A Cohort study of exposure controlled mycopenolic acid in class iii and class IV lupus nephritis in a tertiary care centre in South India.

INTRODUCTION : A prevalence study of systemic lupus erythematosus (SLE) in India showed a crude incidence rate of 4 per 100,000 population per year. Lupus nephritis occurs in about half of SLE patients (range: 35%-73%) in India. Most patients with SLE do not present initially with renal disease; only 25% of patients have this as their initial presenting feature. In 5% of these cases, usually in men older than 40 years, it can be several years before other lupus criteria or serological abnormalities develop. Although the survival of SLE patients have improved in the west with modern treatment to the tune of 80% at 10 years after diagnosis, among Indians the figures are not so good (50%-60% survival at 10 years) as shown by Murali et al in a study of 98 patients between 1981 and 1993. Renal involvement in SLE is a therapeutic challenge for all involved in the care of SLE, since early intervention can dramatically change the disease course. Thirty or more years ago, few patients with severe grade IV nephritis survived more than a year or two, and half of those with less severe form of nephritis used to die within 5 years. After the introduction of Cyclophosphamide into the therapeutic armamentarium of lupus nephritis 20 years later, renal involvement no longer affects the survival rates of these patients. However, long-term treatment with cyclophosphamide for patients with proliferative lupus nephritis is associated with adverse effects, including an increased risk of infection (10–18% per year). Cumulative doses of cyclophosphamide over 9 g, particularly in women over the age of 32 years, are associated with ovarian failure. The aim of treatment therefore, is to induce and maintain remission of active nephritis with minimum toxicity. A major advance in achieving the goal of identifying new therapies for the treatment of severe lupus nephritis occurred in 2000, with the report by Chan [et al.] of the first prospective controlled study comparing the efficacy and toxicity of Mycophenolate Mofetil (MMF) to oral Cyclophosphamide in patients with diffuse proliferative lupus nephritis. Also for maintenance therapy in lupus nephritis MMF seems to be a good alternative to azathioprine. AIM : To evaluate the Outcomes of Exposure-controlled Mycophenolic Acid as Induction and Maintenance therapy in Class III and IV Lupus Nephritis. OBJECTIVES : 1. To study the effect of Exposure-controlled Mycophenolic Acid on Inducing and Maintaining remission in Class III and Class IV Lupus Nephritis patients. 2. To study the side effect profile and complications of Mycophenolic Acid therapy in Lupus Nephritis. CONCLUSIONS : 1. Mycophenolate Mofetil is beneficial as both induction an maintenance therapy in lupus nephritis. 2. With an empiric dosing schedule of 30mg/kg/day of Mycopheolate Mofetil (MMF), 55.8% of patients had 6 hour MPA AUC below the therapeutic range of 30-60mg.h/L and 5.8% of patients had 6 hour MPA AUC above the therapeutic range. 3. After dose adjustment, the average dose of MMF required to attain therapeutic range was 35mg/kg/day in our study population. 4. 57.6% had complete remission at 12 months in exposure controlled Mycophenolic Acid cohort and 50% had partial remission by 3 months. The complete remission rates improved through the maintenance phase to 88% at the end of two years. Partial remission was seen in 50% of the patients at three months. Cumulative remission which is the sum of complete and partial remission was seen in 94% at 3 months. This is comparable to studies on Cyclophosphamide as induction therapy and Azathioprine as maintenance therapy. 5. GFR was the earliest to improve with a median time of 2.6±0.85 months. 6. Proteinuria improved next at a median time of 3±1.3 months followed by Anti dsDNA at 4±0.3 months.C3 was the last to remit among the lab parameters at a median time of 12±2.4months. 7. There were four flares with majority being mild nephritic flares that did not require any modification of immunosuppression. 8. Infectious episodes were present 17.3% in the cohort

Prospective Cohart study of clinical outcomes and prognostic factors in lupus nephritis in a tertiary care centre in South India

INTRODUCTION : Systemic Lupus Erythematosus (SLE), more a syndrome than a disease, is the prototype of immune complex mediated systemic autoimmune diseases. A prevalence study in India showed a crude incidence rate of 4 per 100,000 population per year. It has been diagnosed in 1.5 million people in the United States. Women have a much higher risk of developing SLE, and the woman-to-man ratio is about 10-15:1. Racial differences are present and it is seen that women of black, Hispanic, Asian, and Native American backgrounds are more frequently affected than their white peers. SLE, though a disease known for over half a century, still carries a grim prognosis. More than half of these patients develop irreversible organ damage over time1. Lupus nephritis occurs in about half of SLE patients in India as per published series reporting between 35-73% occurrences. Renal involvement in SLE occurs early in the disease and is usually within 10 years of the appearance of SLE. Studies have suggested that male lupus nephritis patients have more severe disease than their female counterparts. Lupus nephritis is seen more in Asians, African-Caribbeans and African- Americans. In a retrospective study published in 1988 by McCune et al, male sex, young age (<33years), and non-European ancestry were determinants of earlier renal involvement in SLE patients. With modern treatment, the survival of SLE patients have improved in the west to about 80% at 10 years after diagnosis but, the figures for the Asian Indians are not so good. Murali et al in a study of 98 patients between 1981 and 1993 showed 50%-60% survival of SLE patients at 10 years. It is a therapeutic challenge to treat lupus nephritis, since early intervention can dramatically change the disease course. AIM : T o describe the presentation of lupus nephritis, its prognostic factors, outcome measures and their correlation in patients with lupus nephritis on treatment for six months. OBJECTIVES : 1. To describe the presentation of lupus nephritis in our population 2. To describe the clinical outcome of lupus nephritis in patients treated with various regimens at six months. 3. To identify predictors of outcome of lupus nephritis in our population. MATERIALS AND METHODS : Setting Study was conducted among the patients presenting to the in-patient and out-patient services of the Department of Medicine and Nephrology of the Christian Medical College (CMC), Vellore, South India which is an 1800 bedded tertiary care teaching hospital. Duration of Study : August 2004 to July 2006. The recruitment of patients ended in January 2006 and the follow up period in July 2006. Inclusion Criteria : 1. All consecutive adult SLE patients (age >12 years). 2. Diagnosed with lupus nephritis by Renal biopsy in the Department of Medicine and Nephrology. 3. Follow up for 6 months, availing out-patient clinic/ in-patient services between August 2004 and July 2006. Exclusion Criteria : 1. Age < 12 years. 2. Renal disease other than SLE. 3. Less than 6 months of follow up. Study Design : The study was a Prospective Cohort study on consecutive Lupus Nephritis patients diagnosed in our centre. DISCUSSION : 83 consecutive patients who were diagnosed to have SLE and admitted for renal biopsy were recruited into the study. These patients were admitted either in Medicine or in Nephrology wards for biopsy. Follow up was through outpatient visits to either department. Of the 83, 5 were lost to follow up. All the 5 were from the North Eastern region of the country. Attempts to contact them through post was unsuccessful. The analysis was undertaken in the remaining 78 who had six months of follow up. It compares well with the studies done on outcome in lupus nephritis. Study done in our centre by Abraham et al and published in ’99 was done on 29 patients with class IV lupus with a follow up of 5 years. Other studies from the West36,70,71,72,73 had sample size ranging from 34-82. CONCLUSIONS : Seventy percent (55/78) patients of lupus nephritis were treatment responders. Significant predictors of poor outcome were Hypertension, WHO Class IV histology , Creatnine clearance <75ml/min, S.albumin <3.5mg/dl, of which Hypertension was an independent predictor of poor outcome at the end of six months of therapy. Demographic pattern and the clinical presentation of lupus nephritis were in keeping with well established literature from India and elsewhere

Epidemiology, baseline characteristics and risk of progression in the first South-Asian prospective longitudinal observational IgA nephropathy cohort

Introduction: Glomerular Research And Clinical Experiments-IgA Nephropathy in Indians (GRACE-IgANI) is the first prospective South Asian IgAN cohort with protocolized follow-up and extensive biosample collection. Here we report the baseline clinical, biochemical, and histopathologic characteristics of GRACE IgANI and calculate baseline risk of progression for the cohort. Methods: 201 incident adults with kidney biopsy-proven primary IgAN were recruited into GRACE-IgANI between March 2015 and September 2017. As of April 30, 2020, the cohort had completed a median followup of 30 months (interquartile range [IQR] 16-39). Results: The commonest clinical presentation in GRACE IgANI was hypertension, with or without proteinuria, and nephrotic-range proteinuria was present in 34%, despite Conclusions: The predicted risk of progression in this cohort was considerable. Over the next 5 years, we will dissect the pathogenic pathways that underlie this severe South Asian IgAN phenotype

Three-Year Clinical Outcomes of the First South Asian Prospective Longitudinal Observational IgA Nephropathy Cohort

INTRODUCTION: Glomerular Research And Clinical Experiments—IgA Nephropathy in Indians (GRACE-IgANI) is the first prospective South Asian IgA nephropathy (IgAN) cohort with prespecified objectives, protocolized longitudinal follow-up, and extensive biosample collection. The baseline risk scores predicted high risk of kidney disease progression. METHODS: A total of 195 of 201 patients (97%) completed 3-year follow-up in September 2020. All patients received optimized supportive care, and those at high risk of progression were offered systemic corticosteroids. RESULTS: A total of 76 patients (76 of 193, 39.4%) had rapid progression in 3 years (≥5 ml/min per 1.73 m(2) decline in estimated glomerular filtration rate [eGFR] per year). A total of 72 patients (72 of 195, 36.9%) experienced the composite outcome (CO), defined as ≥50% fall in eGFR, eGFR < 15 ml/min per 1.73 m(2), commenced kidney replacement therapy or death, in 3 years. At each scheduled follow-up, achievement of proteinuria level < 1 g/d significantly delayed the time to the CO. The receiver operating characteristic curve of average annual decline in eGFR ≥ 5 ml/min per 1.73 m(2) had 86% sensitivity and 89% specificity for CO in 3 years and had good discrimination from 1 year onwards (area under the curve 0.8, SE 0.04, 95% CI 0.7–0.9, P < 0.0001). The significant predictors of CO by Cox proportional-hazards model were as follows: baseline MEST-T2 score (hazard ratio [HR] 3.3, 95% CI 1.7–6.5, P < 0.001), along with 24-hour urine protein level ≥ 1 g/d (HR 2.1, 95% CI 1.1–3.9, P = 0.02), eGFR < 60 ml/min per 1.73 m(2) (HR 2.9, 95% CI 1.1–7.6, P = 0.03), and rate of eGFR decline ≥ 5 ml/min per 1.73 m(2)/yr (HR 2.7, 95% CI 1.6–4.8, P < 0.001) all measured at 6 months. Mortality was 11 of 195 (5.6%). CONCLUSION: We identified longitudinal clinical variables measured at 6 months and ≥5 ml/min per 1.73 m(2) annual fall in eGFR after kidney biopsy as important predictors for composite outcome in addition to baseline histology

The long-term impact of hepatitis C infection in kidney transplantation in the pre-direct acting antiviral era

Hepatitis C virus (HCV) infection in kidney transplantation is an important issue with effects on patient and graft survival. The current standard of care involves using oral Direct Acting Antiviral drugs. Till recently, pre-transplant treatment with interferon was the only option for treatment. We studied 677 consecutive kidney transplant recipients with HCV infection. 5.2% patients had evidence of HCV infection. 2.0% were newly detected to have HCV infection after transplant (de novo HCV group). Nearly 28.6% had negative antibody tests but positive Nucleic Acid Test at the time of diagnosis. Eighty-five percent of pre-transplant HCV-positive patients were treated with interferon-based regimens. Early virologic response was seen in 66.6%. End of treatment response was achieved by 94.1%. Sustained virologic response was seen in 81.2%. Overall, patient and graft survival were not different between HCV and control groups (log-rank P = 0.154). Comparing HCV and control groups, there was a tendency toward increased fungal (11.4% vs. 5.6%, P = 0.144) and CMV infections (25.7% vs. 17.1%, P = 0.191) in the HCV group, though it did not reach statistical significance. Eighty-percent of the interferon-treated patients suffered side effects. On comparing, the pre-transplant HCV-positive group (85% treated) with the de novo HCV group (none treated), the de novo group had significantly reduced patient survival (P = 0.020) and NODAT (35.7 vs 4.8%, P = 0.028), and a tendency toward higher CMV infections (35.7% vs 19%, P = 0.432). In addition, death and hepatic complications (decompensated liver disease, fibrosing cholestatic hepatitis) occurred only in de novo HCV group. These results highlight the need for continued post-transplant treatment of HCV positive patients. The newer anti-HCV drugs are expected to fulfill this felt-need in kidney transplantation but long-term results are awaited. This study can serve as a benchmark for future studies to compare the long-term effect of Direct Acting Antiviral drugs

Patterns of Renal Dysfunction and Profile of Kidney Biopsies in Hematopoietic Stem Cell Transplant Recipients

Introduction: Post hematopoietic stem cell transplant (HSCT), kidney can be subjected to injury by various causes. Of these, graft versus host disease (GvHD) affecting the kidney is an under-recognized entity with no clear guidelines on its diagnosis, clinicopathological manifestations, and outcomes. Material and Methods: Out of 2,930 patients who underwent HSCT at our center between 2005 and 2020, kidney biopsy was performed in 19 allogenic and 5 autologous recipients. Results: The mean age of the cohort at transplant was 33.2 ± 7 years, and 15 (62%) were males. Median time to kidney biopsy from HSCT was 14 (IQR, 9–30) months. Aplastic anemia was the most common underlying hematological disease (54.2%). All 19 allogenic recipients were classified based on clinicopathological manifestations into either thrombotic microangiopathy (TMA, 12/19 [63%]) or nephrotic syndrome (NS, 7/19 [37%]) pattern. Glomerular tuft “mesangiolysis” was the dominant pattern of injury noted in 9/12 cases of TMA pattern. There was a predominance of acute microangiopathic changes restricted primarily to the glomerular compartment. Of the 7 patients with NS pattern, membranous nephropathy was seen in 4 (57%) and minimal change disease in 3 (43%) patients. Thirty-nine percent (7/18) stained positive for C4d which was predominantly glomerular. Allogenic recipients who did not receive immunosuppression (IS) for renal disease had a lower eGFR at biopsy, a longer latency between withdrawal of GvHD prophylaxis and biopsy, and were significantly at a higher risk of kidney failure (IS: 2/11, 18.1% vs. no IS: 2/6, 33.3%, p = 0.04). “Associated extra-renal GvHD” occurred in 11/19 (57.9%) allogenic recipients. Patients with “associated extra-renal GvHD” had significantly more deaths (6/11, 60% vs. 0, p = 0.02) but comparable renal outcomes. Conclusion: Renal GvHD can present with or without “associated extra-renal GvHD” after a prolonged period of withdrawal of GvHD prophylaxis, requiring careful diagnostic vigilance and consideration of IS