complete or partial renal remissions: 77.3 and 22.7% of the type IV patients, 16.7 and 66.6% of the type V patients, and 14.3 and 71.4% of the type IV plus V patients, respectively (p < 0.0001 for type IV versus type V and for type IV versus type IV plus V). The duration of therapy before renal remissions and normalization of C3 were attained was similar among the three groups of patients. Disease relapse occurred in 4 (18.2%) of 22 IV patients and in 1 of the 5 type V patients in remission. Mortality was not observed, and none of the patients had an increase in serum creatinine level to double the baseline value. Adverse effects related to therapy included: hair loss (42.9%), transient amenorrhea (53.6%), leukopenia (11.4%), febrile episodes (14.3%), and herpes zoster(28.6%). We conclude that sequential use of prednisolone and cyclophosphamide followed by low-dose prednisolone and azathioprine can achieve favorable therapeutic results in the majority of patients with diffuse proliferative and/or membranous lupus nephritis, without excessive toxicities.

Treatment of fibrosing cholestatic hepatitis with lamivudine

Fibrosing cholestatic hepatitis is a histological variant of hepatitis B virus infection with a high rate of mortality. We describe a patient who acquired acute hepatitis B virus infection 8 months after renal transplantation. Clinical features of rapidly progressive liver failure, indicated by prolonged prothrombin time (57 seconds) and increased bilirubin (40.4 mg/dL) and ammonia (129 mumol/L) concentrations, were accompanied by an extremely high serum HBV DNA level (2.153 x 10(6) pg/mL). Liver biopsy specimen showed fibrosing cholestatic hepatitis with widespread balloon degeneration of hepatocytes, focal hepatocyte loss, bile stasis, periportal fibrosis, mild lymphocytic infiltration, and strongly positive immunohistochemical staining for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen. Lamivudine therapy suppressed HBV DNA to < 10 pg/mL within 4 weeks, which was followed by gradual recovery of liver function from a state of hepatic precoma. Twenty-four months after the onset of hepatitis, the patient had normal prothrombin time and bilirubin, transaminase, and albumin levels. She remained HBsAg positive and hepatitis B e antigen negative. Renal allograft function was stable, with a creatinine level of 1.52 mg/dL. HBV DNA remained suppressed after 22 months of lamivudine therapy. Our experience shows that fibrosing cholestatic hepatitis and liver failure caused by HBV infection can be successfully treated with lamivudine.

Tuberculous Peritonitis Complicating Long-Term Peritoneal Dialysis

The characteristics of 5 patients who developed tuberculous peritonitis while receiving long-term peritoneal dialysis (PD) are presented. There were 2 males and 3 females. 3 patients were on intermittent and 2 were on continuous ambulatory peritoneal dialysis when tuberculous peritonitis was first diagnosed. None of the patients had recently received immunosuppression therapy or were diabetics. The clinical presentations were similar to other forms of peritonitis complicating PD except for a more insidious onset. As extraperitoneal involvement and peritoneal lymphocytosis were rarely present, the diagnosis was mainly dependent on the direct demonstration of Mycobacterium tuberculosis with smear (1 patient) and culture (4 patients). In 1 patient with a pleuroperitoneal communication, the diagnosis was made by pleural biopsy and a positive response to antituberculous therapy. All patients responded to treatment with a combination of three antituberculous drugs which included streptomycin, isoniazid, rifampicin and pyrazinamide. Two patients were transferred to hemodialysis. In 3 patients, peritoneal dialysis was continued. Peritoneal clearance and ultrafiltration capacity were unchanged for up to 16 months after treatment in 2 patients who continued peritoneal dialysis but was reduced by 30 and 50%, respectively, in the remaining patient. Only 1 patient died, but her death was not directly related to tuberculous peritonitis. It was concluded that with a high index of suspicion and early institution of treatment, tuberculous peritonitis complicating PD can be successfully treated with low mortality and without compromising the dialysis capacity of the peritoneal membrane.

Castleman’s Disease and Mesangial Proliferative Glomerulonephritis: The Role of Interleukin-6

Renal complications of Castleman’s disease (angiofollicular lymph node hyperplasia) are uncommon. The reported cases are very heterogeneous and their renal pathology ranged from minimal change disease, mesangial proliferative glomerulonephritis, to amyloidosis. We have previously reported two cases of Castleman’s disease with renal complications. We now present two more such cases. In contrast to other reports, all our cases are of the plasma cell type and their renal pathology showed remarkable similarities, namely mesangial proliferation, interstitial plasma cell infiltration and negative immunofluorescence. The level of serum interleukin-6 (IL-6) in both patients was elevated at presentation and came down with immunosuppressive therapy.

Resolution of Membranoproliferative Glomerulonephritis Complicating Angiofollicular Lymph Node Hyperplasia (Castleman’s Disease)

A novel renal complication was reported in a patient with angiofollicular lymph node hyperplasia (Castlemans Disease), who developed acute renal failure due to membranoproliferative glomerulonephritis. Renal biopsy showed marked mesangial hyperplasia, basement membrane thickening with subendothelial electron-dense deposits, interstitial plasma cell infiltration, and glomerular deposition of IgM and complement components. A resolution of systemic manifestations and an improvement in renal function followed prednisolone and azathioprine therapy. Disease relapse, with increasing proteinuria and the development of factor 8 inhibitor, occurred 3 months later. Sustained remission was achieved with prednisolone and cyclophosphamide therapy, which were given for 42 and 12 months, respectively. Renal biopsy during remission showed significant resolution of the mesangial hyperplasia and disappearance of interstitial plasmacytic infiltration as well as subendothelial electron-dense deposits.

Crescentic nodular glomerulosclerosis secondary to truncated immunoglobulin α heavy chain deposition

Nodular glomerulosclerosis secondary to deposition of monoclonal immunoglobulin (Ig) light chains with or without heavy chains is a recognized clinicopathological entity. Recent reports have demonstrated that an identical glomerular lesion may also occur as a result of truncated tau Ig heavy chain deposition. We investigated the nature of Ig deposits in a patient who presented with rapidly progressive renal failure secondary to crescentic nodular glomerulosclerosis. This patient had a relapsing clinical course responsive to treatment with steroid and cyclophosphamide therapy. In this case, both the glomeruli and tubular basement membrane contained granular immune deposits that were reactive to polyclonal antibodies against alpha but not tau or mu Ig heavy chains and nonreactive to anti-kappa and anti-lambda light chain reagents. A monoclonal population of plasma cells secreting alpha and kappa chains was present in the patients marrow despite the finding of a normal percentage of plasma cells. Serum Immunoelectrophoresis was normal, but immunofixation demonstrated the presence of a monoclonal alpha/kappa band. Immunoblot under dissociating and nondissociating conditions showed that both the patients urine and serum contained Ig fragments that comprised dimer or monomer of an abnormally short alpha Ig heavy chain (approximately 26 kd) with or without associated kappa light chain. The identity of the abnormal serum alpha Ig heavy chain with that of the glomerular Ig deposits was supported by the finding that both were nonreactive against alpha 1 and alpha 2 subclass-specific monoclonal antibodies despite their reactivity to polyclonal antibodies. Because these monoclonal antibodies would react with structural determinants, which differ between alpha 1 and alpha 2 Ig heavy chains but not those common between them, and because the differences in amino acid sequence between the two largely lie in the CH1 and CH2 domains of the alpha Ig heavy chain, it is hypothesized that the abnormally short alpha Ig heavy chain produced by plasma cells in this patient contains deleted CH1 and CH2 domains similar to the findings in patients with tau Ig heavy chain deposition disease.

Clinicopathological Features of Hepatitis C Virus Antibody Negative Fatal Chronic Hepatitis C after Renal Transplantation

Clinical course and serial liver histology of a patient who developed fatal chronic active hepatitis C after renal transplantation are presented. This patient developed persistently deranged liver biochemistry 3 months after transplantation, despite normal liver enzyme values during the preceding 3 years on hemodialysis. In addition to increased parenchymal enzyme concentrations, the levels of ductal enzymes were also markedly elevated, with peak levels of alanine aminotransferase and gamma-glutamyl transpeptidase 7 and 100 times, respectively, the normal upper limit. The patient was persistently seronegative for hepatitis C virus (HCV) antibodies, but positive for HCV RNA. Treatment with alpha-interferon for 6 months, initiated after the development of early cirrhosis, resulted in no improvement, and the patient died from liver failure 36 months after renal transplantation. Serial liver histology, examined four times from 11 months to 36 months after transplantation, showed progressive deterioration from chronic active hepatitis to cirrhosis. This patient illustrates the uncommon complication of rapidly progressive and ultimately fatal liver disease due to HCV infection after renal transplantation. Early recognition with anti-HCV and HCV RNA assays as well as histologic assessment are crucial for the identification of patients with a poor prognosis who might benefit from therapeutic intervention before irreversible liver damage.

Mesangial IgA nephropathy with steroid-responsive nephrotic syndrome: disappearance of mesangial IgA deposits following steroid-induced remission.

This report describes the clinical features and renal biopsy pathology in two patients with immunoglobulin A (IgA) nephropathy and nephrotic syndrome before and after steroid-induced remission. Apart from confirming the frequently relapsing course and mild glomerular changes observed in patients with IgA nephropathy and steroid-responsive nephrotic syndrome (SRNS), we were able to show that mesangial expansion and mesangial IgA deposits disappeared or were greatly reduced in repeat renal biopsies following steroid-induced remission. Because mesangial IgA deposits usually persist in repeat biopsies obtained from patients with typical IgA nephropathy, their resolution in our patients following steroid remission would support the proposal that the association of IgA nephropathy and SRNS may represent a distinct clinical syndrome. It is postulated that the presence of mesangial IgA deposits during nephrotic presentation and their disappearance following steroid-induced remission may result from increased mesangial sequestration of IgA circulating immune complexes (CIC) during the period of enhanced glomerular permeability and that the increased load of IgA CICs may reflect a common defect in mucosal immunity or immunoregulation in these patients.

Living-Related Renal Transplantation in a Patient with Nail-Patella Syndrome

Living-related renal transplantation was performed successfully in a patient with nail-patella syndrome. Graft biopsy 18 months post-transplantation showed normal glomerular basement membrane by electron microscopy. Dystrophic nails of both index fingers had also regrown, suggesting the donor kidney might replenish deficient factors.