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Transforming the Care of Patients with Diabetic Kidney Disease.
Brosius, FC, Cherney, D, Gee, PO, Harris, RC, Kliger, AS, Tuttle, KR, Quaggin, SE, ,
Clinical journal of the American Society of Nephrology : CJASN. 2021;(10):1590-1600
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Abstract
Diabetes and its associated complications pose an immediate threat to humankind. Diabetic kidney disease is one of the most devastating complications, increasing the risk of death more than ten-fold over the general population. Until very recently, the only drugs proven and recommended to slow the progression of diabetic kidney disease were angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, which act by inhibiting the renin-angiotensin system. Despite their efficacy as kidney and cardiovascular protective therapies and as antihypertensive agents, renin-angiotensin system inhibitors have been grossly underutilized. Moreover, even when renin-angiotensin system inhibitors are used, patients still have a high residual risk of diabetic kidney disease progression. Finally, the kidney-protective effect of renin-angiotensin system inhibitors has been categorically demonstrated only in patients with macroalbuminuria included in the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trials, not in other individuals. The lack of new therapies to treat diabetic kidney disease over the past 2 decades has therefore represented a tremendous challenge for patients and health care providers alike. In recent years, a number of powerful new therapies have emerged that promise to transform care of patients with diabetes and kidney disease. The challenge to the community is to ensure rapid implementation of these treatments. This white paper highlights advances in treatment, opportunities for patients, challenges, and possible solutions to advance kidney health, and introduces the launch of the Diabetic Kidney Disease Collaborative at the American Society of Nephrology, to aid in accomplishing these goals.
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How Do I Manage Hypertension in Patients with Advanced Chronic Kidney Disease Not on Dialysis? Perspectives from Clinical Practice.
Polychronopoulou, E, Wuerzner, G, Burnier, M
Vascular health and risk management. 2021;:1-11
Abstract
In the general population, the prevalence of moderate and severe chronic kidney disease (CKD) is usually below 5% but this figure is often higher in specific groups of patients such as those with type 2 diabetes. Patients with advanced CKD (CKD stage 3b and 4) are at high or very high cardiovascular risk, and their risk of progressing towards end-stage kidney disease (CKD stage 5) and the need of renal replacement therapy are elevated. Hypertension is a major cause of poor cardiovascular and renal outcomes in severe CKD. Therefore, an adequate control of blood pressure (BP) is mandatory. However, normalizing BP is often challenging in these patients because the clinical management of hypertension in advanced CKD is not well defined and rarely supported by large randomized controlled trials. In the present review, we discuss the characteristics of hypertension in advanced CKD, excluding dialysis, and its management integrating data from recent clinical studies and a pragmatic approach enriched by a long-standing clinical experience.
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Individualized Hemodialysis Treatment: A Perspective on Residual Kidney Function and Precision Medicine in Nephrology.
Hur, I, Lee, YK, Kalantar-Zadeh, K, Obi, Y
Cardiorenal medicine. 2019;(2):69-82
Abstract
BACKGROUND Residual kidney function (RKF) is often expected to inevitably and rapidly decline among hemodialysis patients and, hence, has been inadvertently ignored in clinical practice. The importance of RKF has been revisited in some recent studies. Given that patients with end-stage renal disease now tend to initiate maintenance hemodialysis therapy with higher RKF levels, there seem to be important opportunities for incremental hemo-dialysis by individualizing the dose and frequency according to their RKF levels. This approach is realigned with precision medicine and patient-centeredness. SUMMARY In this article, we first review the available methods to estimate RKF among hemodialysis patients. We then discuss the importance of maintaining and monitoring RKF levels based on a variety of clinical aspects, including volume overload, blood pressure control, mineral and bone metabolism, nutrition, and patient survival. We also review several potential measures to protect RKF: the use of high-flux and biocompatible membranes, the use of ultrapure dialysate, the incorporation of hemodiafiltration, incremental hemodialysis, and a low-protein diet, as well as general care such as avoiding nephrotoxic events, maintaining appropriate blood pressure, and better control of mineral and bone disorder parameters. Key Message: Individualized hemodialysis regimens may maintain RKF, lead to a better quality of life without compromising long-term survival, and ensure precision medicine and patient-centeredness in nephrology practice.
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ACE inhibitors and ARBs: Managing potassium and renal function.
Momoniat, T, Ilyas, D, Bhandari, S
Cleveland Clinic journal of medicine. 2019;(9):601-607
Abstract
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used primarily to treat hypertension and are also useful for conditions such as heart failure and chronic kidney disease, independent of their effect on blood pressure. This article reviews the indications for ACE inhibitors and ARBs and offers advice for managing their adverse effects, particularly declining renal function and hyperkalemia.
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A Meta-analysis of the Association of Estimated GFR, Albuminuria, Diabetes Mellitus, and Hypertension With Acute Kidney Injury.
James, MT, Grams, ME, Woodward, M, Elley, CR, Green, JA, Wheeler, DC, de Jong, P, Gansevoort, RT, Levey, AS, Warnock, DG, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2015;(4):602-12
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Abstract
BACKGROUND Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain. STUDY DESIGN Meta-analysis of cohort studies. SETTING & POPULATION 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts. SELECTION CRITERIA FOR STUDIES Cohorts participating in the CKD Prognosis Consortium. PREDICTORS Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions. OUTCOME Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. RESULTS During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension. LIMITATIONS AKI identified by diagnostic code. CONCLUSIONS Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.
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Endothelin and the glomerulus in chronic kidney disease.
Barton, M, Sorokin, A
Seminars in nephrology. 2015;(2):156-67
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Abstract
Endothelin-1 (ET-1) is a 21-amino acid peptide with mitogenic and powerful vasoconstricting properties. Under healthy conditions, ET-1 is expressed constitutively in all cells of the glomerulus and participates in homeostasis of glomerular structure and filtration function. Under disease conditions, increases in ET-1 are critically involved in initiating and maintaining glomerular inflammation, glomerular basement membrane hypertrophy, and injury of podocytes (visceral epithelial cells), thereby promoting proteinuria and glomerulosclerosis. Here, we review the role of ET-1 in the function of glomerular endothelial cells, visceral (podocytes) and parietal epithelial cells, mesangial cells, the glomerular basement membrane, stromal cells, inflammatory cells, and mesenchymal stem cells. We also discuss molecular mechanisms by which ET-1, predominantly through activation of the ETA receptor, contributes to injury to glomerular cells, and review preclinical and clinical evidence supporting its pathogenic role in glomerular injury in chronic renal disease. Finally, the therapeutic rationale for endothelin antagonists as a new class of antiproteinuric drugs is discussed.
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Endothelin and the renal microcirculation.
Guan, Z, VanBeusecum, JP, Inscho, EW
Seminars in nephrology. 2015;(2):145-55
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Endothelin (ET) is one of the most potent renal vasoconstrictors. Endothelin plays an essential role in the regulation of renal blood flow, glomerular filtration, sodium and water transport, and acid-base balance. ET-1, ET-2, and ET-3 are the three distinct endothelin isoforms comprising the endothelin family. ET-1 is the major physiologically relevant peptide and exerts its biological activity through two G-protein-coupled receptors: ET(A) and ET(B). Both ET(A) and ET(B) are expressed by the renal vasculature. Although ET(A) are expressed mainly by vascular smooth muscle cells, ET(B) are expressed by both renal endothelial and vascular smooth muscle cells. Activation of the endothelin system, or overexpression of downstream endothelin signaling pathways, has been implicated in several pathophysiological conditions including hypertension, acute kidney injury, diabetic nephropathy, and immune nephritis. In this review, we focus on the effects of endothelin on the renal microvasculature, and update recent findings on endothelin in the regulation of renal hemodynamics.
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GFR estimation: from physiology to public health.
Levey, AS, Inker, LA, Coresh, J
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2014;(5):820-34
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Abstract
Estimating glomerular filtration rate (GFR) is essential for clinical practice, research, and public health. Appropriate interpretation of estimated GFR (eGFR) requires understanding the principles of physiology, laboratory medicine, epidemiology, and biostatistics used in the development and validation of GFR estimating equations. Equations developed in diverse populations are less biased at higher GFRs than equations developed in chronic kidney disease (CKD) populations and are more appropriate for general use. Equations that include multiple endogenous filtration markers are more precise than equations including a single filtration marker. The CKD-EPI (CKD Epidemiology Collaboration) equations are the most accurate GFR estimating equations that have been evaluated in large diverse populations and are applicable for general clinical use. The 2009 CKD-EPI creatinine equation is more accurate in estimating GFR and prognosis than the 2006 MDRD (Modification of Diet in Renal Disease) Study equation and provides lower estimates of prevalence of decreased eGFR. It is useful as a "first test" for decreased eGFR and should replace the MDRD Study equation for routine reporting of serum creatinine-based eGFR by clinical laboratories. The 2012 CKD-EPI cystatin C equation is as accurate as the 2009 CKD-EPI creatinine equation in estimating GFR, does not require specification of race, and may be more accurate in patients with decreased muscle mass. The 2012 CKD-EPI creatinine-cystatin C equation is more accurate than the 2009 CKD-EPI creatinine and 2012 CKD-EPI cystatin C equations and is useful as a confirmatory test for decreased eGFR as determined by serum creatinine-based eGFR. Further improvement in GFR estimating equations will require development in more broadly representative populations, including diverse racial and ethnic groups, use of multiple filtration markers, and evaluation using statistical techniques to compare eGFR to "true GFR."
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Implications and importance of skeletal muscle mass in estimating glomerular filtration rate at dialysis initiation.
Zaman, T, Filipowicz, R, Beddhu, S
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2013;(3):233-6
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There is a trend toward "early" initiation of dialysis for renal replacement therapy. However, several observational studies showed an association of increased mortality at higher estimated glomerular filtration rate (eGFR) at dialysis initiation. This surprising result is due to errors in estimation of glomerular filtration rate (GFR). In malnourished patients with low muscle mass, serum-creatinine-based equations overestimate GFR. In patients with higher muscle mass, these equations underestimate GFR. This spurious association of higher prevalence of malnutrition in patients with higher eGFR compared with those with lower eGFR ultimately leads to the appearance of increased mortality with early initiation of dialysis. Therefore, reliable equations that properly account for creatinine production are warranted to estimate GFR at initiation of dialysis. Until then, in those with extremes of nutrition, mean of measured urea and creatinine clearances might provide more accurate GFR estimation for initiation of dialysis than the currently available equations.
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GFR at initiation of dialysis and mortality in CKD: a meta-analysis.
Susantitaphong, P, Altamimi, S, Ashkar, M, Balk, EM, Stel, VS, Wright, S, Jaber, BL
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2012;(6):829-40
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BACKGROUND The proportion of patients with advanced chronic kidney disease (CKD) initiating dialysis therapy at a higher glomerular filtration rate (GFR) has increased during the past decade. Recent data suggest that higher GFR may be associated with increased mortality. STUDY DESIGN A meta-analysis of cohort studies and trials. SETTING & POPULATION Patients with advanced CKD. SELECTION CRITERIA FOR STUDIES We performed a systematic literature search in MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Society of Nephrology abstracts, and bibliographies of retrieved articles to identify studies reporting on GFR at dialysis therapy initiation and mortality. PREDICTOR Estimated or calculated GFR at dialysis therapy initiation. OUTCOME Pooled adjusted hazard ratio (HR) of continuous GFR for all-cause mortality. RESULTS 16 cohort studies and 1 randomized controlled trial were identified (n = 1,081,116). By meta-analysis restricted to 15 cohorts (n = 1,079,917), higher GFR at dialysis therapy initiation was associated with a higher pooled adjusted HR for all-cause mortality (1.04; 95% CI, 1.03-1.05; P < 0.001). However, there was significant heterogeneity (I(2) = 97%; P < 0.001). The association persisted among the 9 cohorts that adjusted analytically for nutritional covariates (HR, 1.03; 95% CI, 1.02-1.04; P < 0.001; residual I(2) = 97%). The highest mortality risk was observed in hemodialysis cohorts (HR, 1.05; 95% CI, 1.02-1.08; P < 0.001), whereas there was no association between GFR and mortality in peritoneal dialysis cohorts (HR, 1.04; 95% CI, 0.99-1.08, P = 0.1; residual I(2) = 98%). Finally, higher GFR was associated with a lower mortality risk in cohorts that calculated GFR (HR, 0.80; 95% CI, 0.71-0.91; P = 0.003), contrasting with a higher mortality risk in cohorts that estimated GFR (HR, 1.04; 95% CI, 1.03-1.05; P < 0.001; residual I(2) = 97%). LIMITATIONS Paucity of randomized controlled trials, different methods for determining GFR, and substantial heterogeneity. CONCLUSIONS Higher estimated rather than calculated GFR at dialysis therapy initiation is associated with a higher mortality risk in patients with advanced CKD, independent of nutritional status. Although there was substantial heterogeneity of effect size estimates across studies, this observation requires further study.