Mohan Rajapurkar

Oxidants in Chronic Kidney Disease

Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once established, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM), or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.

What do we know about chronic kidney disease in India: first report of the Indian CKD registry

BackgroundThere are no national data on the magnitude and pattern of chronic kidney disease (CKD) in India. The Indian CKD Registry documents the demographics, etiological spectrum, practice patterns, variations and special characteristics.MethodsData was collected for this cross-sectional study in a standardized format according to predetermined criteria. Of the 52,273 adult patients, 35.5%, 27.9%, 25.6% and 11% patients came from South, North, West and East zones respectively.ResultsThe mean age was 50.1 ± 14.6 years, with M:F ratio of 70:30. Patients from North Zone were younger and those from the East Zone older. Diabetic nephropathy was the commonest cause (31%), followed by CKD of undetermined etiology (16%), chronic glomerulonephritis (14%) and hypertensive nephrosclerosis (13%). About 48% cases presented in Stage V; they were younger than those in Stages III-IV. Diabetic nephropathy patients were older, more likely to present in earlier stages of CKD and had a higher frequency of males; whereas those with CKD of unexplained etiology were younger, had more females and more frequently presented in Stage V. Patients in lower income groups had more advanced CKD at presentation. Patients presenting to public sector hospitals were poorer, younger, and more frequently had CKD of unknown etiology.ConclusionsThis report confirms the emergence of diabetic nephropathy as the pre-eminent cause in India. Patients with CKD of unknown etiology are younger, poorer and more likely to present with advanced CKD. There were some geographic variations.

Epidemiology and risk factors of chronic kidney disease in India - results from the SEEK (Screening and Early Evaluation of Kidney Disease) study.

BackgroundThere is a rising incidence of chronic kidney disease that is likely to pose major problems for both healthcare and the economy in future years. In India, it has been recently estimated that the age-adjusted incidence rate of ESRD to be 229 per million population (pmp), and >100,000 new patients enter renal replacement programs annually.MethodsWe cross-sectionally screened 6120 Indian subjects from 13 academic and private medical centers all over India. We obtained personal and medical history data through a specifically designed questionnaire. Blood and urine samples were collected.ResultsThe total cohort included in this analysis is 5588 subjects. The mean ± SD age of all participants was 45.22 ± 15.2 years (range 18–98 years) and 55.1% of them were males and 44.9% were females. The overall prevalence of CKD in the SEEK-India cohort was 17.2% with a mean eGFR of 84.27 ± 76.46 versus 116.94 ± 44.65 mL/min/1.73 m2 in non-CKD group while 79.5% in the CKD group had proteinuria. Prevalence of CKD stages 1, 2, 3, 4 and 5 was 7%, 4.3%, 4.3%, 0.8% and 0.8%, respectively.ConclusionThe prevalence of CKD was observed to be 17.2% with ~6% have CKD stage 3 or worse. CKD risk factors were similar to those reported in earlier studies.It should be stressed to all primary care physicians taking care of hypertensive and diabetic patients to screen for early kidney damage. Early intervention may retard the progression of kidney disease. Planning for the preventive health policies and allocation of more resources for the treatment of CKD/ESRD patients are imperative in India.

Serum catalytic iron as a novel biomarker of vascular injury in acute coronary syndromes.

AIMS Catalytic iron is associated with high oxidative stress during vascular injury. We measured catalytic iron in patients with suspected acute coronary syndromes (ACS) and healthy volunteers to evaluate its utility in early detection of patients with acute myocardial infarction (MI) and predicting major adverse cardiac events (MACE). METHODS AND RESULTS Catalytic iron was measured on admission and 24 hours later in 127 patients with acute MI, 51 patients with suspected ACS without MI, and 250 healthy volunteers. Descriptive and decision statistics were performed for catalytic iron and troponin I. Catalytic iron levels at presentation were 1.5+2.0 micromol/l, 0.2+0.16 micromol/l, and 0.1+0.06 micromol/l for acute MI, suspected ACS without MI, and normals, respectively p<0.0001. Catalytic iron was elevated in all patients with MI at presentation. At a cutpoint of 0.30 micromol/L, the sensitivity, specificity, and diagnostic accuracy for identifying MI was 84%, 95%, and 92%, respectively. Increase in catalytic iron at 24 hours compared to baseline was associated with MACE at 30 days. CONCLUSIONS Catalytic iron identified all patients with acute MI at presentation and serial elevation was independently associated with MACE. This biomarker of vascular injury is useful in the rapid serologic assessment of patients with suspected ACS.

Management of patients with diabetes and CKD: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.

Management of Non-neoplastic Renal Hemorrhage by Transarterial Embolization

OBJECTIVES To assess the role of transarterial embolization (TAE) and critically appraise its feasibility and efficacy in the management of non-neoplastic renal hemorrhage. Percutaneous TAE is an effective method for the control of hemorrhage, irrespective of the cause. Injury to the renal artery or its branch, after trauma or during open or percutaneous urologic procedures, can be accurately diagnosed using angiography and treated by percutaneous embolization techniques. Because the technique and technology have evolved, it is now possible to perform highly selective embolization of the injured vessel while preserving vascularity of the rest of the renal parenchyma. METHODS The medical records of all patients who underwent angioembolization for hemorrhagic urologic emergencies at our institute from January 1996 to December 2007 were reviewed. RESULTS A total of 41 patients, aged 7-72 years, underwent TAE because of hemorrhage after percutaneous nephrolithotomy (n = 27), open pyelolithotomy (n = 3), renal biopsy (n = 8), and spontaneous occurrence (n = 3). All patients had a normal coagulation profile before surgery. A total of 35 patients (85.3%) underwent successful embolization and none required a postprocedural blood transfusion. Of those with postpercutaneous nephrolithotomy bleeding, angioembolization failed in 6 patients. Of these, only 2 required nephrectomy to save the patients life. No serious procedure-related complications occurred. CONCLUSIONS TAE is a minimally invasive, safe, simple, and highly effective modality, in expert hands, for the management of postprocedural renal bleeding. This option should be considered early in the management of these cases because it is not only a life-saving, but ultimately a kidney-sparing, procedure.

Increased plasma catalytic iron in patients may mediate acute kidney injury and death following cardiac surgery

Catalytic iron, the chemical form of iron capable of participating in redox cycling, is a key mediator of acute kidney injury (AKI) in multiple animal models, but its role in human AKI has not been studied. Here we tested in a prospective cohort of 250 patients undergoing cardiac surgery whether plasma catalytic iron levels are elevated and associated with the composite outcome of AKI requiring renal replacement therapy or in-hospital mortality. Plasma catalytic iron, free hemoglobin, and other iron parameters were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3. Plasma catalytic iron levels, but not other iron parameters, rose significantly at the end of cardiopulmonary bypass and were directly associated with bypass time and number of packed red blood cell transfusions. In multivariate analyses adjusting for age and preoperative eGFR, patients in the highest compared with the lowest quartile of catalytic iron on postoperative day 1 had a 6.71 greater odds of experiencing the primary outcome, and also had greater odds of AKI, hospital mortality, and postoperative myocardial injury. Thus, our data are consistent with and expand on findings from animal models demonstrating a pathologic role of catalytic iron in mediating adverse postoperative outcomes. Interventions aimed at reducing plasma catalytic iron levels as a strategy for preventing AKI in humans are warranted.

Prognostic Evaluation of Catalytic Iron in Patients With Acute Coronary Syndromes

The potential of iron to generate reactive oxygen species has motivated a long‐standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Circulating catalytic iron (“free” iron) is that which is not bound to transferrin or ferritin and is available to generate reactive oxygen species that may have deleterious vascular effects.

Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease

Compelling experimental evidence exists for the role of oxidants and iron in glomerular disease. In preliminary studies, we confirmed increased urinary catalytic iron in patients with glomerulonephritis and diabetic nephropathy. We conducted two separate single-center, prospective, single-armed, open-labeled, proof-of-concept studies to evaluate the safety and efficacy of an oral iron chelator in patients with glomerulonephritis and diabetic nephropathy. Study 1 comprised 15 patients with biopsy-proven glomerulonephritis who had persistent proteinuria despite treatment with steroids and/or cyclophosphamides. Study 2 comprised 38 adult patients with diabetic nephropathy. Patients in Study 1 were treated with deferiprone (50 mg/kg/day) in three divided doses for 6 months and Study 2 patients were treated for 9 months. In Study 1, two patients had severe gastrointestinal intolerance and withdrew from the study after one dose and are not included in the results. There was a significant reduction (47 ± 9% mean) in 24-h urinary protein (4.01 ± 1.61 to 2.21 ± 1.62 [p = 0.009]), with no significant changes in serum creatinine. In Study 2, treatment with deferiprone resulted in a marked, persistent drop in the mean albumin/creatinine ratio (187 ± 47 at baseline to 25 ± 7 mg/g, [p = 0.01]) and stable renal function over a 9-month period. No clinically significant adverse events were observed in either study. Although these are small, open-labeled, and non-randomized studies, our results suggest that future randomized, double-blind trials examining the utility of deferiprone to treat glomerular diseases appear warranted.

Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Evidence-based cinical practice guidelines improve delivery of uniform care to patients with and at risk of developing kidney disease, thereby reducing disease burden and improving outcomes. These guidelines are not well-integrated into care delivery systems in most low- and middle-income countries (LMICs). The KDIGO Controversies Conference on Implementation Strategies in LMIC reviewed the current state of knowledge in order to define a road map to improve the implementation of guideline-based kidney care in LMICs. An international group of multidisciplinary experts in nephrology, epidemiology, health economics, implementation science, health systems, policy, and research identified key issues related to guideline implementation. The issues examined included the current kidney disease burden in the context of health systems in LMIC, arguments for developing policies to implement guideline-based care, innovations to improve kidney care, and the process of guideline adaptation to suit local needs. This executive summary serves as a resource to guide future work, including a pathway for adapting existing guidelines in different geographical regions.