Sunil Bhandari

Determinants and Consequences of Renal Function Variations With Aldosterone Blocker Therapy in Heart Failure Patients After Myocardial Infarction Insights From the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

Background— We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results— Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of −1.4±0.3 mL · min−1 · 1.73 m−2 compared with placebo ( P 20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02–1.30; P =0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction 20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. Conclusions— In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes. # Clinical Perspective {#article-title-45}Background— We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results— Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of −1.4±0.3 mL · min−1 · 1.73 m−2 compared with placebo (P<0.0001), an effect that appeared within the first month (−1.3±0.4 mL · min−1 · 1.73 m−2) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR >20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02–1.30; P=0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction <35%, and use of eplerenone and loop diuretic. An early decline in eGFR by >20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. Conclusions— In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes.

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

The Effect of Iron and Erythropoietin Treatment on the A1C of Patients With Diabetes and Chronic Kidney Disease

OBJECTIVE To examine the effect of intravenous iron and erythropoietin-stimulating agents (ESAs) on glycemic control and A1C of patients with diabetes and chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS This was a prospective study of patients with type 2 diabetes and CKD stage IIIB or IV undergoing intravenous iron (group A) and/or ESA (group B). Full blood profiles were determined over the study period. Glycemic control was monitored using A1C, seven-point daily glucose three times weekly, and continuous glucose monitoring (CGM). RESULTS There were 15 patients in both group A and group B. Mean A1C (95% CI) values fell in both groups (7.40% [6.60–8.19] to 6.96% [6.27–7.25], P < 0.01, with intravenous iron and 7.31% [6.42–8.54] to 6.63% [6.03–7.36], P = 0.013, ESA). There was no change in mean blood glucose in group A (9.55 mmol/l [8.20–10.90] vs. 9.71 mmol/l [8.29–11.13], P = 0.07) and in group B (8.72 mmol/l [7.31–10.12] vs. 8.78 mmol/l [7.47–9.99], P = 0.61) over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment. CONCLUSIONS Both iron and ESA cause a significant fall in A1C values without a change to glycemic control in patients with diabetes and CKD. At the present time, regular capillary glucose measurements and the concurrent use of CGM remain the best alternative measurements of glycemic control in this patient group.

Evaluation of RBC ferritin and reticulocyte measurements in monitoring response to intravenous iron therapy.

Intravenous (IV) iron therapy can reduce erythropoietin (EPO) requirements in dialysis patients. Monitoring this response accurately is difficult. Estimation of red blood cell ferritin (RBCFer) and reticulocyte indices may give additional valuable information about iron availability to the erythroblasts (erythron). We evaluated the use of RBCFer, mean hemoglobin content of reticulocytes (CHr), and mean hemoglobin concentration of reticulocytes (CHCMr) in a prospective, nonblinded study of 22 hemodialysis patients (16 men and six women with a mean age of 62 years [range, 24 to 80 years]). All patients had an initial serum ferritin of < or = 60 microg/L. Patients with features known to produce EPO resistance and underlying bleeding/hematologic disorders were excluded. Patients were established on subcutaneous EPO and given IV iron therapy. The mean hemoglobin level remained constant throughout the study (P = 0.087). Serum ferritin and RBCFer increased significantly (P < 0.001 and 0.015, respectively) while a reduction in transferrin saturation became significant at the end of the study (P = 0.0047). A sharp increase in reticulocytes occurred in the first 14 days after commencement of IV iron, and there was an initial decrease in the percentage of hypochromic RBCs. An early decline in RBCFer was apparent. CHr increased with IV iron, indicative of increased iron supply to the developing erythron. Measurement of RBCFer and CHr provide evidence of increased iron supply for erythropoiesis during IV iron therapy. These measures help identify patients with functional iron deficiency and allow more accurate monitoring of response to IV iron therapy.

State of the iron: How to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease

Iron deficiency anemia (IDA) frequently occurs in patients suffering from inflammatory bowel disease (IBD) and negatively impacts their quality of life. Nevertheless, the condition appears to be both under-diagnosed and undertreated. Regular biochemical screening of patients with IBD for anemia by the gastroenterology community has to be advocated. Oral iron is a low cost treatment however its effectiveness is limited by low bioavailability and poor tolerability. Intravenous (IV) iron rapidly replenishes iron stores and has demonstrated its safe use in a number of studies in various therapeutic areas. A broad spectrum of new IV iron formulations is now becoming available offering improved tolerability and patient convenience by rapidly restoring the depleted iron status of patients with IBD. The following article aims to review the magnitude of the problem of IDA in IBD, suggest screening standards and highlight existing and future therapies.

Expression of Somatostatin and Somatostatin Receptor Subtypes 1–5 in Human Normal and Diseased Kidney

Somatostatin mediates inhibitory functions through five G protein–coupled somatostatin receptors (sst1-5). We used immunohistochemistry, immunofluorescence, and RT-PCR to determine the presence of somatostatin receptors sst1, sst2A, sst2B, sst3, sst4, and sst5 in normal and IgA nephropathy human kidney. All somatostatin receptors were detected in the thin tubules (distal convoluted tubules and loops of Henle) and thick tubules (proximal convoluted tubules) in the tissue sections from nephrectomy and biopsy samples. Immunopositive sst1 and sst4 staining was more condensed in the cytoplasm of tubular epithelial cells. In normal kidney tissue sections, podocytes and mesangial cells in the glomeruli stained for sst1, sst2B, sst4 and sst5, and stained weakly for sst3. In IgA kidney tissue, the expression of somatostatin receptors was significantly increased with particular immmunopositive staining for sst1, sst2B, sst4, and sst5 within glomeruli. In the epithelial cells, the staining for sst2B and sst4 in proximal tubules and sst1, sst2B, and sst5 in distal tubules was increased. The mRNA expression of sst1-5 was also detected by RT-PCR. Somatostatin and all five receptor subtypes were ubiquitously distributed in normal kidney and IgA nephropathy. The increased expression of somatostatin receptors in IgA nephropathy kidney might be the potential pathogenesis of inflammatory renal disease.

Effect of conversion from mycophenolate mofetil to enteric‐coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation

Despite the potential tolerability advantage of enteric‐coated mycophenolate sodium (EC‐MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC‐MPS permits mycophenolic acid dose to be increased or gastrointestinal side‐effects to be ameliorated. In a randomized, multicenter, open‐label trial, kidney transplant recipients experiencing gastrointestinal side‐effects either remained on MMF or switched to an equimolar dose of EC‐MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC‐MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty‐four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC‐MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC‐MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients (P = 0.007). Kidney transplant patients receiving reduced‐dose MMF because of gastrointestinal side‐effects can tolerate a significant increase in MPA dose after conversion to EC‐MPS. Patient‐reported gastrointestinal outcomes with higher doses of EC‐MPS remained at least as good as in MMF‐treated controls.

Mortality at Low and High Estimated Glomerular Filtration Rate Values: A ‘U’ Shaped Curve

Background: While a low estimated glomerular filtration rate (eGFR) confers an increased risk of dying, the mortality associated with high eGFR values has not been ascertained. Methods: Four variable MDRD-derived eGFR was calculated in a total of 33,386 patients (18,620 F, 14,766 M) aged ≧50 years (median 68 years, IQR 60–76 years) collected by family doctors in 2000. They were then classified according to their eGFR into 30 ml/min/1.73 m2 bands (<30, 30–59, 60–89, 90–119, 120–150). The subsequent mortality status of each patient was determined at 31st December 2006 and cause of death recorded where available. Results: Applying Cox proportional hazards models (adjusted for age and gender), the hazard ratio (HR) of dying compared to a reference of patients with eGFRs of 60–89 ml/min/1.73m2 was, as expected, higher in the low eGFR bands (HR 1.37 (95% CI 1.29–1.45) for 30–59; HR 2.60 (2.31–2.93) for <30 ml/min/1.73 m2, both p < 0.0001). However, it was also greater amongst patients with higher eGFRs (HR 1.29 (1.19–1.41) for 90–119; HR 2.63 (2.16–3.21) for 120–150 ml/min/1.73 m2, p < 0.0001). Circulatory disease was the main cause of death in patients with low eGFRs and respiratory disease/cancer, in patients with high eGFRs. Conclusions: As a marker of mortality, both low and high eGFRs are equally predictive of increased mortality in community patients, exhibiting a ‘U’ shaped curve. Thus, current CKD guidelines which recommend inaction or even the non-reporting of eGFR values greater than 60–90 ml/min/1.73 m2 may not identify patients who are at an equally high risk of dying as those where intervention is recommended.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Uremic Cardiomyopathy and Insulin Resistance: A Critical Role for Akt?

Uremic cardiomyopathy is a classic complication of chronic renal failure whose cause is unclear and treatment remains disappointing. Insulin resistance is an independent predictor of cardiovascular mortality in chronic renal failure. Underlying insulin resistance are defects in insulin signaling through the protein kinase, Akt. Akt acts as a nodal point in the control of both the metabolic and pleiotropic effects of insulin. Imbalance among these effects leads to cardiac hypertrophy, fibrosis, and apoptosis; less angiogenesis; metabolic remodeling; and altered calcium cycling, all key features of uremic cardiomyopathy. Here we consider the role of Akt in the development of uremic cardiomyopathy, drawing parallels from models of hypertrophic cardiac disease.