Efficacy and Outcomes of CYP3A5 Genotype-Based Tacrolimus Dosing Compared to Conventional Body Weight-based Dosing in Living Donor Kidney Transplant Recipients.

Introduction: Clinical use of tacrolimus has been challenging due to its narrow therapeutic index and highly variable pharmacokinetics. In this study, we compared patients who received body weight-based tacrolimus dosing pre-transplant (transplanted from 2016 to 2018) with those who received CYP3A5 genotype-based dosing (2018 to 2020). Methods: Eighty-two renal transplant recipients were non-randomly assigned to genotype-adapted or bodyweight-based tacrolimus dosing groups. The primary end point was to study the proportion of subjects who achieved the target tacrolimus C0 on post-op day 4. Secondary end points included clinical outcomes and safety. Results: The proportion of subjects who achieved the target tacrolimus C0 on postoperative days 4 and 10 were significantly higher in the adapted group, 53.6% and 47.5%, compared to 24.3% and 17% in controls, respectively (P = 0.01). Adapted group subjects achieved their first target tacrolimus C0 significantly earlier (4 days) compared to 25 days in controls (P = 0.01). The total number of tacrolimus dose modifications required in the first postop month were lower in the adapted group; 47 compared to 68 in the controls (P = 0.05). The proportion of subjects with sub-therapeutic tacrolimus exposure on postoperative day 4 was significantly higher in the controls, 56% versus 10% in the adapted group (P < 0.001). There were no significant differences between the groups in the rate of biopsy proven acute rejections, adverse events, and graft function at the end of 3 months follow up. Conclusion: Genotype-based tacrolimus dosing leads to more subjects achieving the target tacrolimus C0 earlier. However, there may be a higher risk of tacrolimus nephrotoxicity.

Rhabdomyolysis Induced Acute Kidney Injury in Acute Myeloid Leukemia: An Unusual Association.

Rhabdomyolysis is a potentially life-threatening syndrome that causes acute kidney injury. Association of acute myeloid leukemia (AML) and myoglobin induced acute tubular necrosis (ATN) is rarely reported in the literature. Here, we report a young male who was admitted with fever of unknown origin. Diagnosed to have AML with renal failure and subsequently succumbed to illness, whose post mortem renal biopsy confirmed myoglobin induced ATN.

Influence of CYP3A5 and ABCB1 Polymorphism on Tacrolimus Drug Dosing in South Indian Renal Allograft Recipients.

INTRODUCTION: Tacrolimus blood levels are influenced by polymorphisms involving Cytochrome 3A subfamily (CYP3A5) and P-Glycoprotein (ABCB-1) genes. However, their role in transplant outcomes was less studied in South Indian population. We studied the prevalence and impact of these polymorphisms in renal transplant recipients from South India. METHODS: An analysis of CYP3A5, ABCB1 genotype done in 101 renal transplant recipients by polymerase chain reaction was correlated with blood tacrolimus trough levels (CLIA method), weight, concentration/dose (L/D) ratio, incidence of biopsy proven early acute rejections, and tacrolimus toxicity. RESULTS: Prevalence of CYP3A5*1/*1, *1/*3 and *3/*3 and ABCB1 (3435C>T) TT, CT, CC genotypes were 12 (11.9%), 48 (47.5%), 41 (40.6%) and 16 (15.8%), 45 (44.6%), 40 (39.6%), respectively. Mean tacrolimus level, median concentration/dose (L/D) ratio were significantly lower in homozygous (CYP3A5*1/*1-6.01 ng/mL; 48.99 ng/mL/mg/kg/day) and heterozygous expresser group (CYP3A5*1/*3-5.84 ng/mL; 68.93 ng/mL/mg/kg/day) when compared with nonexpresser group [CYP3A5*3/*3-7.46 ng/mL (P < 0.001);181.3 ng/mL/mg/kg/day (P < 0.05]. No significant differences observed between the ABCB1 genotypic groups. Incidence of early acute rejections (30% vs. 9.76%; P 0.016) and tacrolimus-related toxicity (14.6% vs. 5%; P 0.039) were significantly higher in CYP3A5 expressers and nonexpressers, respectively. No correlation observed between the ABCB1 polymorphisms between rejection episodes or tacrolimus renal toxicity. Among 101 patients, 40.6% were non-expressers (poor metabolizers) (*3/*3). CONCLUSIONS: CYP3A5 polymorphisms correlated with tacrolimus dose requirements and blood levels, incidence of early acute rejection, and tacrolimus nephrotoxicity. CYP3A5 polymorphism analysis prior to renal transplant will aid more precise early tacrolimus dose calculation to balance between rejection and toxicity.

Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: An unusual association.

Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating IgG antibodies (rarely IgA and IgM) to the carboxyterminal, noncollagenous 1 (NC1) domain of type IV collagen of GBM also known as Goodpasture antigen. Patients typically present with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage in the presence of which it is referred to as Goodpasture's disease. Anti-GBM disease has been reported to coexist with pauci-immune antineutrophil cytoplasmic autoantibody-positive glomerulonephritis and membranous glomerulopathy. The sequential or concurrent presentation of anti-GBM disease with IgA nephropathy has been rarely described. We herein report a case of a 22-year-old female who presented with RPGN, and renal biopsy revealed crescentic glomerulonephritis with strong linear IgG (+2) staining of GBM and extensive mesangial IgA (+3) deposits. The patient was treated with three pulses of IV methylprednisolone followed by oral steroids. Plasmapheresis and cytotoxic agents were not included in the therapeutic armamentarium as the patient had no pulmonary hemorrhage and biopsy revealed established chronic changes. The association of anti-GBM disease with IgA nephropathy could open up new vistas on the implication of these IgA mesangial deposits in the pathogenesis and prognosis of anti-GBM disease.

Deceased donor renal transplantation: A single center experience.

Deceased donor renal transplantation (DDRT) constitutes less than 5% of all kidney transplantats in India. A retrospective analysis of 173 deceased donor renal transplants performed in a public funded government hospital was done. Mean age of the recipients was 36 years (male:female ratio 2.4:1), and that of the donors was 32.3 years (male:female ratio 6:1). The cold ischemic time was 340 ± 170 minutes. Mean follow-up period was 36 months. Forty one patients died, 75% of them in the first post - transplant year. Sepsis and cardiovascular disease were the most common causes of death. Twenty two percent had acute rejection. There was no significant difference in the incidence in the rate of acute rejection, bacterial, fungal infections and death rate between the cohorts of induction and non induction immunosuppression. The patient and death censored graft survival at 1 year were 80 and 82.6% and at 5 years were 76 and 80% respectively.

Follow-up study of post-infectious glomerulonephritis in adults: analysis of predictors of poor renal outcome.

Post-infectious glomerulonephritis (PIGN) still remains one of the most common glomerulonephritis in the developing world. We studied the epidemiology and clinical spectrum of PIGN in adults to identify the clinical, biochemical and histological factors that would predict renal outcome. Data of 102 adult PIGN patients treated between 2009 and 2011 with a mean follow-up of 12 months (6-36 months) were analyzed retrospectively. The mean age of the patients was 32.7±15 years, with a male to female ratio of 1.2:1. At presentation, 99% of the patients had edema and oliguria, 73% had hypertension, 55% had macrohematuria and 60% had nephrotic range proteinuria. About 14% presented with complications (pulmonary edema-6%, seizure-1%, dialysis requiring renal failure-7%) and 9% had comorbid illness. Sixty percent of the patients had serum creatinine>2 mg/dL at presentation, which was persistent in 30% at the end of one week and 68% had hypo-complementemia. Renal biopsy revealed diffuse proliferative glomerulonephritis in 70% of the patients. At 12 months, 2% had persistent hypertension, 10% had persistent proteinuria and hematuria and 11% had serum creatinine>1.5 mg/dL. Univariate analysis with the Fischer Exact test revealed age>40 years, male gender, serum creatinine>2 mg/dL at one week, comorbid illness, requirement of dialysis, crescents in >30% glomeruli and persistent proteinuria and microscopic hematuria at 12 months as significant risk factors for poor renal outcome. Serum creatinine>2 mg/dL at one week and persistent proteinuria at 12 months were the independent risk factors that predicted poor renal outcome at one year.