Asha Moudgil

Efficacy and Safety of Treatment with Rituximab for Difficult Steroid-Resistant and -Dependent Nephrotic Syndrome: Multicentric Report

BACKGROUND AND OBJECTIVES The treatment of idiopathic nephrotic syndrome is often complicated by a refractory and relapsing course, with risk of drug toxicity and progressive renal failure. We report the efficacy and safety of rituximab in patients with steroid-resistant (SRNS) and steroid-dependent nephrotic syndrome (SDNS) refractory to standard therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cohort study in academic, tertiary care centers in India and the United States. Patients with SRNS or SDNS, not responding to medications or showing calcineurin inhibitor toxicity, treated with two to four doses of intravenous rituximab, and followed ≥12 months were included. Remission was termed as complete, partial, or no response. RESULTS Thirty-three patients with SRNS (24 initial, 9 late resistance) and 24 with SDNS, with mean ages of 12.7 ± 9.1 and 11.7 ± 2.9 years, respectively, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 ± 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 ± 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year. CONCLUSIONS Therapy with rituximab was safe and effective in inducing and maintaining remission in a significant proportion of patients with difficult SRNS and SDNS.

Parvovirus B19 infection-related complications in renal transplant recipients : Treatment with intravenous immunoglobulin

BACKGROUND Chronic red cell aplasia can develop in immunocompromised patients including transplant recipients infected with parvovirus B19 (PV B19). Renal involvement with PV B19 infection is not well-recognized. METHODS We diagnosed erythroid hypoplasia associated with PV B19 infection in three renal transplant recipients; one of them developed de novo collapsing glomerulopathy. These patients were treated with intravenous immunoglobulin (IVIG). RESULTS In two patients, anemia responded promptly to IVIG therapy. One of them had recurrence of anemia that responded to a second course of IVIG. Despite IVIG treatment, persistent infection with PV B19, recurrent anemia, and de novo collapsing glomerulopathy leading to allograft failure developed in the third patient, who had received the most intense immunosuppression. CONCLUSIONS These findings indicate that PV B19 infection in transplant recipients can cause chronic red cell aplasia that generally responds to IVIG therapy. In some patients, particularly those who are heavily immunosuppressed, infection may persist despite treatment. As the cellular receptor for PV B19 is expressed in the kidney, persistent infection may result in development of glomerulopathies in these patients.

Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions.

Clinicians are often faced with therapeutic dilemmas and challenges while treating children with frequently relapsing steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS). In the past, children with SDNS have been treated with long-term alternate day steroids cyclophosphamide, cyclosporine (CSA), chlorambucil, levamisole, and azathioprine. The essential aim of these therapies is to maintain remission while limiting exposure to steroids. These medications have variable efficacy and undesirable toxicity profiles. Recently, mycophenolate mofetil (MMF) has emerged as a new therapeutic option for the management of SDNS in a few uncontrolled clinical trials. Preliminary data are encouraging. MMF was found to be useful in maintaining remission and has a steroid-sparing effect. Clearly, more data are needed to further characterize the safety and efficacy of MMF, define adequate length of treatment, and optimize drug exposure and monitoring. The management of SRNS is primarily aimed at decreasing proteinuria and inducing remission, if possible. By doing so, one would aim to preserve renal function. CSA therapy is known to be useful in this regard but has undesirable side effects, the most concerning being nephrotoxicity. MMF in combination with steroids and angiotensin-converting enzyme-inhibitor drugs is known to have some efficacy in the management of SRNS. These preliminary data have prompted the National Institutes of Health to sponsor a multicentric controlled trial to compare the safety and efficacy of MMF with that of CSA in the treatment of steroid-resistant focal segmental glomerulosclerosis (FSGS). If MMF therapy is found to be efficacious, it would help obviate the need for CSA and its associated nephrotoxicity. Clearly, MMF has emerged as an important new therapeutic option for the treatment of childhood nephrotic syndrome and FSGS. Further data are required to assess those conditions most likely to respond.

Successful steroid-sparing treatment of renal limited sarcoidosis with mycophenolate mofetil

Sarcoidosis is a multi-system disorder characterized by non-caseating epithelioid granulomas in multiple organs. The disease usually presents in young adults and is uncommon in children. Renal involvement can usually occur due to granulomatous interstitial nephritis, but renal failure is uncommon. Corticosteroids are the mainstay of therapy. We present the report of a child with severe renal failure secondary to renal limited sarcoidosis who was successfully treated with corticosteroid induction therapy. Because of the severe side effects of corticosteroids, mycophenolate mofetil was added and corticosteroids were tapered off. The child has been in sustained remission for over a year with mycophenolate mofetil monotherapy.

Mutants of 11β-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity: Improved Correlations Between Genotype and Biochemical Phenotype in Apparent Mineralocorticoid Excess

Mutations in the kidney isozyme of human 11-hydroxysteroid dehydrogenase (11-HSD2) cause apparent mineralocorticoid excess, an autosomal recessive form of familial hypertension. We studied 4 patients with AME, identifying 4 novel and 3 previously reported mutations in the HSD11B2 (HSD11K) gene. Point mutations causing amino acid substitutions were introduced into a pCMV5/11HSD2 expression construct and expressed in mammalian CHOP cells. Mutations L179R and R208H abolished activity in whole cells. Mutants S180F, A237V, and A328V had 19%, 72%, and 25%, respectively, of the activity of the wild-type enzyme in whole cells when cortisol was used as the substrate and 80%, 140%, and 55%, respectively, of wild-type activity when corticosterone was used as the substrate. However, these mutant proteins were only 0.6% to 5.7% as active as the wild-type enzyme in cell lysates, suggesting that these mutations alter stability of the enzyme. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, demonstrated in whole cells, when cortisol was used as the substrate. These included the ratio of urinary cortisone to cortisol metabolites (R(2)=0.648, P<0.0001), age at presentation (R(2)=0.614, P<0.0001), and birth weight (R(2)=0.576, P=0.0004). Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1.

Co-infection of polyomavirus-BK and cytomegalovirus in renal transplant recipients.

Background. Polyomavirus-BK (BK) is a significant cause of allograft dysfunction in renal transplant recipients. Cytomegalovirus (CMV) and BK infection are thought to be possible risk factors for one another, but no supporting data are yet available. Methods. The authors monitored BK and CMV infection by quantitative polymerase chain reaction (PCR) in 69 renal transplant recipients with serum creatinine elevation to determine the prevalence of co-infection. In addition, 150 adult renal transplant recipients were also retrospectively analyzed for both infections. Results. Of 69 recipients, 12 were plasma BK-PCR–positive. Eight of the 12 showed high BK levels (>103 copies) and BK nephropathy. Six of the 12 were also CMV-PCR–positive compared with only 3 of 57 plasma BK-negative patients (50% vs. 5.3%, P=0.001). Comparatively, the incidence of Epstein-Barr virus infection was similar in both groups (1 of 12 [8.3%] vs. 2 of 57 [3.5%], P =not significant). In addition, retrospective analysis of CMV-PCR–positivity in 150 adult renal transplant recipients showed similar results (5 of 6 in BK-PCR–positive [83%] vs. 8 of 144 in BK-PCR–negative [5.6%], P=0.00001). More plasma BK-PCR–positive patients had concomitant CMV infection than CMV-PCR–positive patients with BK infection (5 of 6 [83%] vs. 4 of 13 [31%], P=0.05). Conclusions. In conclusion, high plasma BK-positivity (>103) is significantly associated with BK nephropathy. Plasma BK-positivity is highly associated with co-infection of CMV, suggesting possible risk factors for one another. Therefore, detection of either infection strongly suggests the need to monitor for the other. This strategy may lead to the prevention of virus-induced complications by preemptive antiviral therapy in renal allografts.

Treatment of Antineutrophil Cytoplasmic Autoantibody-Positive Systemic Vasculitis and Glomerulonephritis With Pooled Intravenous Gammaglobulin

Antineutrophil cytoplasmic autoantibody (ANCA) is considered a serological marker for disease activity in patients with ANCA(+) systemic vasculitis. Recently, ANCA has been implicated as a pathogenic antibody that may be associated with neutrophil degranulation and release of lytic enzymes. Since intravenous gammaglobulin (IVIG) is known to contain antiidiotypic antibodies to ANCA, which could decrease the activity of the later, we chose to treat two patients with symptomatic ANCA(+) systemic vasculitis and glomerulonephritis with high-dose IVIG. The first patient, a 66-year-old man, developed rapidly progressive renal failure despite treatment with intravenous (IV) cyclophosphamide. The second patient, a 14-year-old boy, had relapsed 3 months after cessation of treatment with prednisone and cyclophosphamide. Both patients improved dramatically after treatment with IVIG, with the former recovering renal function within 11 days of therapy. In both patients, a concomitant reduction in serum ANCA titers was also observed. The second patient is currently in a sustained remission 14 months after his last IVIG dose on no other medication. These cases provide clinical evidence that IVIG has therapeutic benefit in modifying the immune-mediated injury associated with ANCA(+) systemic vasculitis and glomerulonephritis. In addition, IVIG may provide an additional safe therapeutic option to clinicians treating patients with ANCA(+) vasculitis and glomerulonephritis who are not responsive to or are experiencing toxicity from conventional therapy.

Inhibition of allospecific responses in the mixed lymphocyte reaction by pooled human gamma-globulin

Transplantation has emerged as the treatment of choice for end-stage organ failure (e.g. kidney, heart, lung, liver). Despite increasingly sophisticated methods of tissue typing and improvements in immunosuppressive agents, allograft rejection continues to be a major cause of allograft failure. In addition, long-term use of potent immunosuppressive agents can result in significant morbidity for the recipient. Complications include increased risk of infection, nephrotoxicity, marrow toxicity and increased risk of developing malignancies. Clearly, it would be beneficial to have less toxic and more specific immunoregulatory agents that would promote tolerance of the allograft while allowing the immune system to function normally against invading pathogens and malignant cells. Intravenous immunoglobulin (IVIG) preparations contain polyspecific IgGs obtained from plasma pools of up to 20000 healthy blood donors) IVIG was initially designed for use in patients with primary and secondary humoral immune deficiencies; however, it was quickly realized that these preparations had therapeutic efficacy against several vasculitic disorders 2~ and autoimmune diseases) Recent studies suggest that IVIG also has the ability to modulate allospecific immune reactions and could possibly have allograft enhancing properties. 4~ Winston et al. 4 and Conti et al. 5 showed that bone marrow and kidney transplant recipients who received IVIG for cytomegalovirus prophylaxis had decreased incidence of graft-versus-host disease and allograft rejection, respectively. These authors suggested that IVIG might have other immunoregulatory effects independent of modification of cytomegalovirus infection and prevention of interstitial pneumonia. A role for specific antibody regulation of alloimmune responses is also suggested by previous investigations into the mechanism(s) of blood transfusion induced suppression of allospecific immune responses. Those studies w8

Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome.

Abstract Apparent mineralocorticoid excess (AME) syndrome is a rare inherited disorder caused by 11β- hydroxysteroid dehydrogenase (11-HSD 2) isozyme deficiency in the kidney. This enzyme is responsible for oxidizing cortisol to its inactive metabolite cortisone. An elevated tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF) to tetrahydrocortisone (THE) ratio in the urine is pathognomonic of AME syndrome. Clinical features include hypertension, hypokalemia, alkalosis, reduced plasma renin activity (PRA), low aldosterone levels, and occasionally nephrocalcinosis. Here we describe a 13-year-old boy who presented with severe hypertension, hypokalemia, low PRA and aldosterone levels, and elevated THF plus aTHF/THE ratio in the urine consistent with a diagnosis of AME syndrome. On ultrasound examination, he had severe nephrocalcinosis, and bilateral renal cysts. Renal cysts have not been previously reported in AME syndrome. The development of nephrocalcinosis and renal cysts may be associated with chron-ic long-standing hypokalemia. An early diagnosis and treatment of AME syndrome could help to prevent these sequelae, and to preserve renal function.

Ureteritis and cholecystitis: two unusual manifestations of cytomegalovirus disease in renal transplant recipients.

BACKGROUND Common clinical manifestations of cytomegalovirus (CMV) infection include flu-like symptoms with fever, diarrhea, leukopenia, and elevated liver enzymes. Diagnosis is made by detection of the virus by buffy-coat blood culture or by polymerase chain reaction (PCR) analysis. METHODS Here we describe two renal transplant recipients who presented with unusual manifestations of CMV disease (cholecystitis and ureteritis). In both patients, no symptoms or signs of systemic CMV infection were present, and they were thought to have other common causes for cholecystitis and ureteral obstruction. RESULTS Retrospective analysis of peripheral blood by PCR analysis was positive for CMV DNA. Histologic examination of the resected gall bladder and stenotic ureteric segment showed CMV inclusions, confirmed subsequently by in situ hybridization. Thus, we report that CMV infection may present with acute cholecystitis or ureteral obstruction without its classical clinical symptoms. CONCLUSIONS Because CMV infection is common in transplant patients, the atypical manifestations of CMV should be considered in the differential diagnosis of posttransplant complications. Detection of CMV DNA in the peripheral blood by PCR analysis may help identify these patients.