Zand, Ladan

Fibrillary GN (FGN) is a rare glomerular disease that is diagnosed based on the presence of fibrils in glomeruli. The fibrils are typically noncongophilic, randomly oriented, and measure 12–24 nm. Traditionally, electron microscopy (EM) has been an important tool to aid in the diagnosis of FGN by identifying the fibrils and to distinguish it from other entities that could mimic FGN. However, recently DnaJ homolog subfamily B member 9 (DNAJB9) has emerged as both a specific and sensitive biomarker in patients with FGN. It allows prompt diagnosis and alleviates reliance on EM. DNAJB9 is a cochaperone of heat shock protein 70 and is involved in endoplasmic reticulum protein-folding pathways. But its role in the pathogenesis of FGN remains elusive. DNAJB9 may act as a putative antigen or alternatively it may secondarily bind to misfolded IgG in the glomeruli. These hypotheses need future studies to elucidate the role of DNAJB9 in the pathogenesis of FGN. The treatment regimen for FGN has been limited due to paucity of studies. Most patients receive combination immunosuppressive regimens. Rituximab has been studied the most in FGN and it may delay disease progression. Prognosis of FGN remains poor and 50% require dialysis within 2 years of diagnosis. Despite its poor prognosis in native kidneys, the rate of recurrence post-transplantation is low (20%) and patient as well as allograft outcomes are similar to patients without FGN.

Abstract Background Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking. Methods Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment). Results Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2–100) months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5–112) months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9–355) months, no patients developed end-stage renal disease. Conclusions Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs.

Abstract Background Fibrillary glomerulonephritis (FGN) is a rare type of glomerulonephritis with poor prognosis, with no known effective therapies available for treatment. The objective of the study was to evaluate the efficacy and safety of rituximab in treatment of patients with FGN and to investigate the effect of rituximab on DNAJB9 levels. Methods This was a pilot prospective clinical trial in which patients with idiopathic FGN were treated with two courses of rituximab (1 g each) 2 weeks apart at the beginning and then again at 6 months. Primary outcome was defined as preservation of kidney function at 12 months with stable or increased creatinine clearance. Secondary outcome was defined as achieving complete remission (CR) defined as proteinuria <300 mg/24 h or partial remission (PR) with proteinuria <3 g/24 h and at least 50% reduction in the proteinuria. DNAJB9 levels were also measured in the serum at baseline, 6 and 12 months. Results The creatinine clearance did not change significantly during this time, from 47.7 mL/min/1.73 m2 at baseline to 43.7 mL/min/1.73 m2 during follow-up (P = 0.15). Proteinuria declined from 4.43 (1.6–5.53) g/24 h at baseline to 1.9 (0.46–5.26) g/24 h at 12 months but did not reach significance (P = 0.06). None of the patients reached CR, and 3 of the 11 achieved PR. There was no change in the DNAJB9 levels following treatment with rituximab. The most common adverse event was nasal congestion, fatigue and muscle cramps. Conclusions Treatment of patients with two courses of rituximab over a span of 6 months was associated with stabilization of renal function but did not result in a significant change in proteinuria and with no change in the DNAJB9 levels.

Abstract Background Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores. Methods In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf). Results Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P < 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of −0.81 mL/min/1.73 m2 [95% confidence interval (CI) −1.44 to −0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (−3.99 mL/min/1.73 m2; 95% CI −6.9411 to −1.0552, P = 0.008), after similar adjustments. Conclusion Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed.

Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic ( n =49) and normotensive ( n =42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α 1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin + EVs-to-nephrin + EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin + EVs-to-nephrin + EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin + EVs-to-nephrin + EVs ratio and may be mediated by prolonged exposure to cellfree HbF.

Recent reports suggest that deep hematologic responses to chemotherapy are associated with improved renal outcomes in monoclonal immunoglobulin deposition disease (MIDD). Here we describe the long term outcomes and identify prognostic factors after first line treatment of the largest reported series of patients with MIDD. Between March 1992 and December 2014, 88 patients with MIDD were seen at Mayo Clinic, MN. Renal responses were defined using criteria used for light chain amyloidosis (AL) or those used by the IMWG. Sixty‐one (69%) patients had a GFR < 30 mL/min/1.73 m2 and 16 (18%) were on renal replacement therapy at diagnosis. The interval between albuminuria or elevation in creatinine and MIDD diagnosis was 12 months suggesting a delay in diagnosis. Thirty‐seven patients (42%) had at least a hematologic CR/VGPR. Fifty‐three (60%) received an autologous stem cell transplant (ASCT) or proteasome inhibitor (PI)‐based treatments. Patients receiving ASCT or PI‐based therapies were more likely to achieve at least a hematologic CR/VGPR compared to those receiving other therapies: 66% vs 2%, p < 0.0001. Patients that achieved a hematologic CR were more likely to achieve a renal response (53% vs 24%, p = 0.001). Five year overall and renal survival for the entire cohort was 67% and 57%, respectively. In multivariate analyses, a baseline GFR < 20 mL/min/1.73 m2 and a renal response (using AL or IMWG criteria) were independently predictive of progression to dialysis. This study confirms that deep hematologic responses, best achieved with ASCT or PI‐based therapies, are a prerequisite to achieving renal responses. Am. J. Hematol. 91:1123–1128, 2016. © 2016 Wiley Periodicals, Inc.

ABSTRACT Background: An increased number of podocyte-derived extracellular vesicles (pEVs) may reflect podocyte injury in renal disease. Elevated glomerular pressure and other insults may injure podocytes, yet it remains unclear whether the numbers of pEVs are altered in hypertensive patients. We tested the hypothesis that urinary pEV levels would be elevated in patients with renovascular hypertension (RVH) compared with essential hypertension (EH) or healthy volunteers (HVs). Methods: We prospectively enrolled patients with EH (n = 30) or RVH (n = 31) to study renal blood flow (RBF) and cortical perfusion using multidetector computed tomography under controlled condition (regulated sodium intake and renin—angiotensin blockade). After isolation from urine samples, pEVs (nephrin and podocalyxin positive) were characterized by flow cytometry. Fourteen RVH patients were studied again 3 months after stenting or continued medical therapy. HVs (n = 15) served as controls. Results: The fraction of pEV among urinary EVs was elevated in RVH compared with HVs and EH (11.4 ± 6.4, 6.8 ± 3.4 and 6.3 ± 3.7%, respectively; P &lt; 0.001) and remained unchanged after 3 additional months of therapy and after controlling for clinical parameters. However, eGFR- and age-adjusted pEV levels did not correlate with any clinical or renal parameters. Conclusions: In hypertensive patients under controlled conditions, urinary pEV levels are elevated in patients with RVH and low eGFR compared with patients with EH and relatively preserved renal function. These pEVs may reflect podocyte injury secondary to kidney damage, and their levels might represent a novel therapeutic target.

AbstractSecondary hyperparathyroidism almost universally accompanies end‐stage renal disease (ESRD). In some, but not all studies, elevated serum parathyroid hormone (PTH) concentrations are associated with increased fracture rates, cardiovascular disease, and mortality in ESRD. The serum concentration of PTH required for optimal bone health and reduced cardiovascular risk in such patients remains elusive. Recent clinical trials have failed to show substantial changes in morbidity and mortality following reductions of elevated serum PTH concentrations. In this review, we will assess some of the difficulties in evaluating elevated serum PTH concentrations, and their association with skeletal fractures and mortality in ESRD patients. We are of the opinion that in the context of ESRD, elevated PTH concentrations occur in conjunction with other comorbid conditions such as diabetes mellitus, malnutrition, hypertension, volume excess, preexisting heart disease, all of which have prevented establishing a precise association between elevated serum PTH concentrations and global or skeletal outcomes. Age, gender, and racial variability among groups make interpretation exceptionally difficult. Analysis of prevalent ESRD populations with secondary hyperparathyroidism should take all these factors into account. We suggest that future clinical trials which examine the usefulness of reductions in serum PTH concentrations be conducted in age, sex, and racially balanced groups, without or with minimal coexisting confounding disease. Furthermore, trials in such populations should have as their primary outcome a reduction in fractures rather than an alteration in mortality.

Acute interstitial nephritis (AIN) is an important and common cause of acute kidney injury, particularly in hospitalized patients. The classic presentation of AIN includes fever, rash, arthralgias, eosinophilia, and acute kidney injury. While renal biopsy is considered the gold standard for diagnosis, the clinical presentation of fever and rash along with laboratory evidence of peripheral blood eosinophilia, eosinophiluria, and low-grade proteinuria strongly suggest the diagnosis. Histologically, interstitial inflammation with interstitial edema and tubulitis is the hallmark of interstitial nephritis. The most common causative factors are drugs, infections, and certain immune-mediated disorders. Discontinuation of the offending agent is considered the mainstay of therapy while the use of corticosteroids to hasten renal recovery may be beneficial. The role of interstitial nephritis in the pathogenesis of chronic kidney disease and end-stage renal disease is increasingly recognized, further emphasizing the importance of its early diagnosis and timely treatment.