Significance of genetic analysis in adult patients with inherited chronic kidney disease.

Genetic focal segmental glomerulosclerosis (FSGS) is an important but underestimated cause of inherited proteinuric chronic kidney disease (CKD) in adults. We discuss a case of familial CKD due to inverted formin 2 (INF2) gene mutation, where three siblings had disparate phenotypic presentations ranging from CKD with subnephrotic proteinuria to nephrotic-range proteinuria with collapsing FSGS on kidney biopsy over a period of 8 years. The youngest sibling was the index case. The family agreed to undergo genetic testing only after two more siblings were diagnosed with kidney disease. This case highlights how clinical heterogeneity, absence of family history in the index case, initial lack of specific biopsy-proven diagnosis and reluctance to undergo genetic testing can delay the diagnosis of genetic kidney disease in adults.

Clinical Practice Patterns in IgA Nephropathy: A Global Questionnaire-Based Survey.

Introduction: IgA nephropathy (IgAN) displays ethnic differences in disease phenotype. We aimed to examine how this common disease is managed worldwide. Methods: An online 2-step questionnaire-based survey was conducted among nephrologists globally focusing on various management strategies used in IgAN. Results: A total of 422 nephrologists responded to the initial survey and 339 to the follow-up survey. Of the nephrologists, 13.7% do not get MEST-C scores in biopsy reports; 97.2% of nephrologists use renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEi) / angiotensin receptor blockers (ARB) as initial treatment. Other supportive treatments commonly employed are fish oil (43.6%) and sodium-glucose co-transporter-2 (SGLT2) inhibitors (48.6%) with regional differences. Immunosuppression is generally (92.4%) initiated when proteinuria >1 g/d persists for ≥3 months.Main considerations for initiating immunosuppression are level of proteinuria (87.9%), estimated glomerular filtration rate (eGFR) decline (78.7%), lack of response to RAAS blockade (57.6%) and MEST-C score (64.9%). Corticosteroids (89.1%) are universally used as first-line immunosuppression; mycophenolate mofetil is commonly used in resistant patients (49.3%). Only 30.4% nephrologist enroll patients with persistent proteinuria >1 g/d in clinical trials. Nephrologists in Europe (63.6%), North America (56.5%), and Australia (63.6%) are more likely to do so compared to South America (31.3%) and Asia (17.2%). Only 8.1% nephrologists in lower-middle income countries (LMICs) enroll patients in clinical trials, though 40% of them are aware of such trials in their nations. Conclusion: Although most nephrologists agree on common parameters to assess clinical severity of IgAN, use of RAAS blockade, and blood pressure control, there is heterogeneity in use of other supportive therapies and initiation of immunosuppression. There is reluctance to enroll patients in clinical trials with novel treatments, principally in LMICs.

Clinical Profile of Nonproteinuric Kidney Disease in Type 2 Diabetic Patients in India.

Background: Diabetic kidney disease (DKD) is the commonest cause of end-stage renal disease (ESRD) across the world. Development of microalbuminuria is the earliest marker of DKD and predicts progressive decline in estimated glomerular filtration rate (eGFR). However, recent evidence has suggested that a significant proportion of type 2 diabetic patients have chronic kidney disease (CKD) without proteinuria. Methods: In this single-center, prospective observational study, 400 consecutive type 2 diabetic patients with either overt proteinuria (>500 mg/day) and/or renal dysfunction eGFR <60 ml/min/1.73 m2) were recruited. Baseline demographic and clinical data were recorded. eGFR and proteinuria were recorded at 6 months and 1 year. Patients with proteinuric (proteinuria >0.5 g/day) and nonproteinuric phenotypes were compared for progression of renal dysfunction in terms of doubling of serum creatinine and need for dialysis. Results: In our study cohort, 106 (26.5%) were nonproteinuric. Both the groups were similar in terms of gender, duration of diabetes, comorbidities, body mass index (BMI), blood pressure control, and glycemic control. The nonproteinuric group was older (56.5 ± 2.1 vs. 54.7 ± 11.6 years, P = 0.012), had lesser prevalence of diabetic retinopathy (49 [46.2%] vs. 218 [74.1%], P < 0.001), higher hemoglobin levels (11.3 ± 1.7 vs. 10.5 ± 2.0 g/dl, P < 0.001), and higher cholesterol levels (169.3 ± 43.3 vs 157.1 ± 58.1 mg/dl, P = 0.025). The nonproteinuric phenotype had higher eGFR at baseline, 6 months, and 1 year. However, doubling of serum creatinine (10 [9.4%] vs. 48 [16.3%]) and progression to ESRD (5 [4.7%] vs. 19 [6.5%], P = 0.159) were not different between the two phenotypes. Conclusion: Nonproteinuric DKD is common. Patients with nonproteinuric DKD tend to be older with a slower decline in eGFR.

A photoluminescence assay with a portable device for rapid, sensitive and selective detection of europium and terbium.

Rare earth elements are essential in many real-life applications, but their steady supply is being affected by multiple challenges. The recycling of lanthanides from electronic and other waste is thus gaining momentum which makes the detection of lanthanides with high sensitivity and selectivity a critical area of research. We now report a paper-based photoluminescent sensor for the rapid detection of terbium and europium with low detection limit (nM), which has the potential to facilitate recycling processes.

Association of vitamin D status with disease severity and outcome in Indian patients with IgA nephropathy.

BACKGROUND: Vitamin D deficiency has been examined as a risk factor for severity and progression of kidney disease due to its immunomodulatory effects. There is paucity of data about its impact in IgA nephropathy (IgAN). METHODS: In a retrospective cohort study, 25 (OH) vitamin D assay was performed in bio-banked baseline serum samples collected during kidney biopsy of 105 adult patients with primary IgAN diagnosed between 2015 and 2019. A level of < 10 ng/mL was defined as Vitamin D deficiency. RESULTS: Mean age of patients was 34 ± 10.6 years, 69.5% were males. Mean baseline 25(OH) Vitamin D levels was 15.9 ± 11.9 ng/mL and 41(39%) patients had vitamin D deficiency. Serum albumin level was lower in vitamin D deficient patients compared to those who had higher vitamin D levels (3.7 ± 0.9 vs 4.1 ± 0.7 g/dl, p = 0.018)but there was no significant difference in baseline proteinuria and eGFR. Crescentic lesions were more frequent in vitamin D deficient group (19.5% vs 6.3%, p = 0.022). At median follow up of 21.5 months (6 - 56 months), there was no difference in remission (68.3% vs 65.6%, p = 0.777) and disease progression (12.5% vs 9.4%, p = 0.614) in those with and without Vitamin D deficiency respectively. On multivariate cox proportional hazard analysis, vitamin D deficiency was not a significant risk factor for renal survival (HR-1.79, 95% confidence interval:0.50-6.34, p = 0.368). CONCLUSION: There was no association between vitamin D deficiency and disease profile as well as renal outcome in Indian patients with IgAN.

Utility and patient acceptance of telemedicine in nephrology.

PURPOSE: There is an increasing burden of kidney diseases worldwide and access to specialist care is limited. Telemedicine, has been relatively less used in developing countries like India. The current study aims to assess the feasibility and acceptance of telenephrology services at our institute, a public hospital. METHODS: A total of 150 patients were selected by stratified random sampling from the list of attendees who had undergone both in-person outpatient consultation and telenephrology consultation. Patient's attitude towards, and knowledge and acceptance of telenephrology services were evaluated. RESULTS: The average age of the study cohort was 42.52 ± 15.1 years. More than one-third (39.3%) of our patients belonged to the lower middle socioeconomic class. The median distance traveled to reach our outpatient clinic was 113.5 km (3-2249 km). Patients reported lost workdays in 54.7% cases. The majority (95%) of patients managed to consult through teleservices successfully. Ninety percent of the patients gave a satisfaction score of 4 (out of 5) or above for their tele-consultation experience. The most important perceived benefit of teleconsultation was the reduced risk of infection (40.6%) followed by economic benefits (32%). The major disadvantage (36%) was the absence of physical examination. A combination of physical and telenephrology services was the option preferred by 84% of the patients. CONCLUSION: In developing countries like India, with the majority of the population residing outside major cities and with limited medical access, telenephrology has a huge potential to provide quality nephrology care to the remotest parts of the country.

Efficacy of Bacillus Calmette-Guérin (BCG) Vaccination in Reducing the Incidence and Severity of COVID-19 in High-Risk Population (BRIC): a Phase III, Multi-centre, Quadruple-Blind Randomised Control Trial.

INTRODUCTION: Universal coverage of vaccines alone cannot be relied upon to protect at-risk populations in lower- and middle-income countries against the impact of the coronavirus disease 2019 (COVID-19) pandemic and newer variants. Live vaccines, including Bacillus Calmette-Guérin (BCG), are being studied for their effectiveness in reducing the incidence and severity of COVID-19 infection. METHODS: In this multi-centre quadruple-blind, parallel assignment randomised control trial, 495 high-risk group adults (aged 18-60 years) were randomised into BCG and placebo arms and followed up for 9 months from the date of vaccination. The primary outcome was the difference in the incidence of COVID-19 infection at the end of 9 months. Secondary outcomes included the difference in the incidence of severe COVID-19 infections, hospitalisation rates, intensive care unit stay, oxygen requirement and mortality at the end of 9 months. The primary analysis was done on an intention-to-treat basis, while safety analysis was done per protocol. RESULTS: There was no significant difference in the incidence rates of cartridge-based nucleic acid amplification test (CB-NAAT) positive COVID-19 infection [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.54-2.14] in the two groups, but the BCG arm showed a statistically significant decrease in clinically diagnosed (symptomatic) probable COVID-19 infections (OR 0.38, 95% CI 0.20-0.72). Compared with the BCG arm, significantly more patients developed severe COVID-19 pneumonia (CB-NAAT positive) and required hospitalisation and oxygen in the placebo arm (six versus none; p = 0.03). One patient belonging to the placebo arm required intensive care unit (ICU) stay and died. BCG had a protective efficacy of 62% (95% CI 28-80%) for likely symptomatic COVID-19 infection. CONCLUSIONS: BCG is protective in reducing the incidence of acute respiratory illness (probable symptomatic COVID-19 infection) and severity of the disease, including hospitalisation, in patients belonging to the high-risk group of COVID-19 infection, and the antibody response persists for quite a long time. A multi-centre study with a larger sample size will help to confirm the findings in this study. CLINICAL TRIALS REGISTRY: Clinical Trials Registry India (CTRI/2020/07/026668).

The Bacillus Calmette­Guérin (BCG) vaccine has been studied previously in several settings, including reducing childhood mortalities due to viral infections and induction of trained immunity and reducing upper respiratory tract infections and pneumonia in older adults. This multi-centre trial has tried to evaluate the efficacy of BCG revaccination in reducing the incidence and severity of COVID-19 infections in adults between 18 and 60 years of age belonging to the high-risk group owing to the presence of comorbidities including diabetes, chronic kidney disease, chronic liver disease and chronic lung diseases. A single dose of BCG vaccine produced significantly high titres of BCG antibodies lasting for six months. While there was no significant reduction in the incidence of COVID-19 infection, there was an 8.4% reduction in the incidence of symptomatic COVID-19 disease at the end of 9 months of follow-up. In addition, there were significantly fewer severe COVID-19 infections requiring hospital stay and oxygen support. However, the overall numbers of severe COVID-19 infections were low. Thus, the study shows that BCG can protect against symptomatic and severe COVID-19 disease. However, it might not reduce the incidence of new infections. The study results are significant for low- and middle-income countries without adequate coverage of primary doses of COVID-19 vaccination, let alone the booster doses. Future studies should evaluate the BCG vaccine's efficacy as a booster compared with routine COVID-19 vaccine boosters.

Does Laparoscopic Omentectomy Reduce CAPD Catheter Malfunction: A Three-arm Pilot Randomized Trial.

Introduction: Catheter malfunction secondary to omental wrapping is a frequent complication of continuous ambulatory peritoneal dialysis (CAPD). Of the various methods of peritoneal dialysis catheter insertion (PDCI), open surgical insertion under local anesthesia is most widely practiced. Laparoscopic omentectomy is often undertaken as a salvage procedure in case of malfunctioning catheters. However, there is no randomized controlled trial (RCT) to evaluate the role of prophylactic laparoscopic omentectomy on catheter function. This pilot RCT was undertaken to evaluate the impact of laparoscopic omentectomy on the incidence of catheter malfunction. Materials and Methods: Consecutive patients were randomized into three groups: laparoscopic PDCI with omentectomy (Group A), laparoscopic PDCI without omentectomy (Group B) and open surgical PDCI (Group C). The primary outcome was the incidence of catheter malfunction at 6 weeks and 3 months. Results: Forty-one patients completed follow-up, with 16, 11, and 14 patients in Groups A, B, and C, respectively. Incidence of catheter malfunction was 6.2%, 27.3%, and 14.3% in Groups A, B, and C, respectively, at 6 weeks and 6.2%, 36.4%, and 21.4% at 3 months, respectively. In patients with previously failed catheter insertion (n = 23), malfunction at 3 months was 8.3% (1/12) in patients who had omentectomy, compared with 45.5% (5/11) in those who did not (P = 0.069). Operating time was significantly higher (P < 0.001) in Group A. Conclusions: Laparoscopic omentectomy may be associated with a lower incidence of catheter malfunction, especially in patients with previously failed peritoneal dialysis catheter. Data from this pilot RCT can be used to design a large trial with an adequate number of patients.

The International IgA Nephropathy Network Prediction Tool Underestimates Disease Progression in Indian Patients.

Introduction: International IgA nephropathy (IgAN) network (IIgANN) prediction tool was developed to predict risk of progression in IgAN. We attempted to externally validate this tool in an Indian cohort because the original study did not include Indian patients. Methods: Adult patients with primary IgAN were stratified to low, intermediate, higher, and highest risk groups, as per the original model. Primary outcome was reduction in estimated glomerular filtration rate (eGFR) by >50% or kidney failure. Both models were evaluated using discrimination: concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, R2d, Kaplan-Meier survival curves between risk groups and calibration plots. Reclassification with net reclassification improvement and integrated discrimination improvement (IDI) was used to compare the 2 models with and without race. Results: A total of 316 patients with median follow-up of 2.8 years had 87 primary outcome events. Both models with and without race showed reasonable discrimination (C-statistics 0.845 for both models, R2d 49.9% and 44.7%, respectively, and well-separated survival curves) but underestimated risk of progression across all risk groups. The calibration slopes were 1.234 (95% CI: 0.973-1.494) and 1.211 (95% CI: 0.954-1.468), respectively. Both models demonstrated poor calibration for predicting risk at 2.8 and 5 years. There was limited improvement in risk reclassification risk at 5 and 2.8 years when comparing model with and without race. Conclusion: IIgANN prediction tool showed reasonable discrimination of risk in Indian patients but underestimated the trajectory of disease progression across all risk groups.

Ultrasound-guided Percutaneous Embolization of Post Renal Biopsy Gonadal Artery Pseudoaneurysm.

Hemorrhage is the most frequently encountered post renal biopsy complication; reported in 12% to 14% of patients. Although the vast majority of these are due to renal artery injury, involvement of gonadal arteries is also rarely seen. These may be managed by the endovascular route, which has several limitations in this subset of patients. We report a case of a 69-year-old male with rapidly progressive glomerulonephritis, who underwent renal biopsy and developed a testicular artery pseudoaneurysm (PA). Successful embolization of this PA was performed under ultrasound guidance using a direct percutaneous approach. This is the first such case reported in the literature.

Metabolic acidosis in the initial 6 months after renal transplantation: A prospective study.

BACKGROUND: There is limited information about the incidence of metabolic acidosis (MA) after renal transplantation. This single centre prospective study aimed to delineate the incidence and risk factors of MA in the first 6 months after renal transplantation (RTX). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Patients who underwent RTX between November 2018 and July 2020 were monitored with weekly measurement of serum bicarbonate level for 6 months and those who were diagnosed with MA were evaluated further to characterize the type of MA. RESULTS: One hundred and twenty-five patients were included in the study, 89 (71.2%) of whom developed MA. Seventy-two patients developed MA in the first month, 11 during the 2-3 months and 6 between 4 and 6 months after transplantation. Of the 89 patients, 55(61.8%) had type 1 renal tubular acidosis (T1RTA), 27 (30.3%) had type 2 RTA (T2RTA) and 7 (7.9%) type 4 RTA (T4RTA). Two patient who had T1RTA, subsequently developed high anion gap MA following severe graft rejection. On stepwise multivariate regression analysis, serum creatinine at time of diagnosis of MA [OR (95% CI): 12.02 (1.79 to 80.59), p = .01] and high tacrolimus C0 levels [OR (95% CI): 2.43 (1.0 to 5.90), p = .049], were independent risk factors for MA. CONCLUSION: There is a high incidence of MA in the initial 6 months post-transplant with serum creatinine and high tacrolimus C0 levels being independent risk factors.

Characterizing predictors of non-diabetic kidney disease (NDKD) in diabetic patients.

BACKGROUND: Diabetic kidney disease (DKD) is the chief cause of renal involvement in diabetic patients. It is primarily a clinical diagnosis. Non-diabetic kidney disease (NDKD) may be missed if they are not biopsied. In this study, we describe the spectrum of NDKD and evaluate the predictors considered for planning a biopsy in diabetic patients with kidney disease. METHODS: In a retrospective cohort study, diabetic patients who underwent kidney biopsy at our centre between May 2006 and July 2019 were evaluated for NDKD. RESULTS: 321 diabetic patients who underwent kidney biopsy were analyzed. Mean age was 49.3 ± 12.4 years and 71% were males. 75.8% patients had hypertension and 25.2% had diabetic retinopathy. Based on the kidney biopsy, patients were classified as DKD-127 (39.6%), NDKD-179(55.8%) and combined DKD + NDKD-15(4.7%). Overall, the most commonly diagnosed pathology was membranous nephropathy-MN (17%), followed by IgA nephropathy (16.0%) and focal segmental glomerulosclerosis-FSGS (14.9%). In patients with DKD + NDKD, IgA nephropathy (53.3%) was predominant. 165 (51.4%) patients had a diagnosis potentially amenable to a specific therapy. On multivariate analysis, female gender [OR 2.07 (1.08-3.97), p = 0.02], absence of diabetic retinopathy [OR 7.47 (3.71-15), p < 0.001] absence of hypertension [OR 3.17 (1.56-6.45), p = 0.001] and duration of diabetes ≤ 24 months [OR 3.67(1.97-6.84), p < 0.001], were independent predictors for NDKD while the absence of nephrotic range proteinuria [OR 1.73 (0.98-3.05), p 0.05] showed a trend towards significance. CONCLUSION: Astute use of kidney biopsy can detect potentially treatable NDKD in a large number of diabetic patients with glomerular diseases being the predominant diagnosis. A combination of risk factors needs to be considered to guide the need for kidney biopsy in diabetic patients.

Supportive Management of IgA Nephropathy With Renin-Angiotensin Blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) Study.

INTRODUCTION: Renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) is first-line therapy for IgA nephropathy (IgAN). There is a paucity of information on the predictors and magnitude of response to this treatment. METHODS: In a prospective study, treatment-naive patients with IgAN with urinary protein ≥ 1 g/d and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2 received supportive treatment including ACEi (ramipril) or ARB (losartan) in patients intolerant to ACEi, and optimal blood pressure (BP) control to ≤130/80 mm Hg, with a follow-up of 6 months. The primary outcome was remission of proteinuria. Complete remission (CR) was defined as proteinuria < 0.5 g/d and partial remission (PR) as proteinuria < 1g/d with at least a 50% decline from the baseline with stable renal function (≤ 25% reduction in eGFR). RESULTS: A total of 96 patients were analyzed, with a mean age of 33.3 ± 10.2 years, baseline eGFR 74.0 ± 30.9 ml/min per 1.73 m2, and urinary protein 2.6 ± 1.2 g/d. In all, 71.9% patients received ≥ 75% of the maximum approved dose of ACEi/ARB. Remission was observed in 36.5% (CR, 6.3%) patients at 3 months and in 55.2% (CR, 31.3%) at 6 months. Patients who failed to achieve remission had lower baseline eGFR (P = 0.002) and serum albumin levels (P< 0.001), asymptomatic hyperuricemia (P < 0.001), and higher proteinuria (P = 0.076). E1 (P= 0.053) and T1/T2 (P = 0.009) lesions were more frequent on histology. The ACEi/ARB had to be discontinued in 17 (17.7%) patients. These patients were older (P= 0.085) with lower eGFR (P < 0.002) and serum albumin levels (P = 0.001) and more E1 (P = 0.012) and T1/T2 (P = 0.001) lesions on histology. CONCLUSION: Meticulous supportive therapy with optimal use of ACEi/ARB achieved remission in half of IgAN patients in this study. Increasing the treatment duration to 6 months improved remission rates. Patients with severe clinical and histological disease were less likely to tolerate and respond to treatment with RAS blockade.

Pulmonary infections after renal transplantation: a prospective study from a tropical country.

Pulmonary infection is a leading cause of morbidity and mortality in renal transplant recipients. In a prospective study, we characterized their epidemiology in a tropical country with high infectious disease burden. Adult renal transplant recipients presenting with pulmonary infections from 2015 to 2017 were evaluated using a specific diagnostic algorithm. 102 pulmonary infections occurred in 88 patients. 32.3% infections presented in the first year, 31.4% between 1 and 5, and 36.3% beyond 5 years after transplantation. Microbiological diagnosis was established in 69.6%, and 102 microorganisms were identified. Bacterial infection (29.4%) was most common followed by tuberculosis (23.5%), fungal (20.6%), Pneumocystis jiroveci (10.8%), viral (8.8%), and nocardial (6.9%) infections. Tuberculosis(TB) and bacterial infections presented throughout the post-transplant period, while Pneumocystis (72.7%), cytomegalovirus (87.5%) and nocardia (85.7%) predominantly presented after >12 months. Fungal infections had a bimodal presentation, between 2 and 6 months (33.3%) and after 12 months (66.7%). Four patients had multi-drug resistant(MDR) TB. In 16.7% cases, plain radiograph was normal and infection was diagnosed by a computed tomography imaging. Mortality due to pulmonary infections was 22.7%. On multivariate Cox regression analysis, use of ATG (HR-2.39, 95% CI: 1.20-4.78, P = 0.013), fungal infection (HR-2.14, 95% CI: 1.19-3.84, P = 0.011) and need for mechanical ventilation (9.68, 95% CI: 1.34-69.82, P = 0.024) were significant predictors of mortality in our patients. To conclude, community-acquired and endemic pulmonary infections predominate with no specific timeline and opportunistic infections usually present late. Nocardiosis and MDR-TB are emerging challenges.

Multilocus Sequence Typing of Clinical Isolates of Cryptococcus from India.

Cryptococcosis is a life-threatening infection caused by Cryptococcus neoformans and C. gattii species complex. In the present study, to understand the molecular epidemiology of 208 clinical isolates of Cryptococcus from different parts of India, multilocus sequence typing (MLST) using ISHAM MLST consensus scheme for C. neoformans/C. gattii species complex was used. MLST analysis yielded a total of 10 Sequence Types (STs)-7 STs for C. neoformans and 3 for C. gattii species complex. The majority of isolates identified as C. neoformans belonged to molecular type VNI with predominant STs 31 and 93. Only 3 isolates of C. gattii species complex were obtained, belonging to ST58 and ST215 of VGI and ST69 of VGIV. Phylogenetic analysis revealed less diversity among the clinical Indian isolates compared to the global MLST database. No association between prevalent STs and HIV status, geographical origin or minimum inhibitory concentration (MIC) could be established.

An inexpensive and sensitive turn-on luminescence protocol for sensing formaldehyde.

Formaldehyde (FA), the simplest and most widely-used aldehyde, can pose serious health issues when present at elevated concentrations. Here, we report a "turn-on" terbium photoluminescence method for the efficient detection of FA. A pro-sensitizer molecule was designed and synthesised, which releases the sensitizer in the presence of FA inside the terbium cholate hydrogel matrix, resulting in a "turn-on" luminescence response. The introduction of a paper-based sensing approach makes the protocol simpler and cost-effective, and has a detection limit as low as 100 nM.