February 2018

Patient-Centered Care in Renal Medicine: Five Strategies to Meet the Challenge

Ann M. O'Hare

There is growing interest in patient-centered care, defined by the Institute of Medicine as “care that is respectful of and responsive to individual patient preferences, needs, and values.” Although generally accepted as uncontroversial, the notion of “centering” care on our patients is in fact quite revolutionary.

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End-of-Life Care for Patients With Advanced Kidney Disease in the US Veterans Affairs Health Care System, 2000-2011

Susan P.Y. Wong, Margaret K. Yu, Pamela K. Green, Chuan-Fen Liu, Paul L. Hebert, and Ann M. O’Hare
Although advances in medical science and technology have led to improvements in population health and longevity, the potential benefits of interventions intended to prolong life tend to diminish as patients approach the end of life.

January 2018

Outcomes Associated With Left Ventricular Assist Devices Among Recipients With and Without End-stage Renal Disease.

Bansal N, Hailpern SM, Katz R, Hall YN, Tamura MK, Kreuter W, O'Hare AM

Left ventricular assist devices (LVADs) are widely used both as a bridge to heart transplant and as destination therapy in advanced heart failure. Although heart failure is common in patients with end-stage renal disease (ESRD), little is known about outcomes after LVAD implantation in this population. The objective of the study was to determine the utilization of and outcomes associated with LVADs in nationally representative cohorts of patients with and without ESRD.

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Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

Chang SY, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL.

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The Effect of Extended Release Niacin on Markers of Mineral Metabolism in CKD

Malhotra R, Katz R, Hoofnagle A, Bostom A, Rifkin DE, Mcbride R, Probstfield J, Block G, Ix JH

Chronic kidney disease is common and strongly linked with risk of fractures, cardiovascular disease, and end stage renal disease. Kidney disease patients have higher serum phosphate levels, and higher phosphate may be causing the higher risk of these outcomes. We identified that the lipid drug niacin lowers serum phosphate through a unique mechanism. In a randomized clinical trial among patients with CKD, we tested whether niacin lowers serum phosphate and other markers of mineral metabolism over 3 years. We observed a relatively modest lowering of serum phosphorous concentrations but no effect on other markers of mineral metabolism with niacin use over 3 years in participants with CKD.

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Stuck in a Bind With Phosphate Binders

Kestenbaum B, Psaty BM

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Commentary on Lessons from CKD-Related Genetic Association Studies-Moving Forward

Kestenbaum B, Seliger SL

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Impact of Obesity on Modality Longevity, Residual Kidney Function, Peritonitis, and Survival Among Incident Peritoneal Dialysis Patients

Obi Y, Streja E, Mehrotra RRivara MB, Rhee CM, Soohoo M, Gillen DL, Lau WL, Kovesdy CP, Kalantar-Zadeh K.

The association between obesity and clinical outcomes among patients ESRD undergoing peritoneal dialysis (PD) remains unclear in the current era. This observational study analyzed 15,573 PD patients in the US and found that higher body mass index was associated with greater risk for peritonitis-related hospitalizations, rapid decline in residual kidney function, and more frequent transfers to in-center hemodialysis. There was no difference in risk for death among obese patients undergoing PD compared to those treated with hemodialysis.

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Charting the transcriptional landscape of cells of renin lineage following podocyte depletion

McClelland AD, Lichtnekert J, Eng DG, Pippin JW, Gross KW, Gharib SA, Shankland SJ

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December 2017 

Perioperative THR-184 and AKI after Cardiac Surgery

Jonathan Himmelfarb, Glenn M. Chertow, Peter A. McCullough, Thierry Mesana, Andrew D. Shaw, Thoralf M. Sundt, Craig Brown, David Cortville, François Dagenais, Benoit de Varennes, Manuel Fontes, Jerome Rossert, Jean-Claude Tardif

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Acute Kidney Injury and Risk of Incident Heart Failure Among US Veterans

Bansal N, Matheny ME, Greevy RA Jr, Eden SK, Perkins AM, Parr SK, Fly J, Abdel-Kader K, Himmelfarb J, Hung AM, Speroff T, Ikizler TA, Siew ED

In this study of over 300,000 hospitalized U.S. Veterans, we found that acute kidney injury was associated with a 23% greater risk of developing incident heart failure within 2 years from hospital dishcharge.

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Risk profiles for acute health events after incident atrial fibrillation in patients with end-stage renal disease on hemodialysis

Airy M, Chang TI, Ding VY, Goldstein BA, Bansal N, Niu J, Navaneethan SD, Turakhia MP, Winkelmayer WC

Among 85,000 older incident hemodialysis patients in the U.S., atrial fibrillation was diagnosed in 14% of this population. Atrial fibrillation was associated with up to 9-fold increased risk of mortality, particularly in the first 90 days after diagnosis of atrial fibrillation.

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Longitudinal FGF23 Trajectories and Mortality in Patients with CKD

Tamara Isakova, Xuan Cai, Jungwha Lee, Dawei Xie, Xue Wang, Rupal Mehta, Norrina B. Allen, Julia J. Scialla, Michael J. Pencina, Amanda H. Anderson, John Talierco, Jing Chen, Michael J. Fischer, Susan P. Steigerwalt, Mary B. Leonard, Chi-yuan Hsu, Ian H. de Boer, John W. Kusek, Harold I. Feldman, Myles Wolf, Chronic Renal Insufficiency Cohort (CRIC) Study Investigators

FGF-23 is a phosphaturic hormone that may promote cardiovascular disease. People with CKD enrolled in the CRIC study, and those whose blood FGF-23 concentrations rose during follow-up had markedly higher mortality rates than those whose FGF-23 concentrations remained stable or decreased. This provides new evidence that interventions to prevent rising FGF-23 may improve health outcomes in CKD.

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Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease

Marcum ZA, Forsberg CW, Moore KP, de Boer IH, Smith NL, Boyko EJ, Floyd JS

Metformin is the preferred first-line drug used to lower blood glucose for people with diabetes. However, metformin is cleared by the kidneys, and its use has been restricted among patients with CKD. In this observational cohort study of more than 175,000 veterans with diabetes, metformin was associated with better outcomes than a comparator glucose-lowering drug (glipizide) at all evaluated levels of estimated GFR. This supports more widespread use of metformin among people with diabetes and moderate (stage 3) CKD.

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The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study

Ginsberg C, Katz R, de Boer IH, Kestenbaum BR, Chonchol M, Shlipak MG, Sarnak MJ, Hoofnagle AN, Rifkin DE, Garimella PS, Ix JH

In this cohort study, lower 24,25 to 25-hydroxyvitamin D3 ratio was associated with low bone mineral density and increased risk of fracture, providing evidence that impaired vitamin D metabolism affects bone health and suggesting that this ratio may help guide treatments to improve bone in CKD.

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Biomarkers of tubulointerstitial damage and function in type 1 diabetes

de Boer IH, Gao X, Bebu I, Hoofnagle AN, Lachin JM, Paterson A, Perkins BA, Saenger AK, Steffes MW, Zinman B, Molitch ME

This case-control study of people with type 1 diabetes found that 8 urine and plasma biomarkers differed markedly comparing participants with, versus without, albuminuria and low eGFR. The results demonstrate that marked abnormalities in biomarkers accompany reduced eGFR and albuminuria in type 1 diabetes. The results further suggest that diverse aspects of tubulointerstitial damage and function should be evaluated in future studies of diabetic kidney disease and provides new information on specific biomarkers that might be useful for this work.

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Clinical Genetic Testing for APOL1: Are we There Yet?

Young BA, Fullerton SM, Wilson JG, Cavanaugh K, Blacksher E, Spigner C, Himmelfarb J, Burke W.

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Is Kidney Donor Profile Index (KDPI) Valid for Hepatitis C Aviremic Kidneys?

Sibulesky L, Kling CE, Limaye AP, Johnson CK

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November 2017

Recurrent glomerular disease after kidney transplantation

Blosser CD, Bloom RD

Recurrent glomerular disease is an increasingly recognized and significant cause of chronic allograft failure. Improved understanding of the mechanisms of disease have enabled better biomarkers and therapies and are available for some GNs, including Membranous Nephropathy, Primary FSGS, C3G and atypical HUS. The greater risks and opportunities for treatment of recurrent GN necessitate accurate pretransplant diagnoses.

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Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development

Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE, Hughes MR, Cruz NM, Liu Y, Churchill AJ, Wang Y, Fu H, Pippin JW, Lin LY, Shankland S, Vogl AW, McNagny KM, Freedman BS

The presence of podocytes - the specialized filtering cells of the kidney - is one of the most exciting aspects of human kidney organoids. However, the maturity of these podocytes has not been clear from previous studies. Here, we show that organoid podocytes mature to a specific stage in kidney development, and that gene-edited podocytes can faithfully recapitulate disease symptoms at this stage, teaching us new lessons about how the podocyte gets its specialized architecture.

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Histopathology of Veins Obtained at Hemodialysis Arteriovenous Fistula Creation Surgery

Charles E. Alpers, Peter B. Imrey, Kelly L. Hudkins, Tomasz A. Wietecha, Milena Radeva, Michael Allon, Alfred K. Cheung, Laura M. Dember, Prabir Roy-Chaudhury, Yan-Ting Shiu, Christi M. Terry, Alik Farber, Gerald J. Beck, Harold I. Feldman, John W. Kusek, Jonathan Himmelfarb, the Hemodialysis Fistula Maturation Study Group

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Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease

Cruz NM, Song X, Czerniecki SM, Gulieva RE, Churchill AJ, Kim YK, Winston K, Tran LM, Diaz MA, Fu H, Finn LS, Pei Y, Himmelfarb, J., Freedman BS

Polycystic kidney disease is a very common disorder in which tiny tubes in the kidneys and other organs swell up to form balloon-like cysts, eventually causing organ failure. The genes that cause PKD are known, but how they work to prevent cysts is not yet understood. Using gene editing, we created human kidney organoids with mutations that cause PKD. These organoids formed massive cysts when liberated from their surrounding attachments, which were not seen in non-PKD organoids. Our findings indicate a critical and understudied role for the extracellular milieu in PKD.

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Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype

Bhatraju PK, Robinson-Cohen C, Mikacenic C, Harju-Baker S, Dmyterko V, Slivinski NSJ, Liles WC, Himmelfarb, J. Heckbert SR, Wurfel MM

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Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in the Elderly: AGES-Kidney and MESA-Kidney

Foster MC, Levey AS, Inker LA, Shafi T, Fan L, Gudnason V, Katz R., Mitchell GF, Okparavero A, Palsson R, Post WS, Shlipak MG

Factors that are known to influence a renal biomarker’s potential to correctly estimate glomerular filtration rate (GFR) are called the non-GFR determinants (e.g. age, gender, ethnicity, and muscle mass). Although creatinine-based GFR equations give reliable estimates in adults with reduced kidney function, it is known that for older adults, continuous change in muscle mass leads to unreliable creatinine levels for GFR estimation. In this current study we showed that, in two elderly community based cohorts, cystatin C, β2-microglobulin (B2M), and beta-trace protein (BTP) were less affected by age and gender and unaffected by ethnicity than those of creatinine. These findings are important for the development of GFR estimating equations. Improving the accuracy of GFR in the elderly may help to optimize clinical decision making with regard to diagnosing CKD, medication dose-adjustment, initiating renal replacement therapy, and assessing CKD associated CVD risk.

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Coloduodenovesical Fistula After Simultaneous Pancreas-Kidney Transplant: Case Report and Review of the Literature

Rahnemai-Azar AA, Penna M, Morrison SD, Rayhill SC, Sibulesky L, Muczynski KA, Bakthavatsalam R

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Making Sense of Prognostic Information About Maintenance Dialysis versus Conservative Care for Treatment of Advanced Kidney Disease

 Wong S.P.Y., O'Hare A.M.

In an invited editorial, we discuss the findings of a recent meta-analysis of cohort studies comparing survival of patients who opted for maintenance dialysis vs. conservative medical management without dialysis for their end-stage renal disease. While some prior studies have reported longer survival among patients opting for dialysis, other studies have reported no difference in survival for older patients (aged ≥75 years) with a high burden of comorbidity. We discuss the implication of prognostic information comparing dialysis and conservative care in counseling patients with advanced kidney disease in the US context. 

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Embracing Complexity: How to Build an Evidence Base Capable of Supporting Patient-Centered Care

O’Hare A.M.

An editorial that reviews a study that used a Delphi process to identify research priorities for clinical studies in nephrology.  What was radical about this study is that it included patients and caregivers along with nephrology providers in the outcome selection process.  The editorial explains why it is so important to engage patients and their family and friends in formative aspects of study design.  In this way we will be able to develop an evidence base capable of supporting care that prioritizes what matters most to individual patients. 

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Physical Activity Dose for Hemodialysis Patients: Where to Begin? Results from a Prospective Cohort Study

Matsuzawa R, Roshanravan B, Shimoda T, Mamorita N, Yoneki K, Harada M, Watanabe T, Yoshida A, Takeuchi Y, Matsunaga A.

Sedentary lifestyle is associated with increased risk of death in dialysis patients. Although experts encourage regular physical activity among patients on hemodialysis, little is known about the minimal dose of physical activity and the association of the number of steps per day necessary to yield health benefits among patients treated with hemodialysis. This collaborative study is the first to determine how the number of steps taken on a daily basis predicts risk of death in patients treated with hemodialysis. The findings also show that taking at least 4000 steps per day is a good starting point for patients on hemodialysis to realize the health benefits and lower their risk of premature death.

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 WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion

Kaverina NV, Eng DG, Largent AD, Daehn I, Chang A, Gross KW, Pippin JW, Hohenstein P, Shankland SJ

Focal segmental glomerulosclerosis (FSGS) is a progressive form of kidney disease. The number of podocytes covering the glomerular capillaries decreases in (FSGS) and is widely accepted to be responsible for glomerular leak of plasma proteins. Because adult podocytes do not have the ability to proliferate and replace their numbers following disease-induced depletion, several groups have attempted to determine how adult podocytes might regenerate by identifying putative local stem/progenitor cells that might participate in their regeneration. More recently our group focused on cells of renin lineage (CoRL) as candidate adult podocyte progenitors. CoRL are normally restricted to the kidney's extraglomerular vascular smooth muscle compartment, where they are the sole source of renin under normal states. Following the induction of experimental FSGS in four different strains of CoRL reporter mice, we showed that a subpopulation of CoRL that moved to the intraglomerular compartment also coexpressed proteins considered specific to podocytes. Wilms’ tumor suppressor 1 (WT1) plays an important role in controlling cell proliferation and mesenchymal-epithelial balance in normal development and disease. We now show that following podocyte depletion in three experimental models, and in patients with FSGS and membranous nephropathy, WT1 staining increased significantly in cells of renin lineage. When WT1 was selectively deleted in CoRL, as undertaken in this manuscript, in the setting of podocyte loss, their proliferation and migration to the glomerulus, and to some extent their transdifferentiation towards a podocyte fate through mesenchymal to epithelial transition are markedly reduced. These data suggest that WT1 plays a critical role in CoRL biology following podocyte depletion.

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Association of Serum Amyloid A with Kidney Outcomes and All-Cause Mortality in American Indians with Type 2 Diabetes

Saulnier PJ, Dieter BP, Tanamas SK, McPherson SM, Wheelock KM, Knowler WC, Looker HC, Meek RL, Nelson RG, Tuttle KR

Our research team has a longstanding interest in elucidating mechanisms of diabetic kidney disease (DKD) with an overall goal of developing new biomarkers and therapeutics. Serum amyloid A (SAA) is an important candidate for such a targetable DKD biomarker. SAA induces inflammation and apoptosis in podocytes, mesangial cells, and proximal tubular cells, and associates with histologic changes characteristic of DKD in mice and humans. Higher SAA concentrations in blood, are found in two different mouse models of DKD, as well as in people with type 2 diabetes and advanced DKD (macroalbuminuria or low glomerular filtration rate). Higher serum SAA concentrations were previously associated with increased risk of end-stage renal disease (ESRD) and death in persons with type 2 diabetes and advanced DKD. However, SAA may enhance tubular cell proliferation in acute kidney injury (AKI), suggesting that it is also capable of promoting kidney repair under some circumstances.

In the present study, we explored the prognostic value of SAA in American Indians with type 2 diabetes without DKD or with early DKD (microalbuminuria). In these people, higher serum concentration of SAA forecasted a lower risk of ESRD, but not death, over approximately 15 years of follow-up. However, participants in the lowest tertile of SAA concentration also had the highest mean GFR (154±50 mL/min), suggesting they may also have the greatest clearance of SAA from the circulation via glomerular hyperfiltration. Therefore, in early diabetes, hemodynamic changes may predominate and alter the predictive value of circulating SAA. These data also suggest that inflammation, marked by elevation of SAA, could be protective in the absence of established kidney disease. Thus, it may be that in diabetes without DKD or in early DKD, production of SAA could protect against kidney-disease-accelerating experiences such as AKI episodes. Conversely, once DKD is sufficiently advanced, SAA may contribute to pro-inflammatory mechanisms of kidney disease progression. Clarification of conditions under which such disease transitions occur will be key to advancing knowledge of relationships between underlying inflammation and DKD, and ultimately, to inform optimal application of biomarkers for prognosis and therapeutic action.

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Chronic kidney disease and incident apparent treatment-resistant hypertension among blacks: Data from the Jackson Heart Study

Tanner RM, Shimbo D, Irvin MR, Spruill TM, Bromfield SG, Seals SR, Young BA, Muntner P

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Diabetes and CKD in the United States Population, 2009–2014

Leila R. Zelnick, Noel S. Weiss, Bryan R. Kestenbaum, Cassianne Robinson-Cohen, Patrick J. Heagerty, Katherine TuttleYoshio N. Hall, Irl B. Hirsch, Ian H. de Boer

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September 2017

eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study

Nisha BansalLeila R. Zelnick, Alvaro Alonso, Emelia J. Benjamin, Ian H. de Boer, Rajat Deo‖, Ronit Katz, Bryan Kestenbaum, Jehu Mathew, Cassianne Robinson-Cohen, Mark J. Sarnak, Michael G. Shlipak, Nona Sotoodehnia, Bessie Young, Susan R. Heckbert

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See article on this research: Kidney Disease May Boost Risk of Abnormal Heartbeat
US News and World Report 

Heart failure in patients with kidney disease

Tuegel C, Bansal N

This review provides a comprehensive overview of the epidemiology, pathophysiology and treatment of heart failure in patients with kidney disease. Heart failure (HF) is a leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), and the population of CKD patients with concurrent HF continues to grow. The accurate diagnosis of HF is challenging in patients with CKD in part due to a lack of validated imaging and biomarkers specifically in this population.  The pathophysiology between the heart and the kidneys is complex and bidirectional. Patients with CKD have greater prevalence of traditional HF risk factors as well as unique kidney-specific risk factors including malnutrition, acid-base alterations, uremic toxins, bone mineral changes, anemia, and myocardial stunning.  These risk factors also contribute to the decline of kidney function seen in patients with subclinical and clinical HF. The exact mechanisms that link kidney disease with HF are not fully elucidated but likely include inflammation, hemodynamic changes, and alterations in hormonal pathways. More targeted HF therapies may improve outcomes in patients with kidney disease as current HF therapies are under-utilized in this population. 

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Blood Pressure and Risk of Cardiovascular Events in Patients on Chronic Hemodialysis: The CRIC Study (Chronic Renal Insufficiency Cohort) 

Bansal N, McCulloch CE, Lin F, Alper A, Anderson AH, Cuevas M, Go AS, Kallem R, Kusek JW, Lora CM, Lustigova E, Ojo A, Rahman M, Robinson-Cohen C, Townsend RR, Wright J, Xie D, Hsu CY; CRIC Study Investigators

In this paper, we explored the relationship between systolic blood pressure (SBP) with cardiovascular (CVD) events, which has important treatment implications but has not been well-elucidated. Among 383 HD participants enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study, multivariable splines and Cox models were used to study the association between SBP and adjudicated CVD events (heart failure, myocardial infarction, ischemic stroke, peripheral artery disease), controlling for differences in demographics, CVD risk factors and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34, p<0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of CVD events, with the nadir risk between 140-170 mmHg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of CVD events.  In conclusion, among HD patients, although there is a U-shaped (“paradoxical”) association of dialysis-unit-SBP and risk of CVD, there is a linear association of out-of-dialysis-unit-SBP with risk of CVD.  Out-of-dialysis-unit BP provides key information and may be an important therapeutic target.  

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Kidney function is associated with an altered protein composition of high-density lipoprotein

Rubinow KB, Henderson CM, Robinson-Cohen C, Himmelfarb Jde Boer IH, Vaisar T, Kestenbaum B, Hoofnagle AN

High-density lipoprotein cholesterol (HDL-C) is a circulating construction of lipids and proteins that play a major role in cardiovascular disease. In this study, we evaluated 37 HDL-C associated proteins across the spectrum of kidney function. We found significant differences in four HDL-C proteins associated with lower estimated GFR. These alterations provide new insight into impaired lipoprotein metabolism and its potential treatment in chronic kidney disease.

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Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy

Cardenas-Gonzalez M, Srivastava A, Pavkovic M, Bijol V, Rennke HG, Stillman IE, Zhang X, Parikh S, Rovin BH, Afkarian M, de Boer IHHimmelfarb J, Waikar SS, Vaidya VS

MicroRNAs are small RNA molecules that are not transcribed to protein but may affect expression of genes. In this study of people with diabetes or systemic lupus erythematosus, we identified mircoRNAs excreted in the urine that differed in abundance for people with versus without kidney disease. These microRNAs were likely made in the kidney. The microRNAs may serve as targets to prevent or treat disease or biomarkers to better diagnose kidney damage among people with diabetes or lupus.

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Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis)

Tibuakuu M, Zhao D, de Boer IH, Guallar E, Bortnick AE, Lutsey PL, Budoff MJ, Kizer JR, Kestenbaum BR, Michos ED

Low vitamin D promotes pathways of inflammation and calcification; however, associations with human calcific diseases are not well understood. Herein, we determined the association of 25-hypdroxyvitamin D (25-OHD) concentrations with mitral and aortic calcification in 5,530 participants in a multi-ethnic cohort study. Serum 25-OHD concentrations were not associated with incident or prevalent valve calcification after adjustment. These findings diminish enthusiasm for 25-OHD levels as a marker of cardiac valve disease in humans.

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Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD

Batacchi Z, Robinson-Cohen C, Hoofnagle AN, Isakova T, Kestenbaum B, Martin KJ, Wolf MS, de Boer IH

Vitamin D supplements are used widely in people with and without chronic kidney disease (CKD). However, it’s not clear how supplementation affects underlying vitamin D metabolism, and vitamin D metabolism is altered in CKD. In this physiology study, we found that vitamin D supplementation induced the catabolism of circulating 25-hydroxyvitamin D and slowed the rate of conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active vitamin D hormone. These changes were blunted in participants with CKD. These results suggest that vitamin D metabolism changes during vitamin D supplementation to maintain vitamin D homeostasis. These changes are less robust in CKD, suggesting that CKD is a state of stagnant vitamin D metabolism.

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Does Secretory Clearance Follow Glomerular Filtration Rate in Chronic Kidney Diseases? Reconsidering the Intact Nephron Hypothesis 

Chapron A, Shen DD, Kestenbaum BR, Robinson-Cohen C, Himmelfarb J, Yeung CK

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Standardized outcomes in nephrolgoy-peritoneal dialysis (SONG-PD): Study protocol for establishing a core outcome set in PD

Manera KE, Tong A, Craig JC, Brown EA, Brunier G, Dong J, Dunning T, Mehrotra R, Naicker S, Pecoits-Filho R, Perl J, Wang AY, Wilkie M, Howell M, Sautenet B, Evangelidis N, Shen JI, Johnson DW

The aim of the Standardised Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) study is to establish a set of core outcomes for trials in patients on PD based on the shared priorities of all stakeholders, so that outcomes of most relevance for decision- making can be evaluated, and that interventions can be compared reliably. This manuscript describes the methods the researchers will use to develop these core outcomes.

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Timing of Dialysis Initiation: What Has Changed Since IDEAL?

Rivara MBMehrotra R

The optimal timing of initiation of maintenance dialysis in patients with end stage renal disease is currently unknown. The null results of the Initiating Dialysis Early and Late (IDEAL) study, the only randomized trial to have tested the impact of dialysis initiation at two different levels of kidney function on outcomes, have challenged the established paradigm of using estimates of glomerular filtration as the primary guide for initiation of maintenance dialysis.  In this article, we discuss the recent evolution of research findings and trends in dialysis initiation practices in the United States, and suggest that future directions should incorporate comprehensive standardized symptoms assessment, modern shared decision-making practices, and should further explore measurement of novel uremic solutes.”

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Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor α

Dai Y, Chen A, Liu R, Gu L, Sharma S, Cai W, Salem F, Salant DJ, Pippin JW, Shankland SJ, Moeller MJ, Ghyselinck NB, Ding X, Chuang PY, Lee K, He JC

This recent publication in Kidney International was led by Dr. John Cijiang He, Icahn School of Medicine at Mount Sinai. It extends previous work on the effects of the vitamin A derivative retinoic acid (RA) in glomerular disease. The group has previously shown RA reduces proteinuria and glomerulosclerosis in a murine model of HIV-associated nephropathy, by activating the RA receptor-. In this study, the RA receptor- was ablated specifically in podocytes, and nephrotoxic serum induced crescentic nephritis was induced in mice. RA treatment had a beneficial effect on crescent formation, kidney function, glomerular cell proliferation and podocyte injury. These beneficial effects were blunted by the absence of the RA receptor- in podocytes, indicating an important role for the RA receptor- in the pathogenesis of crescentic GN. Additionally, RA itself had direct effects on proliferation and increasing differentiation of parietal epithelial cells (PEC) on Bowman’s capsule to podocytes. Treatment of GN is currently limited to immunosuppressive therapy. Taken together, the results of this study indicate RA and RA receptor- agonists hold great potential in minimizing podocyte injury, decreasing proliferation and increasing PEC differentiation to podocytes in crescentic GN. 

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Association between Endothelin-1 Levels and Kidney Disease among Blacks

Rebholz CM, Harman JL, Grams ME, Correa A, Shimbo D, Coresh J, Young BA

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July 2017

Associations of Vitamin D-Binding Globulin and Bioavailable Vitamin D Concentrations with Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA)

Robinson-Cohen C, Zelnick LR, Hoofnagle AN, Lutsey PL, Burke G, Michos ED Shea SJC, Tracy R, Siscovick DS, Psaty B, Kestenbaum Bde Boer IH

Chronic kidney disease (CKD) causes multiple interrelated disturbances in vitamin D metabolism, including impaired synthesis and catabolism. These disturbances are suspected to interfere with normal vascular functioning. We measured multiple interrelated vitamin D metabolites and vascular functions in 558 people awaiting arteriovenous fistula creation surgery.
Serum concentrations of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and bioavailable vitamin D were not associated with statistical or biologically meaningful differences in flow mediated or nitroglycerine mediated vasodilation. Vitamin D metabolites were also not associated with carotid-femoral or carotid-radial pulse wave velocity.
Despite compelling rationales for CKD related vitamin D disturbances to cause vascular disease, multiple serum markers of vitamin D metabolism were not associated with vascular functions in patients with late stage CKD. Current laboratory measurements of vitamin D are unlikely to provide useful information regarding vascular functions in this setting.

Nephrotic syndrome in pregnancy poses risks with both maternal and fetal complications

De Castro I, Easterling TR, Bansal NJefferson JA

This study shows that in pregnant women with nephrotic syndrome, the maternal and fetal complications are high, even in the absence of significant renal impairment or uncontrolled hypertension.

Persistent Gaps in Use of Advance Directives Among Nursing Home Residents Receiving Maintenance Dialysis

Kurella Tamura M, Liu S, Montez-Rath ME, O'Hare AMHall YN, Lorenz KA

Comparison between Different Measures of Body Fat with Kidney Function Decline and Incident CKD

Madero M, Katz R, Murphy R, Newman A, Patel K, Ix J, Peralta C, Satterfield S, Fried L, Shlipak M, Sarnak M

Over the past two decades the increase in the prevalence of chronic kidney disease (CKD) has paralleled the increase in the prevalence of obesity. Obesity as measured by BMI, has been associated with incident CKD and ESRD. The gold standard and most accurate assessment of subcutaneous, visceral and intermuscular adipose tissue is by computed tomography (CT) scan. The study by Madero and colleagues sought to evaluate whether adiposity assessed by CT was associated with kidney function decline and/or incident CKD and whether it provided a better measure of risk assessment than BMI and waist circumference (WC). Our group compared anthropometric CT and anthropometric measures of obesity with kidney outcomes in the Health Aging and Body Composition Study. The data consisted of 2,489 individuals with mean age 74 years. CKD developed in 17% of participants over a median follow-up of 9 years. Visceral fat, intermuscular fat, BMI, and waist circumference—but not subcutaneous fat—were all associated with kidney function decline and the development of CKD. However, our results demonstrated that CT measures of visceral adiposity do not appear superior to the conventional anthropometric measures of BMI and WC for incident CKD and kidney function decline prognosis assessment.  The results further confirm the link between obesity and CKD and obesity’s importance as an independent risk factor for CKD in elderly people. Future research should be directed to determine whether measures to treat obesity could have an impact on kidney outcomes.

Repression of Interstitial Identity in Nephron Progenitor Cells by Pax2 Establishes the Nephron-Interstitium Boundary during Kidney Development

Natalie Naiman, Kaoru Fujioka, Mari Fujino, M. Todd Valerius, S. Steven Potter, Andrew P. McMahon, Akio Kobayashi

During embryogenesis, multiple cell types are generated to establish the body plan. Although studies in the past revealed how different cell types are induced during development, molecular regulatory mechanisms to maintain different cell lineages are currently much less clear, including in the kidney. In the article in Developmental Cell, Naiman et al. showed that repression of interstitial cell identity in nephron progenitor cells by the Pax2 gene establishes the lineage boundary between the nephron parenchyma and renal interstitium throughout kidney development. Because direct reprogramming to create nephron parenchyma cells requires to overcome the lineage boundary segregating the nephron compartment from other cell lineages, the authors’ observations should ultimately lead to establish novel regenerative therapy by restoring new nephrons, eliminating the need for dialysis and kidney transplantation in patients with kidney disease in the future. 

The article is highlighted by the following perspective articles:

Sex Differences in Hospitalizations with Maintenance Hemodialysis

Adams SV, Rivara M, Streja E, Cheung AK, Arah OA, Kalantar-Zadeh K, Mehrotra R

Patients with end-stage kidney disease treated with hemodialysis in the United States are admitted, on average, twice every year and over 30% are readmitted within 30-days of discharge. This work using a nationally representative data shows for the first time that the risk for hospitalization and readmission within 30 days is greatest for younger women. This study helps identify a high-risk group of patients that may benefit from closer oversight and care. 

Choice of Hemodialysis Access in Older Adults: A Cost-Effectiveness Analysis

Hall RK, Myers ER, Rosas SE, O'Hare AM, Colón-Emeric CS

Among older adults, the cost-effectiveness of an arteriovenous fistula placed within the first month of dialysis diminishes with increasing age and lower life expectancy and is not the most cost-effective option for those with the most limited life expectancy.

Targeting Access to Kidney Care Via Telehealth: The VA Experience

Crowley ST, Belcher J, Choudhury D, Griffin C, Pichler R, Robey B, Rohatgi R, Mielcarek B

The Department of Veterans Affairs (VA) is the largest integrated health care system in the USA.  Part of the challenge for the VA is that Nephrologists only are located in large metropolitan areas.  For example, the area of VISN 20 (which includes the states of Washington, Oregon, Idaho and Alaska) only has Nephrologists in Seattle and Portland.  Renal Specialty Care for Veterans in rural communities, therefore can be challenging, given geographical barriers.   Many Veterans also have severe PTSD and avoid coming to large centers. 
The VA has therefore embraced the use of Telemedicine to overcome some of these barriers to care.  Some of the forms of Telemedicine nclude the use of e-consults that involve a review of the electronic medical record by a specialist.  The VA has also used a provider-to-provider form of Telemedicine that connect PCPs working in rural areas with Nephrologists.  Nephrologist meet with PCPs on a weekly basis using Video Conferencing to provide weekly CME lectures and to actively review cases submitted by the PCPs.  This case based learning has been shown to improve patient care, provider knowledge and patient satisfaction.  The Seattle based Nephrology Telemedicine program for the VA has been identified as one of the most successful renal telemedicine programs in the country. 

Exercise and CKD: Skeletal Muscle Dysfunction and Practical Application of Exercise to Prevent and Treat Physical Impairments in CKD

Roshanravan B, Gamboa J, Wilund K

Reduced kidney function leads to the retention of uremic toxins, culminating in inflammation, oxidative stress, and insulin resistance promoting skeletal muscle dysfunction. Skeletal muscle serves as a debilitating target of chronic kidney disease (CKD) resulting in fatigue, weakness, and poor physical function. Left unabated, skeletal muscle dysfunction can lead to loss of functional independence, mobility disability and further vulnerability to major disease complications. Impaired skeletal muscle metabolism is a sentinel pathologic event in the disablement process among patients with kidney disease. This review focuses on the impact of kidney disease on skeletal muscle dysfunction in the context of the disability process and reviews screening and treatment strategies that kidney health professionals can use in clinical practice to prevent functional decline and disability.

The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Sweetwyne MT, Pippin JW, Eng DG, Hudkins KL, Chiao YA, Campbell MD, Marcinek DJ, Alpers CE, Szeto HH, Rabinovitch PS, Shankland SJ

The mechanisms underlying the changes in the kidney are unknown, and any reversibility has not been adequately shown. This study shows that giving the mitochondrial stabilizing peptide SS-31 to very old mice reduced parietal epithelial cell activation, and improved podocyte and endothelial cell integrity. These studies also showed that under certain conditions, there is some reversibility to the aged kidney.

Diabetic Kidney Disease: Challenges, Progress, and Possibilities

Alicic RZ, Rooney MT, Tuttle KR

This is a state-of-the art review on the current status of diabetic kidney disease (DKD), the most common cause of chronic kidney disease worldwide. The global pandemic of obesity is driving unprecedented rates of diabetes, and consequently, diabetic complications including DKD. The paper takes the reader on a deep dive into epidemiology, risk factors, structural changes in the kidney, natural history, pathophysiology, diagnosis and treatment, as well as novel therapies and population-based approaches to DKD management. The call to action is clear – Transformative efforts, including advocacy with the patient voice, dissemination and implementation of best practices, and strategic research to improve clinically meaningful outcomes, are vital to reduce the devastating consequences of DKD.

Factors associated with maintenance of body mass index in the Jackson Heart Study: A prospective cohort study secondary analysis

Auerbach BJ, Katz R, Tucker K, Boyko EJ, Drewnowski A, Bertoni A, Dubbert P, Hickson DA, Correa A, Young BA

The purpose of the study was to compare the association of diet quality, physical activity, and environmental factors with body mass index (BMI) maintenance in African American adults. The study looked at 4401 participants from the Jackson Heart Study, a prospective cohort study based in Jackson, Mississippi.. The outcome measured was weight loss or weight maintenance over a mean of 5 years. During this time, 63% of participants lost or maintained weight; 37% gained weight. An ideal diet quality was associated with increased likelihood of BMI maintenance; living in an unsafe environment was associated with lower likelihood of BMI maintenance. A poor food environment and physical activity were not associated with BMI maintenance. Diet was associated with BMI maintenance whereas exercise was not in black adults in Mississippi.