Context: Membranous nephropathy (MN) is an immune-mediated glomerular disease that can lead to nephrotic syndrome and progressive kidney function loss. The cyclic steroid-cyclophosphamide regimen (the modified Ponticelli protocol) and the monoclonal anti-CD20 antibody rituximab have been advocated as effective therapies to improve renal outcomes, but a direct comparison of these treatments had never been carried out in a prospective study. Subject of Review: Scolari et al. [J Am Soc Nephrol. 2021;32:972–82] recently reported the results of a pilot randomized controlled trial (RI-CYCLO) designed to provide direct estimates of the effect of rituximab (1 g × 2) compared to the cyclic steroid-cyclophosphamide regimen in 74 patients with MN. The proportion of patients with complete remission at 12 months was higher in the cyclic regimen arm than that of rituximab (32 and 16%, respectively), but the difference was not statistically significant in intention-to-treat analyses. Interestingly, differences in the cumulative incidence of complete and partial remissions between treatment arms progressively reduced over the follow-up and became virtually nonexistent from 24 months (>80% in both groups). The frequency of serious and nonserious adverse events was similar between the 2 treatment arms. Infusion reactions and drug discontinuation were more common with rituximab, while infections and leukopenia were more frequently observed with the cyclic regimen. The risk of cancer was similar in the 2 allocation groups, but the limited follow-up length did not allow to draw definitive conclusions. Independent of treatment allocation, 18% of patients experienced at least 1 relapse after achieving complete or partial remission. Second Opinion: Notwithstanding the intrinsic limitations of a pilot study, the RI-CYCLO trial represents an important milestone in the treatment of MN. Findings from this study support the hypothesis that the cyclic regimen and rituximab may have comparable efficacy in inducing disease remission over the long term. Considering its potentially better–albeit not yet formally proven–long-term safety profile, rituximab could be considered as a first-line therapy for most patients with MN. Several questions remain to be addressed, including rituximab ideal dose and its efficacy in patients with a significant reduction in glomerular filtration rate. In light of RI-CYCLO results, a large-scale trial to assess rituximab noninferiority to the cyclic regimen would require the enrollment of thousands of patients, and it would be probably unfeasible within a reasonable time frame. In our opinion, resources should be allocated to provide an answer to the pressing matter of treatment nonresponse and intolerance, which may be addressed in the near future with novel therapeutic strategies.

Background: Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) disease is a well-known antibody-induced autoimmune disease. The pathogenesis of AAV has not yet been completely clarified, but may be related to heredity, infection, environmental factors, cellular immunity, etc. In recent years, complement in AAV pathogenesis has become the latest research hotspot, and the decrease of serum complement C3 is associated with poor prognosis of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. In the current study, we investigated the associations between serum complement C3 and kidney injury in AAV children. Methods: Twenty-four children with AAV admitted to our hospital from June 2014 to June 2019 were divided into the low C3 group and the normal C3 group. All the children have undergone renal biopsy. The clinical manifestations, laboratory tests, renal pathology, treatment, and prognosis of the 2 groups were observed. The primary end point was end-stage renal disease (ESRD). Results: It was shown that kidney injury was more obvious in patients with low C3 than in patients with normal C3 serum. The values of ESR, Scr, and UA before treatment in the low C3 group were higher than those in the normal C3 group (p < 0.01); the values of RBC, Hb, PLT, ALB, LDH, and eGFR in the normal C3 group were higher than those in the low C3 group (p < 0.01). The values of urinary protein and NAG enzyme in the low C3 group were higher than those in the normal C3 group (p < 0.01). The area of glomerular abandonment, sclerosis, segmental sclerosis, crescent, cellular crescent, cellular fibrous crescent, fibrous crescent, segmental loop necrosis, and the number of cases with acute renal tubulointerstitial lesions in the low C3 group were bigger than those in the normal C3 group (p < 0.05 and < 0.01). The number of cases with C3 deposition in the low C3 group was higher than that in the normal C3 group (p < 0.05). The number of patients receiving CRRT and PE in the low C3 group was higher than that in the normal C3 group (p < 0.05 and < 0.01). In this study, 3 children entered the stage of ESRD and 1 died in the low C3 group. Conclusion: The kidney injury of AAV children with low complement C3 is serious, and the prognosis is poor. We should pay attention to the influence of decreased complement C3 on the condition and prognosis of AAV children.

Antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) is characterized by systemic inflammation and is the most common cause of new-onset glomerulonephritis in adults older than 50 years. Renal disease secondary to AAV can lead to chronic kidney disease (CKD) requiring renal replacement therapy in approximately 20–25% of patients. Relapses are infrequent in the population on dialysis, and treatment guidelines do not specify these patients. Reports regarding the clinical course, survival, or relapse rate after beginning dialysis are scarce. The authors present 3 cases of CKD patients on hemodialysis who presented with AAV relapse, successfully treated with rituximab, and provide a literature review on relapse treatment.

Recently, a new full-age spectrum equation was proposed by the European Kidney Function Consortium (EKFC) to overcome the difficulty of using multiple glomerular filtration rate (GFR) estimation equations and problems of implausible changes in GFR during the transition from adolescence to adulthood and address GFR overestimation in young adults and in the older adults. To verify the impact on patient classifications, we applied the new equation to data of 38,188 adult patients, comparing GFR estimation using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and EKFC equations. As expected, our data indicate that a significant proportion of patients will be reclassified downward by the EKFC compared to the CKD-EPI equation with a particular reference between CKD stages 1–2 and 2–3 and age categories of 18–30 and ≥61 years, respectively. Clinicians should be aware that any replacement for the EKFC equation will entail a period of different results in estimated GFR during the transition from the previous to the new equation.

Introduction: Further understanding of adverse clinical events in patients with chronic kidney disease (CKD) is needed. This study aimed to describe characteristics of patients with nondialysis-dependent (NDD) and dialysis-dependent (DD) CKD and to assess incidence rates of uncommon adverse clinical events of interest in these patients. Methods: This retrospective study used electronic medical record data from USA CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² between January 1, 2010, and December 31, 2018, obtained from the USA-based TriNetX database. NDD-CKD and DD-CKD were diagnosed and staged from ≥2 consecutive eGFR readings, recorded ≥90 days apart. Dialysis was identified using procedure codes for renal replacement therapy. Outcomes assessed were select uncommon adverse clinical events, defined by International Classification of Disease, 9th and 10th Revision codes. Results: Incidence rates of adverse clinical events per 100 person-years (95% confidence interval) were generally higher in patients with DD-CKD versus NDD-CKD. Differences were particularly pronounced for hyperkalemia (26.9 [26.2–27.6] vs. 4.5 [4.5–4.6]), acidosis (15.1 [14.7–15.6] vs. 3.4 [3.4–3.4]), and sepsis (14.6 [14.2–15.1] vs. 3.3 [3.3–3.4]). Among DD-CKD patients, incidence rates of adverse events were particularly high during the first 3 months following dialysis initiation. Incidence of adverse clinical events generally increased with decreasing eGFR among patients with NDD-CKD and with hemoglobin <10 g/dL in both NDD- and DD-CKD patients. Conclusions: Our results help establish baseline rates of uncommon adverse clinical events and provide additional evidence of increased morbidity for patients with DD-CKD versus NDD-CKD.

Context: Alterations in the plasma sodium concentration ([Na⁺]_p) is predicted based on changes in the mass balance of Na⁺, K⁺, and H₂O. However, it is well appreciated that Na⁺ retention results in both osmotically active and osmotically inactive Na⁺ storage and that only osmotically active Na⁺ contributes to the modulation of the [Na⁺]_p^. Subject of Review: Recent clinical studies suggested that prediction of changes in the [Na⁺]_p based on the mass balance of Na⁺, K⁺, and H₂O is inaccurate since the osmotically inactive Na⁺ storage pool is dynamically regulated. In contrast, animal studies demonstrated that changes in the [Na⁺]_p can be predicted if the total body Na⁺, K⁺, and H₂O were to be accurately accounted for. Second Opinion: Our analysis demonstrated that alterations in the [Na⁺]_p are predictable at the total body level if all sources of input and output of Na⁺, K⁺, and H₂O can be accurately accounted for despite the paradoxical finding that there are changes in the osmotically inactive Na⁺ storage pool at the tissue level. However, future prospective clinical studies are needed to corroborate the findings in the animal studies. We proposed that the fundamental question as to whether changes in the [Na⁺]_p can be predicted in the face of osmotically inactive sodium storage is best addressed by serial measurements of total body exchangeable Na⁺ and K⁺ and total body water by isotope dilution at different time intervals.

Introduction: CKD, a common complication of type-2 diabetes (T2D), causes considerable disease burden. Patients with T2D and CKD are considered high-risk for complications; however, studies describing patients with T2D and incident CKD identified from real-world data using the diagnostic gold-standard criteria – estimated glomerular filtration rate and urine albumin-to-creatinine ratio (UACR) – are scarce. Methods: In this population-based cohort study, we sought to estimate the rates of cardiovascular and renal outcomes among patients with T2D and CKD by comorbidity subgroups and CKD severity. Patients were sampled between 2008 and 2017 from de-identified US administrative claims enriched with laboratory data. Analyses were stratified by prevalent heart failure (HF), anemia, and resistant hypertension and the KDIGO categories at index. Results: We identified 106,369 patients with T2D and incident CKD. The rate of all-cause hospitalization was 189 [95% CI: 187, 191] per 1,000 person-years with cardiovascular-related hospitalizations being more frequent than kidney-related outcomes. The rate of acute kidney failure was 77.3 [95% CI: 76.2, 78.5] per 1,000 person-years. Patients with HF experienced a 4-times higher rate for cardiovascular events compared to those without. Rates of hospitalization increased from 5- to 6-fold with increasing KDIGO severity. Conclusions: Multimorbidity and advance stages of CKD increase the risk of cardiovascular and renal complications among patients with T2D diabetes. Earlier CKD diagnosis as well as interventions and coordinated care addressing other comorbid conditions present at diagnosis may reduce the overall disease burden in this population.

Introduction: IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN), due to overlapping clinical and pathological features. The key factor in the pathogenesis of IgAN is galactose-deficient IgA1 (Gd-IgA1). However, the mechanism of glomerular IgA deposition in patients with IgA-IRGN is unclear. Therefore, we evaluated whether Gd-IgA1 could be a useful biomarker to distinguish between these 2 diseases. Methods: A case-control study was conducted to analyze the clinical and pathological characteristics of 12 patients with IgA-IRGN. The intensity and distribution of glomerular Gd-IgA1 (KM55) staining in renal biopsies were assessed. The control group consisted of 15 patients diagnosed with IgAN and an additional 17 patients with glomerulopathy involving IgA deposition. Results: The main clinical manifestations of patients with IgA-IRGN were nephrotic-range proteinuria, hematuria, acute renal injury, and hypocomplementemia. Active lesions were the leading pathological feature, while focal segmental sclerosis was rare. Half of the patients exhibited hump-shaped subepithelial deposits. Glomerular KM55 staining was negative in 7 patients, trace in 4 patients, and 2+ in 1 patient. The median intensity of KM55 staining in IgA-IRGN patients was 0 (range 0∼2+), which was significantly lower than that of primary IgAN patients (median 2+, range 1+∼3+). The receiver operating characteristic analysis demonstrated that the optimal cutoff level to identify these 2 diseases was 0.5+. Conclusions: Glomerular KM55 staining intensity might be helpful to distinguish IgA-IRGN from primary IgAN. Weak or negative staining may favor IgA-IRGN. In addition, integrated analysis including clinical data, pathological findings, and prognostic information would further improve the differential diagnosis.

Background: Hepatitis B virus-associated glomerulonephritis (HBV-GN) can occur in patients with negative HBV serological antigens. Little is known about the treatment of seronegative HBV-GN (sn HBV-GN). The aim of this prospective study was to evaluate the efficacy and safety of corticosteroids in the treatment of sn HBV-GN. Methods: Twenty-six patients with nephrotic syndrome induced by seronegative HBV-associated membranous nephropathy were enrolled. The patients were given methylprednisolone (0.8 mg/kg/day) for 12–24 weeks, tapered by a 2-mg reduction every 1–3 months. Patients were followed up for 6–36 months. Complete remission (CR) was defined as proteinuria <0.3 g/24 h. Partial remission (PR) was defined as proteinuria of 0.3–3.5 g/24 h that was reduced ≥50% of the baseline level. Results: The effective remission (including CR and PR) rates of nephrotic syndrome were 23.1%, 61.5%, 73.1%, 76.2%, 90.5%, and 81.0%, respectively, after 1, 3, 6, 12, 24, and 36 months. Nineteen patients achieved effective remission after 11.68 ± 7.15 months. The level of serum albumin improved from 24.34 ± 6.71 g/L at baseline to 39.61 ± 7.45 g/L at the 36th month significantly. After treatment, the level of serum Cr was similar to the baseline. Only 2 patients relapsed. The primary adverse reaction was infection. None of the patients showed evidence of HBV replication. Conclusion: The long-term middle-dose corticosteroid therapy without antiviral drugs is effective and safe for membranous sn HBV-GN patients. For sn HBV-GN patients, the monitoring of HBV DNA and HBV markers in the serum is necessary during the corticosteroid monotherapy. Trial Registration: The Chinese Clinical Trial Registry (ChiCTR1900022518).