High Risk For Kidney Disease Research Articles

P099 Renal Safety of Tenofovir Alafenamide in Patients at High Risk of Kidney Disease

Background/introduction Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) results in significantly reduced plasma tenofovir (TFV) and has demonstrated less impact on surrogate markers of renal and bone health in multiple populations, but renal outcomes in treatment-naive subjects at risk for chronic kidney disease (CKD) have not been characterised. Aim(s)/objectives Renal outcomes in treatment-naive subjects at risk for chronic kidney disease (CKD) were investigated. Methods Treatment naive HIV-1+ adults were randomised 1:1 to a single tablet regimen of elvitegravir, cobicistat, emtricitabine, with TAF (E/C/F/TAF) or (E/C/F/TDF) once daily in two double blind studies. Assessments of renal function including markers of proximal renal tubulopathy were carried out. A post-hoc analysis of renal function by group with high risk vs low risk for development of CKD is described. Results Of 1,733 participants, those with high CKD risk was similar by treatment arm (E/C/F/TAF 28%, E/C/F/TDF 32%). Among high CKD risk participants, significantly fewer subjects on E/C/F/TAF experienced a decline in eGFR to below 60 mL/min compared to E/C/F/TDF: 4.9% vs 9.6% (p = 0.044). Participants with high CKD risk who initiated E/C/F/TAF also had significant declines in multiple measures of quantitative proteinuria. Within the low CKD risk group, significantly fewer participants receiving E/C/F/TAF experienced a decline in eGFR by ≥25% (11.5% vs 24.9%, p Discussion/conclusion Among participants with both low and high CKD risk, participants receiving E/C/F/TAF had more favourable renal outcomes compared with those treated with E/C/F/TDF. These data support the improved renal safety profile of TAF.

Generalization of Associations of Kidney-Related Genetic Loci to American Indians

CKD disproportionally affects American Indians, who similar to other populations, show genetic susceptibility to kidney outcomes. Recent studies have identified several loci associated with kidney traits, but their relevance in American Indians is unknown. This study used data from a large, family-based genetic study of American Indians (the Strong Heart Family Study), which includes 94 multigenerational families enrolled from communities located in Oklahoma, the Dakotas, and Arizona. Individuals were recruited from the Strong Heart Study, a population-based study of cardiovascular disease in American Indians. This study selected 25 single nucleotide polymorphisms in 23 loci identified from recently published kidney-related genome-wide association studies in individuals of European ancestry to evaluate their associations with kidney function (estimated GFR; individuals 18 years or older, up to 3282 individuals) and albuminuria (urinary albumin to creatinine ratio; n=3552) in the Strong Heart Family Study. This study also examined the association of single nucleotide polymorphisms in the APOL1 region with estimated GFR in 1121 Strong Heart Family Study participants. GFR was estimated using the abbreviated Modification of Diet in Renal Disease Equation. Additive genetic models adjusted for age and sex were used. This study identified significant associations of single nucleotide polymorphisms with estimated GFR in or nearby PRKAG2, SLC6A13, UBE2Q2, PIP5K1B, and WDR72 (P<2.1 × 10(-3) to account for multiple testing). Single nucleotide polymorphisms in these loci explained 2.2% of the estimated GFR total variance and 2.9% of its heritability. An intronic variant of BCAS3 was significantly associated with urinary albumin to creatinine ratio. APOL1 single nucleotide polymorphisms were not associated with estimated GFR in a single variant test or haplotype analyses, and the at-risk variants identified in individuals with African ancestry were not detected in DNA sequencing of American Indians. This study extends the genetic associations of loci affecting kidney function to American Indians, a population at high risk of kidney disease, and provides additional support for a potential biologic relevance of these loci across ancestries.

EDITORIAL

EDITORIAL

Association Between Lack of Health Insurance and Risk of Death and ESRD: Results From the Kidney Early Evaluation Program (KEEP)

Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000-2011 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) to examine this association. The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables. Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) or urine albumin-creatinine ratio ≥ 30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56-2.12; P < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33-2.22; P < 0.001). The association between insurance and outcomes varied by CKD stage. Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.

Advances in CKD Detection and Determination of Prognosis: Executive Summary of the National Kidney Foundation–Kidney Early Evaluation Program (KEEP) 2012 Annual Data Report

During 2012, the National Kidney Foundation (NKF)–Kidney Early Evaluation Program (KEEP) continued its efforts toward early detection of chronic kidney disease (CKD) in populations at high risk for kidney disease and in improving awareness of CKD across the globe. Through the completely volunteer participation of the nephrology community, including physicians and our allied health care partners, KEEP continues to screen volunteer participants as part of a national effort to detect and track CKD. In 2012, we observed some changes in the CKD landscape, including questions regarding the utility of CKD screening and detection strategies from the US Preventive Services Task Force.1 Through the years, data derived from KEEP have provided important observations regarding detection and risk-stratification strategies using estimated glomerular filtration rate (eGFR) and proteinuria.2–4 In this past year, KEEP provided new information on topics including blood pressure control, disorders of mineral metabolism, and awareness of CKD and access to health care as related to CKD outcomes.5–11 In this supplement to AJKD, we focus on the variable nature of CKD progression. Interest is increasing in exploring factors that influence disease progression beyond traditional measures such as blood pressure and glycemic control, and in determining the contribution of socioeconomic factors.12;13 We present three articles highlighting factors that influence disease progression in KEEP participants: 1) Chang et al describe risk factors for progression to end-stage renal disease (ESRD) among KEEP participants with preserved eGFR at screening, with and without albuminuria14; 2) Amin et al report on whether or not synergism in using eGFR and albuminuria enhances risk prediction for death and disease progression15; and 3) Jurkovitz et al report on insurance status as a risk factor for disease progression.16

Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes

An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population. In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits. Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates. The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).

National Kidney Foundation's Kidney Early Evaluation Program (KEEP) Annual Data Report 2009: Executive Summary

M M R his year, 2010, the National Kidney Foundation’s (NKF) Kidney Early Evaluation Proram (KEEP) marks a decade of data collection s a part of its multicenter screening program for olunteer participants at risk of chronic kidney isease (CKD). During the years, KEEP has ielded important inferences regarding CKD epiemiologic characteristics and risk factors, and elated comorbid conditions, including hypertenion, metabolic syndrome, diabetes, bone and ineral disorder, anemia, and heart disease, have een characterized and reported. This suppleent to the American Journal of Kidney Disases highlights 4 articles: (1) a 10th anniversary ummary of KEEP milestones; (2) a comparison f CKD among elderly KEEP participants, the ational Health and Nutrition and Examination urvey (NHANES), and Medicare recipients; (3) n examination of the cluster of obesity and etabolic syndrome in racial categories; and (4) description of the impact of microalbuminuria n CKD identification.

Hypertension Awareness, Treatment, and Control in Chronic Kidney Disease

Background Hypertension prevalence, awareness, treatment, and blood pressure control rates in the population with chronic kidney disease are limited. The objective of this study was to determine the state of blood pressure control in patients with chronic kidney disease. Methods This is a cross-sectional analysis of data of participants with chronic kidney disease from the Kidney Early Evaluation Program. The Kidney Early Evaluation Program is a national-based health screening program for individuals at high risk for kidney disease conducted in 49 states and the District of Columbia. Of 55,220 adults with kidney disease, 10,813 completed information for demographic and medical characteristics used in the analysis. Predictors of blood pressure control were assessed using multiple logistic regression analysis. Results Hypertension prevalence, awareness, and treatment proportions in the screened cohort were high (86.2%, 80.2%, and 70.0%, respectively), but blood pressure control rates were low (13.2%). These proportions increased with advancing stage of kidney disease. Elevated systolic blood pressure accounted for the majority of inadequate control. Male gender (odds ratio [OR] 0.86; 95% confidence interval [CI], 0.75-0.99), non-Hispanic black race (OR 0.76; 95% CI, 0.65-0.89), and body mass index of 30 kg/m 2 or more (OR 0.83; 95% CI, 0.73-0.94) were inversely related with blood pressure control. Those with stage 3 kidney disease were more likely to have blood pressure at goal than those with stage 1 kidney disease (OR 2.08; 95% CI, 1.55-2.80). Conclusion We conclude that despite increased awareness and treatment of hypertension, control rates in these participants are poor. This poor control rate centers around elevated systolic pressure in people who are obese, non-Hispanic black, or male. These data suggest that those who are aware of their kidney disease are more likely to achieve blood pressure control.

Chronic kidney disease and medicare.

Since 1972, Medicare has covered the cost of end-stage renal disease (ESRD). Consequently, Medicare pays a large proportion of ESRD's costs. However, before implementation of Medicare Part D, employer health plans paid most ESRD-associated prescription costs. The ESRD population faces significant hurdles when using the new Part D benefit. To understand those challenges, a basic understanding of Part D is needed. Medicare Part D has unique implications for chronic kidney disease (CKD) populations (dialysis, kidney transplant, and CKD patients not on dialysis). Approximately 405,000 ESRD patients were eligible for Part D coverage in 2006. Drug coverage is available for many drugs via Medicare Part B or Part D; however, the Medicare Part B and Part D medication coverage divide is confusing to most clinicians, including pharmacists. Many ESRD patients fall into the dual-eligible category -- they are covered by both Medicare and Medicaid. These patients now receive their medications through Part D and must enroll in a prescription drug plan (PDP). However, many PDP plans may not have the drugs that were covered in state-sponsored Medicaid programs. Dialysis-specific issues also abound because of the high-cost, high-use medications needed to treat the numerous comorbid conditions (diabetes, hypertension, anemia, bone and mineral metabolism disorders, and cardiovascular disorders) that flourish in the ESRD population. Managed care demonstration projects are underway to better understand if enrolling these patients into managed care plans with disease management models (i.e., special needs plans) can provide quality care in an effective and efficient manner. Screening patients at high risk for kidney disease, identifying patients with early kidney disease, preventing progression to ESRD, and effectively managing comorbid conditions may reduce long-term medical costs and maintain work productivity. Health care providers need to make an active effort to help CKD patients select kidney-friendly formularies. Medicare requires medication therapy management (MTM) services for certain beneficiaries (called "targeted beneficiaries") enrolled in PDP plans to improve medication optimization. Approximately 80% of the typical ESRD population has more than 2 targeted comorbidities. Thus, many ESRD patients should be targeted for MTM services, a task that represents an opportunity for pharmacists.

Automatic Reporting of Estimated Glomerular Filtration Rate—Jumping the Gun?

In 2002, the Kidney Disease Outcomes Quality Initiative recommended the use of an estimated glomerular filtration rate (eGFR) to detect early kidney disease (1). Subsequently, the National Kidney Disease Education Program (NKDEP) has taken the lead in promoting the use of eGFR. In their recommendations to health professionals (2), the NKDEP suggested determining an eGFR, as well as measuring a spot urine albumin/creatinine ratio, in patients at high risk for kidney disease, i.e., those with diabetes, hypertension, or a family history of kidney disease. The NKDEP defines chronic kidney disease (CKD) as a GFR persistently 30 mg/g creatinine. For calculating eGFR in adults, the NKDEP recommends using either of 2 versions of the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. In their Suggestions for Laboratories , the NKDEP “strongly encourages clinical laboratories to automatically report eGFR when serum creatinine is reported” (3). Beginning in late 2003, members of various kidney societies were asked to strongly encourage their local laboratories to report an eGFR with each creatinine result. Recently, this encouragement has extended to the proposal in several states of laws requiring the reporting of eGFR with every creatinine result (4). Laboratorians (and legislatures) should consider several reservations before adopting automatic reporting of eGFR. Most creatinine measurements are not made to assess renal function in persons who have CKD or are at high risk for CKD. The great majority of creatinine measurements are ordered as part of a Basic Metabolic Panel. The Basic Metabolic Panel is used for assessment and monitoring of hundreds of conditions, many unrelated to renal function. The most common indication in most hospital laboratories is for routine monitoring of inpatients. The recommendation to report an eGFR with every creatinine measurement becomes, in effect, a …

Nephron Number, Hypertension, Renal Disease, and Renal Failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Identification of persons at high risk for kidney disease via targeted screening: The NKF Kidney Early Evaluation Program

More than 340,000 individuals were receiving renal replacement therapy in the United States at the end of 1999; this number is projected to double by the year 2010. Almost half had a primary diagnosis of diabetes mellitus particularly type 2, and more than one quarter a primary diagnosis of hypertension. Studies have demonstrated effective maneuvers to prevent or delay the rate of progression of kidney disease, and decrease morbidity and mortality. The objective of early diagnosis is early detection of asymptomatic disease at a time when intervention has a reasonable potential to have a positive impact on outcome. In 1997, the National Kidney Foundation launched KEEP trade mark (Kidney Early Evaluation Program), a free community-based screening that targets first order relatives of persons with hypertension, diabetes or kidney disease, and those with a personal history of diabetes or hypertension. Of the 889 individuals screened in the pilot study, 71.4% had at least one abnormality. The program includes an educational component and referral to a physician for follow-up of abnormal values. Targeted screenings are an effective means of identifying persons at risk for kidney disease, and can identify individuals at risk early enough in the course of their disease to allow for effective intervention.