BACKGROUND:

We report a 7-year-old boy with high-degree steroid-dependent idiopathic nephrotic syndrome (SDNS) who went into remission with rituximab (RTX) maintenance therapy. CASE-DIAGNOSIS/TREATMENT: Four months after this patient received his first RTX infusion, there was a progressive and sustained decrease of immunoglobulin (Ig)G and IgM levels. Thirteen months after the initiation of RTX therapy he was in sustained remission without any steroid or oral immunosuppressive therapy; however, B cell depletion was still present. At this time he developed a fulminant myocarditis due to enterovirus. Despite aggressive treatment and the administration of intravenous polyvalent immunoglobulins there was no clinical improvement. He successfully underwent heart transplant surgery.

CONCLUSIONS:

We conclude that B cell depletion with RTX is efficacious in the treatment of paediatric SDNS but that it may be associated with severe infectious complications. Therefore, we recommend a close monitoring of Ig levels in children who have received RTX therapy and a supplementation with intravenous Ig as soon as the Ig levels fall below the lower limit of the normal range.

SESSION TYPE: Pleural Cases IIPRESENTED ON: Wednesday, October 24, 2012 at 11:15 AM - 12:30 PM

INTRODUCTION:

Chronic graft-versus-host disease (cGVHD) is a well-known complication following allogeneic hematopoietic stem cell transplantation (HSCT) that varies in time of onset, clinical course and organ involvement. The most commonly effected organ systems are the skin, mucous membranes, liver and eyes. We report a rare case of polyserositis secondary to cGVHD presenting with dyspnea on exertion, pericardial effusion and large bilateral pleural effusions that resolved following the institution of systemic steroids.

CASE PRESENTATION:

A 30-year-old male with pre-B-cell acute lymphoblastic leukemia, status post allogeneic HSCT who had been doing well until 6 months after transplant when he developed an erythematous rash. Shortly thereafter, the patient presented with increasing dyspnea on exertion and peripheral edema, unresponsive to diuretic therapy. Computed tomography of the chest revealed large bilateral pleural effusions without parenchymal abnormalities, and a significant pericardial effusion. Transthoracic echocardiogram confirmed the pericardial effusion and noted mild hemodynamic compromise with preserved ejection fraction. The patient underwent thoracentesis, consistent with transudative effusion. Pleural fluid contained 48% lymphocytes and cytology was consistent with reactive T lymphocytes without evidence of malignancy by cytology and immunostaining. Viral infection and nephrotic syndrome were excluded as other etiologies of serositis. The patient was started on prednisone with gradual, almost complete resolution of pleural and pericaridal effusions.

DISCUSSION:

Chronic GVHD is one of the most common problems affecting patients surviving allogeneic HSCT. It is the leading cause of non-relapse mortality in patients surviving more than 2 years after allogeneic HSCT. cGVHD can also impact functional status and quality of life. Development of serositis as a clinical manifestation of cGVHD has been reported but not well described. The pleural fluid is typically transudative as in this case. Pericardial involvement has been reported; however only one retrospective study has been done which showed the incidence of large pericardial effusion to be less than 1%.

CONCLUSIONS:

Polyserositis as a complication of cGVHD should be considered in patients post-HSCT presenting with dyspnea on exertion. Presence of pleural effusions should prompt an evaluation for other locations of serositis particularly pericardial effusions which may be massive and result in hemodynamic compromise. Early recognition and treatment with immunosuppressive therapy may prevent further morbidity and mortality.1) Lee, SJ et al. 2003; Chronic Graft-versus-Host Disease. Biology of Blood and Marrow Transplantation 9: 215-233.2) Norkin, M et al. 2011; Large pericardial effusion as a complication in adults undergoing SCT. Bone Marrow Transplantation 46: 1353-1356DISCLOSURE: The following authors have nothing to disclose: Jessica Boehmler, Kristin Miller, Harold ChungNo Product/Research Disclosure InformationVirginia Commonwealth University, Richmond, VA.

BACKGROUND:

Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes and the increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes.

METHODS:

Sera and peripheral blood mononuclear cells (PBMCs) were collected from subjects with MCD in relapse and remission and from normal controls. Immortalized human podocytes were incubated with culture media containing patient sera or supernatants from patient and control PBMC cultures. CD80 expression was measured by quantitative PCR and western blot analysis.

RESULTS:

Sera collected from patients with MCD in relapse, but not in remission, significantly increased CD80 expression (mean ± standard deviation: 1.8 ± 0.7 vs. 0.8 ± 0.2; p < 0.004) and CD80 protein secretion by podocytes (p < 0.05 between relapse and normal controls). No such CD80 increase was observed when podocytes were incubated with supernatants of PBMC cultures from patients in relapse.

CONCLUSIONS:

Sera from MCD patients in relapse, but not in remission, stimulated CD80 expression in cultured podocytes. Identifying this factor in sera could provide insights into the pathogenesis of this disorder. No role in CD80 expression by podocytes was found for cytokines released by PBMCs.

In recent years, significant advances have been made in understanding the pathogenesis and etiology of membranoproliferative glomerulonephritis (MPGN). A new classification system based on pathological immunofluorescence findings has been proposed to replace the traditional clinical classification system in order to better identify the underlying causes of MPGN and to provide guidance for more individualized treatment. We conducted a retrospective survey of the MPGN patients treated in our hospital from 2000 to 2012 and report here the validation of this new classification system in this cohort. A total of 34 patients were diagnosed with MPGN, including 25 males and 9 females. There were 3 cases of secondary MPGN, including 1 case due to monoclonal gammopathy of undetermined significance (MGUS) and 2 cases related to hepatitis B virus (HBV) infection. Clinical presentations included nephrotic syndrome (76.5%), microscopic hematuria (79.4%), hypocomplementemia (58.8%), renal insufficiency (82.4%), hypertension (100%), and peripheral edema (100%). All patients were treated with prednisone and immunosuppressive agents, mainly cyclophosphamide. During follow-up (median 6 months, range 3-47 months), 4 patients were lost to follow-up and 2 patients progressed to end-stage renal disease. In Western countries the main cause of secondary MPGN was hepatitis C virus or HBV infection, here however we report 2 cases related to HBV infection. MGUS-associated MPGN was less frequent in the Chinese cohort. Future studies should be designed to evaluate the association of the new classification system and clinical outcomes of MPGN.

Although idiopathic membranous nephropathy (IMN) is the most common cause of adult-onset nephrotic syndrome, the management of IMN remains controversial. The aim of this prospective study was to compare the efficacy and drug safety of tacrolimus with that of cyclophosphamide (CTX; control group) in IMN patients receiving corticosteroid therapy. A total of 100 IMN patients with nephrotic syndrome were randomly assigned to receive a combination of corticosteroid therapy and either CTX or tacrolimus. During a follow-up period of at least 18 months, the remission rate after 2 months in the tacrolimus group was 65.1%, which was higher than that of the CTX group (44.2%) (p = 0.02). The mean time to partial or complete remission was 2.20 months in the tacrolimus group and 3.92 months in the CTX group (p < 0.001). We also found significantly greater improvements in the serum albumin levels in the tacrolimus group compared with the CTX group at the 2-month (p = 0.003) and 3-month time points (p = 0.01). The serum creatinine levels remained stable in both groups. Although remission was quicker and more common in the tacrolimus group (compared with the CTX group) before 3 months, there was no superiority of tacrolimus after 6 months. Glucose intolerance, urinary tract infections, and pneumonia were the major side effects observed in this study. All of the side effects were mild and controlled, and there were fewer side effects in the tacrolimus group compared with the CTX group, indicating a better treatment tolerance in the tacrolimus group.

Short-term complications of membranous nephropathy (MN) are important components of the process and their proper management can significantly alter the outcomes of patients with this disease. These complications vary from the non-specific ones associated with many types of chronic kidney disease such as hypertension, proteinuria and the symptoms associated with the nephrotic syndrome including edema and dyslipidemia. These are briefly discussed in the chapter. In addition, there are some specific issues more commonly associated with MN than other types of glomerulonephritis. This includes a hypercoagulable state and the associated thromboembolism. There is more recent information in this domain and this is included in the chapter. The associated increased risk of infection in MN patients is the final chapter component. This section is included to remind us not only of the direct impact of that disease process on reducing resistance to infection, but also to indicate the need to consider prophylactic antibiotics when the addition of potent immunosuppressive drug treatment is required for these patients.

Primary nephrotic syndrome (PNS) is the most common glomerular disease seen in children. The pathogenic basis of PNS, in context of witnessed immunological dysfunction and its relationship with slit diaphragm and the podocyte cytoskeleton, has been explored for years. The outcome and management of PNS in children is determined by the response to corticosteroids and the frequency of relapses. The first episode of nephrotic syndrome should be treated adequately, both in terms of dose and duration of steroids, aiming at reducing the risk for subsequent relapses. While patients with steroid-sensitive nephrotic syndrome have a favorable long-term outcome, almost half of them relapse frequently and are at risk of adverse effects of steroids. Immunosuppressive agents are suggested for patients with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome. Calcineurin inhibitors are strongly recommended for patients who show resistance to steroids. Rituximab is a new therapy that could be a potential area but still requires further trials. The aim of therapy is to induce and maintain remission of proteinuria while avoiding medication-related adverse effects.

This study aimed to analyze the treatment, clinical outcomes, and risk factors that affect the prognosis of patients with primary focal segmental glomerulosclerosis (FSGS) and to provide theoretical evidence for various treatment options in these patients. The study reviewed the clinical, laboratory, and pathological data of 168 patients with primary FSGS treated at Ruijin Hospital between January 2002 and October 2011. Of these patients, 108 were male (64.3%) and 60 were female (35.7%). The median age of disease onset was 38 years (range 12-78 years). The median case history was 10 months (range 4 days to 30 years). The mean proteinuria level was 2.3 ± 0.6 g/day. 75 (44.6%) patients had nephrotic syndrome. The mean serum creatinine was 108.1 ± 8.9 μmol/l. Over a follow-up period of 25.3 ± 11.4 months, end-stage renal failure occurred in 4 patients, and all 4 survived. In the group treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, the following factors were identified as risk factors for experiencing a 50% increase in serum creatinine over the baseline: a baseline eGFR <60 ml/min, proteinuria >1 g/day during the follow-up period, glomerular sclerosis >grade 1, and tubulointerstitial lesions >stage 1. In the group treated with steroids, patients who achieved a stable remission had better preserved renal function and milder glomerular sclerosis than steroid-dependent patients (p < 0.01). Steroid-resistant FSGS patients had a worse histological severity of glomerular sclerosis than steroid-dependent patients (p < 0.01). The prognosis of FSGS was correlated with the amount of proteinuria, the level of serum creatinine, and the severity of glomerular sclerosis and tubulointerstitial lesions. Steroids may be more effective in those who have better preserved renal function and milder glomerular sclerosis.

Objective:

Focal segmental glomerular sclerosis (FSGS) is one of the most important causes of end-stage renal disease (ESRD). The pathogenesis, clinical manifestation, pathological changes and treatment of FSGS differ in patients with and without a family history of the disease. Few studies have compared familial FSGS (FFSGS) and sporadic FSGS (SFSGS). The aim of this study was to assess the clinical and pathological features and the prognosis of FSGS in patients with and without a family history of the disease.

Methods:

We enrolled 124 FFSGS patients and 124 age- and sex-matched SFSGS patients in the study. All patients underwent a renal biopsy to determine FSGS. The mean follow-up time was 28.3 ± 12.5 months for the FFSGS group and 26.5 ± 19.5 months for the SFSGS group (p > 0.05). Baseline clinical characteristics were recorded for all participants. The primary outcomes of the study were ESRD and remission of proteinuria (defined as a 50% reduction of the baseline urine protein level). The pathological changes were assessed by focal/global glomerulosclerosis and the tubulointerstitial lesion score.

Results:

There were no age or gender differences between the two groups. A total of 43.75% of the FFSGS patients and 35.16% of the SFSGS patients had high blood pressure, but the difference was not statistically significant (p = 0.079). In addition, patients in the FFSGS group had a lower urine protein excretion rate (1.4 ± 1.4 vs. 2.0 ± 1.8 g/24 h) and a higher serum albumin value (3.6 ± 6.2 vs. 3.0 ± 1.1 g/dl) than patients in the SFSGS group (p < 0.01). A total of 62.9% of the FFSGS patients and 22.9% of the SFSGS patients had hematuria, and the difference was statistically significant (p = 0.0001). Nephrotic syndrome occurred less frequently in the FFSGS group than in the SFSGS group (13.3 vs. 22.6%, p = 0.003). The baseline serum creatinine, uric acid and eGFR values were similar in the two groups. When pathological changes were examined, the FFSGS patients showed more severe global glomerulosclerosis and tubular interstitial injury than the SFSGS patients. During the follow-up period, the FFSGS group had a lower proteinuria remission rate (23.08 vs. 48.39%, p = 0.006) and a lower median renal survival time (96 vs. 72 months, p = 0.04) than the SFSGS group.

Conclusions:

Compared to SFSGS patients, FFSGS patients displayed distinct clinicopathological features that were associated with less response to treatment and worse renal outcomes.

Various drugs have been used for the treatment of focal segmental glomerular sclerosis (FSGS) or minimal change disease (idiopathic nephrotic syndrome, INS) including methylprednisolone pulses, alkylating agents and calcineurin inhibitors, often without a strong rationale. For some drugs the rationale has been recently provided by the identification of mechanisms regulating proteinuria. The characterization of molecules acting as permeability factors, including hemopexin, soluble urokinase receptor and cardiotrophin-like cytokine-1, supports plasma exchange in severe cases of INS, particularly in patients at high risk of recurrence of FSGS after transplantation. The collaboration of B and T cells for the production of permeability factors has provided a rationale for targeting B cells using rituximab. Several studies in children and adults, mostly in steroid-dependent cases, or after recurrence in grafted kidneys, have reported improved outcomes after rituximab. Podocyte actin cytoskeleton is a new target for therapy. Calcineurin inhibitors block the dephosphorylation of the cytoskeleton component synaptopodin, and steroids increase actin polymerization and stability. High doses of methylprednisolone and cyclosporine proved to be beneficial in patients with a high risk of FSGS recurrence. An interesting new target for blunting the INS pathogenetical mechanisms is the transcription factor nuclear factor-κB (NF-κB) which was reported to be activated in circulating mononuclear cells of these patients. NF-κB is regulated by the proteasome and saquinavir, a HIV protease inhibitor, is provided with antiproteasome activity. Using saquinavir associated with small doses of calcineurin inhibitors, we treated a small series of very difficult cases of INS with insufficient response to steroid therapy and multiple immunosuppressive drugs. Saquinavir allowed a significant reduction of steroid cumulative doses and disappearance of features of steroid toxicity. In conclusion, recent reports have allowed a new insight into the pathogenetical mechanism regulating proteinuria in INS, offering new targets for treating severe cases.