Dana C. Miskulin

Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review.

Background: Clinical laboratories are increasingly reporting estimated glomerular filtration rate (GFR) by using serum creatinine assays traceable to a standard reference material. Purpose: To review the performance of GFR estimating equations to inform the selection of a single equation by laboratories and the interpretation of estimated GFR by clinicians. Data Sources: A systematic search of MEDLINE, without language restriction, between 1999 and 21 October 2011. Study Selection: Cross-sectional studies in adults that compared the performance of 2 or more creatinine-based GFR estimating equations with a reference GFR measurement. Eligible equations were derived or reexpressed and validated by using creatinine measurements traceable to the standard reference material. Data Extraction: Reviewers extracted data on study population characteristics, measured GFR, creatinine assay, and equation performance. Data Synthesis: Eligible studies compared the MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations or modifications thereof. In 12 studies in North America, Europe, and Australia, the CKD-EPI equation performed better at higher GFRs (approximately >60 mL/min per 1.73 m 2 ) and the MDRD Study equation performed better at lower GFRs. In 5 of 8 studies in Asia and Africa, the equations were modified to improve their performance by adding a coefficient derived in the local population or removing a coefficient. Limitation: Methods of GFR measurement and study populations were heterogeneous. Conclusion: Neither the CKD-EPI nor the MDRD Study equation is optimal for all populations and GFR ranges. Using a single equation for reporting requires a tradeoff to optimize performance at either higher or lower GFR ranges. A general practice and public health perspective favors the CKD-EPI equation. Primary Funding Source: Kidney Disease: Improving Global Outcomes.

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

The HALT Polycystic Kidney Disease Trials: Design and Implementation

BACKGROUND AND OBJECTIVES Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m(2) were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively. RESULTS This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life. CONCLUSIONS HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.

Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). METHODS In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

Which Targets in Clinical Practice Guidelines Are Associated with Improved Survival in a Large Dialysis Organization

Professional organizations have developed practice guidelines in the hope of improving clinical outcomes. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has set targets for dialysis dosage (single-pool Kt/V), hematocrit, serum albumin, calcium, phosphorus, parathyroid hormone, and BP for hemodialysis (HD) patients. Several guidelines are largely based on results from observational studies. In contrast to other parameters, BP values within the KDOQI guidelines have been associated with increased mortality. Therefore, it was postulated that having multiple parameters that satisfy the current guidelines, except those for BP, is associated with improved survival among HD patients. A retrospective analysis was conducted of incident HD patients who were treated at facilities operated by Dialysis Clinic Inc., a not-for-profit dialysis provider, between January 1, 1998, and December 31, 2004 (n = 13,792). Cox proportional hazards models were used to assess the association between satisfying guidelines and mortality. Values within guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphorus, and parathyroid hormone were associated with decreased mortality (P < or = 0.0001). The largest survival benefit was found for serum albumin (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.24 to 0.31). Satisfying these six guidelines simultaneously was associated with an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19]). Conversely, BP values satisfying the guideline were associated with increased mortality (HR 1.90; 95% CI 1.73 to 2.10). Because this target was largely extrapolated from the general population, a randomized, controlled trial is needed to identify the optimal BP for HD patients.

Comorbidity Assessment in Hemodialysis and Peritoneal Dialysis Using the Index of Coexistent Disease

The purpose of this paper is to describe the ICED, summarize outcomes of prior studies in which it was used, and describe the adaptations that have lead to the present instrument. We will then demonstrate its use in quantifying the burden of comorbid conditions in a sample of hemodialysis and peritoneal dialysis patients from our center, and show the relationship between ICED levels and outcomes in peritoneal dialysis patients.

Disordered mineral metabolism in hemodialysis patients: an analysis of cumulative effects in the Hemodialysis (HEMO) Study.

BACKGROUND Serum markers of disordered mineral metabolism have been associated with adverse outcomes in patients requiring long-term dialysis therapy. Although the values of these markers often evolve over time, no study has examined the accumulated effects of these abnormalities on important clinical end points. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 1,846 prevalent hemodialysis patients randomly assigned in the Hemodialysis (HEMO) Study. PREDICTORS Serum phosphorus, calcium, calcium-phosphorus (Ca x P) product, and intact parathyroid hormone, each analyzed at the time of randomization (baseline), as a standard time-dependent covariate and as a cumulative time-dependent covariate. OUTCOMES All-cause mortality and the composite of all-cause mortality and first cardiac hospitalization. MEASUREMENTS Cox proportional hazards models. RESULTS In all analyses, serum phosphorus level greater than 6 mg/dL was associated with a heightened risk of mortality of approximately 25% compared with phosphorus values of 4.1 to 5 mg/dL. Serum calcium level greater than 11 mg/dL was associated with a 60% greater risk of death, but only when this parameter was analyzed as either a time-dependent or cumulative time-dependent variable. Ca x P product greater than 50 mg(2)/dL(2) was strongly associated with mortality, but only when assessed cumulatively. Similar relationships were observed when phosphorus, calcium, and Ca x P product values were related to the composite end point of all-cause mortality and first cardiac hospitalization. No relationships between baseline, time-dependent, and cumulative time-dependent intact parathyroid hormone levels and the outcomes of interest were observed. LIMITATIONS Residual confounding, lack of access to patient information before randomization in the HEMO Study, and concerns regarding generalizability given changes in practice patterns since the completion of the HEMO Study. CONCLUSIONS Cumulative time-dependent analyses provide a different framework for analyzing the impact of factors that may mediate adverse events in hemodialysis patients. Our findings support maintaining serum phosphorus levels at less than 6 mg/dL, calcium levels at less than 11 mg/dL, and Ca x P product at less than 50 mg(2)/dL(2).

The Influence of Age on Changes in Health-Related Quality of Life over Three Years in a Cohort Undergoing Hemodialysis

OBJECTIVES: To assess the extent to which persons aged 70 and older undergoing hemodialysis (HD) had greater changes in health‐related quality of life (HRQOL) over 3 years than younger patients undergoing HD.

Age, Race, Diabetes, Blood Pressure, and Mortality among Hemodialysis Patients

Observational studies involving hemodialysis patients suggest a U-shaped relationship between BP and mortality, but the majority of these studies followed large, heterogeneous cohorts. To examine whether age, race, and diabetes status affect the association between systolic BP (SBP; predialysis) and mortality, we studied a cohort of 16,283 incident hemodialysis patients. We constructed a series of multivariate proportional hazards models, adding age and BP to the analyses as cubic polynomial splines to model potential nonlinear relationships with mortality. Overall, low SBP associated with increased mortality, and the association was more pronounced among older patients and those with diabetes. Higher SBP associated with increased mortality among younger patients, regardless of race or diabetes status. We observed a survival advantage for black patients primarily among older patients. Diabetes associated with increased mortality mainly among older patients with low BP. In conclusion, the design of randomized clinical trials to identify optimal BP targets for patients with ESRD should take age and diabetes status into consideration.

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of >60 ml/min per 1.73 m(2); 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m(2); 42 normotensive subjects with ADPKD and eGFR of >60 ml/min per 1.73 m(2); and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F(2α (8-epi-PGF2α)) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. RESULTS The hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of >60, and hypertensive ADPKD with eGFR of >60. The normotensive ADPKD eGFR >60, hypertensive ADPKD eGFR >60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF(2α) and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. CONCLUSIONS Inflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.