Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Renal Replacement Therapy and Incremental Hemodialysis for Veterans with Advanced Chronic Kidney Disease.

Each year approximately 13,000 Veterans transition to maintenance dialysis, mostly in the traditional form of thrice-weekly hemodialysis from the start. Among >6000 dialysis units nationwide, there are currently approximately 70 Veterans Affairs (VA) dialysis centers. Given this number of VA dialysis centers and their limited capacity, only 10% of all incident dialysis Veterans initiate treatment in a VA center. Evidence suggests that, among Veterans, the receipt of care within the VA system is associated with favorable outcomes, potentially because of the enhanced access to healthcare resources. Data from the United States Renal Data System Special Study Center "Transition-of-Care-in-CKD" suggest that Veterans who receive dialysis in a VA unit exhibit greater survival compared with the non-VA centers. Substantial financial expenditures arise from the high volume of outsourced care and higher dialysis reimbursement paid by the VA than by Medicare to outsourced providers. Given the exceedingly high mortality and abrupt decline in residual kidney function (RKF) in the first dialysis year, it is possible that incremental transition to dialysis through an initial twice-weekly hemodialysis regimen might preserve RKF, prolong vascular access longevity, improve patients' quality of life, and be a more patient-centered approach, more consistent with "personalized" dialysis. Broad implementation of incremental dialysis might also result in more Veterans receiving care within a VA dialysis unit. Controlled trials are needed to examine the safety and efficacy of incremental hemodialysis in Veterans and other populations; the administrative and health care as well as provider structure within the VA system would facilitate the performance of such trials.

Non-dialysis dependent chronic kidney disease is associated with high total and out-of-pocket healthcare expenditures.

BACKGROUND: Previous studies have documented the high costs of non-dialysis dependent chronic kidney disease (CKD) but out-of-pocket healthcare expenditures remain poorly explored. This study described total direct and out-of-pocket expenditures for adults with non-dialysis dependent CKD and compared expenditures with those for cancer or stroke. METHODS: This study used data from the 2011-2013 Medical Expenditure Panel Survey, a national survey of healthcare expenditures in the U.S. POPULATION: Expenditures were determined for adults with the following chronic diseases: CKD defined by 585 ICD9 codes (n = 52), cancer (colon, breast or bronchus/lung) (n = 870), or stroke (n = 1104). These represent adults who were aware of their conditions or visited a healthcare provider for the condition during the study period. Generalized linear models were used to estimate the marginal effects of CKD, cancer or stroke on adjusted expenditures compared to adults without CKD, cancer or stroke (n = 72,241) while controlling for demographics and co-morbidities and incorporating the sample weights of the complex survey design. RESULTS: The mean age for group with CKD, cancer or stroke was 65.5, 66.1, and 68.2 years, respectively, while mean age for group without CKD, cancer or stroke was 47.8 years. Median values of total direct and out of pocket healthcare expenditures ranged from as high as $12,877 (Interquartile Range [IQR] $5031-$19,710) and $1439 ($688-$2732), respectively, with CKD, to as low as $1189 (IQR $196-$4388) and $226 (IQR $20-$764) in the group without CKD, cancer or stroke. After adjusting for demographics and comorbidities, the adjusted difference in total direct healthcare expenditures was $4746 (95% CI $1775-$7718) for CKD, $8608 (95% CI $6167-$11,049) for cancer and $5992 (95% CI $4208-$7775) for stroke vs. group without CKD, cancer or stroke. Adjusted difference in out-of-pocket healthcare expenditures was highest for adults with CKD ($760; 95% CI 0-$1745) and was larger than difference noted for cancer ($419; 95% CI 158-679) or stroke ($246; 95% CI 87-406) relative to group without CKD, cancer or stroke. CONCLUSIONS: Total and out of pocket health expenditures for adults with non-dialysis dependent CKD are high and may be equal to or higher than expenditures incurred by adults with cancer or stroke.

Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Structured Exercise in Obese Diabetic Patients with Chronic Kidney Disease: A Randomized Controlled Trial.

BACKGROUND: Patients with type 2 diabetes mellitus (DM), obesity, and chronic kidney disease (CKD) are generally physically inactive and may benefit from exercise. Our objective was to determine the effects of structured exercise on physical fitness, kidney function, endothelial function, inflammation, and body composition in such patients. METHODS: In this randomized, controlled trial, 36 male patients (age 49-81) were randomly assigned to exercise + diet management (n = 18) or diet alone (n = 18). Participants were eligible if they had type 2 DM, body mass index >30 kg/m2, CKD stages 2-4, and persistent proteinuria (>200 mg/g creatinine for >3 months). The exercise intervention was a 12-week (3 days per week) program of aerobic and resistance training followed by 40 weeks of home exercise. The primary outcome measure was change from baseline in urine protein to creatinine ratio (UPCR) at 12 and 52 weeks. RESULTS: Thirty-two participants completed the study (14 exercise + diet, 18 diet-alone group). The change from baseline in UPCR was slightly greater in the diet-alone group at 12 weeks but not at 52 weeks. Changes in both symptom-limited and constant-workrate treadmill times were significantly higher in the exercise + diet group at 12 weeks but not at 52 weeks. There were no significant differences in urine albumin to creatinine ratio, estimated glomerular filtration rate, endothelial function, inflammation, or body composition between the groups. CONCLUSIONS: In obese diabetic subjects with CKD, structured exercise improved exercise capacity but not body composition or renal function. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Pentoxifylline for Diabetic Nephropathy: an Important Opportunity to Re-purpose an Old Drug?

Diabetic nephropathy, or diabetic kidney disease (DKD), is the most serious complication of diabetes mellitus (DM). Despite recent advances in therapy, DKD still often progresses to end-stage renal disease (ESRD). Recent studies have suggested that pentoxifylline (PTX) may be efficacious in the treatment of DKD. PTX is a rheologic modifier approved for use in the USA for the symptomatic relief of claudication. It competitively inhibits phosphodiesterase (PDE), resulting in increased intracellular cyclic AMP (cAMP), activation of protein kinase A (PKA), inhibition of interleukin (IL) and tumor necrosis factor (TNF) synthesis, and reduced inflammation. PTX improves red blood cell deformability, reduces blood viscosity, and decreases platelet aggregation. In combination with renin-angiotensin-aldosterone (RAAS) blockers, PTX may help prevent progression to ESRD in patients with DKD. This review focuses on the possible mechanisms of action of PTX in DKD and studies suggesting possible efficacy of this old drug for a new indication.

Magnesium and Dialysis: The Neglected Cation.

Disorders of magnesium homeostasis are very common in dialysis patients but have received scant attention. In this review, we address measurement of plasma magnesium, magnesium balance and the factors that affect magnesium flux during dialysis, the prevalence of hypo- and hypermagnesemia in dialysis patients, and the potential clinical significance of hypo- and hypermagnesemia in dialysis patients. Many factors can affect plasma magnesium concentration, including diet, nutritional status (including plasma albumin level), medications (such as proton pump inhibitors), and dialysis prescription. Further interventional studies to determine the effect of normalization of plasma magnesium concentration on clinical outcomes are needed. At the present time, we recommend that predialysis plasma magnesium be measured on a regular basis, with the dialysate magnesium concentration adjusted to maintain plasma magnesium concentration within the normal range.

Hypomagnesemia in hemodialysis patients: role of proton pump inhibitors.

BACKGROUND: Recent observations have associated hypomagnesemia with increased risk of cardiovascular morbidity and mortality in hemodialysis patients. METHODS: We did a 3-month chart review of 62 chronic hemodialysis patients at a single US hospital. All were dialyzed using a dialysate [Mg] of 0.75-1.0 mEq/l. Patients were divided into two groups: hypomagnesemic (mean predialysis plasma [Mg] <1.5 mEq/l) and non-hypomagnesemic (mean predialysis plasma [Mg] ≥1.5 mEq/l). RESULTS: All patients were male; mean age was 64.3 ± 8.7 years and the majority (73%) diabetic. 24 patients (39%) had hypomagnesemia and 38 (61%) were not hypomagnesemic. There were no significant differences between the two groups in age, diabetes status, blood pressure, duration of dialysis, plasma calcium, phosphorus, albumin, intact parathyroid hormone (PTH), dialysis adequacy (Kt/V), or dietary protein intake (as estimated by normalized protein catabolic rate, nPCR). However, use of proton pump inhibitors (PPIs) was significantly associated with hypomagnesemia (plasma [Mg] 1.48 ± 0.16 mEq/l in the PPI group vs. 1.65 ± 0.26 mEq/l in the non-PPI group, p = 0.007). Adjustment for age, diabetes status, duration of dialysis, plasma albumin, Kt/V, nPCR, and diuretic use did not affect the association between PPI use and hypomagnesemia. CONCLUSIONS: Use of PPIs in patients dialyzed using a dialysate [Mg] of 0.75-1.0 mEq/l is associated with hypomagnesemia. We suggest monitoring plasma [Mg] in patients taking PPIs, with discontinuation of the medication if possible and/or adjustment of dialysate [Mg] to normalize plasma [Mg].

Hyponatremia in a Patient With Vasodilatory Shock Due to Overdose of Antihypertensive Medications: A Case Report.

Vasodilatory shock can be caused by septic shock, neurogenic shock, anaphylaxis, drugs, and toxins. Vasopressin is commonly used for the restoration of vasomotor tone in vasodilatory shock due to sepsis. This agent exerts its vasoconstrictive effect via smooth muscle V1 receptors and has antidiuretic activity via kidney V2 receptors. Stimulation of V2 receptors results in the integration of aquaporin 2 channels into the apical membrane of collecting ducts leading to free water reabsorption. This antidiuretic action of vasopressin predisposes to hyponatremia. Yet, the development of hyponatremia with the use of vasopressin in critically ill patients with sepsis is rare. A 75-year-old female presented after a suicidal attempt by ingestion of amlodipine and lisinopril. Despite adequate intravenous fluids administration, she remained hypotensive, requiring the initiation of vasopressors. She developed hyponatremia after initiation of vasopressin due to the absence of endotoxemia, and her serum sodium normalized once vasopressin was discontinued. We recommend monitoring for hyponatremia as a complication of vasopressin, especially in patients without sepsis.

Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy.

BACKGROUND: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans. STUDY DESIGN: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. SETTING & PARTICIPANTS: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls. PREDICTORS: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes. OUTCOMES: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1. RESULTS: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001). LIMITATIONS: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy. CONCLUSIONS: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.

Using herbs medically without knowing their composition: are we playing Russian roulette?

Herbal medicine, a form of complementary and alternative medicine (CAM), is used throughout the world, in both developing and developed countries. The ingredients in herbal medicines are not standardized by any regulatory agency. Variability exists in the ingredients as well as in their concentrations. Plant products may become contaminated with bacteria and fungi during storage. Therefore, harm can occur to the kidney, liver, and blood components after ingestion. We encourage scientific studies to identify the active ingredients in herbs and to standardize their concentrations in all herbal preparations. Rigorous studies need to be performed in order to understand the effect of herbal ingredients on different organ systems as well as these substances' interaction with other medications.

Acute Kidney Injury Associated With Semaglutide.

Case reports of acute kidney injury in patients taking the glucagon-like peptide 1 (GLP-1) receptor agonists exenatide and liraglutide have been reported. We report 2 patients with chronic kidney disease due to diabetic kidney disease who experienced rapid worsening of kidney function and increased proteinuria after being prescribed the GLP-1 receptor agonist semaglutide. In 1 patient, kidney biopsy showed advanced diffuse and nodular glomerulosclerosis accompanied by interstitial lymphoplasmacytic and eosinophilic infiltrate and evidence of acute tubular injury. At this time, the long-term outcomes of patients who experience acute kidney injury associated with GLP-1 receptor agonists is not known. We recommend that caution be used with these agents in patients with moderate to severe chronic kidney disease due to limited kidney reserve in the event of an adverse kidney event. Because most adverse kidney events have occurred in patients who experience adverse gastrointestinal symptoms, such patients should have laboratory tests and discontinuation of the medication if there is acute worsening of kidney function.

Proton-pump inhibitors associated with decreased urinary citrate excretion.

INTRODUCTION: Proton-pump inhibitors (PPIs) may increase the risk of kidney stone formation, but the mechanism has not been elucidated. There is a paucity of literature evaluating the effects of PPIs on urinary metabolites and urine pH. METHODS: We performed a retrospective review of nephrolithiasis patients treated at our institution and compared patients who were taking PPIs to those who were not at the time of their 24-h urine collections. Hierarchical multivariate linear regression was used to evaluate the independent relationship between PPI use and urinary mineral composition. RESULTS: We identified 301 consecutive patients, 88 (29%) of whom were taking PPIs at the time of their 24-h urine collections. Patients taking PPIs were older and more likely to have medical comorbidities associated with metabolic syndrome such as hypertension, diabetes, and dyslipidemia (p < 0.01). Controlling for these factors, patients taking PPIs were found to have 12% lower 24-h urine citrate excretion (ß = - 0.12, ΔF = 4.24, p = 0.04). There were no other differences in urinary mineral composition between the groups. CONCLUSION: Our findings suggest that patients who take PPIs regularly may be at risk for decreased urinary citrate excretion. The consequent decrease in urinary citrate may become clinically significant for patients with other predisposing factors for hypocitraturia.

Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Diabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD. METHODS AND ANALYSIS: Veterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period. ETHICS AND DISSEMINATION: This study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT03625648.

Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration-approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

Aerobic exercise in obese diabetic patients with chronic kidney disease: a randomized and controlled pilot study.

BACKGROUND: Patients with obesity, diabetes, and chronic kidney disease (CKD) are generally physically inactive, have a high mortality rate, and may benefit from an exercise program. METHODS: We performed a 24-week randomized controlled feasibility study comparing aerobic exercise plus optimal medical management to medical management alone in patients with type 2 diabetes, obesity (body mass index [BMI] > 30 kg/m2), and stage 2-4 CKD (estimated glomerular filtration rate [eGFR] 15-90 mL/min/1.73 m2 with persistent proteinuria). Subjects randomized to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised home exercise. The primary outcome variable was change in proteinuria. RESULTS: Seven subjects randomized to exercise and 4 control subjects completed the study. Exercise training resulted in an increase in exercise duration during treadmill testing, which was accompanied by slight but insignificant decreases in resting systolic blood pressure and 24-hour proteinuria. Exercise did not alter GFR, hemoglobin, glycated hemoglobin, serum lipids, or C-reactive protein (CRP). Caloric intake and body weight and composition also did not change with exercise training. CONCLUSION: Exercise training in obese diabetic patients with CKD is feasible and may have clinical benefits. A large-scale randomized controlled trial to determine the effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative stress in diabetic patients with CKD is planned.

Low statin use in nondialysis-dependent chronic kidney disease in the absence of clinical atherosclerotic cardiovascular disease or diabetes.

BACKGROUND: Both reduced glomerular filtration rate and increased urine albumin excretion, markers of chronic kidney disease (CKD), are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). However, CKD is not recognized as an ASCVD risk equivalent by most lipid guidelines. Statin medications, especially when combined with ezetimibe, significantly reduce ASCVD risk in patients with nondialysis-dependent CKD. Unless physicians recognize the heightened ASCVD risk in this population, statins may not be prescribed in the absence of clinical cardiovascular disease or diabetes, a recognized ASCVD risk equivalent. We examined statin use in adults with nondialysis-dependent CKD and examined whether the use differed in the presence of clinical ASCVD and diabetes. METHODS: This study ascertained statin use from pharmacy dispensing records during fiscal years 2012 and 2013 from the US Department of Veterans Affairs Healthcare System. The study included 581 344 veterans aged ≥50 years with nondialysis-dependent CKD Stages 3-5 with no history of kidney transplantation or dialysis. The 10-year predicted ASCVD risk was calculated with the pooled risk equation. RESULTS: Of veterans with CKD, 62.1% used statins in 2012 and 55.4% used statins continuously over 2 years (2012-13). Statin use in 2012 was 76.2 and 75.5% among veterans with CKD and ASCVD or diabetes, respectively, but in the absence of ASCVD, diabetes or a diagnosis of hyperlipidemia, statin use was 21.8% (P < 0.001). The 10-year predicted ASCVD risk was ≥7.5% in 95.1% of veterans with CKD, regardless of diabetes status. CONCLUSIONS: Statin use is low in veterans with nondialysis-dependent CKD in the absence of ASCVD or diabetes despite high-predicted ASCVD risk. Future studies should examine other populations.

Statin use among Veterans with dialysis-dependent chronic kidney disease.

INTRODUCTION: The benefits of statin medications in patients receiving maintenance dialysis remains controversial and clinical trials overall have shown no benefit. Potential side effects of statin medications include myalgias, myopathy, and memory loss and risk of side effects associated with statin medications increase with higher statin doses. We examined statin use and statin dose among Veterans with dialysis dependent CKD. Such information may help clinicians modulate medication use and reduce pill burden in appropriate patients. METHODS: This cross-sectional analysis ascertained medication utilization by linking records from the U.S. Department of Veteran's Affairs (VA) Managerial Cost Accounting Pharmacy National Data Extracts and Medicare Part D during calendar year 2013 for Veterans with dialysis-dependent CKD enrolled in and/or using VA healthcare. The venue of dialysis and patient characteristics were ascertained by linking VA Medical SAS datasets, VA Fee Basis datasets (for non-VA care paid for by VA), Medicare claims and the United States Renal Data Systems patient core files. FINDINGS: We identified 18,494 Veterans with dialysis-dependent CKD who were enrolled in and/or used VA healthcare, had no history of kidney transplantation, and were alive on January 1, 2014. More than half (58.1%) of Veterans with dialysis-dependent CKD used statins and 35.7% of statin utilization was high dose. Statins were the third most commonly prescribed medication after beta blockers (64.8%) and phosphate binders (64.5%). DISCUSSION: Statins are a commonly prescribed medication among Veterans receiving maintenance dialysis and approximately one-third of statin utilization is high dose in this population. Future studies should examine patient preferences, comorbidities, and dialysis characteristics that impact the risks and benefits of statin use in order to identify those patients who will or will not benefit from continued statin use.