Meryl Waldman

Adult Minimal-Change Disease: Clinical Characteristics, Treatment, and Outcomes

Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and alternate-day-treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis

Glomerulonephritis (GN) is an important cause of morbidity and mortality in patients of all ages throughout the world. Because these disorders are relatively rare, it is difficult to perform randomized clinical trials to define optimal treatment for many of the specific glomerulopathies. In the absence of high-grade evidence to guide the care of glomerular diseases, in June 2012, KDIGO (Kidney Disease: Improving Global Outcomes) published an international clinical guideline for GN. The Work Group report represents an important review of the literature in this area and offers valid and useful guidelines for the most common situations that arise in the management of patients with glomerular disease. This commentary, developed by a panel of clinical experts convened by the National Kidney Foundation, attempts to put the GN guideline into the context of the US health care system. Overall, we support the vast majority of the recommendations and highlight select areas in which epidemiological factors and medical practice patterns in this country justify modifications and adjustments in order to achieve favorable outcomes. There remain large gaps in our knowledge of the best approaches to treat glomerular disease and we strongly endorse an expanded clinical research effort to improve the health and long-term outcomes of children and adults with GN.

Parvovirus B19 and the Kidney

Infection with parvovirus B19 causes several clinical syndromes (fifth disease, transient aplastic crisis, pure red cell aplasia, and hydrops fetalis) and may contribute to other illnesses. B19 has been linked to renal disease in three settings: As a cause of acute glomerulopathy and as a cause of anemia in ESRD and kidney transplantation. Case reports implicate parvovirus in the pathogenesis of proliferative glomerulonephritis and collapsing glomerulopathy, but a causal relationship has not been established. A proposed role for B19 infection is based on the temporal association of renal findings with viral infection, positive serology, and identification of the viral genome in the glomerulus. Mechanisms may include cytopathic effects on glomerular epithelial cells and/or endothelial cells and glomerular deposition of immune complexes. Patients who require dialysis may have increased susceptibility to acute and chronic anemia after parvoviral infection. Factors that predispose this population to complications of B19 infection include impaired immune response, deficient erythropoietin production, and possibly decreased erythrocyte survival. The clinical burden of parvovirus B19 infection in renal transplant recipients may be underestimated; these individuals may develop persistent viremia as a result of a dysfunctional immune response. Chronic anemia and pure red blood cell aplasia are the most common complications of parvovirus infection in this population; the diagnosis should be considered in transplant recipients with unexplained anemia or pancytopenia. Allograft rejection and dysfunction have been reported in association with infection, but a cause-effect relationship has not been proved. Further investigation of the relationship between B19 and kidney disease is warranted.

Identification of the Immunodominant Epitope Region in Phospholipase A2 Receptor-Mediating Autoantibody Binding in Idiopathic Membranous Nephropathy

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Recent clinical studies established that >70% of patients with idiopathic (also called primary) MN (IMN) possess circulating autoantibodies targeting the M-type phospholipase A2 receptor-1 (PLA2R) on the surface of glomerular visceral epithelial cells (podocytes). In situ, these autoantibodies trigger the formation of immune complexes, which are hypothesized to cause enhanced glomerular permeability to plasma proteins. Indeed, the level of autoantibody in circulation correlates with the severity of proteinuria in patients. The autoantibody only recognizes the nonreduced form of PLA2R, suggesting that disulfide bonds determine the antigenic epitope conformation. Here, we identified the immunodominant epitope region in PLA2R by probing isolated truncated PLA2R extracellular domains with sera from patients with IMN that contain anti-PLA2R autoantibodies. Patient sera specifically recognized a protein complex consisting of the cysteine-rich (CysR), fibronectin-like type II (FnII), and C-type lectin-like domain 1 (CTLD1) domains of PLA2R only under nonreducing conditions. Moreover, absence of either the CysR or CTLD1 domain prevented autoantibody recognition of the remaining domains. Additional analysis suggested that this three-domain complex contains at least one disulfide bond required for conformational configuration and autoantibody binding. Notably, the three-domain complex completely blocked the reactivity of autoantibodies from patient sera with the full-length PLA2R, and the reactivity of patient sera with the three-domain complex on immunoblots equaled the reactivity with full-length PLA2R. These results indicate that the immunodominant epitope in PLA2R is exclusively located in the CysR-FnII-CTLD1 region.

Treatment of Idiopathic Membranous Nephropathy

Exciting progress recently has been made in our understanding of idiopathic membranous nephropathy, as well as treatment of this disease. Here, we review important advances regarding the pathogenesis of membranous nephropathy. We will also review the current approach to treatment and its limitations and will highlight new therapies that are currently being explored for this disease including Rituximab, mycophenolate mofetil, and adrenocorticotropic hormone, with an emphasis on results of the most recent clinical trials.

Parvovirus-B19-associated complications in renal transplant recipients

Parvovirus B19 is a common human pathogen, causing erythema infectiosum in children, hydrops fetalis in pregnant women, and transient aplastic crisis in patients with chronic hemolytic anemia. Immunosuppressed patients can fail to mount an effective immune response to B19, resulting in prolonged or persistent viremia. Renal transplant recipients can develop symptomatic B19 infections as a result of primary infection acquired via the usual respiratory route or via the transplanted organ, or because of reactivation of latent or persistent viral infection. The most common manifestations of B19 infection in immunosuppressed patients are pure red cell aplasia and other cytopenias. Thus, this diagnosis should be considered in transplant recipients with unexplained anemia and reticulocytopenia or pancytopenia. Collapsing glomerulopathy and thrombotic microangiopathy have been reported in association with B19 infection in renal transplant recipients, but a causal relationship has not been definitively established. Prompt diagnosis of B19 infection in the renal transplant recipient requires a high index of suspicion and careful selection of diagnostic tests, which include serologies and polymerase chain reaction. Most patients benefit from intravenous immunoglobulin therapy and/or alteration or reduction of immunosuppressive therapy. Conservative therapy might be sufficient in some cases.

Controversies in the treatment of idiopathic membranous nephropathy

Optimum treatment of idiopathic membranous nephropathy is both controversial and challenging. The most extensively studied and frequently used immunosuppressive regimens for this disease comprise alkylating agents plus corticosteroids or ciclosporin. All of these treatment options have inherent problems: they are not effective in all patients, partial—rather than complete—remissions are common, adverse effects are worrisome, and relapses after treatment cessation remain problematic. Alternative immunosuppressive agents have been tested in an effort to overcome these unresolved issues. This paper reviews the available evidence regarding both established and new agents for the treatment of patients with idiopathic membranous nephropathy, with an emphasis on the results of the most recent clinical trials.

Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses

Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B-cell tolerance in 3H9 anti-DNA transgenic mice.

Viruses and Kidney Disease: Beyond HIV

SUMMARY Human immunodeficiency virus (HIV)-infected patients may acquire new viral co-infections; they also may experience the reactivation or worsening of existing viral infections, including active, smoldering, or latent infections. HIV-infected patients may be predisposed to these viral infections owing to immunodeficiency or risk factors common to HIV and other viruses. A number of these affect the kidney, either by direct infection or by deposition of immune complexes. In this review we discuss the renal manifestations and treatment of hepatitis C virus, BK virus, adenovirus, cytomegalovirus, and parvovirus B19 in patients with HIV disease. We also discuss an approach to the identification of new viral renal pathogens, using a viral gene chip to identify viral DNA or RNA.

Thrombotic Microangiopathy In Metastatic Melanoma Patients Treated with Adoptive Cell Therapy and Total Body Irradiation

Thrombotic microangiopathy (TMA) is a complication that developed in some patients receiving 12 Gy total body irradiation (TBI) in addition to lymphodepleting preparative chemotherapy prior to infusion of autologous tumor‐infiltrating lymphocytes (TIL) with high‐dose aldesleukin (IL‐2). This article describes the incidence, presentation, and course of radiation‐associated TMA.