State-of-Art Therapeutics in IgA Nephropathy.

Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.

An Unusual Case of Myoglobin Cast Nephropathy in a Patient with Bartter Syndrome: A Rare Entity.

A 5-year-old male child with complaints of failure to thrive (since 4 months of age) and developmental delay presented to the nephrology department with complaints of weakness in all four limbs for 5 days. On examination, he was hypotensive, dehydrated, and had reduced tone in all four limbs. Biochemistry revealed acute kidney injury (AKI), hyponatremia, hypocalcemia, and hypokalemia. Renal needle biopsy (in view of unexplained AKI) revealed ropy, granular pigment casts with marked tubular injury. Myoglobin stain was positive. The positive genetic analysis of the patient (CLCNKB gene) confirmed the clinical diagnosis of Bartter syndrome (BS). The child was managed with aggressive intravenous hydration with potassium and calcium supplementation, and AKI recovered.

Dialysis Distress.

This communication conceptualizes and characterizes the phenomenon of dialysis distress, commonly encountered in persons living with end stage kidney disease on dialysis. Dialysis distress can be defined as an emotional state, marked by extreme apprehension, anxiety, despair and/or dejection, due to a perceived inability to cope with the challenges and demands of living with dialysis. This concept can be extrapolated to persons who undergo renal replacement therapy such as renal transplant. Dialysis distress should be identified in a timely manner, and managed using appropriate support, counselling and education, delivered in an empathic manner.

Plasma levels and dietary intake of minerals in patients with type 2 diabetes and chronic kidney disease: A case-control study.

BACKGROUND AND AIM: Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease (CKD) worldwide. Altered mineral levels leading to adverse outcomes are widely reported in diabetes but limited in DKD, in the Indian scenario, hence this study was taken up to address this issue. METHODS: A hospital-based case-control study was taken up with 54 healthy controls (C) and 140 subjects with type 2 diabetes wherein 74 subjects with diabetes and CKD formed the DKD group, and 66 subjects with diabetes but no CKD formed the diabetic no-chronic kidney disease (DNCKD) group. High-resolution inductively coupled plasma mass spectrometry was used to evaluate the blood levels of minerals (calcium (Ca), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), and selenium (Se)), and a raw food-based food frequency questionnaire for dietary intakes. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (mL/min/1.73 m2) and albuminuria. Spearman's rank correlation was used to evaluate the relationship between the categorical variables. RESULTS: The median values of plasma Ca in the DKD group were significantly lower compared with the DNCKD and C groups (10.5 mg/dL vs. 11.0 mg/dL and 11.7 mg/dL, p<0.001). Furthermore, plasma Ca levels lowered with declining kidney function, as evidenced by the eGFR and albuminuria segregation. Dietary intake of minerals did not correlate with the corresponding plasma levels. However, in the DKD group, eGFR correlated positively with the plasma levels of Ca (r= 0.422, p=0.001), Cr (r= 0.351, p=0.008), Mn (r= 0.338, p=0.011), Fe (r= 0.403, p=0.002), Cu (r= 0.274, p=0.041) and negatively with Se (r= -0.486, p<0.001). CONCLUSION: Plasma Ca levels are lower in the DKD group with a strong positive association with eGFR, indicating its role in predicting the onset and progression of kidney function decline.

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

Equity and Quality of Global Chronic Kidney Disease Care: What Are We Waiting for?

BACKGROUND: Chronic kidney disease (CKD) is an important but insufficiently recognized public health problem. Unprecedented advances in delaying progression of CKD and reducing kidney failure and death have been made in recent years, with the addition of the sodium-glucose cotransporter 2 inhibitors and other newer medication to the established standard of care with inhibitors of the renin-angiotensin system. Despite knowledge of these effective therapies, their prescription and use remain suboptimal globally, and more specially in low resource settings. Many challenges contribute to this gap between knowledge and translation into clinical care, which is even wider in lower resource settings across the globe. Implementation of guideline-directed care is hampered by lack of disease awareness, late or missed diagnosis, clinical inertia, poor quality care, cost of therapy, systemic biases, and lack of patient empowerment. All of these are exacerbated by the social determinants of health and global inequities. SUMMARY: CKD is a highly manageable condition but requires equitable and sustainable access to quality care supported by health policies, health financing, patient and health care worker education, and affordability of medications and diagnostics. KEY MESSAGES: The gap between the knowledge and tools to treat CKD and the implementation of optimal quality kidney care should no longer be tolerated. Advocacy, research and action are required to improve equitable access to sustainable quality care for CKD everywhere.

Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE): Design and Methods.

Background and Aim: Primary glomerular disease accounts for one-sixth of all chronic kidney diseases (CKDs) in India. We remain limited in our ability to effectively treat these conditions because of lack of understanding of the disease mechanisms and lack of predictors to identify the clinical course and therapeutic responsiveness. We propose to develop a network of investigators in glomerular diseases, collect information in a systematic fashion to understand the clinical outcomes, answer translational research questions better, and identify and recruit patients for clinical trials. Materials and Methods: This is a prospective, observational study. The Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE) cohort will enroll patients (>18 years) with biopsy-proven minimal change disease (MCD), focal segmental glomerulonephritis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), or membranoproliferative glomerulonephritis (MPGN) (immune complex- and complement-mediated), with first biopsy taken within 2 years of enrollment. Patients with estimated glomerular filtration (eGFR) rate <15 ml/min/1.73 m2 for >3 months at the time of screening, kidney transplant or bone marrow transplant recipients, patients with active malignancy, and patients with active hepatitis B/C replication or human immunodeficiency virus (HIV)-I/II will be excluded. Clinical details including history, medication history and details, and family history will be obtained. Consenting patient's blood and urine samples will be collected and stored, aligned to their clinical follow-up. Expected Outcomes: The network will allow accurate ascertainment of disease burden of glomerular diseases across study sites, establishment of the treatment pattern of common glomerular diseases, investigation of medium- and long-term outcomes (remission, relapse, rate of eGFR decline), and building a suitable infrastructure to carry out clinical trials in primary glomerular disease.

Practice of dialysis access interventional nephrology procedures in the Asia-Pacific region: Getting lay of the land.

AIM: This cross-sectional survey aimed to determine the prevalence of Interventional Nephrology (IN) practice amongst nephrologists in the Asia-Pacific Region (APR), specifically related to dialysis access (DA). METHODS: The Association of VA and intervenTionAl Renal physicians (AVATAR) Foundation from India conducted a multinational online survey amongst nephrologists from the Asia-Pacific to determine the practice of IN in the planning, creation, and management of dialysis access. The treatment modalities, manpower and equipment availability, monthly cost of treatment, specifics of dialysis access interventions, and challenges in the training and practice of IN by nephrologists were included in the survey. RESULTS: Twenty-one countries from the APR participated in the survey. Nephrologists from 18 (85.7%) countries reported performing at least one of the basic dialysis access-related IN procedures, primarily the placement of non-tunnelled central catheters (n-TCC; 71.5%). Only 10 countries (47.6%) reported having an average of <4% of nephrologists performing any of the advanced IN access procedures, the most common being the placement of a peritoneal dialysis (PD) catheter (20%). Lack of formal training (57.14%), time (42.8%), incentive (38%), institutional support (38%), medico-legal protection (28.6%), and prohibitive cost (23.8%) were the main challenges to practice IN. The primary obstacles to implementing the IN training were a lack of funding and skilled personnel. CONCLUSION: The practice of dialysis access-related IN in APR is inadequate, mostly due to a lack of training, backup support, and economic constraints, whereas training in access-related IN is constrained by a lack of a skilled workforce and finances.

Efficacy and Safety of Directly Acting Antivirals in Patients with Hepatitis C Infection on Hemodialysis.

INTRODUCTION: The high prevalence of hepatitis C virus (HCV) infection among patients on maintenance hemodialysis (MHD) has been reported in India. Due to the strong association of HCV infection with death and cardiovascular disease, it is important to treat the infection. However, treatment poses a challenge since only a few directly acting antivirals recommended in the guidelines for HCV treatment in the dialysis population are available in India. Pangenotypic sofosbuvir has concerns about its safety due to its renal elimination. MATERIALS AND METHODS: This prospective study was undertaken between 2019 and 2020 among patients on hemodialysis with HCV infection. Clinical details, biochemical parameters, viral load, and genotyping were recorded and the outcome of treatment with sofosbuvir in combination with velpatasvir/daclatasvir for 12 weeks was noted. Descriptive and inferential statistical analysis was carried out. The Chi-squared/Fisher exact test was used. RESULTS: In the present study, 54 hemodialysis patients with HCV were treated with full doses of sofosbuvir and velpatasvir/daclatasvir. Genotype 1 was the most common, seen in 75.9% (n = 41). Around 96.29% (n = 52) of patients achieved sustained virological response (SVR) at the end of the study. None of the patients experienced serious side effects requiring dose reduction or discontinuation of the treatment. CONCLUSION: Sofosbuvir combination therapy offers an excellent response in dialysis patients irrespective of the genotype and presence of cirrhosis with minimal monitoring as in non-chronic kidney disease (CKD) patients.

NOTTO Guidelines for Vaccine Induced Thrombotic Thrombocytopenia in Organ Donation and Transplantation.

From the context of organ donation, COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT) is important as there is an ethical dilemma in utilizing versus discarding organs from potential donors succumbing to VITT. This consensus statement is an attempt by the National Organ and Tissue Transplant Organization (NOTTO) apex technical committees India to formulate the guidelines for deceased organ donation and transplantation in relation to VITT to help in appropriate decision making. VITT is a rare entity, but a meticulous approach should be taken by the Organ Procurement Organization's (OPO) team in screening such cases. All such cases must be strictly notified to the national authorities like NOTTO, as a resource for data collection and ensuring compliance withprotocols in the management of adverse events following immunization. Organs from any patient who developed thrombotic events up to 4 weeks after adenoviral vector-based vaccination should be linked to VITT and investigated appropriately. The viability of the organs must be thoroughly checked by the OPO, and the final decision in relation to organ use should be decided by the expert committee of the OPO team consisting of a virologist, a hematologist, and atreating team. Considering the organ shortage, in case of suspected/confirmed VITT, both clinicians and patients should consider the risk-benefit equationbased on available experience, and an appropriate written informed consent of potential recipients and family members should be obtained before transplantation of organs from suspected or proven VITT donors.

South Asian Transplant Infectious Disease Guidelines for Solid Organ Transplant Candidates, Recipients, and Donors.

These guidelines discuss the epidemiology, screening, diagnosis, posttransplant prophylaxis, monitoring, and management of endemic infections in solid organ transplant (SOT) candidates, recipients, and donors in South Asia. The guidelines also provide recommendations for SOT recipients traveling to this region. These guidelines are based on literature review and expert opinion by transplant physicians, surgeons, and infectious diseases specialists, mostly from South Asian countries (India, Pakistan, Bangladesh, Nepal, and Sri Lanka) as well as transplant experts from other countries. These guidelines cover relevant endemic bacterial infections (tuberculosis, leptospirosis, melioidosis, typhoid, scrub typhus), viral infections (hepatitis A, B, C, D, and E; rabies; and the arboviruses including dengue, chikungunya, Zika, Japanese encephalitis), endemic fungal infections (mucormycosis, histoplasmosis, talaromycosis, sporotrichosis), and endemic parasitic infections (malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, strongyloidiasis, and filariasis) as well as travelers' diarrhea and vaccination for SOT candidates and recipients including travelers visiting this region. These guidelines are intended to be an overview of each topic; more detailed reviews are being published as a special supplement in the Indian Journal of Transplantation .

Assessment of Biomedical Waste Generation in Dialysis Units: A Prospective Observational Study-Is it Time for "Green Dialysis"?

Introduction: Chronic kidney disease and as a consequence end-stage kidney disease (EKSD) is increasing globally. More and more people across the world are requiring hemodialysis (HD). The HD procedure produces a large quantity of biomedical waste. In addition, HD consumes a large quantity of water. In this study, we estimated the waste generated from our government-funded HD unit. Materials and methods: It is a prospective study that was carried out in the dialysis unit in the nephrology department over a period of 1 year. The daily dialysis waste generated by the unit was measured using a spring balance. The proportion of plastic and nonplastic waste was determined. The quantity of biomedical waste generated per person in 1 year was calculated. Water input to the dialysis unit was noted. Water consumption per dialysis was calculated. Liquid chemical waste consumed was determined. Electricity consumed by the unit was measured by the electricity meter. The cost of waste disposal was calculated. The cost of electricity consumption and water consumption was also calculated. Results: The approximate weight of waste disposables generated in one dialysis was 0.75 kg. Approximately each person generates 1.29 kg of waste per dialysis. Each dialysis required 125 L of reverse osmosis (RO) water and to generate 125 L of RO water 250 L of raw water was used. This happens as 125 L of water are rejected during the generation of 125 L of RO water. Thus, the net water consumption for each dialysis was 250 L. Chemical waste generated per dialysis includes 90 mL citric acid per dialysis and 130 mL bleach. Each dialysis consumes 3 kWh (three units) of electricity. The cost of electricity for each dialysis was 25.5 INR and the cost of water was 25 INR per dialysis. The cost of waste disposal for each dialysis bed was 6 INR. Discussion: Each dialysis patient produced 1.29 kg of waste per dialysis which was like other studies. Unlike other studies, the waste was not being reprocessed or recycled. Conclusion: Hemodialysis produces substantial biomedical waste. Proper waste disposal techniques and policies to promote reduction, reuse, and recycling will go a long way toward promoting green dialysis and reducing environmental as well as economic burdens. How to cite this article: Sahay M, Sahay RK, Seshadri B, et al. Assessment of Biomedical Waste Generation in Dialysis Units: A Prospective Observational Study-Is it Time for "Green Dialysis"? J Assoc Physicians India 2023;71(10):49-52.

Protocol and Methods: Role of Levothyroxine on the Progression of Chronic Kidney Disease in Subclinical Hypothyroid Populations (LP-CKD) - A Multicenter Randomized Controlled Trial.

Introduction: Subclinical hypothyroidism (SCH) is highly prevalent and associated with chronic kidney disease (CKD). However, it is still unanswered whether the restoration of euthyroid status in these patients will be beneficial in retarding a decline in glomerular filtration rate in early CKD patients. We aim to evaluate the efficacy of levothyroxine therapy versus placebo in slowing estimated glomerular filtration rate (eGFR) decline among CKD patients (stage 2-4) with SCH. Methods: This study will be a multicentric, double-blind, randomized, parallel-group, placebo-controlled study. A total of 500 CKD patients, 250 patients in the treatment group and 250 patients in the placebo group, will be randomized. The randomization between the treatment arm and placebo arm will be performed as per the computer-generated random number table in a 1:1 ratio. The sample size was calculated based on the assumed reduction in eGFR after 1-year follow-up in the treatment and placebo groups of 10% and 25%, respectively, at a minimum two-sided 99% confidence interval and 90% power of the study and considering 20% loss on follow-up. Each patient will be followed every 3 months for at least 1 year after randomization. Individuals completing 1-year follow-up visits will be considered for analysis. The baseline and follow-up data will be compared between the treatment and placebo groups. The study will evaluate the efficacy and safety of levothyroxine therapy versus placebo in slowing eGFR decline among CKD patients (stage 2-4) with SCH. The primary endpoint will be the end of follow-up of the patients, reduction of eGFR by ≥50% from a baseline of that patient, or development of ESKD or death of the patients. The secondary endpoint will be any cardiovascular event or arrhythmia after the institution of the drug.

The Role of Registries in Kidney Transplantation Across International Boundaries.

Transplant professionals strive to improve domestic kidney transplantation rates safely, cost efficiently, and ethically, but to increase rates further may wish to allow their recipients and donors to traverse international boundaries. Travel for transplantation presents significant challenges to the practice of transplantation medicine and donor medicine, but can be enhanced if sustainable international registries develop to include low- and low-middle income countries. Robust data collection and sharing across registries, linking pretransplant information to post-transplant information, linking donor to recipient information, increasing living donor transplant activity through paired exchange, and ongoing reporting of results to permit flexibility and adaptability to changing clinical environments, will all serve to enhance kidney transplantation across international boundaries.