Spotlight on Kidney Health

March 2020

Introduction

Kidney disease has been called an underestimated killer because it kills more Americans (90,000 per year) than breast and prostate cancers combined. Early kidney disease is difficult to detect. As it worsens, complications such as high blood pressure, arteriosclerosis, anemia, weak bones, and nerve damage can develop. In late stages, dialysis is required to do the work of the kidneys¹.

VA has a long history of research regarding kidney health. Dr. Thomas Starzl conducted the first in a series of long-term successful kidney transplants in 1962 at the Denver VA Medical Center. In 2002, researchers led by Dr. Denise Hynes discovered that subdermal erythropoietin injections require smaller doses than intravenous injections. In 2012, VA established a National Kidney Disease Registry in collaboration with the University of Michigan².

Below are highlights of more recent research into ways HSR&D research is working to improve treatment of kidney disease, manage its symptoms, and deliver better outcomes to Veterans.

• ESP Management eBrief - End-stage Renal Disease and Depression: A Systematic Review
• Improving Transplant Medication Safety through a Technology and Pharmacist (ISTEP) Intervention in Veterans
• Improving Safety and Quality of Care Among Veterans Following Acute Kidney Injury
• Understanding the Initiation of Maintenance Dialysis among Older Veterans

ESP Management eBrief - End-stage Renal Disease and Depression: A Systematic Review

Impact: Review findings will be used to help guide the selection and implementation of depression screening for Veterans with end-stage renal disease (ESRD), and the interventions for those with comorbid depressive disorders. Clinicians should be prepared to validate positive screens prior to making treatment decisions that may be burdensome or introduce the possibility of harm.

The incidence and prevalence of end-stage renal disease in the United States have increased steadily over the past four decades. Veterans experience a higher burden of chronic kidney disease (CKD) and ESRD than the general population. In addition, patients with ESRD experience major depressive disorder (MDD) at three to more than six times that of the general US population, and Veterans experience MDD at more than twice the rate of the general US population. The Centers for Medicare and Medicaid Services (CMS) requires routine depression screening for patients with ESRD. However, due to the lack of system-wide screening tool requirements, there is wide variation in the tools used to initially screen for depression. In addition, there is no established standard guiding the treatment of patients with ESRD and comorbid MDD. Given the wide variation in depression screening and treatment options for Veterans with ESRD, an understanding of the validity of screening tools used in both VA and community settings – and the subsequent depression treatment-related outcomes for Veterans in all US healthcare settings – is vital.

The purpose of this review was to identify depression screening tools (and/or thresholds) appropriate for Veterans with ESRD—and to better understand the impact, benefits, and harms of depression screening and subsequent treatment for depression in Veterans (and Veteran subpopulations) with ESRD. Investigators with VA’s Evidence Synthesis Program (ESP) Center in Portland, OR searched the literature, including Ovid MEDLINE, PsycINFO, Elsevier EMBASE, and Ovid EBM Reviews Cochrane Database of Systematic Reviews from inception through April 2019. After reviewing 7,452 studies (149 articles received full text review), they included 20 randomized controlled trials (RCTs) and 16 diagnostic accuracy studies for this analysis.

Findings:

• In adults with ESRD, the Beck Depression Inventory-II (BDI-II) with a cutoff of ≥16 provides a good balance of sensitivity and specificity. More research is needed to support the use of other tools.
• Investigators found low-strength evidence that the antidepressant sertraline with cognitive behavioral therapy (CBT) provides benefit for depressive symptoms.
• There is low-strength evidence that CBT is more effective than psychotherapy or placebo for depressive symptoms and quality of life.
• There is low-strength evidence that acupressure is more effective for reducing depression than sham acupressure or usual care.
• There is moderate-strength evidence that high-dose vitamin D3 is ineffective.

Principal Investigator: Karli Kondo, PhD, is an investigator with the Evidence-based Synthesis Program at the Portland VA Health Care System and the Oregon Health and Science University, Portland, OR.

To view the full report, go to vaww.hsrd.research.va.gov/publications/esp/esrd-depression.cfm (Intranet only, copy and paste the URL into your browser if you have intranet access.)

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Improving Transplant Medication Safety through a Technology and Pharmacist (ISTEP) Intervention in Veterans

Impact: This study will develop a feasibly deployable, technology-enabled intervention with the goal of demonstrating substantial improvements in immunosuppressant medication safety, clinical outcomes, and health care costs in Veteran kidney and other organ transplant recipients. Findings will hopefully provide justification to further develop a VA-specific pharmacist learning collaborative to improve care and reduce costs for organ transplant recipients across VA.

Organ transplant is the gold-standard treatment for patients with end organ diseases of the kidney, liver, heart, and lungs, as it substantially improves survival and quality of life. Over the past 20 years, the use of contemporary immunosuppression has reduced the risk of acute rejection rates by more than 80%, yet long-term transplant survival remains suboptimal. Studies have demonstrated that late graft loss is predominantly driven by immunosuppression-adverse events and late graft rejection episodes from medication errors and non-adherence - issues directly related to medication safety. Earlier research demonstrates that medication errors occur in nearly two-thirds of transplant recipients, leading to hospitalization in 1 in 8 recipients. Recipients that develop significant medication errors are at considerably higher risk of graft loss, leading to higher mortality and costs. Thus, in order to improve medication safety and long-term outcomes in transplant recipients, enhancements in immunosuppressant therapy management is needed.

The central hypothesis for the ISTEP study (Improving Transplant Medication Safety through a Technology and Pharmacist Intervention) is that pharmacist-led immunosuppressant therapy management, facilitated through the use of innovative technology, will significantly improve immunosuppressant safety and clinical outcomes in Veteran transplant recipients. In a 2-year randomized controlled trial at 10 VA sites, the intervention arm used an expanded pharmacist’s dashboard that identifies transplant recipients with potential drug-related problems, including non-adherence, drug interactions, and missing and worrisome trends in labs. The dashboard alerts the pharmacist, who will determine its relevance and intervene in an appropriate protocol-guided manner. At this time the expanded dashboard has been implemented at five VA sites across the country.

Preliminary  Findings:

• Early findings have demonstrated similar rates of hospitalization and ED visits between sites
• Alerts to pharmacists have required refinement to make them more clinically relevant and actionable

Principal Investigator: David J. Taber, PharmD, is and investigator with the Charleston Health Equity and Rural

Outreach Innovation Center (HEROIC), and a pharmacist at the the Ralph H Johnson VA Medical Center, Charleston, SC.

Publications:

Taber DJ, Ward R, Axon RN, Walker RJ, Egede LE, Gebregziabher M. The Impact of Dual Health Care System Use for Obtaining Prescription Medications on Nonadherence in Veterans With Type 2 Diabetes. The Annals of pharmacotherapy. 2019 Jul 1; 53(7):675-682.

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Improving Safety and Quality of Care Among Veterans Following Acute Kidney Injury

Impact: The incidence for acute kidney injury (AKI) is growing and optimal care has not been defined. This study will examine the poor intermediate and long-term clinical outcomes experienced by survivors of AKI, identify those at highest risk, and uncover potentially modifiable risk factors for their development.   Findings will inform the level of concern for this growing population and suggest potential strategies to reduce the risk of poor clinical outcomes for patients who experience AKI.  

Acute kidney injury is a common condition among hospitalized patients that is associated with mortality, accelerates kidney disease progression, is a risk factor for cardiovascular disease, and worsens quality of life. The incidence of AKI is growing rapidly and with it, the number of survivors at risk for these outcomes. Developing optimal care strategies for this population will require better understanding of the interim outcomes and processes of care provided to these patients in the post-hospitalization period.

This study seeks to characterize the long-term patterns of renal recovery and recurrent AKI, determine their association with kidney disease progression, identify poor outcomes experienced by AKI survivors, and to identify modifiable risk factors that may improve or hinder poor outcomes among AKI survivors.

Findings:

• One in four Veterans hospitalized with an episode of AKI who survive 1 year will be hospitalized with another AKI event within 1 year. Patients with a discharge diagnosis of heart failure, decompensated liver disease, malignancy, acute coronary syndrome, or volume depletion were at highest risk.
• In a matched cohort of more than150,000 patients, those with AKI experienced incident AKI more frequently than non-AKI patients, translating to a 23% increase in overall risk.
• AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future chronic kidney disease (CKD).
• AKI is associated with a 27% increased risk of hypoglycemia, suggesting that patients with diabetes who survive an episode of AKI are at elevated risk for hypoglycemia.
• Between 15-20% of AKI survivors may be taking non-steroidal anti-inflammatory agents (NSAIDs) regularly. Given their known potential for harm to the kidneys, careful consideration to educating patients and providers regarding their potential hazards in AKI survivors is warranted.
• In a matched cohort of approximately 90,000 matched AKI and non-AKI pairs, patients with AKI were at higher risk for having proteinuria after hospitalization compared to patients hospitalized without AKI.  
• Among 48,000 patients with moderate to severe AKI, delayed renal recovery is associated with a faster subsequent rate of kidney function decline than patients with AKI who recover earlier.

Principal Investigator: Edward D. Siew, MD, MSc, is a Research Scientist with the Tennessee Valley Healthcare System Nashville Campus, and an Associate Professor in the Department of Medicine, Division of Nephrology and Hypertension, at Vanderbilt University School of Medicine, Nashville, TN.

Recent Publications (for complete list, see study abstract):

Siew, ED, Abdel-Kader, K, Perkins, AM, Greevy, RA, Parr, SK, Horner, J, Vincz, AJ, Denton, J, Wilson, OD, Hung, AM, Robinson-Cohen, C, Matheny, MD.  Timing of Recovery from Moderate to Severe AKI and the Risk for Future Loss of kidney Function.  American Journal of Kidney Disease, 2020; 75(2):204-13.

Bansal N, Matheny ME, Greevy RA, Eden SK, Perkins AM, Parr SK, Fly J, Abdel-Kader K, Himmelfarb J, Hung AM, Speroff T, Ikizler TA, Siew ED. Acute Kidney Injury and Risk of Incident Heart Failure Among US Veterans. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2018 Feb 1; 71(2):236-245.

Hung AM, Siew ED, Wilson OD, Perkins AM, Greevy RA, Horner J, Abdel-Kader K, Parr SK, Roumie CL, Griffin MR, Ikizler TA, Speroff T, Matheny ME. Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury. Diabetes Care. 2018 Mar 1; 41(3):503-512.

Parr SK, Matheny ME, Abdel-Kader K, Greevy RA, Bian A, Fly J, Chen G, Speroff T, Hung AM, Ikizler TA, Siew ED. Acute kidney injury is a risk factor for subsequent proteinuria. Kidney international. 2018 Feb 1; 93(2):460-469.

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Understanding the Initiation of Maintenance Dialysis among Older Veterans

Impact: VA's integrated health care system and financing appear to favor lower-intensity treatment for kidney failure in older patients, without a corresponding increase in mortality. This finding highlights the potential for unintended consequences of expanding access to non-VA care if care is not coordinated across health care systems. In addition, findings describing the predicted benefit of dialysis at different ages and levels of kidney function can support shared decision making for dialysis. Findings also highlight opportunities to improve advance care planning and the documentation of patient preferences for patients with kidney failure.

With more than 27,000 Veterans receiving treatment for kidney failure, or end-stage renal disease (ESRD) annually, the decision to initiate maintenance dialysis for older Veterans with ESRD affords one of the greatest opportunities to improve value in specialty care. The burden of ESRD among Veterans is projected to double over the next decade, largely due to higher incidence and treatment rates of ESRD among Veterans over the age of 75. Treatment of ESRD with maintenance dialysis is resource intensive and outcomes are often poor among older adults with serious comorbidity. Similar to other intensive procedures performed near the end of life, there are wide regional variations in the use of dialysis among older adults, suggesting that intensity of treatment for ESRD is determined by practice style or the supply of medical resources rather than the likelihood of benefit.

This series of studies seeks to identify factors associated with use of maintenance dialysis among older Veterans with ESRD, characterize decision-making when treatment decisions are not aligned with evaluated need, and compare survival and healthcare use for older Veterans who initiate maintenance dialysis to those who receive conservative management.

Findings:

• In the first study, investigators compared the use of dialysis and mortality for 11,215 Veterans with incident ESRD who received nephrology care in Medicare versus VA.
  • Veterans who received care in Medicare were more likely to start dialysis compared to Veterans who received care in VA (82% vs. 53%); and yet those who were treated in Medicare were also more likely to die within 2 years compared to those in VA.

• In a second study, investigators modeled the survival benefit of dialysis versus medical management in a sample of Veterans age >65 with advanced kidney disease.
  • Over the mean follow-up of 3 years, 15% of patients started dialysis and 52% of the sample population died.
  • At a level of kidney function that is typical for starting dialysis treatment, (, the modeled difference in median life expectancy between dialysis versus medical management was less than one year.

• In a third study, investigators reviewed the medical records of 821 Veterans with incident ESRD to ascertain the frequency and timing of dialysis and goals of care discussions.
  • Discussions surrounding dialysis preferences, including supportive care as an alternative to dialysis, are infrequently documented in the medical record and decoupled from advanced care planning discussions.
  • Among patients at high risk for mortality, almost one in four had no documentation of goals-of-care discussions.

Principal Investigator: Manjula Kurella Tamura, MD, MPH, is a professor of medicine (nephrology) and investigator with the VA Palo Alto Health Care System, Palo Alto, CA.

Publications:

Kurella Tamura M, Thomas IC, Montez-Rath ME, Kapphahn K, Desai M, Gale RC, Asch SM. Dialysis Initiation and Mortality Among Older Veterans With Kidney Failure Treated in Medicare vs the Department of Veterans Affairs. JAMA Internal Medicine. 2018 May 1; 178(5):657-664.

Bradshaw CL, Gale RC, Chettiar A, Ghaus S, Thomas IC, Fung E, Lorenz K, Asch SM, Anand S, Kurella Tamura M.  Medical Record Documentation of Goals-of-Care Discussions Among Older Veterans with Incident Kidney Failure.  Am J Kidney Dis 2019 Oct 31 (epub).

Kurella Tamura M, Desai M, Kapphahn KI, Thomas IC, Asch SM, Chertow GM. Dialysis versus Medical Management at Different Ages and Levels of Kidney Function in Veterans with Advanced CKD. Journal of the American Society of Nephrology : JASN. 2018 Aug 1; 29(8):2169-2177.

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