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.

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.

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.

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.

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.

Spectrum of biopsy-proven renal disease in northern India: A single-centre study.

AIM: Pattern of kidney diseases varies across geographies due to multiple factors. There is a paucity of information from South Asia due to the absence of nationwide/regional biopsy registries. This study aimed to delineate the spectrum of renal parenchymal diseases in our region. METHODS: Records of kidney biopsies done in our nephrology department between 2006 and 2016 were analysed. Clinico-pathological correlation was done from the available records. RESULTS: Of the 3275 biopsy evaluated, 61.9% were males, and mean age was 33.2 ± 14.2 years. 6.2% patients were elderly (age ≥ 60 years). Nephrotic syndrome (60.3%) was the commonest indication for biopsy. On histology, 73.0% patients had primary glomerulonephritis (GN), 15.5% secondary GN, 5.3% tubulo-interstitial and 3.7% vascular disease. Focal segmental glomerulosclerosis (FSGS) was the commonest primary GN accounting for 18.2% of all GNs, followed by minimal change disease (16.8%), membranous nephropathy (MN) (16.0%) and IgA nephropathy (10.4%). Lupus nephritis (10.6%) and amyloidosis (3.7%) were the commonest secondary GN. The commonest cause of nephrotic syndrome was minimal change disease (22.9%), acute nephritic syndrome was lupus nephritis (30.6%), rapidly progressive renal failure was pauci-immune crescentic GN (24.5%). IgA nephropathy was the commonest etiology of asymptomatic urinary abnormalities (26.3%) and gross haematuria (50%). About 60.9% patients of undetermined chronic kidney disease had glomerular diseases, and 13.6% had chronic tubulointerstitial nephritis. Lupus nephritis and acute cortical necrosis were significantly more common in females compared with males. CONCLUSION: This is one of the largest cohorts of kidney biopsies from India, and it delineates the unique features and differences in the pattern of kidney disease in our population.

Significance of serum galactose deficient IgA1 as a potential biomarker for IgA nephropathy: A case control study.

BACKGROUND: IgA nephropathy(IgAN) is a common glomerular disease with a higher risk of progression to end stage renal disease (ESRD) in certain ethnic populations. Since galactose deficient IgA1(Gd-IgA1) is a critical molecule in its pathogenesis, it has generated interest as a biomarker for this disease. METHODS: We measured serum Gd-IgA1 levels using a non- lectin based enzyme linked immunoassay(ELISA) in 136 immunosuppression naïve patients with primary IgAN and 110 controls(60-non IgA glomerular diseases, 50-healthy volunteers). RESULTS: Median serum Gd-IgA1 levels were significantly higher in IgAN patients [13135.6(2723.3,59603.8)ng/ml] compared to those with non IgA glomerular disease [4954.8(892.9,18256.2) ng/ml] and healthy controls [6299.5(1993.2,19256) ng/ml] and this was observed even after log transformation and adjustment for age and gender(p<0.0001). Considering a cut-off value of serum Gd-IGA1≥7982.1ng/ml, the sensitivity for diagnosing IgAN compared to healthy controls was 74.3% and specificity was 72.0% with a positive predictive value of 87.8% and negative predictive value of 50.7%. The serum Gd-IgA1 level did not co-relate with baseline estimated glomerular filtration rate, urine protein creatinine ratio and the M, E, S, T and C scores on renal biopsy. The renal survival (absence of >30% decrease in eGFR, ESRD or death) was lower in patients with higher serum Gd-IgA1 levels(≥7982ng/ml) than those who had lower levels but it was not statistically significant(p = 0.486). CONCLUSION: Serum Gd-IgA1 level is higher in IgAN patients compared to non-IgA glomerular diseases and healthy controls and has a good positive predictive value for diagnosis. However, it does not correlate with clinical and histological characteristics of disease severity and does not predict disease progression.

Impact of estimated glomerular filtration rate on diabetic macular edema.

PURPOSE: Diabetic macular edema (DME) is a major cause of visual impairment in patients with diabetes and is influenced by various systemic factors. This study evaluates the effect of renal status on DME using estimated glomerular filtration rate (eGFR) as a study marker. METHODS: This was a prospective observational cross-sectional study. One hundred and ninety-five patients of diabetic retinopathy (DR) were included. Group 1 had patients of DR without DME (n = 100), and group 2 had patients of DR with DME (n = 95). All patients were evaluated for DR/DME-related risk factors. eGFR was calculated in all patients. Spectral domain optical coherence tomography (SDOCT) was done to identify the various patterns and severity of DME. RESULTS: Group 2 patients had significantly higher comorbidities than those in group 1 (p < 0.001). Hba1c, total cholesterol, triglycerides, LDL/HDL ratio, systolic and diastolic blood pressures were significantly higher in group II (p < 0.001 in each). There was no significant difference between the groups in terms of blood urea, serum creatinine or eGFR. eGFR did not show a significant association with a specific SDOCT pattern or severity of DME. CONCLUSION: Comorbidities are more common and more severe in patients with DME. However, eGFR as a marker was not useful in predicting either the severity or pattern of DME. eGFR, in its present form, may not be useful in the evaluation and management of patients with DME.

BK polyomavirus infection after renal transplantation: Surveillance in a resource-challenged setting.

BACKGROUND: There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India. METHODS: We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12 months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (≥10 000 copies/mL) detected ≥2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction. RESULTS: All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12 months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6 months. Nine (14.5%) patients had SSBKV. There was no biopsy-proven BKVAN. At the end of 1 year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV. CONCLUSION: Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6 months. Most clear their viremia by 12 months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients.

Clinical and histopathologic profile of patients with primary IgA nephropathy seen in a tertiary hospital in India.

BACKGROUND: IgA nephropathy (IgAN) is known to have an aggressive course in Asians. There is a paucity of data regarding the Oxford classification pattern of Indian patients with IgAN. This study aims to characterize the clinical and histopathologic profile of these patients. METHODS: All patients diagnosed to have primary IgAN by kidney biopsy in the nephrology department from July 2009 to July 2014 were included in this study. All kidney biopsies were reviewed and the MEST score was assigned as per the Oxford classification. The clinical features and Oxford classification score of patients were characterized. RESULTS: Nephrotic range proteinuria (NRP) (65/103, 63.1%) with or without edema was the commonest presentation. 67.0% patients had eGFR ≥ 60 mL/min and 16.5% patients had eGFR < 30 mL/min. Of the 103 patients, 80 (77.7%) had M1, 10 (9.7%) had E1, 45 (43.7%) had S1 and 41 (39.8%) had T1/T2 lesions by the Oxford criteria and 11 (10.7%) patients had crescents. 62 patients had eGFR ≥ 30 mL/min and follow up for at least 6 months (median -17.7 (6-65.1) months) of whom 52(83.9%) had received ACEi/ARBs and 38 (61.3%) had received immunosuppression. 11/62 (17.7%) patients developed renal worsening in this period of which 7 (11.3%) developed end stage kidney disease (ESKD). CONCLUSION: Indian patients with primary IgA nephropathy have a unique profile. They commonly present with nephrotic range proteinuria. A significant proportion of these patients have normal renal function despite heavy proteinuria. Mesangial proliferative lesions are predominant with a paucity of endocapillary proliferation and crescents compared to other Asian populations. Immunosuppressive use is more common in Indian patients.

Pattern of biopsy-proven kidney disease in the elderly in a tertiary care hospital in India: a clinicopathological study.

BACKGROUND: An aging population is an important demographic issue in India. The knowledge base about kidney diseases among the elderly Indians is inadequate. We aim to delineate the clinical profile and spectrum of biopsy-proven kidney disease in elderly patients. METHODS: Records of all elderly patients (≥60 years) who had undergone kidney biopsy in the nephrology department from January 2010 to December 2014 were reviewed. Their clinical details and laboratory investigations at the time of biopsy were noted. Details of kidney biopsy were recorded from their biopsy reports. RESULTS: In total, 1728 patients underwent kidney biopsy during this period and 124 were elderly (7.2%). Their mean age was 64.9 ± 4.9 years, and they were predominantly males (63.7%). Mean serum creatinine was 3.0 ± 2.8 mg/dl, proteinuria was 4.0 ± 2.7 g/day, and 39.5% had microscopic hematuria. The most common indications for biopsy were nephrotic syndrome (NS)--39.5% and acute kidney injury/rapidly progressive glomerulonephritis (AKI/RPGN)--24.2%. Another 8.1% patients had NS with AKI. MN (39.0%) was the chief cause of NS, and pauci-immune crescentic glomerulonephritis (GN) (28.2%) was the leading cause of AKI/RPGN. MN, pauci-immune crescentic GN and acute on chronic tubulointerstitial nephritis (A/CTIN) and acute tubular injury (ATI) were more common in the elderly, while MCD, FSGS, IgA nephropathy and lupus nephritis were more frequent in the younger patients. 68.5% of the elderly patients biopsied were diagnosed with a renal disease which was potentially amenable to specific treatment. CONCLUSION: The spectrum of biopsy-proven kidney disease in the elderly Indians seen in our tertiary care hospital varies from the younger population. Kidney biopsy provides useful information with therapeutic and prognostic implications in these patients. The percentage of elderly patients among the total biopsied population is low in India, and these patients present late with renal dysfunction. Prospective studies are needed to assess the outcome of the commonly seen kidney diseases in elderly patients.

Monoclonal gammopathy of renal significance with light-chain deposition disease diagnosed postrenal transplant: a diagnostic and therapeutic challenge.

Patients with light-chain deposition disease (LCDD) frequently do not meet criteria for myeloma. In such cases, despite low tumor burden, the circulating monoclonal immunoglobulins cause renal damage, are responsible for post-transplant recurrence, and are rightly categorized as monoclonal gammopathy of renal significance (MGRS) requiring chemotherapy. A 65-year male with uncharacterized nodular glomerulopathy presented with proteinuria 3 years postrenal transplant. His allograft biopsies were diagnostic of light-chain deposition disease (likely recurrent), and in the absence of myeloma, he was labeled as MGRS. Based on the limited literature available, he was treated with bortezomib which resulted in normalization of serum-free light-chain ratios and resolution of proteinuria. He, however, later succumbed to complications of chemotherapy. This case highlights the diagnostic difficulties in LCDD, the importance of an accurate pretransplant diagnosis, and treatment of the malignant clone, in the absence of which post-transplant management of recurrence is challenging with poor outcomes.

Prevalence of systemic co-morbidities in patients with various grades of diabetic retinopathy.

BACKGROUND & OBJECTIVES: Though diabetes affects multiple organs, most studies highlight the occurence of only one complication in isolation. We conducted a hospital-based study to estimate the co-existence of significant systemic co-morbid conditions in patients with varying grades of diabetic retinopathy. METHODS: A total of 170 consecutive patients with diabetic retinopathy were prospectively recruited for the study between June 2009 to June 2010 at a tertiary care eye centre in north India. Retinopathy was graded by fundus biomicroscopy and fundus photography and classified into three categories (mild-moderate nonproliferative retinopathy, proliferative retinopathy requiring only laser and proliferative retinopathy requiring surgery). Nephropathy was classified by calculating the six variable estimated glomerular filtration rate (eGFR) for all patients. Nerve conduction studies and clinical assessment were used to determine presence of neuropathy. Co-existence of macrovascular disease and peripheral vascular disease was also ascertained. RESULTS: The percentages of patients with overt nephropathy in the three groups were 19.2, 38.0 and 41.2, respectively. Significant linear trends were observed for serum creatinine (P=0.004), albumin (P=0.017) and eGFR (P=0.030). A higher per cent had abnormal nerve conduction on electrophysiology than that diagnosed clinically (65.4 vs. 44.2, 76.0 vs. 40.0 and 64.8 vs. 48.6, respectively). The odds ratio (95% CI) for co-existence of nephropathy, neuropathy, CVA (cerebrovascular accidents) and PVD (peripheral vascular disease) was 2.9, 0.9, 4.8 and 3.5, respectively. Independent of retinopathy severity, patients with clinically significant macular oedema (CSME) had a higher percentage of nephropathy ( p0 < 0.005). INTERPRETATION & CONCLUSIONS: The co-existence of overt nephropathy, nerve conduction based neuropathy and macrovascular co-morbidity in patients with early grades of diabetic retinopathy was significant. Screening for overt nephropathy by eGFR should be considered in all patients with clinically significant macular oedema.

Acute renal failure in a patient with acute lymphoblastic leukemia: a rare cause.

A young adult was diagnosed to have acute lymphoblastic leukemia, T-cell immunophenotype and was initiated on chemotherapy. He presented with acute renal failure two days after the completion of his induction regimen. A renal biopsy showed features of necrotizing crescentic glomerulonephritis (GN). Serology for c-anti-neutrophil cytoplasmic antibody (ANCA) was positive and a final diagnosis of ANCA-associated necrotizing crescentic GN was made. Aggressive immunosuppression could not be used due to the presence of nosocomial pneumonia and the patient expired 26 days after the renal biopsy diagnosis. We report for the first time the association of acute lymphoblastic leukemia with crescentic GN and, hence, expand the list of malignancy-related ANCA-positive GN.

Bone marrow cells contribute to tubular epithelium regeneration following acute kidney injury induced by mercuric chloride.

BACKGROUND & OBJECTIVES: Acute tubular necrosis (ATN) caused by renal ischaemia, renal hypo-perfusion, or nephrotoxic substances is the most common form of acute kidney injury (AKI). There are a few treatment options for this life-threatening disease and the mortality rate exceeds 50 per cent. In critical cases of AKI the only option is renal transplantation. In the present study we evaluated whether bone marrow cells (BMCs) are involved in regeneration of kidney tubules following acute tubular necrosis in the mouse. METHODS: Six to eight week old C57BL6/J and congenic enhanced green fluorescence protein (eGFP) mice were used. The relative contributions of eGFP-expressing BMCs were compared in two different approaches to kidney regeneration in the mercuric chloride (HgCl 2 )-induced mouse model of AKI: induced engraftment and forced engraftment. In vitro differentiation of lineage-depleted (Lin - ) BMCs into renal epithelial cells was also studied. RESULTS: In the forced engraftment approach, BMCs were found to play a role in the regeneration of tubules of renal cortex and outer medulla regions. About 70 per cent of donor-derived cells expressed megalin. In vitro culture revealed that Lin - BMCs differentiated into megalin, E-cadherin and cytokeratin-19 (CK-19) expressing renal epithelial cells. INTERPRETATION & CONCLUSIONS: The present results demonstrate that Lin - BMCs may contribute in the regeneration of renal tubular epithelium of HgCl 2 -induced AKI. This study may also suggest a potential role of BMCs in treating AKI.