Novel mutation patterns in children with steroid-resistant nephrotic syndrome.

Background: Idiopathic nephrotic syndrome (NS) in children poses treatment challenges, with a subset developing steroid-resistant nephrotic syndrome (SRNS). Genetic factors play a role, yet data on paediatric SRNS genetics in India are scarce. We conducted a prospective study using whole-exome sequencing to explore genetic variants and their clinical correlations. Methods: A single-centre prospective study (October 2018-April 2023) enrolled children with SRNS, undergoing renal biopsy and genetic testing per institutional protocol. Clinical, histological, and genetic data were recorded. DNA isolation and next-generation sequencing were conducted for genetic analysis. Data collection included demographics, clinical parameters, and kidney biopsy findings. Syndromic features were evaluated, with second-line immunosuppressive therapy administered. Patient and renal outcomes are presented for patients with and without genetic variants. Results: A total of 680 paediatric NS patients were analysed, with 121 (17.8%) having SRNS and 96 consent to genetic analysis. 69 (71.9%) had early SRNS, 27 (28.1%) late. Among participants, 62 (64.58%) had reportable genetic variants. The most common were in COL4A genes, with 20 (31.7%) positive. Renal biopsy showed focal segmental glomerulosclerosis in 31/42 (74%) with variants, 16/28 (57.1%) without variants. Second-line immunosuppressions varied, with CNIs the most common. Outcomes varied, with partial or complete remission achieved in some while others progressed to ESRD. Conclusion: The study underscores the importance of genetic analysis in paediatric SRNS, revealing variants in 65.7% of cases. COL4A variants were predominant. Variants correlated with varied renal outcomes, highlighting potential prognostic implications. These findings emphasize the value of personalized approaches and further research in managing paediatric SRNS.

Severe and Recurrent Acute Kidney Injury Following Dichlorvos Exposure - A Case Report.

Dichlorvos, an organophosphate compound, has the potential to cause acute kidney injury (AKI) besides its well-known neuromuscular complications. We report a case of severe-recurrent AKI that progressed to end-stage-renal-disease (ESRD) following accidental exposure to Dichlorvos. A 52-year-old male farmer presented with breathlessness after accidental exposure while spraying in the field. He required mechanical ventilation due to allergic pneumonitis and developed anuric AKI, requiring renal replacement therapy (RRT). Biopsy revealed severe acute tubulointerstitial nephritis (ATIN), which responded to steroids, and the patient became dialysis-independent by 4 weeks. Two weeks later, the patient had recurrent AKI requiring RRT. A repeat biopsy revealed severe ATIN. However, despite steroid treatment, he progressed to ESRD. Organophosphate compounds can cause renal injury with a wide spectrum of presentations, ranging from subclinical AKI to severe dialysis-dependent renal failure, which may eventually progress to end-stage renal disease.

Clinicopathologic Manifestations of Immunoglobulin A Nephropathy in a Northern Indian Cohort: A Mute Assassin with Delayed Diagnosis.

Introduction: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, but there is a marked geographic difference in its prevalence and prognosis. IgAN is known to have an aggressive course in Asians. However, its exact prevalence and clinicopathologic spectrum in North India are not well documented. Materials and Methods: The study included all patients aged above 12 years with primary IgAN on kidney biopsy from January 2007 to December 2018. Clinical and pathological parameters were noted. Two histopathologists independently reviewed all kidney biopsies, and MEST-C score was assigned as per the Oxford classification. Results: IgAN was diagnosed in 681 (11.85%) out of 5751 native kidney biopsies. The mean age was 32 ± 12.3 years, and the male to female ratio was 2.5:1. At presentation, 69.8% had hypertension, 68% had an estimated glomerular filtration rate (eGFR) of less than 60 ml/min, 63.2% had microscopic hematuria, and 4.6% had gross hematuria. The mean proteinuria was 3.61 ± 2.26 g/day, with 46.8% showing nephrotic range proteinuria and 15.2% showing nephrotic syndrome manifestation. Histopathologically, 34.4% of patients had diffuse global glomerulosclerosis. Oxford MEST-C scoring revealed M1 in 67%, E1 in 23.9%, S1 in 46.9%, T1/T2 in 33%, and crescents in 19.6% of biopsies. The mean serum creatinine was significantly higher in cases with E1, T1/2, and C1/2 scores (P < 0.05). Hematuria and proteinuria were significantly higher (P < 0.05) with E1 and C1/2 scores. Coexisting C3 was associated with higher serum creatinine at presentation (P < 0.05). Conclusion: IgAN patients with late presentation and advanced disease became less amenable to immunomodulation in our cohort. The implementation of point-of-care screening strategies, early diagnosis, and retarding disease progression should be prioritized in the Indian strategy.

Two Decades Outcomes of Posttransplant Immunoglobulin A Nephropathy in Live Donor Renal Transplantation.

Background: The data on long-term outcomes of posttransplant immunoglobulin A nephropathy (IgAN) are confounding and vary with geography and ethnicity worldwide. We aimed to study the long-term graft outcomes of patients with posttransplant IgAN in the northern Indian cohort. Methods: The long-term graft outcomes of 51 live donor renal transplant recipients with biopsy-proven posttransplant IgAN (recurrence/de novo) were analyzed. The risk factors for graft failure in the posttransplant IgA groups were analyzed using the Cox regression analysis. Results: Out of the total of 51 patients who had posttransplant IgAN, 40 patients had a biopsy-proven native kidney IgAN. The mean duration of the clinical presentation of posttransplant IgAN was 62.4 months (5.2 years) posttransplant. Proteinuria at the time of biopsy was 3.03 ± 2.2 g/day, and 41.2% had proteinuria of more than 3 g/day at the time of biopsy. The estimated 1, 5, 10, and 20 years patient survival was 98%, 95.4%, 75.9%, and 25.2%, respectively, and the estimated 1, 5, 10, and 20 years graft survival was 98%, 88.5%, 44.6%, and 11.9%, respectively, in patients who had posttransplant IgA. Many of the traditional risk factors associated with progression in native kidney IgAN, such as the degree of proteinuria, Oxford MEST (mesangial and endocapillary hypercellularity, segmental sclerosis, and interstitial fibrosis/tubular atrophy) scoring, recipient's age, and sex were not predictive of early graft failure among patients with posttransplant IgAN. In our cohort, the only significant graft failure predictor was serum creatinine at 5 years. Chronic antibody-mediated rejection (ABMR) was seen in 21.6% of patients with posttransplant IgAN. Whether this coexistence of chronic ABMR is an incidental finding or posttransplant IgAN predisposes to chronic ABMR requires further investigation. Conclusion: Posttransplant IgAN is associated with poor long-term graft outcomes in live donor renal transplants. Proteinuria and MEST scoring were not predictive of graft failure in living donor posttransplant IgAN.

Mimetic Self-Reflexivity and Intersubjectivity in Complementary and Alternative Medicine Practices: The Mirror Neuron System in Breast Cancer Survivorship.

This study examines complementary and alternative medicine (CAM) providers' practices in the treatment of their breast cancer survivor (BCS) clients and interprets these practices within the context of existing neuroscientific research on the mirror neuron system (MNS). Purposive and snowball sampling was conducted to recruit CAM providers (N = 15) treating BCSs from integrative medicine centers, educational institutions, private practices, and professional medical associations across the United States. In-depth semi-structured interviewing (N = 252 single-spaced pages) and inductive qualitative content analysis reveal CAM therapeutic practices emphasize a diachronic form of mimetic self-reflexivity and a serendipitous form of mimetic intersubjectivity in BCS pain management to allow the providers to tune-in to their clients' internal states over time and experience themselves as an embodied subject in an imaginative, shared space. By employing imagination and an intentional vulnerability in their embodied simulation of the others' internal states, CAM providers co-create experiences of pain while recognizing what about the other remains an unknown. Although MNs provide the mechanism for imitation and simulation underlying empathy through a neuronally wired grasp of the other's intentionality, the study suggests that examining mimetic self-reflexivity and intersubjectivity in the therapeutic space may allow for a shared simulation of participants' subjective experiences of pain and potentially inform research on self-recognition and self-other discrimination as an index of self-awareness which implicates the MNS in embodied social cognition in imaginative ways.

Hidden Granzyme B-Mediated Injury in Chronic Active Antibody-Mediated Rejection.

OBJECTIVES: Antibody-mediated injury in chronic active antibody-mediated rejection, possibly with other effector T cells, may play a role in graft injury. The role of inflammatory cells in the inflammation and fibrosis and tubular atrophy region has been recently advocated in the progression of injury. Cytotoxic T cells play a prominent role in T-cell-mediated rejection; however, the possible role of cytotoxic T cells in circulation and the intragraft compartment in chronic active antibody-mediated rejection, a common immunological cause of long-term graft failure, has not been well-studied. MATERIALS AND METHODS: We measured the frequency of circulating cytotoxic T cells with flow cytometry, serum granzyme B level by enzyme-linked immunosorbent assay and intragraft granzyme B+ cell, and mRNA by immunohistochemistry and real-time polymerase chain reaction in biopsy tissue from living donor renal allograft recipients with stable graft function and chronic active antibody-mediated rejection. RESULTS: The frequency of CD3+ and CD3+CD8+ T cells was similar in both stable graft function patients and chronic active antibody-mediated rejection patients. The frequency of CD3+CD8+granzyme B+ cytotoxic T cells was significantly lower in peripheral blood. Serum granzyme B level and intragraft number of granzyme B+ cells (counts/mm²) were also significantly higher in the chronic active antibody-mediated rejection group compared with that of patients with stable graft function. The intragraft granzyme B+ T cell count was positively correlated with serum creatinine and 24-hour urine proteinuria but negatively correlated with estimated glomerular filtration rate. CONCLUSIONS: Granzyme B mediates covert graft injury in patients with chronic active antibody-mediated rejection in addition to antibody-mediated injury.

Endovascular biopsy in Takayasu arteritis.

Takayasu arteritis is a chronic inflammatory arteriopathy of the large vessels, mainly the aortic arch and its branches. The disease progression varies, ranging from a rapid progression to quiescence reached within 2 years. The activity of the disease is evaluated by biochemical markers, but at times, there is a discrepancy between the clinical picture and biochemical markers. Histopathology helps in assessing the disease activity, but it is not included in the antemortem diagnosis because of the invasiveness of the procedure and the availability of noninvasive vascular imaging. However, it may be performed simultaneously with angioplasty. Here we present a case of endovascular aortic biopsy conducted to detect active inflammation in the aortic wall.

Is en-bloc transurethral resection of bladder tumor for non-muscle invasive bladder carcinoma better than conventional technique in terms of recurrence and progression?: A prospective study.

PURPOSE: Conventional, transurethral resection of bladder tumor (TURBT) involves piecemeal resection of the tumor and has a very high recurrence rate. We evaluated the outcome of en-bloc TURBT (ET) in comparison with conventional TURBT (CT) in non-muscle invasive bladder carcinoma in terms of recurrencew and progression. MATERIALS AND METHODS: From September 2007 to June 2011, in a prospective non-randomized interventional setting, ET was compared with CT in patients with solitary tumor of 2-4 cm size in terms of recurrence and progression. Pedunculated tumors, size >4 cm, tumors with associated hydroureteronephrosis and biopsy specimen with absent detrusor muscles were excluded. Fisher's exact test and survival analyses were used to compare the demography and the outcome. RESULTS: A total of 21 patients of ET were compared with 24 patients of CT. Mean tumor size was 2.8 cm in ET and 3.3 cm in CT group. Location of tumor, stage and grade were comparable in both groups. Recurrence rate was 28.6% versus 62.5% (P = 0.03) and progression rate was 19% versus 33.3% (P = 0.32) in ET versus CT group respectively. Recurrence free survival was 45.1 (95% CI: 19.0-38 months) and 28.5 (95% CI: 35.4-54.7 months) in ET and CT group (P = 0.018). Progression free survival in ET and CT was 48.32 (95% CI: 35.5-53.0 months) and 44.26 (95% CI: 39.0-57.5 months), P = 0.46. CONCLUSION: There was a significant reduction in the recurrence rate and time to recurrence with ET. Rate of progression was also relatively less with ET, though not statistically significant.

Primary hypothyroidism, precocious puberty and hypothalamic obesity in Langerhans cell histiocytosis.

A 5 year old girl presented with central diabetes insipidus and primary hypothyroidism. No clinical or radiological evidence of Langerhans cell histiocytosis (LCH) was present. Absent posterior pituitary bright spot was seen in magnetic resonance imaging of the brain. She subsequently developed severe headache, massive obesity, accelerated growth and thelarche. A repeat MRI of the brain revealed hypothalamic tumor. Hormonal investigations revealed, paradoxically, undetectable growth hormone on a clonidine stimulation test. Langerhans cell histiocytosis was proved on electron microscopy of the thyroid tissue. There needs to be a high degree of suspicion for LCH as an etiology of primary hypothyroidism, especially in the presence of diabetes insipidus. Precocious puberty, accelerated growth despite growth hormone deficiency, hypothalamic obesity may occur in pediatric LCH. CNS lesions may have an evolving course, thus repeat neuroimaging is important.

An unusual case of CMV cutaneous ulcers in a renal transplant recipient and review of literature.

Cytomegalovirus (CMV) infection involving the skin is rare. We present a case of a renal transplant recipient who developed fever and axillary, scrotal and penile skin ulcers after renal transplantation. The skin ulcers did not heal with antibiotics. The skin biopsy revealed CMV inclusion bodies, CMV antigen on immunohistochemistry and high CMV DNA copies. The patient was diagnosed with CMV cutaneous ulcers. The skin ulcers healed after treatment with intravenous ganciclovir and oral valganciclovir. The diagnosis of CMV disease should be considered in the febrile immunosuppressed patient with skin ulcers. The biopsy of the cutaneous lesions may provide the diagnostic clue in such patients.