Katrin Uhlig

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.

Systematic Review: Blood Pressure Target in Chronic Kidney Disease and Proteinuria as an Effect Modifier

BACKGROUND The optimal blood pressure target in patients with chronic kidney disease (CKD) is unclear. PURPOSE To summarize trials comparing lower versus higher blood pressure targets in adult patients with CKD and focus on proteinuria as an effect modifier. DATA SOURCES MEDLINE and the Cochrane Central Register of Controlled Trials (July 2001 through January 2011) were searched for reports from randomized, controlled trials with no language restriction. STUDY SELECTION Authors screened abstracts to identify reports from trials comparing blood pressure targets in adults with CKD that had more than 50 participants per group; at least 1-year follow-up; and outcomes of death, kidney failure, cardiovascular events, change in kidney function, number of antihypertensive agents, and adverse events. DATA EXTRACTION Reviewers extracted data on study design, methods, sample characteristics, interventions, comparators, outcomes, number of medications, and adverse events and rated study quality and quality of analyses for proteinuria subgroups. DATA SYNTHESIS Three trials with a total of 2272 participants were included. Overall, trials did not show that a blood pressure target of less than 125/75 to 130/80 mm Hg is more beneficial than a target of less than 140/90 mm Hg. Lower-quality evidence suggests that a low target may be beneficial in subgroups with proteinuria greater than 300 to 1000 mg/d. Participants in the low target groups needed more antihypertensive medications and had a slightly higher rate of adverse events. LIMITATIONS No study included patients with diabetes. Trial duration may have been too short to detect differences in clinically important outcomes, such as death and kidney failure. Ascertainment and reporting of adverse events was not uniform. CONCLUSION Available evidence is inconclusive but does not prove that a blood pressure target of less than 130/80 mm Hg improves clinical outcomes more than a target of less than 140/90 mm Hg in adults with CKD. Whether a lower target benefits patients with proteinuria greater than 300 to 1000 mg/d requires further study.

KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

This commentary provides a US perspective on the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). KDIGO is an independent international organization with the primary mission of the promotion, coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for the care of patients with kidney disease. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI), recognizing that international guidelines need to be adapted for each country, convened a group of experts to comment on the application and implementation of the KDIGO guideline for patients with CKD in the United States. This commentary puts the KDIGO guideline into the context of the supporting evidence and the setting of care delivered in the United States and summarizes important differences between prior KDOQI guidelines and the newer KDIGO guideline. It also considers the potential impact of a new bundled payment system for dialysis clinics. The KDIGO guideline addresses the evaluation and treatment of abnormalities of CKD-MBD in adults and children with CKD stages 3-5 on long-term dialysis therapy or with a kidney transplant. Tests considered are those that relate to laboratory, bone, and cardiovascular abnormality detection and monitoring. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. Limitations of the evidence are discussed. The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas.

Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis

OBJECTIVE To study the role of the chemokine receptors CCR5 and CCR2 in patients with arthritis. METHODS CCR5 expression on peripheral blood leukocytes was compared with the expression on leukocytes isolated from the synovial fluid of 20 patients with different rheumatic joint diseases. Three additional samples were studied for CCR2 expression. The expression of chemokine receptors on blood and synovial fluid leukocytes was determined by 3-color flow cytometry analysis. To test CCR5 receptor down-modulation from the cell surface, leukocytes were incubated in vitro with a RANTES (regulated on activation, normal T cell expressed and secreted) derivative, aminooxypentane (AOP)-RANTES. Patients were genotyped for the delta32 CCR5 deletion by polymerase chain reaction. RESULTS A high percentage of CCR5-expressing CD4+ and CD8+ T cells (74% and 81%, respectively), monocytes (51%), and natural killer cells (35%) was found in the synovial fluid of all patients, whereas in the peripheral blood, only a small percentage of these cells expressed CCR5 (13%, 32%, 7.8%, and 4%, respectively). Infiltration of CCR5-positive leukocytes was not reduced in CCR5-heterozygous patients. A similar, but less pronounced, distribution was observed for CCR2-positive T cells. In vitro, CCR5 was completely down-modulated on synovial fluid leukocytes by AOP-RANTES. CONCLUSION The predominance of CCR5-positive mononuclear cells in the synovial effusions of patients with arthritis suggests an important role for CCR5 in the process of joint inflammation, and identifies CCR5 as a possible new target for therapeutic intervention.

Self-Measured Blood Pressure Monitoring in the Management of Hypertension: A Systematic Review and Meta-analysis

BACKGROUND Clinical guidelines recommend that adults with hypertension self-monitor their blood pressure (BP). PURPOSE To summarize evidence about the effectiveness of self-measured blood pressure (SMBP) monitoring in adults with hypertension. DATA SOURCES MEDLINE (inception to 8 February 2013) and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter 2012). STUDY SELECTION 52 prospective comparative studies of SMBP monitoring with or without additional support versus usual care or an alternative SMBP monitoring intervention in persons with hypertension. DATA EXTRACTION Data on population, interventions, BP, other outcomes, and study method were extracted. Random-effects model meta-analyses were done. DATA SYNTHESIS For SMBP monitoring alone versus usual care (26 comparisons), moderate-strength evidence supports a lower BP with SMBP monitoring at 6 months (summary net difference, -3.9 mm Hg and -2.4 mm Hg for systolic BP and diastolic BP) but not at 12 months. For SMBP monitoring plus additional support versus usual care (25 comparisons), high-strength evidence supports a lower BP with use of SMBP monitoring, ranging from -3.4 to -8.9 mm Hg for systolic BP and from -1.9 to -4.4 mm Hg for diastolic BP, at 12 months in good-quality studies. For SMBP monitoring plus additional support versus SMBP monitoring alone or with less intense additional support (13 comparisons), low-strength evidence fails to support a difference. Across all comparisons, evidence for clinical outcomes is insufficient. For other surrogate or intermediate outcomes, low-strength evidence fails to show differences. LIMITATION Clinical heterogeneity in protocols for SMBP monitoring, additional support, BP targets, and management; follow-up of 1 year or less in most studies, with sparse clinical outcome data. CONCLUSION Self-measured BP monitoring with or without additional support lowers BP compared with usual care, but the BP effect beyond 12 months and long-term benefits remain uncertain. Additional support enhances the BP-lowering effect. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Graft use in transvaginal pelvic organ prolapse repair: A systematic review

OBJECTIVE: To estimate the anatomic and symptomatic efficacy of graft use in transvaginal prolapse repair and to estimate the rates and describe the spectrum of adverse events associated with graft use. DATA SOURCES: Eligible studies, published between 1950 and November 27, 2007, were retrieved through Medline and bibliography searches. METHODS OF STUDY SELECTION: To assess anatomic and symptomatic efficacy of graft use, we used transvaginal prolapse repair studies that compared graft use with either native tissue repair or repair with a different graft. To estimate rates of adverse events from graft use, all comparative studies and case series with at least 30 participants were included. For spectrum of adverse events, all study designs were included. TABULATION, INTEGRATION AND RESULTS: Eligible studies were extracted onto standardized forms by one reviewer and confirmed by a second reviewer. Comparative studies were classified by vaginal compartment (anterior, posterior, apical, or multiple), graft type (biologic, synthetic-absorbable, synthetic nonabsorbable) and outcome (anatomic, symptomatic). We found 16 comparative studies, including six randomized trials, 37 noncomparative studies with at least 30 women, 11 case series with fewer than 30 women, and 10 case reports of adverse events. One randomized trial and one prospective comparative study evaluating synthetic, nonabsorbable graft use in the anterior compartment reported favorable anatomic and symptomatic outcomes with graft use. Data regarding graft use for posterior and apical compartments or for biologic or synthetic absorbable graft use in the anterior compartment were insufficient to determine efficacy. Rates and spectrum of adverse events associated with graft use included bleeding (0–3%), visceral injury (1–4%), urinary infection (0–19%), graft erosion (0–30%), and fistula (1%). There were insufficient data regarding dyspareunia, sexual, voiding, or defecatory dysfunction. CONCLUSION: Overall, the existing evidence is limited to guide decisions regarding whether to use graft materials in transvaginal prolapse surgery. Adequately powered randomized trials evaluating anatomic and symptomatic efficacy as well as adverse events are needed.

Low Rates of Testing and Diagnostic Codes Usage in a Commercial Clinical Laboratory: Evidence for Lack of Physician Awareness of Chronic Kidney Disease

Improving outcomes for chronic kidney disease (CKD) requires early identification and recognition by physicians. There are few data on rates of testing or use of diagnostic codes for CKD. A cross-sectional analysis was performed of patients who were older than 40 yr and had one or more laboratory tests between April 1, 2002, and March 31, 2003, at a Laboratory Corporation of America regional laboratory. Objectives were to determine the frequency of testing for serum creatinine; prevalence of CKD, defined as estimated GFR <60 ml/min per 1.73 m2; and sensitivity of diagnostic codes for CKD for patients with and without risk factors for CKD and with or without cardiovascular disease (CVD). Of the 277,111 patients, 19% had serum creatinine measured, compared with 33 and 71% who had measurements of serum glucose and lipids, respectively. Patients with hypertension, diabetes, and age >60 yr were more likely to be tested for serum creatinine with odds ratio (OR; 95% confidence interval) of 2.09 (2.05 to 2.14), 1.22 (1.19 to 1.25), and 1.24 (1.22 to 1.27) respectively. Among patients tested, 30% had CKD. Sensitivity and specificity of kidney disease diagnostic codes compared with CKD defined by estimated GFR <60 ml/min per 1.73 m2 were 11 and 96%, respectively. In patients with hypertension, diabetes, age >60 years, and CVD, rates of testing and sensitivity of diagnostic codes were 53 and 14%, respectively. Low rates of testing for serum creatinine and insensitivity of diagnostic codes for CKD, even in high-risk patients, suggests inadequate physician awareness of CKD and limited utility of administrative databases for identification of patients with CKD.

Interferon Treatment in Hemodialysis Patients With Chronic Hepatitis C Virus Infection: A Systematic Review of the Literature and Meta-analysis of Treatment Efficacy and Harms

BACKGROUND Hepatitis C virus (HCV) infection is prevalent in patients undergoing hemodialysis and is associated with greater mortality. We determined the efficacy and harms of interferon (IFN) and pegylated IFN (PEG-IFN) treatment of hemodialysis patients with chronic HCV infection and identified factors associated with these outcomes. STUDY DESIGN Meta-analysis and meta-regression of randomized controlled trials, uncontrolled trials, and prospective observational studies. SETTING & POPULATION Hemodialysis patients with chronic HCV infection. SELECTION CRITERIA FOR STUDIES MEDLINE indexed studies since 1966, sample size greater than 10. INTERVENTION IFN-based treatment, including PEG-IFN with and without ribavirin. OUTCOMES Sustained virological response (SVR) 6 months after treatment, rate of treatment discontinuation caused by adverse events, and factors associated with these outcomes. RESULTS 20 studies of 459 IFN-treated patients, 3 studies of 38 PEG-IFN-treated patients, and 2 studies of 49 PEG-IFN and ribavirin-treated patients met inclusion criteria. The overall SVR rate was 41% (95% confidence interval [CI], 33 to 49) for IFN and 37% (95% CI, 9 to 77) for PEG-IFN. Treatment discontinuation rates were 26% (95% CI, 20 to 34) for IFN and 28% (95% CI, 12 to 53) for PEG-IFN. SVR was higher with 3 million units (MU) or higher of IFN 3 times weekly, with lower mean HCV RNA, and with lower rates of cirrhosis, HCV genotype 1 or elevated transaminase, but these findings were not statistically significant. Treatment discontinuation rates were greater in studies using larger doses. LIMITATIONS Publication bias, few randomized controlled trials, and limitations in generalizability to all hemodialysis patients. CONCLUSION IFN treatment of hemodialysis patients results in an SVR rate of 41%. Higher dose, lower mean HCV RNA level, and lower rates of cirrhosis, transaminase level increase, and HCV genotype 1 may be associated with greater SVR rates, but additional studies using individual patient data are needed.

Risk prediction models for patients with chronic kidney disease: a systematic review.

BACKGROUND Patients with chronic kidney disease (CKD) are at increased risk for kidney failure, cardiovascular events, and all-cause mortality. Accurate models are needed to predict the individual risk for these outcomes. PURPOSE To systematically review risk prediction models for kidney failure, cardiovascular events, and death in patients with CKD. DATA SOURCES MEDLINE search of English-language articles published from 1966 to November 2012. STUDY SELECTION Cohort studies that examined adults with any stage of CKD who were not receiving dialysis and had not had a transplant; had at least 1 year of follow-up; and reported on a model that predicted the risk for kidney failure, cardiovascular events, or all-cause mortality. DATA EXTRACTION Reviewers extracted data on study design, population characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness. DATA SYNTHESIS Thirteen studies describing 23 models were found. Eight studies (11 models) involved kidney failure, 5 studies (6 models) involved all-cause mortality, and 3 studies (6 models) involved cardiovascular events. Measures of estimated glomerular filtration rate or serum creatinine level were included in 10 studies (17 models), and measures of proteinuria were included in 9 studies (15 models). Only 2 studies (4 models) met the criteria for clinical usefulness, of which 1 study (3 models) presented reclassification indices with clinically useful risk categories. LIMITATION A validated risk-of-bias tool and comparisons of the performance of different models in the same validation population were lacking. CONCLUSION Accurate, externally validated models for predicting risk for kidney failure in patients with CKD are available and ready for clinical testing. Further development of models for cardiovascular events and all-cause mortality is needed. PRIMARY FUNDING SOURCE None.

THE CLINICAL EPIDEMIOLOGY OF CARDIOVASCULAR DISEASES IN CHRONIC KIDNEY DISEASE: Traditional Cardiac Risk Factors in Individuals with Chronic Kidney Disease

Individuals with chronic kidney disease (CKD) are at increased risk for the development and progression of cardiovascular disease (CVD). The increased risk is due to a higher prevalence of both traditional risk factors as well as nontraditional risk factors. In this review we focus on individuals at all stages of CKD and discuss modifiable traditional risk factors, namely hypertension, dyslipidemia, diabetes mellitus and poor glycemic control, smoking, and physical inactivity. The prevalence of each risk factor and its relationship with CVD is described. Treatment recommendations are provided using evidence available from populations with CKD or evidence extrapolated from the general population when there are insufficient data on individuals with CKD.