Zand, Ladan

Objective There is a paucity of population‐based studies investigating the epidemiology of lupus nephritis (LN) in the US and long‐term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well‐defined 8‐county region in the US. Methods Patients with incident LN between 1976 and 2018 in Olmsted County, Minnesota (1976–2009) and an 8‐county region in southeast Minnesota (2010–2018) were identified. Age‐ and sex‐specific incidence rates and point prevalence over 4 decades, adjusted to the projected 2000 US population, were determined. Standardized mortality ratios (SMRs), survival rates, and time to end‐stage renal disease (ESRD) were estimated. Results There were 72 patients with incident LN between 1976 and 2018, of whom 76% were female and 69% were non‐Hispanic White. Mean ± SD age at diagnosis was 38.4 ± 16.24 years. Average annual LN incidence per 100,000 population between 1976 and 2018 was 1.0 (95% CI 0.8–1.3) and was highest in patients ages 30–39 years. Between the 1976–1989 and 2000–2018 time periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 per 100,000 in 1985 to 21.2 per 100,000 in 2015. Patients with LN had an SMR of 6.33 (95% CI 3.81–9.89), with no improvement in the mortality gap in the last 4 decades. At 10 years, survival was 70%, and 13% of LN patients had ESRD. Conclusion The incidence and prevalence of LN in this area increased in the last 4 decades. LN patients have poor outcomes, with high rates of ESRD and mortality rates 6 times that of the general population.

ABSTRACTThe risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14–25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX.A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12 months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12 months of 16.0% for those at high risk or with a serum creatinine >5.7 mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations.However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12 months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed countries. Kidney injuries related to CLL can occur via several mechanisms. Approximately 30%–40% of CLL patients with a kidney biopsy have monoclonal-protein related lesions. However, such lesions mostly involve glomeruli with only rare instances of tubule-interstitial disorders. There is only a single case report of a CLL patient who presented with crystalline light chain proximal tubulopathy (LCPT). Fanconi syndrome (FS) may provide clinical clues in these patients. We report a case of a CLL patient who presented with hypokalemia in the setting of advanced kidney failure in which serum monoclonal IgG kappa was detected. The patient demonstrated typical signs and symptoms of FS. The urinary retinol binding protein was also extremely elevated (638 times upper normal limit). A kidney biopsy revealed non-crystalline LCPT with CLL infiltration. FS in CLL is an extremely rare presentation, as only four cases had been previously reported. Of these, only a single case had crystalline LCPT. Our case is the first report of non-crystalline LCPT in a CLL patient. Obinutuzumab and Venetoclax were started to address the CLL, and an improvement in kidney function was noted thereafter.

Background and objectives Kidney biopsy is the current gold standard to diagnose membranous nephropathy. Approximately 70%–80% of patients with primary membranous nephropathy have circulating anti-phospholipase A2 receptor antibodies. We previously demonstrated that in proteinuric patients with preserved eGFR and absence of associated conditions ( e.g., autoimmunity, malignancy, infection, drugs, and paraproteinemia), a positive anti-phospholipase A2 receptor antibody test by ELISA and immunofluorescence assay confirms the diagnosis of membranous nephropathy noninvasively. These data have not been externally validated. Design, setting, participants, & measurements The clinical and pathologic characteristics of patients with a positive anti-phospholipase A2 receptor antibody test at the Mayo Clinic, the University Hospital Vall D’Hebron (Barcelona), and the Columbia University Medical Center (New York) were retrospectively reviewed. Biopsy findings and presence or absence of a potential associated condition were assessed. Results From a total of 276 patients with positive anti-phospholipase A2 receptor serology, previously reported patients ( n =33), kidney transplant recipients ( n =9), pediatric patients ( n =2), and patients without kidney biopsy ( n =69) were excluded. Among the 163 remaining patients, associated conditions were identified in 47 patients, and 15 patients had diabetes mellitus. All 101 patients of the final cohort had a primary diagnosis of membranous nephropathy on kidney biopsy. In the 79 patients with eGFR≥60 ml/min per 1.73 m 2 , none of the biopsy findings altered diagnosis or management. Among the 22 patients with decreased eGFR, additional findings included superimposed acute interstitial nephritis ( n =1). Conclusions In patients with preserved eGFR and absence of associated conditions or diabetes, a positive anti-phospholipase A2 receptor test by either ELISA >20 RU/ml or a positive immunofluorescence assay confirms the diagnosis of membranous nephropathy, precluding the requirement for a kidney biopsy.

Significance Statement Treatment of proliferative GN with monoclonal Ig deposition (PGNMID), in which direct deposition of the monoclonal proteins damages the kidney, is not established. Daratumumab, a monoclonal anti-CD38 antibody, has shown effectiveness as multiple myeloma therapy. In an open-label, phase 2 study, the authors evaluated safety and efficacy of a 6-month course of intravenous daratumumab in 11 patients with PGNMID and one with C3 glomerulopathy with monoclonal gammopathy. Five episodes of serious adverse events (two of which were infection related) occurred. All ten patients with PGNMID who received at least one daratumumab dose experienced a significant reduction in proteinuria at 6 months, which was sustained in seven patients by 12 months. Overall, in this pilot study, daratumumab’s acceptable toxicity profile and significant improvement in proteinuria, while stabilizing kidney function, suggest further investigation is warranted. Background Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID. Methods We evaluated daratumumab’s safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m 2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria <500 mg/d with <15% decline in baseline eGFR) or partial remission (>50% reduction in 24-hour proteinuria with <30% decline in eGFR) and proteinuria at 6 and 12 months. Results One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months. Conclusions Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation. Clinical Trial registry name and registration number: Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118

AbstractAdvances in the diagnosis and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have led to continued improvement in survival and prognosis over the course of the last 4 decades. Nevertheless, the most acute and severe disease manifestations, including severe kidney disease and alveolar hemorrhage, continue to be associated with increased early mortality from disease activity or treatment complications as well as risk for the development of end-stage kidney disease (ESKD), which in turn directly affects the overall prognosis of ANCA-associated vasculitis. Plasma exchange (PLEX) has long been proposed and used for these most severe disease manifestations under the assumption that its effects are swift and supported by our understanding of the pathogenic role of ANCA. Yet convincing evidence of a beneficial effect of PLEX in ANCA-associated vasculitis has been lacking, as early studies and small trials have generated conflicting results. The controversy regarding PLEX has been accentuated recently as the largest randomized controlled trial ever conducted in ANCA-associated vasculitis, the Plasma Exchange and Glucocorticoids in Severe ANCA-associated Vasculitis trial, which was specifically designed to evaluate the efficacy of PLEX in patients with severe renal disease or alveolar hemorrhage, failed to show a difference in the combined primary outcome measure of death or ESKD in patients who received PLEX versus those who did not. In light of these disappointing results, we herein review the currently available data on PLEX for ANCA-associated vasculitis and explain why we believe that these data no longer support the use of PLEX in ANCA-associated vasculitis.

Proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) and C3 glomerulopathy (C3G) with monoclonal gammopathy (MG) are kidney diseases related to monoclonal gammopathy of renal significance (MGRS). Rituximab or combination of cyclophosphamide, bortezomib and dexamethasone have been used with variable success but no clinical trial has been performed up to now. In this phase 2 trial, we evaluated the safety and efficacy of daratumumab (an anti-CD38 plasma therapy) in patients with PGNMID and C3G with MG. The primary objective was safety and tolerability of daratumumab. The secondary objective was the response rate to daratumumab. Response was defined by complete remission (CR) (proteinuria &lt;500 mg/d and no more than 10% drop in eGFR) or partial remission (PR) (50% reduction in proteinuria with no more than 30% drop in eGFR) at 6 and 12 months. Daratumumab was administered intravenously at a dose of 16mg/kg once weekly for 8 weeks followed by once every other week for an additional 8 doses. Twelve patients were recruited. There was only one patient with C3G with MG recruited and one patient with PGNMID did not finish the first infusion of daratumumab. Both were excluded from evaluation of the secondary objective. The patient with C3G was excluded as later it was noted that the disease was not triggered by the MG but rather due to activation of her alternative complement pathway due to high-risk allele for complement Factor H (CFH) and C3. Mean age was 51.2 ± 22.6 (18-87) years. All patients were White and 5 were male. For the primary objective, there were five serious adverse events (SAE). Two were serious infections that occurred in the patient with C3G with MG. At the time of these infections, patient was receiving additional immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. One was a febrile episode attributed to a virus that resolved with stopping additional immunosuppression, and another was an episode of C. difficile colitis that resolved following treatment. There were 3 episodes of uncomplicated UTI that resolved following antibiotic therapy and one episode of URI that required no treatment. The other two SAE were eye chemosis and headache in the same patient that resolved. Last SAE was an episode of acute closed angle glaucoma that occurred 45 min into the 1st infusion. This patient was withdrawn from the study. The most common side effect was infusion related reaction (with first infusion) that included cough, congestion, and throat irritation that resolved by the end of the infusion. There were no grade 3 or 4 anemia, thrombocytopenia or leukopenia. At 6 months, 2 patients achieved CR, 6 achieved PR and 2 had no response (NR). At 12 months, the 2 patients who had NR had entered PR and 2 additional patients that had achieved PR entered CR, but 3 patients relapsed (1 from CR and 2 from PR group). Overall, at 12 months, 3 patients achieved CR, 5 achieved PR and 2 had NR (due to relapse). The median 24hr baseline urinary protein declined from 4346 mg (3245 - 7943) to 702 mg (435 - 3057), at 6 months (p=0.001) and 1264 mg (463 - 3645) at 12 months (p = 0.004). There was also significant improvement in serum albumin, hemoglobin, total and LDL cholesterol, and complement 3 levels from baseline to 12 months follow-up (Table 1). Estimated GFR remained unchanged from 61.1 ± 31.9 to 65.0 ± 31.7 at 12 months (p=0.4). In this trial, daratumumab has shown to be safe and well tolerated. Daratumumab was also shown to be effective in reducing the proteinuria dramatically in patients with PGNMID secondary to MGRS along with stabilization of renal function. In conclusion, this is the first clinical trial of daratumumab in patients with MGRS and the promising results deserves further study. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Daratumumab - off label use for treatment of PGNMID

Significance Statement Efficacy of rituximab (RTX) in ANCA-associated vasculitis (AAV) in patients with severe renal involvement (eGFR<30 ml/min per 1.73 m 2 ) has not been addressed in clinical trials. This observational study did not find statistically significant differences between RTX and cyclophosphamide (CYC) for remission-induction therapy or any apparent benefit from the addition of plasma exchange (PLEX) to standard remission-induction therapy for patients with AAV and severe renal involvement. Although our analyses suggest that the benefits and risks of these therapeutic choices (RTX versus CYC with and without PLEX) are balanced, a randomized, controlled trial is needed to confirm these findings. Background Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX). Methods A retrospective cohort study of MPO- or PR3-ANCA–positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m 2 ). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared. Results Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC ( n =161) or RTX ( n =64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m 2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P =0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P =0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P =0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P =0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P =0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P =0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P =0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P =0.330). Conclusions The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.

Significance Statement It is not known how frequently a kidney biopsy specimen reveals monoclonal gammopathy (MG) of renal significance (MGRS) in patients with MG or what factors predict this finding. In a review of medical records of 6300 patients with MG, the authors found that only 160 (2.5%) had a biopsy. Of those, 96 (60%) had lesions unrelated to MG, with arteriosclerosis and diabetic nephropathy accounting for most cases. Among 64 patients with MGRS, amyloid light chain amyloidosis and proliferative GN with monoclonal Ig deposition were the most common lesions. An elevated serum free light chain ratio, proteinuria ≥1.5 g/d, and hematuria were the strongest independent predictors of finding MGRS on biopsy specimens. These findings will assist nephrologists in determining which patients with MG and CKD would be at high risk of having MGRS. Background Little is known about the rate and predictors of finding lesions of monoclonal gammopathy (MG) of renal significance (MGRS) on kidney biopsy specimens among patients with MG. Methods We reviewed the medical records from 2013 to 2018 at the Mayo Clinic in Rochester, Minnesota, to identify patients with MG and whether they had undergone a kidney biopsy. In a more select group of patients with MG from 2017 to 2018, we conducted a review of records to determine how many had underlying CKD, which of those with CKD had undergone a kidney biopsy, and reasons for deferring a kidney biopsy. Results Between 2013 and 2018, we identified 6300 patients who had MG, 160 (2.5%) of whom had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion; amyloid light chain amyloidosis, the most common finding, accounted for nearly half of these lesions. In the non-MGRS group comprising 96 patients, 23 had arteriosclerosis, the most common finding. In multivariate analysis, strong predictors of finding an MGRS lesion included the presence of an elevated free light chain ratio, proteinuria, and hematuria. Among 596 patients with CKD and MG from 2017 to 2018, 62 (10.4%) underwent a kidney biopsy. Kidney biopsy was deferred for 70 patients (20%); for 62 of the 70, the diagnosis was already known, and eight were not candidates for therapy. Younger age and higher proteinuria and serum creatinine levels increased the likelihood that the patient would undergo a kidney biopsy. Conclusions Proteinuria ≥1.5 g/d, hematuria, and an elevated free light chain ratio increase the likelihood of finding MGRS, and a kidney biopsy should be highly considered in such patients.