Donor-Derived Cell-Free DNA and Active Rejection in Renal Allografts.

Background: Renal allograft rejection contributes to significant morbidity and graft loss. In this setting, early detection of rejection is of paramount importance, which currently relies on histopathology. A reliable non-invasive marker to predict rejection would make surveillance and decision-making easier. Donor-derived cell-free DNA (dd-Cf-DNA) has recently been reported as an emerging tool to predict rejection noninvasively. The utility of cell-free DNA in clinical practice has so far not been studied in an Indian setting. As it offers direct clinical application, we have chosen to investigate this biomarker as a tool to predict rejection. Materials and Methods: A pilot study with convenient sample size was designed, as this is the first of its kind study so far reported from India. Patients being evaluated with a graft biopsy for graft dysfunction were included. Patients with stable graft function, defined as creatinine within 10% of their best creatinine and no proteinuria for the preceding 12 months, were also included. Ten milliliters of whole blood from each of the recipients was collected in DNA isolation tubes. Two milliliters of donor blood was also obtained in ethylenediaminetetraacetic acid (EDTA) tubes. All recipients also provided a buccal swab. Total cell-free DNA was extracted from 2 ml of recipient plasma using circulating DNA isolation kit. Upon identification of the donor-specific DNA marker for each of the patients from the paired donor sample, presence of the cell-free DNA fraction in the recipient's plasma was detected and quantified. Renal biopsy reports and clinical details were also recorded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were analyzed. Receiver operating characteristic (ROC) curve analysis was also performed. Results: A total of 31 patients were recruited. Twenty patients underwent graft biopsies for graft dysfunction, of which 12 patients had features of active rejection and eight had nonrejection causes of graft dysfunction. Eleven patients with stable graft were included in the study. In our study, dd-Cf-DNA performed best in predicting antibody-mediated rejection (ABMR) and higher grades of T-cell-mediated rejection (TCMR) (1B). It did not detect TCMR 1A accurately. It serves as a good marker to rule out rejection. It gave a NPV of 100% for TCMR 1B or ABMR, 100% for ABMR alone, and 81% for any rejection. dd-Cf-DNA percentages outperform absolute concentrations in their discriminatory ability. Conclusion: We have demonstrated the diagnostic accuracy of dd-Cf-DNA in predicting active rejection of the renal allograft. It performs well in ABMR and higher grades of TCMR. This is the first of its kind study reported from India, to the best of our knowledge. This tool serves as a good rule out test for ABMR and higher grades of TCMR. It performs poorly in TCMR 1A.

Rhabdomyolysis-associated Acute Kidney Injury.

Introduction: Acute kidney injury represents one of the most severe complications of rhabdomyolysis. Methods: We performed a prospective observational study to analyze the etiology, clinical manifestations, laboratory profile, and outcome in patients with biopsy-proven pigment-induced nephropathy between January 2017 and September 2019. History, clinical examination findings, laboratory investigations, and outcomes were recorded. Results: A total of 26 patients were included. Mean age was 34.81 ± 11.89 years. Mean peak serum creatinine was 6.79 ± 4.07 mg/dL. Median values of Creatine phosphokinase (CPK) and Lactate dehydrogenase (LDH) were 12500 U/L (3187, 17167.50) and 447 U/L (354.50, 908.75), respectively. Of the patients presenting with rhabdomyolysis, 12 patients (46%) had traumatic causes and 14 patients (54%) had nontraumatic causes. Nontraumatic etiology of rhabdomyolysis included seizures (1), wasp sting (1), paraphenylenediamine ingestion (2), rat killer ingestion (2), leptospirosis (2), dehydration (3), acute limb ischemia (1), Gloriosa superba ingestion (1), and prolonged immobilization (1). On renal biopsy, 16 patients had myoglobin cast nephropathy and one had immunoglobulin A deposits in addition to pigment nephropathy. Twenty (76.9%) were initiated on hemodialysis, and two patients (7.6%) were treated with peritoneal dialysis and four patients (15.5%) were treated with forced alkaline diuresis. A total of four patients died (15.4%) due to sepsis/disseminated intravascular coagulation and respiratory failure. At the mean follow-up of 6 months, two patients (7.7%) progressed to chronic kidney disease (CKD). Conclusions: Rhabdomyolysis-associated acute kidney injury is an important cause of renal failure requiring renal replacement therapy. In our study, it was more common in males. Traumatic and nontraumatic causes played an equal causative role. Most of the patients recovered from AKI. Forced alkaline diuresis was found useful in nontraumatic rhabdomyolysis AKI.

Clinical Profile, Histopathology, and Outcomes in Infection-Related Glomerulonephritis - Single-Center Experience.

Background: Infection-related glomerulonephritis (IRGN) is an important source of renal morbidity with adverse outcomes in adults. Data from large centers in India is lacking on this common, yet poorly understood entity. Materials and Methods: We performed a prospective observational study of all patients diagnosed with IRGN at our center over a 3-year period between 2017 and 2019. "Typical IRGN" patients were diagnosed based on clinical and laboratory assessment; others underwent renal biopsy. Renal and patient survival outcomes were assessed in addition to factors that help predict outcomes. Results: One hundred and twenty-five patients with a diagnosis of IRGN were included in the study, including 86 patients who underwent renal biopsy. This represented 24% of all biopsies during this time period, and IRGN was the most common nondiabetic kidney disease identified in diabetic biopsies at our center. Female preponderance and a seasonal variation were striking. Atypical sources of infection like otomycosis, tooth abscess, and dengue virus infection were noted. Male gender and diabetes were important risk factors for severe disease. Rapidly progressive glomerulonephritis (RPGN), atypical serum complement profiles, and comorbid illnesses were common in adults. Though children had more benign disease and outcomes, life-threatening complications were also noted. C3 dominance was the most striking immunofluorescence (IF) finding and was associated with poorer outcomes. Crescentic IRGN was rare, and four cases of IgA-dominant IRGN were noted. Also, 24% of the cohort required renal replacement therapy. RPGN presentation of IRGN portended worst prognosis with end-stage renal disease (ESRD) in 31% and death in 22% of patients. Conclusion: IRGN is a common clinical entity in adults with the potential for adverse renal and survival outcomes. We have identified clinical and biopsy characteristics that are associated with ESRD and death.

Association of IgA Nephropathy with Squamous Cell Carcinoma of the Tongue: - Case Report and Review of Literature.

A 32-year-old habitual tobacco chewer was diagnosed with squamous cell carcinoma of the tongue. He was initiated on chemo-radiation therapy. After completing 23 cycles of radiation and four cycles of cisplatin-based chemotherapy, he presented with acute nephritic syndrome. Renal biopsy showed IgA nephropathy and acute tubular injury. With supportive care, renal function stabilised with a reduction in proteinuria. We wish to highlight the poorly understood association between mucosal malignancies and IgA nephropathy. It is also interesting to note the peculiar temporal profile of glomerular involvement in our patient, where the onset of the glomerulonephritis was after the initiation of chemo-radiotherapy. This is unlike what has been described earlier.

Tuberculous myositis and cellulitis in a renal transplant recipient.

Tuberculosis, a disease known as White plague, caused by Mycobacterium tuberculosis, is known for its diverse manifestations. The atypical manifestations of tuberculosis pose a great diagnostic challenge to the clinicians. Though low oxygen and high lactic acid content in skeletal muscle makes it an unfavourable site for the survival of these aerobic bacilli, they still can infect muscles and present as myositis. Tuberculous myositis and cellulitis are such a rare entity, that they are never considered as a possible differential diagnosis even in tuberculosis endemic countries. In this case report, we share our experience with a renal transplant recipient who presented to us with right lower limb pain and swelling.

Post-Renal Transplant Miliary Mottling: Not Always Tuberculosis.

A 28-year-old male, 3 years post renal transplant with stable graft function, presented with vomiting for 2 days. He had graft dysfunction and graft biopsy done revealed acute cell - mediated rejection BANFF-IA. After receiving glucocorticoids for rejection, he developed severe enterocolitis and impending respiratory failure. Chest X-ray and computed tomography of the chest revealed miliary mottling. Evaluation showed presence of filariform larvae of Strongyloides stercoralis in the stool and sputum. A diagnosis of Strongyloides Hyperinfection Syndrome (SHS) was made. After a prolonged course of treatment with noninvasive ventilation, broad-spectrum antimicrobials, parenteral ivermectin and oral albendazole therapy, he eventually recovered. This case report is to highlight that Strongyloides Hyperinfection Syndrome should also be considered in the differential in any immunocompromised patient presenting with miliary mottling in imaging.

The Role of Far Infrared Therapy in the Unassisted Maturation of Arterio-venous Fistula in Patients with Chronic Kidney Disease.

INTRODUCTION: The goal of arterio-venous fistula (AVF) creation is to achieve a well-functioning access that can be cannulated repetitively and can provide adequate flow for the dialysis. The objective of this study was to assess the role of far infrared (FIR) therapy in the unassisted maturation of newly created AVF in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: In this prospective open labeled randomised control trial, 107 patients were randomized. Participants in the control arm received oral clopidogrel 75 mg once daily for 30 days along with isometric hand exercise, whereas those in the test arm received FIR therapy twice weekly, 40 min session each, for 4 weeks. A biopsy from venous end was taken during fistula surgery. Doppler study of AVF was done at the end of the 4th and 12th week to assess AVF. Vascular access guidelines proposed by National Kidney Foundation -Kidney Disease Outcomes Quality Initiative (NKF- KDOQI) in 2006 were adapted to define the maturation of AVF. RESULTS: Out of 107 patients, 51 were randomized to the test arm and 56 to the control arm. During follow-up, the blood flow rate through AVF (Qa) and the diameter of the cephalic vein draining (CVd) the AVF were measured. At the end of 3 months, Qa in Radio-Cephalic Fistula (RCF) was high in the test arm (p-0.003). The AVF failures were 5 (10.2%) and 14 (28%) in the test and control arms, respectively (p: 0.025). However, when adjusted for AVF failure within 6 h of surgery (may be related to surgical technique) this difference in AVF patency was statistically insignificant (p: 0.121). The mean Qa was high in patients with an arterial intimal medial thickness (AIMT) <0.5 mm. The IMT of the anastomosed artery had statistically significant correlation with the primary failure rate of AVF (P < 0.001). CONCLUSION: In patients with CKD, FIR therapy was effective in increasing the AVF blood flow rate at the end of 3 months, though the difference in primary failure rate was statistically insignificant.

Post Renal Transplant Collapsing Glomerulopathy is Associated with Poor Outcomes.

INTRODUCTION: Collapsing glomerulopathy (CG) is a distinct morphologic pattern of proliferative renal parenchymal injury. It differ from focal segmental glomerulosclerosis (FSGS) by clinicopathologic pattern and its adverse outcome. The clinical significance of CG in renal allograft biopsies is not yet clear due to scant data and less occurrence of CG in renal transplant recipients. We conducted this single-center retrospective study to evaluate the prevalence, clinicopathological features, and outcome of post renal transplant CG. SUBJECTS AND METHODS: We studied 127 renal allograft biopsies performed over a period of 45 months (Jan 2015-Oct 2018). A diagnosis of CG was made if at least one glomerulus demonstrated global or segmental collapse of the glomerular capillary walls, associated marked hyperplasia, and hypertrophy of the overlying visceral epithelial cells. We analyzed clinical, biochemical, and pathological characteristics and its impact on renal allograft outcome. Statistical analysis was performed and continuous variables were expressed as means ± standard deviation (SD) or medians (interquartile range and noncontinuous data were expressed in percentage and numerical values. RESULTS: The prevalence of CG was 5.3% (7/127) of allograft biopsies. Out of the seven patients, six patients had undergone live donor transplant and one patient had undergone deceased donor renal transplant. The native kidney disease was unknown in these patients except one (IgA nephropathy). The median duration of diagnosis for CG was 17 months after transplantation (range 5-132months). Presenting symptoms were pedal edema and hypertension in 71.4% (5) patients each. All patients had proteinuria of more than 1 gm and renal allograft dysfunction and median serum creatinine of 3.05 mg/dl (1.5-4.8 mg/dl). All patients received standard triple immunosuppression. Over a period of 2-20 months, 57.14% (4) patients developed a graft failure and 43% (3) of the other patients had functioning grafts with serum creatinine of 1.5-4.2 mg/dl. CONCLUSIONS: CG presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients.

Volume Assessment in Hemodialysis: A Comparison of Present Methods in Clinical Practice with Sonographic Lung Comets.

Dry weight assessment in dialysis patients remains a challenging endeavor owing to the limitations of the available methods for volume assessment. Lung ultrasound is emerging as an invaluable tool to assist in the appropriate assessment and assignment of dry weight. The objectives of this study are (1) to determine the reliability of clinical signs and symptoms for volume assessment, (2) to compare lung ultrasound with High Resolution Computed Tomography (HRCT) chest-A noninvasive gold standard tool for detecting pulmonary congestion and with inferior vena cava diameter (IVCD) - another time-tested volume assessment method, and (3) to analyze if lung ultrasound could detect dialysis induced fluid status variations. The cross-sectional study involves 50 patients on maintenance hemodialysis. Lung ultrasound for B line estimation and ultrasonographic measurement of IVCD performed before and after hemodialysis by a nephrologist trained in ultrasonography. Limited HRCT was obtained just before hemodialysis. Edema, crackles, and dyspnea had a poor sensitivity of 37.9%, 11.5%, and 52.6%, respectively, to detect clinically significant pulmonary congestion by lung ultrasound. A highly significant correlation was obtained between B-line score and HRCT signs of pulmonary congestion (P < 0.001) before dialysis. B lines showed statistically significant reduction with dialysis. The absolute reduction of B lines showed significant correlation with ultrafiltration volume and weight loss. Bedside lung ultrasound appears a sensitive tool for evaluating real-time changes in extravascular lung water and would serve to optimize volume status in dialysis patients.

Post-Renal Transplant Metabolic Acidosis: A Neglected Entity.

Metabolic acidosis is a prevalent yet overlooked entity among renal transplant recipients (RTRs) and incurs adverse effects on graft function. Although graft dysfunction and calcineurin inhibitor usage have been linked with renal tubular acidosis (RTA), there is no Indian data on prevalence or risk factors of post-transplant acidosis. A cross-sectional study was conducted on 106 adult RTRs, with a transplant duration of >6 months and an estimated glomerular filtration rate (GFR) >40 ml/min/1.73 m2. Acidosis was diagnosed on basis of plasma bicarbonate and arterial pH. Serum and urine electrolytes with anion gap were determined to diagnose and type RTA. Acidosis was diagnosed in 44 of 106 patients (41.5%) with 23 (52.27%) having severe acidosis. Type I RTA was the most common subtype (52.5%) followed by type IV (30.9%) and type II RTA (7.5%). The correlation between estimated glomerular filtration rate and acidosis was minimally linear (r = 0.1088), with multivariate analysis revealing previous acute rejection episodes, current serum tacrolimus levels, cotrimoxazole usage and intake of animal proteins to be independent risk factors. The serum albumin levels were low in the acidosis group and showed linear correlation with bicarbonate levels (r = 0.298). There is a high prevalence of metabolic acidosis in RTRs with type I RTA being most common subtype. Screening of RTRs on a regular basis is a feasible approach for early diagnosis and intervention. However, prospective studies are needed to demonstrate the effect of acidosis on graft survival and benefit of bicarbonate therapy in RTRs.

Lupus nephritis in a patient with retroviral infection.

A 38-year-old woman, diagnosed as Person Living with Human Immunodeficiency Virus (HIV) on Highly Active Antiretroviral Therapy (HAART) for three years, presented with features of fever, rashes, joint pain, dyspnea and pedal edema. On evaluation, a diagnosis of Systemic Lupus Erythematosus with Lupus Nephritis (LN) triggered by HIV infection was made based on clinical and serological evidence. She was continued on HAART, and immuno-suppressive therapy was co-administered resulting in the resolution of her symptoms. Lupus-like histopathological findings have been reported in patients with HIV-related kidney diseases. This case report is to highlight the co-existence of LN in a patient with HIV infection.

Collapsing glomerulopathy associated with pulmonary tuberculosis.

Collapsing glomerulopathy (CG) usually presents with reduced glomerular filtration rate, heavy proteinuria and has unfavorable prognosis. Numerous associations with CG are found. We encountered a case of CG associated with pulmonary tuberculosis presenting with proteinuria and dialysis-requiring severe renal failure. Our patient made partial recovery of his renal function and became dialysis-independent after antituberculous therapy and oral steroids. Long-term follow-up is needed to assess the progression of the disease.