Use of Rituximab as an off-Label medication in Glomerular Diseases: Clinical Perspective

Objectives: We review rituximab (RTX) use and outcomes in immune-mediated glomerular diseases (GN) and compare it to established literature. Methods: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with literature supporting RTX use. Lupus nephritis (LN), 1o focal segmental glomerulosclerosis (1o FSGS), IgA nephropathy (IgAN), IgG4 related disease, and C3GN had insufficient literature support for RTX use. Clinical Remission was assessed six months after receiving RTX. Results: A total of 61 cases analyzed. RTX was an add on therapy in 87%. Remission rate was 95% in MCD and MN vs. 56 % in off-label group (P=.002). LN patients had a mean initial eGFR of 69mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. Mean initial eGFR for 1o FSGS was 33mL/min and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-related disease cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission achieved in only 2 ANCA vasculitis cases, and none in IgA vasculitis cases. Conclusion: Our data support RTX use in resistant MCD and MN. RTX showed success in LN and IgG4 related disease, but not FSGS or C3GN. The small vasculitis cases number does not allow drawing a conclusion on RTX effectiveness.

The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin—low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Biopsy Proven Kidney Disease From A Rural Tertiary Care Centre — A Social And Epidemiological Perspective

The prevalence of chronic kidney disease (CKD) is rising in rural areas. Screening of high risk cases, early detection and referral by the physicians reduces the prevalence of kidney disease in the population. Hereditary disorders, Glomerular diseases, Obstructive nephropathies are common causes in CKD in rural areas. Kidney biopsy is an essential diagnostic tool in to diagnose glomerular diseases. This prospective study done at tertiary care teaching hospital between 2017 and 2020 to understand the profile of glomerular diseases in rural area. Forty patients were included in the Study. Primary glomerular disease (PGD) was present in 26 patients and Secondary glomerular disease (SGD) in 10 and primary tubulointerstitial pathology in 4 patients. The most common Secondary glomerular disease was lupus. Glomerular diseases are amenable to immunomodulatory therapy leading to change in clinical outcome of the disease. However, Kidney biopsy is underutilized particularly in elderly patients, hypertensive nephropathy patients, suspected non diabetic kidney disease and lupus patients. Financial and social issues play dominant role in the treatment plan of chronic diseases in rural areas. Regional registry of kidney biopsy of urban and rural areas separately helps in paving a way of understanding the profile of glomerular diseases and its prevention.

A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes

Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways.

Synthetic ACTH for Treatment of Glomerular Diseases: A Case Series

Rationale: Synthetic adrenocorticotropic hormone (Tetracosactide) has been used in the treatment of refractory glomerular diseases. Literature surrounding the use of this medication is limited to small case series and there is conflicting data on the rate of adverse events associated with this medication. Presenting concerns of the patient: Glomerulonephritis not in remission after at least 6 months of treatment with conservative care. Stable doses of concurrent immunosuppression were permitted. Diagnoses: Membranous nephropathy, IgA nephropathy, minimal change disease, and focal and segmental glomerulosclerosis. Intervention: Intramuscular synthetic adrenocorticotropic hormone (Tetracosactide, Synacthen Depot) with doses of either 1 mg weekly or 1 mg twice weekly. Outcomes: Five of 12 patients had at least a partial remission with Tetracosactide. Median time to response was 6 months for responders. Five of the 12 patients had adverse events documented, 2 of which led to treatment discontinuation. No patients with focal and segmental glomerulosclerosis responded to treatment. Lessons Learned: Higher rate of adverse events than previously reported with synthetic adrenocorticotropic hormone and uncertain treatment efficacy.

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

No abstract

De Novo Minimal Change Disease following Vaccination with the Pfizer/BioNTech SARS-CoV-2 Vaccine in a Living Kidney Donor

Coronavirus disease 2019 has developed as a pandemic. Immunization with the introduction of vaccines against COVID-19 seems be the only way to end this pandemic. We report on a case of a kidney donor, who developed minimal change disease (MCD) within 4 days post-vaccination with the SARS-CoV-2 BNT162b2 mRNA vaccine (Pfizer/BioNTech). She donated her kidney to her husband 4 years ago. After receiving the 1st vaccine dose, she presented with nephrotic syndrome, with complete remission 5 days later. She proceeded with the second dose of the BNT162b2 vaccine at the appointed time. Two days later, she presented with a relapse of full-blown nephrotic syndrome with preserved renal function. We performed an ultrasound-guided percutaneous kidney biopsy and the final diagnosis was consistent with minimal change disease. Oral prednisolone was promptly initiated at a dosage of 1 mg/kg daily and complete remission was achieved 10 days later. More data about this rare appearance of de novo glomerular diseases after SARS-CoV-2 vaccination are emerging and should be interpreted rigorously.

Glomerular Disease Education Experience across Nephrology Fellowship Programs: An International Survey

Introduction: Glomerular disease (GN) education is an important, albeit a challenging component of nephrology fellowship training. We hypothesized that trainee experience varies widely across programs, leading to differences in self-reported comfort levels in the diagnosis and management of glomerular diseases. Methods: The Glomerular Disease Study & Trial Consortium (GlomCon) conducted an anonymous online survey to determine the educational experience of nephrology trainees. We used multiple-choice questions to obtain data about a) curriculum-based education, b) dedicated specialty clinic, and c) exposure to pathology. We leveraged a visual analogue scale of 1-100 (with a higher number indicating a higher comfort level) to assess self-reported levels of clinical comfort. The survey was disseminated via email to the subscribing members of GlomCon, and through Twitter. Results: In total, there were 109 respondents to our survey, and 56% were from training programs in the United States. Exposure to a specialized GN clinic was reported by 45%, while 77% reported the presence of an onsite nephropathologist at their training program. Self-reported comfort scores were 59±25 and 52±25 for diagnosis and treatment of glomerular diseases respectively. Days spent in GN clinic per year, years of fellowship and dedicated nephropathology didactics were associated with higher diagnosis and treatment comfort scores. Conclusion: Trainees report a wide variation in glomerular disease education across fellowship programs. A lack of nephropathology exposure and a dedicated GN curriculum were associated with lower scores in self-reported clinical comfort in caring for patients with glomerular disease.

The Spectrum of Children's Kidney Diseases—2403 Renal Biopsy-Proven Cases from a Single Centre in China Between 1999 and 2019

Background: This study aimed to investigate the clinical and pathological characteristics and the changes in glomerular diseases in 2403 pediatric renal biopsies from 1999 to 2019.Methods: Renal biopsies performed on children aged ≤18 years between 1999 and 2019 were analysed at our center. We analysed the clinical and histological characteristics, distribution of pediatric glomerular diseases with various clinical presentations, and changes in the glomerular disease patterns during the study period.Results: The most common primary glomerular disease was IgA nephropathy (IgAN) (24.3%), followed by minimal change disease (MCD) (15.3%) and membranous glomerulonephritis (MN) (13.1%). Henoch-Schonlein purpura nephritis (HSPN) (18.1%) and lupus nephritis (LN) (7.2%) were the most frequently recorded secondary glomerular diseases. Alport syndrome and thin basement membrane nephropathy (TBMN) were the most common inherited glomerular diseases, accounting for 1.2% and 0.6% of the total glomerular diseases in children, respectively. The number of boys with IgAN, MCD and IgM nephropathy (IgMN) was higher than that of girls, while the number of girls with MN and LN was higher than that of boys. The frequencies of MCD, MN, IgMN and endocapillary proliferative glomerulonephritis (EnPGN) in the 13-18-year-old group were higher than those in the 0-12-year-old group, while the frequencies of IgAN, mesangial proliferative glomerulonephritis (MsPGN) and focal proliferative glomerulonephritis (FPGN) were lower than those in the 0-12-year-old group. The ratio of Alport syndrome and TBMN in the 0-12-year-old group was higher than that in the 13-18-year-old group. The proportion of patients with MCD and MN in 2010-2019 was higher than that in 1999-2009, while the ratio of IgAN, MsPGN, IgMN, EnPGN, membranoproliferative glomerulonephritis (MPGN), HSPN and HBV-associated glomerulonephritis (HBV-GN) decreased. MCD (28.5%) was the most common cause of nephrotic syndrome (NS). In children with haematuria and proteinuria, HSPN (38.8%) and IgAN (36.9%) were more common than other glomerular diseases. IgAN (39.4%) was the most common cause of AKI. Sclerosing glomerulonephritis (SGN) (21.1%) was the main cause of progressive chronic kidney disease (CKD).Conclusions: Glomerular diseases in children were related to sex and age. From 1999 to 2019, the spectrum of children's kidney disease in our center changed significantly.