Background

It is unclear whether benefits outweigh harms for routine screening and prophylactic revascularization to prevent coronary artery disease (CAD) in asymptomatic kidney transplant candidates.

Study Design

Pilot feasibility study with prospective observational data collection and patient interviews.

Setting and Participants

Consecutive patients referred for kidney and/or pancreas transplant at 26 major transplant centers in the US.

Predictors

Older age, diabetes, prior cardiovascular disease and multiple traditional CAD risk factors.

Outcomes

Eligibility and willingness to participate in a randomized controlled trial (RCT) to study the effect of CAD screening on major adverse cardiac events.

Measurements

Patients who would be candidates for a hypothetical RCT of CAD screening were interviewed and asked if they would participate in such a trial. Sample size for the trial was estimated using data on Medicare patients in the United States Renal Data System with major adverse cardiac events as the primary endpoint.

Results

Among consecutive eligible patients, CAD evaluation was not indicated in 398 (24%), already completed before referral in 602 (36%), and pending (and hence eligible for a RCT) in 665 (40%). Of 241 interviewed, 73% indicated they would be willing to participate in a RCT. We estimated that approximately 4000 would need to be enrolled to detect a 20% reduction in major adverse cardiac events at greater than 80% power at P<0.05.

Limitations

Willingness to participate in an actual clinical trial may be different than indicated in an interview.

Conclusion

A RCT to compare the effects of routine screening for CAD versus no screening on major adverse cardiac events is feasible.

Background

Using both estimated glomerular filtration rate (eGFR) and proteinuria to classify the severity of chronic kidney disease (CKD) has been proposed. The utility of a staging system incorporating both eGFR and proteinuria for guiding evaluation of concurrent CKD complications is not known.

Study design

Cross-sectional analysis

Setting & participants

30,528 participants in the US National Health and Nutrition Examination Survey conducted in 1988–1994 and 1999–2006 (n=8,242 for hyperparathyroidism).

Predictors

Classification system that uses both eGFR and proteinuria (alternative) and a system that primarily uses eGFR (NKF-KDOQI; the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative)

Outcomes

Prevalence of anemia, acidosis, hyperphosphatemia, hypoalbuminemia, hyperparathyroidism and hypertension

Measurements

GFR estimated from the CKD-Epidemiology Collaboration (CKD-EPI) equation and proteinuria assessed using urine albumin-creatinine ratio (ACR)

Results

The prevalence of hypoalbuminemia, hypertension and hyperparathyroidism increased with more severe CKD using the NKF-KDOQI system. For example, the prevalence of hyperparathyroidism was 9.1%, 11.1%, 28.2% and 72.5% for Stages 1, 2, 3 and 4, respectively. Similarly the prevalence of anemia, acidosis and hyperphosphatemia increased progressively from Stage 2 through 4. With the alternative system, the prevalence of anemia, hyperphosphatemia, hypertension and hyperparathyroidism was lower in Stage 3 compared to Stage 2. For example, the prevalence of hyperparathyroidism was 13.5%, 40.3%, 22.2%, and 63.4% for stages 1, 2, 3 and 4, respectively. Applying the alternative system, participants without each complication were more likely to be appropriately reclassified to lower stages (for example, overall net reclassification index of −6.5% for hyperparathyroidism). However, participants with complications (except for hypoalbuminemia) were more likely to be inappropriately reclassified to lower stages.

Limitations

Use of single creatinine to estimate GFR and single measure to assess ACR. Small number of participants with CKD Stage 4.

Conclusions

The NKF-KDOQI system may better identify patients with certain concurrent CKD complications compared to systems using eGFR and proteinuria.

Uromodulin, also known as Tamm-Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. Although the physiologic functions of this protein remain elusive, significant progress has been made over the last decade that highlights the importance of uromodulin in the pathophysiology of various diseases, such as medullary cystic kidney disease, urinary tract infections, and nephrolithiasis. Meanwhile, there is a renewed interest in the role of uromodulin in kidney injury, both acute and chronic. In this article, we review the existing evidence that supports a role for uromodulin in acute kidney injury (AKI), chronic kidney disease (CKD), and renal inflammation. Contrary to the conventional view of uromodulin as an instigator in kidney injury, new data from uromodulin knockout mice reveal a protective role for this protein in AKI, possibly through down-regulating interstitial inflammation. In CKD, uromodulin excretion, when adjusted for kidney function, is increased; the significance of this remains unclear. Although it has been suggested that uromodulin exacerbates progressive kidney injury, we propose that the elevation in uromodulin secretion is instead reactive to injury, and reflects an increase of uromodulin in the renal parenchyma where it slows the injury process.

Background

Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.

Study Design

Cohort Study.

Setting & Participants

5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.

Predictor

The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).

Outcome

Infection-related hospitalizations during a median follow-up of 11.5 years.

Results

In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.

Limitations

No measures of urinary protein, study limited to principal discharge diagnosis.

Conclusions

Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.

Background

Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants.

Study Design

Cross-sectional analysis

Setting and Participants

Participants were aged 21–74 years with CKD using age-based glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois from 2005–2008 while CRIC included Hispanics and non-Hispanics recruited at seven clinical centers from 2003–2007.

Factor

Race/ethnicity

Outcomes

Blood pressure, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, CKD-associated complications

Measurements

Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols

Results

Among H-CRIC/ CRIC participants, 497 were Hispanic, 1650 non-Hispanic Black, and 1638 non-Hispanic White. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (p<0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic Blacks (51%) and Whites (40%) (p<0.01). Blood pressure > 130/80 mmHg was more common in Hispanics (62%) compared with Blacks (57%) and Whites (35%) (p<0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (p<0.05), even after stratifying by entry eGFR. Hispanics had the lowest receipt of ACE inhibitor/ARB among high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure > 130/80 mmHg. Mean eGFR (ml/min/m2) was lower in Hispanics (39.6) than in Blacks (43.7) and Whites (46.2), while median proteinuria was higher in Hispanics (0.72 g/d) than in Blacks (0.24 g/d) and Whites (0.12 g/d) (p<0.01).

Limitations

Generalizability; observed associations limited by residual bias and confounding

Conclusions

Hispanics with CKD in CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.

The pathogenesis of minimal change disease (MCD), considered to be the simplest form of nephrotic syndrome, has been one of the major unsolved mysteries in kidney disease. In this review, recent landmark studies that have led to the unraveling of MCD are discussed. A study published earlier this year now explains the molecular basis of major clinical and morphological changes in MCD. The overproduction of angiopoietin-like 4 (ANGPTL4) in podocytes in MCD causes binding of ANGPTL4 to the glomerular basement membrane (GBM), development of nephrotic-range selective proteinuria, diffuse effacement of foot processes, and loss of GBM charge, but is not associated with changes shown by light microscopy in the glomerular and tubulointerstitial compartments. At least some of this ability of ANGPTL4 to induce proteinuria is linked to a deficiency of sialic acid residues, since oral supplementation with sialic acid precursor N-acetyl-D-mannosamine improves sialylation of podocyte secreted ANGPTL4 and significantly reduces proteinuria. Animal models of MCD, recent advances in potential biomarkers, and studies on upstream factors that may initiate glomerular changes are also discussed. In summary, recent progress in understanding MCD is likely to influence the diagnosis and treatment of MCD in the near future.

Background

African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans.

Study Design

Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.

Setting & Participants

Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls.

Predictors

Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes.

Outcomes

APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1.

Results

The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001).

Limitations

Non-pooled GWAS have not been performed in AA nondiabetic nephropathy.

Conclusions

This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.

Background

African-Americans (AA) develop hypertension earlier with more target manifestations than Whites despite having higher GFR for any level of serum creatinine.

Study Design and Participants

This study tested the hypothesis that increased GFR and sodium reabsorption in AA is associated with increased metabolic work and medullary hypoxia in 49 non-diabetic, essential hypertensive subjects (29 Whites and 20 AAs) taking constant sodium diet (150 mEq/d) and renin-angiotensin system blockade.

Predictors

Ethnicity, age, measured GFR, sodium excretion, and body mass index.

Outcomes

We examined cortical and medullary volumes and blood flows using multi-detector CT and intra-renal deoxyhemoglobin (R2*) using blood oxygen level dependent (BOLD) MR.

Results

Blood pressure and sodium excretion were similar, while AA were more obese and had higher iothalamate GFR. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in AA (32.3 ± 11.2 vs 24.9±7.4 cc/m2 BSA, p<.001). Sodium reabsorption and blood flows were higher in AA. Basal cortical deoxyhemoglobin was similar between ethnic groups, while medullary R2* was higher in AA (39.7± 5.1 vs 36.3± 6.5 /sec, p=.02), but fell to levels similar to Whites after furosemide. The circulating isoprostane prostaglandin F2α was higher in AA and daily urinary prostaglandin F2α excretion in AAs correlated directly with renal blood flow (R=0.71, p<.01).

Limitations

Studies were limited to treated, volunteer subjects with normal kidney function without knowledge of prior nutrient intake.

Conclusions

These data demonstrate for the first time that increased sodium reabsorption in obese, hypertensive AA patients was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostanes. Our results support a model of increased oxygen consumption and oxidative stress in AA that may accelerate hypertension and target-organ injury compared to white essential hypertensive patients.

The last decade has seen the evolution and ongoing refinement of a disease-oriented approach to chronic kidney disease (CKD). Disease-oriented models of care assume a direct causal association between observed signs and symptoms and underlying disease pathophysiology. Treatment plans target underlying disease mechanisms with the goal of improving disease-related outcomes. Because average levels of glomerular filtrate rate (GFR) tend to decrease with age, CKD becomes increasingly prevalent with advancing age, and those who meet criteria for CKD are disproportionately elderly. However, several features of geriatric populations may limit the utility of disease-oriented models of care. In older adults, complex comorbidity and geriatric syndromes are common, signs and symptoms often do not reflect a single underlying pathophysiologic process, there can be substantial heterogeneity in life expectancy, functional status and health priorities, and information on the safety and efficacy of interventions is often lacking. For all these reasons, geriatricians have tended to favor an individualized patient-centered model of care over more traditional disease-based approaches. An individualized approach prioritizes patient preferences and embraces the notion that observed signs and symptoms often do not reflect a single unifying disease process, and instead reflect the complex interplay between many different factors. This approach emphasizes modifiable outcomes that matter to the patient. Prognostic information related to these and other outcomes is generally used to shape rather than dictate treatment decisions. We herein argue that an individualized patient-centered approach to care may have more to offer than a traditional disease-based approach to CKD in many older adults.

Background

The association of subclinical vascular disease and early declines in kidney function has not been well studied.

Study Design

Prospective cohort study

Setting & Participants

MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years

Predictors

Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.

Outcomes

kidney function decline

Measurements

SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.

Results

Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.

Limitations

We had no direct measure of GFR, in common with nearly all large population based studies.

Conclusions

Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.

Background

Recent genome-wide association studies have identified multiple genetic loci that increase the risk of chronic kidney disease (CKD) in the general population. We hypothesized that knowledge of these loci might permit improved CKD risk prediction beyond that provided by traditional phenotypic risk factors.

Study design

Observational cohort study

Setting and participants

Participants who attended the 15th (1977–1979) and 24th (1995–1998) examination cycles of the Original cohort or the 6th (1995–1998) and 8th cycles (2005–2008) of the Offspring cohort of the Framingham Heart Study (n=2,489).

Predictors

Single-nucleotide polymorphisms (SNPs) at 16 stage 3 CKD loci were genotyped and used to construct a genetic risk score. Standard clinical predictors of incident stage 3 CKD were also used.

Outcomes and Measurements

Incident stage 3 CKD was defined as eGFR <60 mL/min/1.73m2 at follow-up. Participants with baseline stage 3 CKD were excluded. Logistic regression was used to generate C statistics, which measured the power of the genetic risk score to discriminate risk of incident CKD stage 3 with and without traditional risk factors.

Results

There were 270 new stage 3 CKD cases during an average of 10.8 years follow-up. The mean (±SD) genetic risk score was 17.5±2.8 among those who developed stage 3 CKD and 17.3±2.6 among those who did not (P-value for genotype score difference=0.2). The odds ratio for stage 3 CKD was 1.06 (95% CI, 1.01–1.11; p=0.03) per additional risk allele, adjusting for age and sex. In the age and sex-adjusted model, the C statistic was 0.748 without the genotype score and 0.751 with the score (P-value for difference=0.3). The risk score was not statistically significant in a multivariable model adjusted for standard stage 3 CKD risk factors (p=0.07).

Limitations

Participants all of European ancestry; genotype score may not be valid in different ancestral groups.

Conclusions

A genetic score generated from 16 known CKD risk alleles did not predict new cases of stage 3 CKD in the community beyond knowledge of common, clinical risk factors alone.

There are few studies evaluating exercise in the nondialysis chronic kidney disease (CKD) population. This review covers the rationale for exercise among patients with CKD not requiring dialysis and the effects of exercise training on physical functioning, progression of kidney disease, and cardiovascular risk factors. In addition, we address the issue of the risk of exercise and make recommendations for implementation of exercise in this population.

Evidence from uncontrolled studies and from small randomized controlled trials shows that exercise training results in improved physical performance and functioning among patients with CKD. In addition, although there are no studies examining cardiovascular outcomes, several studies suggest that cardiovascular risk factors such as hypertension, inflammation, and oxidative stress, may be improved with exercise training in this population. Although the current literature does not allow for definitive conclusions about whether exercise training slows the progression of kidney disease, no study has reported worsening of kidney function as a result of exercise training. In the absence of guidelines specific to the CKD population, recent guidelines developed for older individuals and patients with chronic disease should be applied to the CKD population.

In sum, exercise appears to be safe in this patient population if begun at moderate intensity and increased gradually. Indeed, the evidence suggests that the risk of remaining inactive is higher. Patients should be advised to increase their physical activity when possible and referred to physical therapy or cardiac rehabilitation programs when appropriate.

Background

Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (GFR) and serum creatinine, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP), to predict ESRD and mortality has yet to be established.

Study Design

Randomized clinical trial followed by an observational cohort study.

Setting & Participants

865 African American individuals with hypertensive CKD enrolled in a clinical trial of two levels of blood pressure control and three different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study.

Predictors

Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based estimated GFR (eGFRSCr), cystatin C, and BTP.

Outcomes and Measurements

Incidence of ESRD and mortality.

Results

A total of 246 participants reached ESRD over a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP and ESRD was stronger than those for the other markers, including mGFR. All the markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all p<0.05), with BTP retaining the strongest association (HR for highest versus lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined endpoint of ESRD or mortality (n=390) were weaker, but remained significant for cystatin C (p=0.05) and BTP (p=0.004).

Limitations

The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and among individuals with CKD due to other causes is unknown.

Conclusions

Plasma BTP and cystatin C may be useful adjuncts to serum creatinine and mGFR in evaluating risk for progression of kidney disease.

Background

Primary care physicians (PCPs) care for the majority of non-dialysis-dependent chronic kidney disease (CKD) patients. Studies suggest that PCPs may deliver suboptimal CKD care. One means to improve PCP treatment of CKD is clinical decision support systems (CDSS).

Study Design

Cluster randomized controlled trial

Setting & Participants

Thirty PCPs in a university-based outpatient general internal medicine practice and their 248 moderate to advanced CKD patients who had not been referred to a nephrologist.

Intervention

Two CKD educational sessions were held for PCPs in both arms. The 15 intervention arm PCPs also received real-time automated electronic medical record alerts for patients with estimated glomerular filtration rates < 45 ml/min/1.73m2 recommending renal referral and urine albumin quantification if not done within the prior year.

Outcomes

Primary outcome was referral to a nephrologist; secondary outcomes were albuminuria/proteinuria assessment, CKD documentation, optimal blood pressure (i.e., < 130/80), and use of renoprotective medications.

Results

The intervention and control arms did not differ in renal referrals (9.7% vs. 16.5%, respectively; between group difference, −6.8% (95% CI, −15.5% to 1.8%; P=0.1)) or proteinuria assessments (39.3% vs. 30.1%, respectively; between group difference, 9.2% (95% CI, −2.7% to 21.1%; P=0.1)). Among intervention and control group patients without a baseline proteinuria assessment, 27.7% versus 16.3%, respectively had one at follow-up (P=0.06). After controlling for clustering, these findings were largely unchanged and no significant differences were apparent between the groups.

Limitations

Small single-center university based practice, use of a passive CDSS that required PCPs to trigger the electronic order set.

Conclusions

PCPs were willing to partake in a randomized trial of CDSS to improve outpatient CKD care. While CDSS may possess potential, larger studies are needed to further explore how best to deploy them to enhance CKD care.

Background

Vasoconstrictor therapy has been advocated as treatment for hepatorenal syndrome (HRS). Our aim was to explore whether across all tested vasoconstrictors, achievement of a substantial rise in arterial blood pressure is associated with recovery of kidney function in HRS.

Study Design

Pooled analysis of published studies identified by electronic database search.

Setting & Population

Data pooled across 501 subjects from 21 studies.

Selection Criteria for Studies

Human studies evaluating the efficacy of a vasoconstrictor administered for ≥ 72 hours in adults with HRS Type 1 or 2.

Intervention

Vasoconstrictor therapy.

Outcomes & Measurements

Cohorts’ mean arterial pressure (MAP), serum creatinine, urinary output and plasma renin activity (PRA) at baseline and at subsequent time points during treatment. Linear regression models were constructed to estimate the mean daily change in MAP, serum creatinine, urinary output and PRA for each study subgroup. Correlations were used to assess for association between variables.

Results

An increase in MAP is strongly associated with a decline in serum creatinine but not associated with an increase in urinary output. The associations were stronger when analyses were restricted to randomized clinical trials and were not limited to cohorts with either lower baseline MAP or lower baseline serum creatinine. The majority of the studies tested terlipressin as vasoconstrictor, whereas fewer studies tested ornipressin, midodrine, octreotide or norepinephrine. Excluding cohorts of subjects treated with terlipressin or ornipressin did not eliminate the association. Furthermore, a fall in PRA correlated with improvement in kidney function.

Limitations

Studies were not originally designed to test our question. We lacked access to individual patient data.

Conclusions

A rise in MAP during vasoconstrictor therapy in HRS is associated with improvement in kidney function, across the spectrum of drugs tested to date. These results support consideration for a goal-directed approach to the treatment of HRS.

Background

Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors.

Methods

This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000–2008, with estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, not on regular dialysis, and without previous kidney transplant. Albuminuria (urine albumin-creatinine ratio [ACR] ≥ 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region.

Results

Albuminuria prevalence was 8% (n = 2303) in whites, 11% (n = 2310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted odds ratio 1.93, 95% confidence interval 1.70–2.20), then Asians (1.42, 1.26–1.61), African Americans (1.38, 1.29–1.47), and Hispanics (1.19, 1.08–1.31).

Conclusions

In the KEEP study population, albuminuria prevalence was higher among African Americans, Hispanics, Asians, and American Indians/Alaska Natives than among non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially among people at increased risk, in the community primary care setting.

The explosion of podocyte biology over the last decade has radically altered our views on the pathophysiology of proteinuria, glomerular disease, and progressive kidney disease. In this review, we highlight some of these landmark findings, but focus on recent advances in the field and the implications for translating this biology into therapy for podocyte diseases.

Background

M[ND1]enopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.

Study Design & Setting

Cross-sectional study among ambulatory individuals with prevalent cardiovascular disease.

Predictors

Sex, and among women, use or non-use of estrogen.

Outcomes

Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to GFR (TMP/GFR), and plasma FGF-23 concentrations.

Results

Among 987 participants, the mean age was 67 ± 11 years, 182 (18%) were female; 46 (25%) were taking estrogen. The mean eGFR was 71 ± 23 (SD) ml/min/1.73m2. Compared to women who were not taking estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 in RU/ml were 68.7 (95% CI, 59.7–79.0) in non estrogen using women, 43.8 (95% CI, 41.2–46.5) in men, and 45.1 (95% CI, 35.2–57.4) in women using estrogen in adjusted analysis (P< 0.001).

Limitations

The majority of participants were men. Estrogen therapy was not randomly assigned.

Conclusions

Older women who are not taking estrogen have higher FGF-23 levels than either men or women taking estrogen. In the context of prior literature, these data suggest that post-menopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.

Background

Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.

Study Design

Prospective cohort study.

Setting and Participants

A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.

Predictors

Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.

Outcomes

Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.

Results

Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).

Limitations

single measure of albuminuria and eGFR, screening test of cognition

Conclusions

When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.

Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to CKD patients, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance progression of vascular calcification including (1) transition of vascular smooth muscle cells (VSMC) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters; (2) induction of apoptosis of VSMC; (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells; (4) elevation of fibroblast growth factor 23 levels; and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis is currently unknown. The current review discusses these mechanisms in-depth, exploring the interplay among vascular calcification promoters, inhibitors and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.

Background

Cardiovascular disease (CVD) and cognitive impairment are common in dialysis patients. Given the proposed role of microvascular disease on cognitive function, particularly cognitive domains that incorporate executive functions, we hypothesized that prevalent systemic CVD would be associated with worse cognitive performance in hemodialysis patients.

Design

Cross-sectional cohort

Setting and Participants

200 maintenance hemodialysis patients without prior stroke from 5 Boston-area hemodialysis units

Predictor

CVD, defined by history of coronary disease or peripheral vascular disease

Outcome

Performance on a detailed neurocognitive battery. Primary analyses quantified cognitive performance using principal components analysis to reduce cognitive tests to a processing speed/executive function domain and a memory domain. Multivariable linear regression models adjusted for age, sex, education, race and other clinical and demographic characteristics.

Results

Mean (SD) age of participants was 62 (18) years and 75 (38%) had CVD. Individuals with CVD were older, more likely to be men, diabetic, and current or former smokers. In adjusted models, individuals with CVD performed 0.50 standard deviations worse (p<0.001) on tests assessing processing speed/executive function, while there was no difference in performance on tests of memory. Similar results were seen when assessing individual tests, with performance on the block design, digit symbol coding and Trail Making Tests A and B significantly associated with CVD in age, sex, education and race-adjusted analyses and approaching toward significance in fully adjusted models.

Limitations

CVD ascertainment dependent on patient recall and dialysis unit documentation. No brain imaging.

Conclusions

The presence of CVD is associated with worse cognitive performance on tests of processing speed and executive functioning in hemodialysis patients and identifies a high risk population for greater difficulty with complex tasks.

Background

An increased frequency of venous thromboembolism (VTE) has been shown among patients with reduced kidney function as measured by a decreased estimated glomerular filtration rate (eGFR). However, current practices with respect to VTE prevention and management in patients with a reduced eGFR in general population settings remain uncertain.

Study Design

Observational study.

Setting & Participants

Community investigation of 1,509 metropolitan Worcester (Massachusetts) residents with validated VTE during 1999, 2001, and 2003 with further follow-up for up to 3 years.

Predictor

VTE patients further classified according to their eGFR on presentation: < 30, 30-59, 60-89, or ≥ 90 ml/min/1.73m2 (reference group).

Outcomes

Recurrent VTE, major bleeding episodes, and all-cause mortality.

Measurements

Demographic and clinical characteristics, treatment practices, and study outcomes were extracted from patients’ hospital and outpatient medical records; eGFR was estimated using the Chronic Kidney Disease Epidemiology equation.

Results

VTE patients with eGFR < 30 ml/min/1.73m2 were at an increased risk for recurrent VTE (HR, 1.83; 95% CI, 1.03-3.25), major bleeding episodes (HR, 2.30; 95% CI, 1.28-4.16) and all-cause mortality (HR, 1.70; 95% CI, 1.12-2.57) over 3-year follow-up. Patients with reduced eGFR also presented with more co-morbidities and were less likely to be discharged on any form of anticoagulant therapy (72.6%, 81.0%, 82.1%, and 87.3% for eGFR < 30, 30-59, 60-89, and ≥ 90 mL/min/1.73m2, respectively; p<0.001).

Limitations

Reduced eGFR status is presumed based on creatinine values on clinical presentation. The impact of drug dosage, timing, type of anticoagulant therapy, and medication adherence on study outcomes could not be evaluated.

Conclusions

Severe reductions in eGFR are associated with an increased risk of long-term recurrent VTE, bleeding, and total mortality in patients with VTE. A greater frequency of serious co-morbidities, difficulties implementing available management strategies, and suboptimal VTE prophylaxis during hospital admissions likely contributed to our findings.