Pascual M

Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy.

Fibrosing cholestatic hepatitis (FCH) has recently been described after solid organ transplantation in patients with hepatitis C virus (HCV) infection. Typically, FCH is characterized by an ominous clinical course leading to progressive hepatic failure and death if liver transplantation is not performed. Two HCV-infected patients underwent cadaveric renal transplantation for end-stage renal disease resulting from membranous nephropathy and diabetic nephropathy. The time intervals between transplantation and the biopsy diagnosis of FCH for the two patients were 7 months and 10 years. Both patients presented with jaundice, hyperbilirubinemia, and mild-to-moderate elevations in serum aspartate aminotransferase. One patient was also found to have type II mixed cryoglobulinemia. Interferon-alpha therapy was begun after a diagnosis of FCH was established by liver biopsy. Liver test abnormalities normalized rapidly. When cholestatic hepatic deterioration develops in an HCV-infected organ allograft recipient, the diagnosis of FCH should be considered and a liver biopsy performed. Our observations indicate that FCH can respond to antiviral therapy.

Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation.

Background and Aims. There is a strong epidemiologic association between diabetes mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic basis for this association has not been established. We sought to evaluate the association between insulin resistance (IR), &bgr;-cell dysfunction, and HCV among orthotopic liver transplant (OLT) recipients. Methods. We performed a cross sectional analysis comparing 39 HCV(+) with 60 HCV(−) OLT recipients. IR and &bgr;-cell function were calculated using validated measures and were correlated with clinical variables. Results. By multivariate analysis of the entire cohort, HCV infection and body mass index (BMI) were independent predictors of IR (P =0.04 and 0.0006, respectively). HCV infection was associated with 35% increase in IR. Because the model used to calculate IR was derived from nondiabetic subjects, we performed additional analysis of patients who did not meet criteria for diabetes at the time of their study evaluation. In this analysis, HCV(+) subjects had greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 &mgr; U/mL and 3.8) compared with HCV(−) patients (10.7 &mgr; U/mL and 2.5) (P =0.03, 0.03). There was no difference in &bgr;-cell function or hepatic insulin extraction between the HCV (+) and (−) groups. HCV (P =0.0005), BMI (P <0.0001), and high high-density lipoprotein (P =0.039) were the only independent predictors of IR. The presence of HCV infection and a 10-fold increase in HCV RNA were associated with a 62% and 8% increase in IR, respectively. Conclusions. HCV is independently associated with increased IR after OLT. These findings provide a possible pathogenetic basis for the association of DM with HCV.

Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C.

Abstract:u2002 Background:u2002 Histological recurrence of the hepatitis C virus (HCV) occurs in the majority of persons transplanted for cirrhosis as a result of HCV. Herein we analyze our experience with the use of both conventional and pegylated (PEG) interferon (IFN) in combination with ribavirin (RBV) in liver transplant recipients with recurrent HCV.

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

De novo collapsing glomerulopathy in renal allografts.

BACKGROUNDnCollapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts.nnnMETHODSnWe reviewed 892 allograft biopsies from a population of 1079 recipients who received renal transplants between 1978 and 1996.nnnRESULTSnFive cases of de novo collapsing glomerulopathy were identified (0.6% of biopsies; 3.2% since 1993). None occurred before 1993. The patients were 31 to 66 years of age and they presented 6 to 25 months after transplantation. The 24-hr urinary protein ranged from 1.8 to 11.8 g. All patients and donors were negative for the human immunodeficiency virus and had no risk factors for human immunodeficiency virus infection. Diffuse or focal, global or segmental collapse of glomerular capillaries, swelling and hypercellularity of the visceral epithelium, hyaline arteriolosclerosis, and interstitial fibrosis were characteristic histologic features. Two cases had concomitant glomerular immune complex deposits. Progressive decline in allograft function occurred within 2-24 months after diagnosis, culminating in return to dialysis in all patients.nnnCONCLUSIONnCollapsing glomerulopathy can arise in renal allografts as a de novo disease. Although its pathogenesis remains to be clarified, it is important to distinguish this lesion in allografts as it can be associated with rapidly progressive graft failure.

Chronic rejection and chronic cyclosporin toxicity in renal allografts

Recent evidence indicates that growth factors are critically important in both chronic rejection and chronic cyclosporin A toxicity, suggesting that these two entities share a common pathophysiological pathway, leading to progressive allograft failure. Here, Manuel Pascual and colleagues discuss the relevance of growth factors to chronic allograft nephropathy, and the implications for therapy in view of the great choice of immunosuppressive drugs now available.

New treatments for acute humoral rejection of kidney allografts

Acute antibody-mediated rejection (acute humoral rejection; AHR) of organ allografts usually presents as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition with renal dysfunction, associated with circulating donor-specific anti-human leukocyte antigen alloantibodies, is diagnostic of AHR in kidney allografts. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), tacrolimus, mycophenolate mofetil and/or intravenous immunoglobulins, as well as rituximab or splenectomy, have been recently used to successfully treat AHR. However, the optimal protocol to treat AHR still remains to be defined. Anti-CD20+ monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as rescue therapy in some episodes of steroid- and antilymphocyte-resistant humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunological risk patients in anticipation of a previously cross-match positive (or ABO incompatible) kidney transplantation. In the near future, the possible role of new specific anti-B-cell approaches or, possibly, of new anti-T-cell activation approaches using selective agents such as belatacept should be assessed to further refine the present treatment of humoral rejection.

Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease.

BACKGROUNDnPrimary and secondary forms of focal segmental glomerulosclerosis (FSGS) are common causes of glomerular proteinuria. Secondary forms of FSGS seem to be the result of adaptive changes that follow a reduction in renal mass. We saw an elderly patient with severe bilateral renal vascular disease (RVD) who had FSGS on percutaneous biopsy. To find out whether elderly patients with atherosclerotic RVD are predisposed to the development of FSGS, we reviewed all cases of FSGS at our institution between 1990 and 1995.nnnMETHODSnWe identified 59 cases of biopsy-proven FSGS and examined clinical, histological, and radiographic records.nnnFINDINGSnOf the 59 patients, 24 were older than 50 years; eight of these had RVD. No patient under the age of 50 had RVD. Seven of the eight patients with RVD and FSGS had substantial proteinuria at presentation. All had typical glomerular lesions with focal segmental tuft collapse and synechiae; other glomeruli were hypertrophic. All patients showed further decline in renal function on follow-up.nnnINTERPRETATIONnThe association of FSGS and RVD may represent an under-recognised aetiology of significant proteinuria in elderly patients.

Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome

Tumor necrosis factor alpha (TNFa) has been shown to be the primary cytokine responsible for the OKT3-induced acute clinical syndrome (OKT3-ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) is a dimer of the p80 TNF receptor, which binds both TNFa and lymphotoxin (LT). Renal allograft recipients undergoing OKT3 therapy for steroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decreasing the severity of OKT3-ACS and in restoring renal function. Six of 12 patients were given TNFR:Fc prior to each of the first two injections of OKT3. All patients were monitored for manifestations of OKT3-ACS and changes in renal function. In addition, serial serum samples were assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L929). No adverse side effects were identified in patients receiving TNFR:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms by day 2 of OKT3, and had a lower overall incidence of chills and arthralgias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group. Antigenic TNFa levels increased in the control group from < 10 pg/ml pre OKT3 to a mean peak level of 30 +/- 13 pg/ml on day 1 and decreased to pretreatment levels by day 2. TNFR:Fc-treated patients had a mean peak TNFa level of 235 +/- 135 pg/ml, suggesting a carrier effect of TNFR:Fc. In contrast, bioactivity was barely detectable (mean 20 +/- 14 pg/ml) in the day 1 samples from TNFR:Fc-treated patients, whereas significant bioactivity (peak mean 60 +/- 35 pg/ml) was detected in sera from control patients. TNF receptor levels reached 600 ng/ml in treated patients and remained elevated for up to 18 days confirming the long half-life of TNFR:Fc. This phase 1 trial demonstrates that TNFR:Fc is well tolerated and may limit the severity of OKT3-ACS. The most significant observation was a more rapid improvement in renal function in the TNFR:Fc-treated patients. The absence of TNFa bioactivity indicates that TNFR:Fc functions as a TNF antagonist. Further evaluation of higher doses of TNFR:Fc in OKT3-treated patients is currently in progress.

The clinical usefulness of the renal allograft biopsy in the cyclosporine era : A prospective study

BACKGROUNDnThe renal allograft biopsy is generally accepted as the gold standard for clarifying the cause of renal dysfunction. However, the clinical usefulness of this procedure has rarely been studied prospectively, nor have most studies included follow-up of patients to delineate the influence of the biopsy on clinical outcome. In this study, we evaluated prospectively the clinical usefulness of the allograft biopsy in renal transplant recipients receiving cyclosporine (CyA).nnnMETHODSnDuring a 21-month period, 82 biopsies were performed. In 54 instances (47 patients), we outlined a presumed diagnosis and tentative treatment plan before the procedure. After the biopsy, a definitive diagnosis was made and an appropriate patient management approach was instituted. We analyzed the incidence of change in patient management that resulted from histological findings. All patients were followed to monitor their response to treatment and allograft survival. In cases of biopsy-proven acute cellular rejection (ACR) or cyclosporine (CyA) toxicity, clinical and laboratory data from the day of the biopsy were reviewed to determine their diagnostic value.nnnRESULTSnOne biopsy specimen was inadequate for definitive interpretation. The biopsy findings resulted in a change in patient management in 22 (41.5%) of the remaining 53 cases (change group). The incidence of altered patient management was 38.7% in biopsy specimens taken in the first month, 55.6% between 1 and 12 months, and 38.5% after 1 year posttransplantation. A change in management was required in 2 of 2 patients with chronic allograft dysfunction, in 44.4% of the 45 patients with acute allograft dysfunction, and in none of the patients with delayed graft function (n=6). Within the first week of treatment 19 of 22 (86.4%) in the change group and 25 of 31 (80.6%) in the no change group had a positive response to therapy. The 1-year allograft survival rate was also similar between the two groups. None of the clinical and laboratory data was useful in distinguishing ACR from CyA toxicity.nnnCONCLUSIONSnRenal allograft biopsy findings alter patient management recommendations in approximately 40% of patients in whom a presumptive diagnosis had been made on the basis of clinical and laboratory findings. Patients who had a change in patient management because of biopsy findings demonstrated a response to therapy and allograft survival similar to those of patients who had no alteration in management plan after the biopsy.