Bortezomib for Reduction of Proteinuria in IgA Nephropathy.

INTRODUCTION: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria. METHODS: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m2 of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day. RESULTS: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease. CONCLUSION: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.

Minimal change disease: an unusual presentation of marginal zone MALT lymphoma.

Minimal change disease (MCD) in association with low-grade extra-nodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) (MALT lymphoma) is a rare clinicopathologic entity. We report a 68-year-old male who presented with nephrotic range proteinuria as the first manifestation of underlying MZL, confirmed with standard set of investigations. Being a steroid non-responder, he was treated with rituximab demonstrating a marked response with resolution of proteinuria. However, he relapsed after 3 months. Upon relapse, a combination of rituximab and bendamustine (R-Benda) was initiated achieving sustained resolution of proteinuria. No additional treatment was administered and the proteinuria has remained in remission for over a year.

Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy.

BACKGROUND: Diabetes is the leading cause of end stage renal disease (ESRD) in the United States, representing 44% of incident cases [1]. In this study, serum and peripheral blood collected from diabetic patients in five stages of chronic kidney disease (CKD), as defined by glomerular filtration rate (GFR), were compared to healthy (non-CKD) subjects. METHODS: Serum samples were analyzed for 39 inflammatory or immune mediator protein levels and peripheral blood samples were analyzed for expression of 35 gene transcripts. RESULTS: In serum, MCP-1, FGF-2, VEGF, and EGF levels were elevated above controls at all stages of DN. Five mediator levels, GM-CSF, IL-1α, IL-1RA, IL-6, and MIP1ß increased with disease progression until stage 4-5, at which point a decrease was observed paralleling a loss of functional renal mass that occurs in late stage CKD. Five mediator levels: GRO, IFNγ, MDC, Eotaxin, and G-CSF significantly differed from controls at one or more stages without apparent correlation with disease stage. Only a single mediator, sIL2RA, exhibited a linear increase with disease severity consistent with declining GFR. In peripheral blood, the transcript level of seven mediators, ICAM1, TNF-α, TGF-ß, IL-8, IL17RA, IFNγ, and MYD88 were significantly elevated at all disease stages as compared to control. CONCLUSION: Statistically significant differences in protein and transcripts levels between diseased and control can be detected in serum and peripheral blood utilizing high content profiling. These changes occur as early as stage 1-2 before a significant decline in renal function.

Prevention of recurrent episodes of rhabdomyolysis with tacrolimus in a transplant recipient with myopathy.

Genetic muscular disorders are known risk factors for rhabdomyolysis, which may result in acute kidney injury. Recurrent episodes of acute kidney injury can lead to chronic kidney disease and eventually end-stage renal failure. We describe a patient with chronic kidney disease that developed in the setting of recurrent rhabdomyolysis, resulting in the requirement for renal transplantation. After transplantation, the maintenance of tacrolimus trough concentrations above what is typically prescribed for standard renal transplant recipients appeared to confer protection from further episodes of rhabdomyolysis. This is consistent with previous case series that demonstrated a therapeutic benefit of the calcineurin inhibitor cyclosporine in collagen VI myopathies in the nontransplant population. This case report suggests the potential application of higher tacrolimus targets in patients who have undergone renal transplantation in the setting of recurrent rhabdomyolysis leading to end-stage renal failure.

Clinically significant proteinuria following the administration of sirolimus to renal transplant recipients.

BACKGROUND: Sirolimus is the latest immunosuppressive agent used to prevent rejection, and may have less nephrotoxicity than calcineurin inhibitor (CNI)-based regimens. To date there has been little documentation of clinically significant proteinuria linked with the use of sirolimus. We have encountered several patients who developed substantial proteinuria associated with sirolimus use. In each patient, the close temporal association between the commencement of sirolimus therapy and proteinuria implicated sirolimus as the most likely etiology of the proteinuria. METHODS: We analyzed the clinical and laboratory information available for all 119 patients transplanted at the Washington Hospital Center between 1999-2003 for whom sirolimus was a component of their immunosuppressant regimen. In these patients, the magnitude of proteinuria was assessed on morning urine samples by turbidometric measurement or random urine protein:creatinine ratios, an estimate of grams of proteinuria/day. Laboratory results were compared between prior, during and following sirolimus use. RESULTS: Twenty-eight patients (24%) developed increased proteinuria from baseline during their post-transplantation course. In 21 patients an alternative cause of proteinuria was either obvious or insufficient data was available to be conclusive. In 7 of the 28 patients there was a striking temporal association between the initiation of sirolimus and the development of nephrotic-range proteinuria. Proteinuria correlated most strongly with sirolimus therapy when compared to other demographic and clinical variables. In most patients, discontinuation of sirolimus resulted in a decrease, but not resolution, of proteinuria. CONCLUSIONS: Sirolimus induces or aggravates pre-existing proteinuria in an unpredictable subset of renal allograft recipients. Proteinuria may improve, but does not resolve, when sirolimus is withdrawn.