Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

OBJECTIVES: Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. MATERIALS AND METHODS: Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. RESULTS: BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. CONCLUSIONS: BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Comparison of Clinico-pathologic features and outcomes of ANCA negative and ANCA positive pauci immune crescentic glomerulonephritis: A single centre study.

Introduction: Pauci-immune crescentic glomerulonephritis (PICN) is an important cause of rapidly progressive renal failure. 10-40% of PICN cases have ANCA (antineutrophil cytoplasmic antibody) negative serology. The present study compared clinico-pathologic features, Brix's renal risk score, Berden's histopathological classes and differences in outcome between ANCAnegative vs ANCA positive PICN patients. Materials and Methods: Sixty-one patients of biopsy-proven PICN were studied. Biochemical findings and ANCA serology were recorded. Renal biopsy slides were reviewed along with direct immunofluorescence. Clinical and histological features were compared between ANCA negative and positive PICN using the Man Whitney U test and Chi-square test. Patients were compared for distribution in Berden's histological classes and Brix's renal risk categories. Patient and renal survival were compared using Kaplan-Meier survival analysis. Results: ANCA negative PICN patients were younger (44.9 ± 16.5 years vs 53.6 ± 15.1 years, P = 0.049). Nasal (0 vs 18%, P = 0.035) and pulmonary involvement (9% vs 38%, P = 0.014) were lower in ANCA negative group. Both ANCA groups had similar renal biochemical profiles, percentage normal glomeruli, 16.3 ± 18.2 vs 21.7 ± 20.4 and percentage glomeruli with crescents, 64.5 ± 28.1 vs 64.3 ± 27.1. Twenty-seven per cent of ANCA negative cases fell in the sclerotic class in Berden's classification vs just 2.5% in ANCA positive group (p = 0.037) without significant difference in Brix's renal risk categories (p = 0.329). Thirteen per cent of ANCA negative patients achieved complete remission on treatment compared to 33% in ANCA positive patients. Patient survival and overall probability of progressing to ESRD were similar in the two groups. Conclusion: ANCA negative PICN cases present at younger ages. Nasal and pulmonary involvement is uncommon in these patients. Patient survival and progression to ESRD are similar in both ANCA groups.

Prevalence, risk, and outcomes of venous thromboembolic events in kidney transplant recipients: a nested case-control study.

INTRODUCTION: Thromboembolism is more common in kidney transplant recipients (KTRs) than in the general population. Studies evaluating arterial and venous thromboembolism (VTE) in KTRs are scarce and the magnitude and risk factors are mostly undefined. METHODS: A nested control study was conducted from January 1, 2007, to December 31, 2019. Adult KTRs who were detected to have VTE events during this period were included. The primary outcome was to assess the prevalence of VTE in this population. Secondary outcomes were the assessment of the time to occurrence of the thromboembolic events after transplantation and assessing the risk factors and patient survival. For each subject studied, 4 controls were matched from the data set. RESULTS: Amongst 2158 patients, 97 (4.5%) were found to have VTE. The median follow-up time was 3.9 years (6-156 months). A total of 101 VTE events were recorded. The most common site of VTE was the lower limb deep vein thrombosis in 79 patients (0.03%)).In multivariate Cox regression analysis, serum creatinine of more than 3 mg/dl [HR 1.30, 95% CI (1.03-1.38)] was independently associated with increased VTE risk. Patients who developed a VTE had higher mortality as compared to patients who did not develop VTE. No increased risk of graft failure was found in VTE patients. CONCLUSION: This study suggests that kidney transplantation surgery is a moderate risk factor for VTE, and VTE is associated with higher morbidity and mortality. However, prospective studies are needed to establish a definite role of VTE in outcomes in KTRs.

Atypical HUS Triggered by COVID-19: A Case Report.

We hereby present a case of an atypical hemolytic uremic syndrome (aHUS) precipitated by coronavirus disease 2019 (COVID-19). A 26-year-old male was diagnosed with COVID-19 and acute kidney injury. His kidney biopsy was suggestive of thrombotic microangiopathy. Five sessions of plasmapheresis were done but were discontinued in view of nonrecovery of kidney function. He was then referred for a kidney transplant. On genetic analysis, he was found to have mutations in the complement system (CFHR1 and CFHR3), which suggested this was a case of aHUS precipitated by COVID-19. In view of the high risk of recurrence of the primary disease in live-related kidney donor transplantation, he was advised for simultaneous liver and kidney transplants.

Short- and long-term outcomes of early initiation of peritoneal dialysis following catheter insertion.

INTRODUCTION: Early-start peritoneal dialysis (PD) (use of PD catheter within 48 hours of insertion) is an innovative approach for prompt initiation of PD. AIM: This study was conducted to analyze the outcomes of early-start PD. MATERIALS AND METHODS: A total of 100 patients on PD were retrospectively analyzed. Patients were grouped according to the "break-in period": < 48 hours (PD1) and ≥ 14 days (PD2). PD was initiated with low dwell volumes (500 mL) in a recumbent position within 48 hours of surgery. PD prescription was gradually incremented over 10 days to minimize any complications. RESULTS: In our study, there were 48 patients in the PD1 group and 52 in the PD2 group. The most common cause of end-stage kidney disease (ESKD) was diabetes mellitus in both groups. Incidence of early mechanical complications (within 30 days of catheter insertion), such as catheter obstruction, early catheter leakage, catheter malposition, tip migration, and infectious complications, were not found to be higher in the PD1 group. 1- and 4-year catheter patency rates were 97.0% and 96.2% in the PD1 group, respectively. These rates were comparable with those in the PD2 group. Early-start PD was not associated with an increased incidence of catheter failure (HR = 1.0, 95% CI 0.28 - 3.47). CONCLUSION: An early break-in period of < 48 hours is a feasible option for ESKD patients without any significantly increased risk of mechanical or infectious complications. It offers a safe and efficacious option for renal replacement therapy.

Anti-T-Lymphocyte Immunoglobulin (Grafalon) as an Induction Agent for Renal Transplantation: A Real-World, Retrospective, Single-Center Experience.

OBJECTIVES: Polyclonal antithymocyte globulins are widely used in the induction regimens of solid-organ transplant recipients; however, their doses and outcomes remain to be standardized in Indian patients. We report our clinical experience from the real-world use of Grafalon (an anti-T-lymphocyte globulin; ATG-Fresenius) as an induction agentin renal transplant recipients from India. MATERIALS AND METHODS: In this retrospective, single- center, observational study, we analyzed the medical records of 177 consecutive, kidney-only transplant recipients who received induction therapy with Grafalon from September 2016 to March 2018 at our center. Incidences of biopsy-proven acute rejection and graft dysfunction, immunosuppression protocol, Grafalon dosage, 18-month post-transplant graft and patient survival, treatment-related adverse events, and infective complications were reported. RESULTS: Mean age of patients was 41.46 years (range, 14-68 years), (85% were males). The average dose of Grafalon was 5.81 ± 1.95 mg/kg (range, 2.41 to 10.07 mg/kg). Graft dysfunction (ie, at least 20% increase in serum creatinine from baseline) was observed in 26 patients (14%): 11 patients (6.2%) had biopsy-proven acute rejections, 11 patients (6.2%) had acute tubular necrosis, and 4 patients (2.2%) had calcineurin inhibitor toxicity. Seven deaths were recorded: 2 each from fungal pneumonia, bacterial pneumonia, and acute coronary syndrome and 1 with urinary tract infection with septicemia. Death-censored graft survival was 100% at 12 months and 98% at 18-month follow-up; overall patient survival was 96%. Infective complications occurred in 40 patients (22.5%), with the most common being urinary tract infection in 32 patients (18%). No malignancies were reported. CONCLUSIONS: Use of a potent induction therapy like anti-T-lymphocyte globulin (Grafalon) is often restricted by the risk of side effects and lack of local clinical evidence supporting its role in long-term graft survival. Real-world evidence support the safe and effective use of anti-T-lymphocyte globulin as an induction agent in renal transplant recipients with an individualized dosing approach.

Post-transplant Lymphoproliferative Disorder Presenting as Breast Nodule and Intestinal Obstruction in a Renal Transplant Recipient: A Case Report.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication among kidney transplant recipients. The clinical presentation of patients with PTLD is highly variable. The type of PTLD and the area of involvement determine its presentation, which includes constitutional symptoms such as fever, weight loss, fatigue, and other symptoms related to dysfunction of involved organs, or compression of surrounding structures. Most present with extranodal masses involving the gastrointestinal tract (stomach, intestine), lungs, skin, liver, central nervous system, and the allograft itself. In our case, a 33-year-old woman developed Epstein-Barr virus-negative PTLD plasmablastic lymphoma (PbL) in her right breast and small intestine presenting as intestinal obstruction, 15 years after renal transplant. Her condition was managed with intestinal mass resection and chemotherapy. A follow-up positron emission tomography scan showed near-complete resolution. Thus, PTLD should always be kept in mind in renal transplant recipients who present with features of a mass effect involving any organ.

Double whammy: anticoagulant-related nephropathy with leukocytoclastic vasculitis due to warfarin.

Anticoagulation-related nephropathy (ARN) is a rare form of acute kidney injury where the use of anticoagulation causes hemorrhage in various compartments of nephron including glomerulus, renal tubules, and interstitial compartment. Also, warfarin-induced vasculitis is an extremely rare condition characterized by the appearance of purpuric lesions on the skin which on biopsy are suggestive of leukocytoclastic vasculitis (LV). We hereby report a case presenting with coexistent warfarin-induced nephropathy and cutaneous vasculitis. A 64-year-old male, on warfarin for 10 years, presented with complaints of palpable purpuric rashes over lower limbs, hematuria, and decrease urine output. INR was in the supratherapeutic range (INR-6.3). Skin biopsy of the lesion was suggestive of LV and kidney biopsy showed RBCs in Bowman's capsule, RBCs and RBC casts in tubules suggestive of ARN. All vasculitic markers were negative. Thus, a diagnosis of warfarin-induced nephropathy and cutaneous vasculitis was made. Warfarin was discontinued and oral steroids were started. Gradually, his skin lesions improved, and he became dialysis independent. He was then discharged on apixaban. On follow-up after 3 months, his skin lesions had disappeared with partial recovery of kidney function (cr-5.49).

IgA Nephropathy with Wilson's Disease: A Case Report and Literature Review.

The most common glomerulonephritis seen in the world is immunoglobulin A nephropathy (IgAN). It can be primary or secondary associated with various conditions like Chronic Liver disease, Crohn's disease, neoplasms, etc. However, IgAN secondary to Wilson's disease is very rare. A 9 year old boy presented with gross hematuria and proteinuria. He had a history of recurrent jaundice in the past. Ultrasonography (USG) whole abdomen showed altered echotexture of the liver with normal-sized kidneys. An extended workup for liver disease was done, and the diagnosis of Wilson's disease was confirmed with decreased serum ceruloplasmin levels, increased urinary copper, and the Kayser-Fleischer ring. Urine routine microscopy showed numerous red blood cells, few red blood cell casts, and mild proteinuria. Renal biopsy showed IgAN. The patient was started on D-penicillamine. On follow-up at 3 months, he showed complete resolution of proteinuria and hematuria. Thus, we suggest that Wilson's disease should be considered as one of the causes of secondary IgAN in pediatric patients with hematuria, proteinuria with liver dysfunction.

Granulomatosis with Polyangiitis Masquerading as Renal Mass: Case Report and Literature Review.

Wegener's granulomatosis or granulomatosis with polyangiitis (GPA) is multisystemic vasculitis. Kidney involvement in GPA often presents with rapidly progressive renal failure and requires urgent treatment. A 60-year-old female presented with prolonged history of fever, generalized weakness, decreased appetite, and weight loss over 4 months. Her renal function was normal; urine culture was sterile. On further evaluation, she was found to have large, hypodense solid lesion in mid pole of the right kidney on CECT. CT guided renal biopsy was done, which showed granulomatous interstitial nephritis with focal crescents. On further evaluation, she was found to have high titers of anti-MPO antibody. She was started on steroid and methotrexate with subsidence of fever. Follow-up after 12 months showed resolution of the lesion. GPA solely presenting as solid mass like lesion in the kidney is extremely rare presentation. Early diagnosis and prompt initiation of the treatment can prevent the progression of the disease.

Role of Tunneling Nanotubes in Viral Infection, Neurodegenerative Disease, and Cancer.

The network of tunneling nanotubes (TNTs) represents the filamentous (F)-actin rich tubular structure which is connected to the cytoplasm of the adjacent and or distant cells to mediate efficient cell-to-cell communication. They are long cytoplasmic bridges with an extraordinary ability to perform diverse array of function ranging from maintaining cellular physiology and cell survival to promoting immune surveillance. Ironically, TNTs are now widely documented to promote the spread of various pathogens including viruses either during early or late phase of their lifecycle. In addition, TNTs have also been associated with multiple pathologies in a complex multicellular environment. While the recent work from multiple laboratories has elucidated the role of TNTs in cellular communication and maintenance of homeostasis, this review focuses on their exploitation by the diverse group of viruses such as retroviruses, herpesviruses, influenza A, human metapneumovirus and SARS CoV-2 to promote viral entry, virus trafficking and cell-to-cell spread. The later process may aggravate disease severity and the associated complications due to widespread dissemination of the viruses to multiple organ system as observed in current coronavirus disease 2019 (COVID-19) patients. In addition, the TNT-mediated intracellular spread can be protective to the viruses from the circulating immune surveillance and possible neutralization activity present in the extracellular matrix. This review further highlights the relevance of TNTs in ocular and cardiac tissues including neurodegenerative diseases, chemotherapeutic resistance, and cancer pathogenesis. Taken together, we suggest that effective therapies should consider precise targeting of TNTs in several diseases including virus infections.

Renal Biopsy and Clinical Outcomes in Patients With ABO-Incompatible Renal Transplant: Experience From a Tertiary Care Hospital.

OBJECTIVES: Renal transplant with ABO-incompatible donors expands the donor pool. Earlier studies have focused the use of protocol biopsies in ABO-incompatible transplant patients. Our study described outcomes of indication (for cause) renal biopsies and clinical outcomes in patients with ABO-incompatible renal transplant. MATERIALS AND METHODS: This retrospective study included 164 patients from January 2012 to June 2019. Biochemical parameters, serial immunoglobulin G anti-ABO titers, and class I and II donor-specific antibody findings were obtained from hospital records, and renal graft biopsies were reviewed according to the Banff 2017 update. RESULTS: We analyzed the results of 65 biopsies from 54 patients. Biopsy-proven acute antibody-mediated rejection (12.8%) was found to be more prevalent than acute cellular rejection (1.8%). Patients with antibodymediated rejection all had microvascular inflammation (g+ptc score of 2 or more, where g+ptc is the sum of the glomerulitis and peritubular capillaritis scores) and were positive for C4d. Acute tubular injury per se was seen in 10.3% of patients; 65% of these patients had C4d positivity in peritubular capillaries, and only 1 patient developed chronic active antibody-mediated rejection on follow-up. Patient and death-censored graft survival rates were 92% and 98% at 1 year after transplant and 88% and 91% at 3 years, respectively. Patients with an episode of antibody-mediated rejection had lower rates of patient (76.5%) and deathcensored graft survival (84.6%) at 1 year. CONCLUSIONS: The microvascular inflammation score (g+ptc score of 2 or higher) is more reliable than diffuse C4d positivity to determine antibody-mediated rejection in ABO-incompatible transplants because diffuse C4d positivity may also be seen in etiologies unrelated to antibody-mediated rejection. Acute tubular injury with C4d positivity without microvascular injury does not confirm antibody-mediated rejection. We suggest that Banff classification be updated in ABO-incompatible transplants to include diagnostic criteria for the diagnosis of antibody-mediated rejection.

CMV presenting as a skin growth in renal transplant patient.

CMV infection is one of the most common opportunistic infection in kidney transplant patients. If not treated, it is associated with increased mortality and graft loss. It can present as viremia or CMV disease in the form of CMV syndrome or tissue invasive CMV disease. The cutaneous presentation of CMV disease is a rare finding. Its identification is vital as cutaneous CMV infection can signal systemic infection and poor prognosis. In our case, 46-year-old male who was a post renal allograft recipient (RAR) presented as a protuberant growth over the medial side of the left ankle. On skin biopsy, nucleomegaly and inclusion bodies were seen in the epithelial cells. Immunohistochemistry was positive for CMV infection. Patient was treated with Ganciclovir, however, he succumbed to death because of severe sepsis due to secondary bacterial infection. Thus, CMV disease should always be kept in mind in immunocompromised patients like post RAR patients who present with cutaneous features like ulcerative lesions or fungating growth.

Clinical Remission of Immunoglobulin A Nephropathy after Bariatric Surgery in a Young Morbidly Obese Patient.

A 23-year-old girl with morbid obesity, diabetes mellitus, hypertension, obstructive sleep apnea, and immunoglobulin A nephropathy (IgAN) attended a bariatric clinic after multiple failed attempts at weight loss. In the past, she was diagnosed with IgAN with nephrotic syndrome and raised blood pressure at the age of 11 years. Apart from optimization of blood pressure with angiotensin receptor blocker, she required steroid to maintain her remission in initial four years which was later switched to mycophenolate mofetil (MMF). She was diagnosed with diabetes at the age of 13 years; her blood sugars remained poorly controlled despite therapy with oral hypoglycemic agents and insulin. She underwent sleeve gastrectomy with no post-operative complications. During the follow-up, she showed a steady reduction in her weight, along with maintaining normal blood sugars and pressure without medications. At 18 months of follow-up, IgAN remained in remission after stopping MMF at four months after the surgery. Obesity is considered an important cofactor in the progression of IgAN. This case highlights the importance of weight reduction to halt the progression of the disease.

Evaluation of Factors Influencing Outcomes in Pauci-Immune Crescentic Glomerulonephritis: Single Centre Experience of 51 Cases.

INTRODUCTION: Pauci-immune crescentic glomerulonephritis (PICGN) is rare form of glomerulonephritis that frequently presents as rapidly progressive renal failure. Several prior studies have evaluated role of various factors influencing outcomes in patients with PICGN. The histopathological classification proposed by Berden a decade earlier described difference in the outcomes of patients in the focal, crescentic, mixed and sclerotic category with best prognosis for focal and worst for sclerotic group. The newly proposed renal risk score of Brix takes into account both the histopathological parameters (% of normal glomeruli, tubular atrophy and interstitial fibrosis) and clinical parameter (eGFR) which influences outcome. METHODS: Retrospective study was performed between 2014 to 2018. Biochemical parameters and ANCA details were recorded and renal histopathology slides were reviewed and classified according to Berden's histopathologic classes. All the cases were further characterized into three groups based on renal risk score (Brix et al). Univariate, multivariate analysis for risk factors predicting ESRD and Kaplan Meier Survival Analysis were done. RESULTS: In the present study, we found eGFR (P 0.024), % of normal glomeruli (P 0.023) and IFTA (P 0.001) as important factors influencing renal outcome in patients with PICGN. More than 60% patients achieved complete remission with low renal risk score as compared to patients with high renal risk score in which 80% patients developed ESRD or death at follow up. We also found significant difference in survival among various renal risk categories (Log-Rank P = 0.001) as compared to Berden's international histological classification (Log-Rank P = 0.037) on Kaplan -Meier survival analysis. CONCLUSION: PICGN is a significant cause of mortality and morbidity. Renal histological factors such as % normal glomeruli at time of biopsy, degree of IFTA and renal risk score play an important role in assessing prognosis in these patients.

Tacrolimus-induced Epidermoid Cysts in the Renal Transplant Patient.

Epidermal cysts are common benign cystic lesions that occur mostly sporadically. Common sites involved are arms, face, and trunk. The cyst may progress slowly and remain for years. These cysts arise as a result of the plugging of the follicular orifice. Etiology has largely remained unknown although local trauma, ultraviolet rays, and human papilloma virus (HPV) have been implicated in a few cases. Calcineurin inhibitors (CNIs) especially cyclosporine has been discredited for cutaneous side effects such as hirsutism and gingival hyperplasia. Epidermoid cysts have been also associated with patients with solid organ transplant recipients on cyclosporine. Tacrolimus is considered to be free of dermatological side effects. Herein, we report a case of 56-year-old renal allograft recipient on tacrolimus, who develop more than >100 epidermoid cysts over the face, trunk, back, and extremities. The lesions ceased to progress once the tacrolimus was stopped.

Inhibition of Human Cytomegalovirus Entry into Host Cells Through a Pleiotropic Small Molecule.

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

Co-inheritance of pathogenic variants in PKD1 and PKD2 genes presenting as severe antenatal phenotype of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by pathogenic variants in either PKD1 or PKD2 genes. Disease severity is dependent on various factors including the presence of modifier genes. We describe a family with recurrent foetal presentation of ADPKD due to co-inheritance of pathogenic variants in both PKD1 [c.3860T > C; p.(Leu1287Pro)] and PKD2 [(c.1000C > A; p.(Pro334Thr)] genes. Familial segregation studies revealed the mother and the father to be heterozygous for the same variants in the PKD1 and PKD2 genes, respectively, as found in the foetus. Renal ultrasonography detected evidence of cystic disease in the mother and two of her family members. No cysts were detected in the father, however the paternal grandfather died of renal cystic disease. The absence of disease in the father can be explained by the phenomenon of incomplete penetrance, or Knudson's two-hit hypothesis of cystogenesis in the grandfather. This case underscores the importance of sequencing PKD2 gene even in the presence of a familial PKD1 variant, as well as genetic testing of the cysts for evidence of the second hit.