Associations among Estimated Glomerular Filtration Rate,Proteinuria, and Adverse Cardiovascular Outcomes

Summary

Background and objectives

Most studies of chronic kidney disease (CKD) and outcomes focus on mortality and ESRD, with limited data on other adverse outcomes. This study examined the associations among proteinuria, eGFR, and adverse cardiovascular (CV) events.

Design, setting, participants, & measurements

This was a population-based longitudinal study with patients identified from province-wide laboratory data from Alberta, Canada, between 2002 and 2007. Selected for this study from a total of 1,526,437 patients were 920,985 (60.3%) patients with at least one urine dipstick measurement and 102,701 patients (6.7%) with at least one albumin-creatinine ratio (ACR) measurement. Time to hospitalization was considered for one of four indications: congestive heart failure (CHF), coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), peripheral vascular disease (PVD), and stroke/transient ischemic attacks [TIAs] (cerebrovascular accident [CVA]/TIA).

Results

After a median follow-up of 35 months, in fully adjusted models and compared with patients with estimated GFR (eGFR) of 45 to 59 ml/min per 1.73 m² and no proteinuria, patients with heavy proteinuria by dipstick and eGFR ≥ 60 ml/min per 1.73 m² had higher rates of CABG/PCI and CVA/TIA. Similar results were obtained in patients with proteinuria measured by ACR.

Conclusions

Risks of major CV events at a given level of eGFR increased with higher levels of proteinuria. The findings extend current data on risk of mortality and ESRD. Measurement of proteinuria is of incremental prognostic benefit at every level of eGFR. The data support use of proteinuria measurement with eGFR for definition and risk stratification in CKD.     

Relationship between blood pressure and incident chronic kidney disease in hypertensive patients

Summary

Background and objectives

Hypertension is an important cause of chronic kidney disease (CKD). Identifying risk factors for progression to CKD in patients with normal kidney function and hypertension may help target therapies to slow or prevent decline of kidney function. Our objective was to identify risk factors for development of incident CKD and decline in estimated GFR (eGFR) in hypertensive patients.

Design, setting, participants, & measurements

Cox proportional hazards models were used to assess the relationship between incident CKD (defined as eGFR <60 ml/min per 1.73 m²) and potential risk factors for CKD from a registry of hypertensive patients.

Results

Of 43,305 patients meeting the inclusion criteria, 12.1% (5236 patients) developed incident CKD. Diabetes was the strongest predictor of incident CKD (hazard ratio, 1.96; 95% confidence interval, 1.84 to 2.09) and was associated with the greatest rate of decline in eGFR (−2.2 ml/min per 1.73 m² per year). Time-varying systolic BP was associated with incident CKD with risk increasing above 120 mmHg; each 10-mmHg increase in baseline and time-varying systolic BP was associated with a 6% increase in the risk of developing CKD (hazard ratio, 1.06; 95% confidence interval, 1.04 to 1.08 for both). Time-weighted systolic BP was associated with a more rapid decline in eGFR of an additional 0.2 ml/min per 1.73 m² per year decline for every 10-mmHg increase in systolic BP.

Conclusions

We found that time-varying systolic BP was associated with incident CKD, with an increase in risk above a systolic BP of 120 mmHg among individuals with hypertension.     

Fibroblast Growth Factor 23 and Incident CKD in Type 2 Diabetes

Background and objectives

High levels of fibroblast growth factor 23 are associated with accelerated progression of CKD. Whether high fibroblast growth factor 23 levels also predict incident CKD is uncertain.

Design, setting, participants, & measurements

A prospective case-cohort study was conducted within the Action to Control Cardiovascular Risk in Diabetes Trial. The analytic sample consisted of a random subcohort of 590 patients with type 2 diabetes without prevalent CKD at baseline, 124 of whom developed incident CKD during follow-up, and 520 additional patients with incident CKD outside the random subcohort. The association between serum intact fibroblast growth factor 23 and incident CKD, defined as the new onset of eGFR<60 ml/min per 1.73 m² that represented a ≥25% decrease from baseline in an individual with eGFR≥60 ml/min per 1.73 m² and no microalbuminuria (<30 mg/g creatinine) at baseline, was tested.

Results

The mean baseline eGFR in the random subcohort was 90.9±22.7 ml/min per 1.73 m². During a median follow-up of 4.7 years, there was a total of 644 patients with incident CKD. The median baseline fibroblast growth factor 23 level was modestly higher among patients with incident CKD versus controls (43.5, interquartile range=34.7–55.1 versus 39.8, interquartile range=31.9–49.5 pg/ml; P<0.001). Higher baseline fibroblast growth factor 23 levels were associated with higher risk of incident CKD in unadjusted and demographics-adjusted models, but the effect was attenuated after additional adjustment for clinical risk factors and baseline eGFR (hazard ratio per SD of natural log fibroblast growth factor 23, 1.09; 95% confidence interval, 0.94 to 1.27), which was the strongest predictor of incident CKD. Consistent with the results of primary analyses, baseline fibroblast growth factor 23 was not associated with eGFR slope.

Conclusions

Higher fibroblast growth factor 23 levels are not independently associated with higher risk of incident CKD in patients with type 2 diabetes.     

Progression of Pediatric CKD of Nonglomerular Origin in the CKiD Cohort

Background and objectives

Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD.

Design, setting, participants, & measurements

Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study.

Results

A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m² (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m² per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m² per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m² per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m² per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria.

Conclusions

Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.     

Lifetime Risk of Stage 3–5 CKD in a Community-Based Sample in Iceland

Background and objectives

Lifetime risk estimates of CKD can be used effectively in public education campaigns. This study sought to estimate lifetime risk of incident CKD stage 3 and higher in Iceland for people without CKD by the age of 45 years.

Design, setting, participants, & measurements

This was a prospective cohort study with longitudinal creatinine measurements of residents in Reykjavik, Iceland, from 1967 to 2005. CKD was ascertained by two consecutive eGFR measurements <60 ml/min per 1.73 m², development of treated kidney failure, one eGFR<60 ml/min per 1.73 m² if the participant died before the next evaluation, or one eGFR<45 ml/min per 1.73 m² if it was the last eGFR.

Results

Mean follow-up was 25 (SD 10) years. Of the study participants, 727 (19%) developed the outcome and 942 (24%) died first. By age 85 years, the lifetime risks for 45-year-old women and men without prevalent CKD were 35.8% (95% confidence interval [95% CI], 32.7 to 38.9) and 21.3% (95% CI, 18.7 to 23.8), respectively. Risk was higher in individuals with a lower eGFR, hypertension, and a higher body mass index. Lifetime risk for higher stages of CKD 3b and 4 were less common than stage 3a; by age 85 years, the lifetime risks for CKD stages 3a, 3b, and 4 in women were 38.5% (95% CI, 25.8 to 51.1), 19.4% (95% CI, 8.9 to 29.9), and 3.6% (95% CI, 2.2 to 5.0), respectively.

Conclusions

The lifetime risk of developing CKD stage 3 or higher is substantial, emphasizing the importance of strategies to prevent development of CKD throughout the course of life. Estimates are lower than reported using single estimates of GFR, emphasizing the importance of confirming estimates of reduced GFR in studies of CKD.     

Serum Uric Acid and Risk of CKD in Type 2 Diabetes

Background and objective

Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes.

Design, setting, participants, & measurements

Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m² and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m², albuminuria, and their combination at 4 years.

Results

At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m² with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m², and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m². The incidence of eGFR <60 ml/min per 1.73 m² increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m².

Conclusions

Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.     

A Nurse-coordinated Model of Care versus Usual Care for Stage 3/4 Chronic Kidney Disease in the Community: A Randomized Controlled Trial

Summary

Background and objectives

It is unclear how to optimally care for chronic kidney disease (CKD). This study compares a new coordinated model to usual care for CKD.

Design, setting, participants, & measurements

A randomized trial in nephrology clinics and the community included 474 patients with median estimated GFR (eGFR) 42 ml/min per 1.73 m² identified by laboratory-based case finding compared care coordinated by a general practitioner (controls) with care by a nurse-coordinated team including a nephrologist (intervention) for a median (interquartile range [IQR]) of 742 days. 32% were diabetic, 60% had cardiovascular disease, and proteinuria was minimal. Guided by protocols, the intervention team targeted risk factors for adverse kidney and cardiovascular outcomes. Serial eGFR and clinical events were tracked.

Results

The average decline in eGFR over 20 months was −1.9 ml/min per 1.73 m². eGFR declined by ≥4 ml/min per 1.73 m² within 20 months in 28 (17%) intervention patients versus 23 (13.9%) control patients. Control of BP, LDL, and diabetes were comparable across groups. In the intervention group there was a trend to greater use of renin-angiotensin blockers and more use of statins in those with initial LDL >2.5 mmol/L. Treatment was rarely required for anemia, acidosis, or disordered mineral metabolism. Clinical events occurred in 5.2% per year.

Conclusions

Patients with stage 3/4 CKD identified through community laboratories largely had nonprogressive kidney disease but had cardiovascular risk. Over a median of 24 months, the nurse-coordinated team did not affect rate of GFR decline or control of most risk factors compared with usual care.     

Age-specific associations of reduced estimated glomerular filtration rate with concurrent chronic kidney disease complications

Summary

Background and objectives

It has been suggested that moderate reductions in estimated GFR (eGFR) among older adults may not reflect chronic kidney disease (CKD).

Design, setting, participants, & measurements

We examined age-specific (<60, 60 to 69, 70 to 79, and ≥80 years) associations between eGFR level and six concurrent CKD complications among 30,528 participants from the National Health and Nutrition Examination Survey (NHANES) 1988 to 1994 and 1999 to 2006 (n = 8242 from NHANES 2003 to 2006 for hyperparathyroidism). Complications included anemia (hemoglobin <12 g/dl women, <13.5 g/dl men), acidosis (bicarbonate <22 mEq/L), hyperphosphatemia (phosphorus ≥4.5 mg/dl), hypoalbuminemia (albumin <3.5 mg/dl), hyperparathyroidism (intact parathyroid hormone ≥70 pg/ml), and hypertension (systolic/diastolic BP ≥140/90 mmHg or antihypertensive use).

Results

Among participants ≥80 years old, compared with those with estimated GFR (eGFR) ≥60 ml/min per 1.73 m², the multivariable adjusted prevalence ratios (95% confidence interval) associated with eGFR levels of 45 to 59 and <45 ml/min per 1.73 m² were 1.39 (1.11 to1.73) and 2.06 (1.59 to 2.67) for anemia, 1.33 (0.89 to 1.98) and 2.47 (1.52 to 4.00) for acidosis, 1.11 (0.70 to 1.76) and 2.16 (1.36 to 3.42) for hyperphosphatemia, 2.04 (1.39 to 3.00) and 2.83 (1.76 to 4.53) for hyperparathyroidism and 1.09 (1.03 to 1.14), and 1.12 (1.05 to 1.19) for hypertension, respectively. Higher prevalence ratios for these complications at lower eGFR levels were also present at younger ages. Reduced eGFR was associated with hypoalbuminemia only for adults <70.

Conclusions

Reduced eGFR was associated with a higher prevalence of several concurrent CKD complications, regardless of age.     

Serum 25-Hydroxyvitamin D Level and Kidney Function Decline in a Swiss General Adult Population

Background and objectives

Molecular evidence suggests that levels of vitamin D are associated with kidney function loss. Still, population-based studies are limited and few have considered the potential confounding effect of baseline kidney function. This study evaluated the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline, and incidence of CKD and albuminuria.

Design, setting, participants, & measurements

Baseline (2003–2006) and 5.5-year follow-up data from a Swiss adult general population were used to evaluate the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline (annual loss >3 ml/min per 1.73 m²), and incidence of CKD and albuminuria. Serum 25-hydroxyvitamin D was measured at baseline using liquid chromatography–tandem mass spectrometry. eGFR and albuminuria were collected at baseline and follow-up. Multivariate linear and logistic regression models were used considering potential confounding factors.

Results

Among the 4280 people included in the analysis, the mean±SD annual eGFR change was −0.57±1.78 ml/min per 1.73 m², and 287 (6.7%) participants presented rapid eGFR decline. Before adjustment for baseline eGFR, baseline 25-hydroxyvitamin D level was associated with both mean annual eGFR change and risk of rapid eGFR decline, independently of baseline albuminuria. Once adjusted for baseline eGFR, associations were no longer significant. For every 10 ng/ml higher baseline 25-hydroxyvitamin D, the adjusted mean annual eGFR change was −0.005 ml/min per 1.73 m² (95% confidence interval, −0.063 to 0.053; P=0.87) and the risk of rapid eGFR decline was null (odds ratio, 0.93; 95% confidence interval, 0.79 to 1.08; P=0.33). Baseline 25-hydroxyvitamin D level was not associated with incidence of CKD or albuminuria.

Conclusions

The association of 25-hydroxyvitamin D with eGFR decline is confounded by baseline eGFR. Sufficient 25-hydroxyvitamin D levels do not seem to protect from eGFR decline independently from baseline eGFR.     

Masked Hypertension and Elevated Nighttime Blood Pressure in CKD: Prevalence and Association with Target Organ Damage

Background and objectives

Masked hypertension and elevated nighttime BP are associated with increased risk of hypertensive target organ damage and adverse cardiovascular and renal outcomes in patients with normal kidney function. The significance of masked hypertension for these risks in patients with CKD is less well defined. The objective of this study was to evaluate the association between masked hypertension and kidney function and markers of cardiovascular target organ damage, and to determine whether this relationship was consistent among those with and without elevated nighttime BP.

Design, setting, participants, & measurements

This was a cross-sectional study. We performed 24-hour ambulatory BP in 1492 men and women with CKD enrolled in the Chronic Renal Insufficiency Cohort Study. We categorized participants into controlled BP, white-coat, masked, and sustained hypertension on the basis of clinic and 24-hour ambulatory BP. We obtained echocardiograms and measured pulse wave velocity in 1278 and 1394 participants, respectively.

Results

The percentages of participants with controlled BP, white-coat, masked, and sustained hypertension were 49.3%, 4.1%, 27.8%, and 18.8%, respectively. Compared with controlled BP, masked hypertension independently associated with low eGFR (−3.2 ml/min per 1.73 m²; 95% confidence interval, −5.5 to −0.9), higher proteinuria (+0.9 unit higher in log₂ urine protein; 95% confidence interval, 0.7 to 1.1), and higher left ventricular mass index (+2.52 g/m^2.7; 95% confidence interval, 0.9 to 4.1), and pulse wave velocity (+0.92 m/s; 95% confidence interval, 0.5 to 1.3). Participants with masked hypertension had lower eGFR only in the presence of elevated nighttime BP (−3.6 ml/min per 1.73 m²; 95% confidence interval, −6.1 to −1.1; versus −1.4 ml/min per 1.73 m²; 95% confidence interval, −6.9 to 4.0, among those with nighttime BP <120/70 mmHg; P value for interaction with nighttime systolic BP 0.002).

Conclusions

Masked hypertension is common in patients with CKD and associated with lower eGFR, proteinuria, and cardiovascular target organ damage. In patients with CKD, ambulatory BP characterizes the relationship between BP and target organ damage better than BP measured in the clinic alone.     

Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function

Background and objectives

Patients with CKD are more likely than others to have abnormalities in serum potassium (K⁺). Aside from severe hyperkalemia, the clinical significance of K⁺ abnormalities is not known. We sought to examine the association of serum K⁺ with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K⁺ and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K⁺.

Design, setting, participants, & measurements

A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m²) with serum K⁺ data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K⁺, eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk.

Results

During the study, serum K⁺ levels of 5.5–5.9 and ≥6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50–59 ml/min per 1.73 m² versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m². Serum K⁺ level <3.5 mEq/L was present in 1.2%–1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K⁺ and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K⁺ levels <3.5 mEq/L and ≥6.0 mEq/L, respectively. Within eGFR strata, there were U-shaped associations of serum K⁺ with rates of MACE, hospitalization, and discontinuation of RAAS blockers.

Conclusions

Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K⁺ improve outcomes in this population.     

GFR Decline and Mortality Risk among Patients with Chronic Kidney Disease

Summary

Background and objectives

Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD.

Design, setting, participants, & measurements

We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009.

Results

A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were −4.8, −0.6, and 3.5 ml/min per 1.73 m²/yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups.

Conclusions

eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated.     

Association of Sarcopenia with eGFR and Misclassification of Obesity in Adults with CKD in the United States

Background and objectives

Muscle wasting is common among patients with ESRD, but little is known about differences in muscle mass in persons with CKD before the initiation of dialysis. If sarcopenia was common, it might affect the use of body mass index for diagnosing obesity in people with CKD. Because obesity may be protective in patients with CKD and ESRD, an accurate understanding of how sarcopenia affects its measurement is crucial.

Design, setting, participants, & measurements

Differences in body composition across eGFR categories in adult participants of the National Health and Nutrition Examination Survey 1999–2004 who underwent dual-energy x-ray absorptiometry were examined. Obesity defined by dual-energy x-ray absorptiometry versus body mass index and sarcopenia as a contributor to misclassification by body mass index were examined.

Results

Sarcopenia and sarcopenic obesity were more prevalent among persons with lower eGFR (P trend <0.01 and P trend <0.001, respectively). After multivariable adjustment, the association of sarcopenia with eGFR was U-shaped. Stage 4 CKD was independently associated with sarcopenia among participants ≥60 years old (adjusted odds ratio, 2.58; 95% confidence interval, 1.02 to 6.51 for eGFR=15–29 compared with 60–89 ml/min per 1.73 m²; P for interaction by age=0.02). Underestimation of obesity by body mass index compared with dual-energy x-ray absorptiometry increased with lower eGFR (P trend <0.001), was greatest among participants with eGFR=15–29 ml/min per 1.73 m² (71% obese by dual-energy x-ray absorptiometry versus 41% obese by body mass index), and was highly likely among obese participants with sarcopenia (97.7% misclassified as not obese by body mass index).

Conclusions

Sarcopenia and sarcopenic obesity are highly prevalent among persons with CKD and contribute to poor classification of obesity by body mass index. Measurements of body composition beyond body mass index should be used whenever possible in the CKD population given this clear limitation.     

High Prevalence of Obstructive Sleep Apnea and Its Association with Renal Function among Nondialysis Chronic Kidney Disease Patients in Japan: A Cross-Sectional Study

Summary

Background and objectives

Obstructive sleep apnea (OSA) affects one of five adults in the general population. Although a high prevalence of OSA has been reported among dialysis patients, the association between nondialysis chronic kidney disease (CKD) and OSA has not been fully investigated. This cross-sectional study aimed to investigate the prevalence of OSA among nondialysis CKD patients in Japan and the association between renal function and OSA.

Design, setting, participants, & measurements

Consecutive nondialysis CKD patients hospitalized mainly for CKD educational program, regardless of their sleep complaints, were enrolled. The diagnosis of OSA and its severity were measured using a type 3 portable monitor.

Results

Overall (n = 100, 68.0% male, median age 66.5 years, body mass index [BMI] 23.1 kg/m², estimated GFR [eGFR] 28.5 ml/min per 1.73 m²), 65% were diagnosed as OSA: mild OSA (apnea-hypopnea index [AHI] 5.0 to 14.9) in 32%, moderate OSA (AHI 15.0 to 29.9) in 25%, and severe OSA (AHI ≥ 30.0) in 8%. Multivariate logistic regression analysis revealed that a 10-ml/min per 1.73 m² decrease in eGFR was associated with a 42% increased odds of OSA after adjustment for age, BMI, and diabetes mellitus. Moreover, in a generalized linear model, eGFR was inversely correlated with AHI after adjustment for covariates.

Conclusions

This study demonstrated a high prevalence of OSA among nondialysis CKD patients in Japan and that the increased risk of OSA was significantly associated with decreased GFR among these patients. Further investigations are warranted to determine OSA''s direct influence on cardiovascular disease.     

Presence and Outcomes of Kidney Disease in Patients with Pulmonary Hypertension

Background and objectives

Pulmonary hypertension is associated with higher mortality rates. The associations of nondialysis-dependent CKD and all-cause mortality in patients with pulmonary hypertension were studied.

Design, setting, participants, & measurements

The study population included those patients who underwent right heart catheterization for confirmation of pulmonary hypertension between 1996 and January 2011. Pulmonary hypertension was defined as the presence of mean pulmonary artery pressure≥25 mmHg at rest measured by right heart catheterization. CKD was defined as the presence of two measurements of eGFR<60 ml/min per 1.73 m² 90 days apart. The risk factors associated with CKD as well as the association between CKD and death in those patients with pulmonary hypertension using logistic regression and Cox proportional hazard models were examined.

Results

Of 1088 patients with pulmonary hypertension, 388 (36%) patients had CKD: 340 patients had stage 3 CKD, and 48 (4%) patients had stage 4 CKD. In the multivariable analysis, older age, higher hemoglobin, and higher mean right atrial pressures were independently associated with CKD. During a median follow-up of 3.2 years (interquartile range=1.5–5.6 years), 559 patients died. After adjusting for relevant covariates, presence of stage 3 CKD (hazard ratio, 1.37; 95% confidence interval, 1.14 to 1.66) and stage 4 CKD (hazard ratio, 2.69; 95% confidence interval, 1.88 to 3.86) was associated with all-cause mortality in those patients with pulmonary hypertension. When eGFR was examined as a continuous measure, a 5 ml/min per 1.73 m² lower eGFR was associated with a 5% (95% confidence interval, 1.03 to 1.07) higher hazard for death. This higher risk with CKD was similar irrespective of demographics, left ventricular function, and pulmonary capillary wedge pressure.

Conclusion

In a clinical population referred for right heart catheterization, presence of CKD was associated with higher all-cause mortality in those patients with pulmonary hypertension. Mechanisms that may underlie these associations warrant additional studies.     

Albuminuria and Estimated Glomerular Filtration Rate as Predictors of Diabetic End-Stage Renal Disease and Death

Summary

Background and objectives

We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes.

Design, setting, participants and measurements

Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression.

Results

During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR < 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m² was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m². Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m² lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37.

Conclusions

These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death.     

Implantable Cardioverter-Defibrillators in Patients with CKD: A Propensity-Matched Mortality Analysis

Background and objectives

Benefits of transvenous implantable cardioverter-defibrillators (ICDs) in prevention of sudden cardiac death among the general population are proven. However, the benefit of ICDs remains unclear in CKD. A propensity-matched analysis was conducted to examine the survival benefits of ICDs placed for primary prevention in those with CKD not on dialysis (eGFR<60 ml/min per 1.73 m²).

Design, setting, participants, & measurements

The Cleveland Clinic CKD registry was utilized to identify individuals who had an echocardiogram at the institution (between 2001 and October 2011). A propensity score of the likelihood of receiving an ICD was developed with the following variables: demographics, comorbid conditions, use of cardioprotective medications, eGFR, left ventricular ejection fraction, and ventricular arrhythmia. One-to-one greedy matching was used with 0.1 caliper width to match patients with and without an ICD. A Cox proportional hazards model was used to examine survival of matched patients with and without an ICD.

Results

This study included 1053 ICD patients and 9435 potential controls. Of 1053 ICD patients (60%), 631 were matched to the control group. During a median follow-up of 2.9 years (25th and 75th percentiles, 1.5, 4.7), 578 patients died. After adjusting for covariates, the hazard of mortality among propensity-matched patients was 0.69 (95% confidence interval [95% CI], 0.59 to 0.82) for the ICD group compared with the non-ICD group. A significant interaction was found between ICDs and eGFR (P=0.04). Presence of an ICD was associated with a lower risk of death among those with eGFRs of 45–59 ml/min per 1.73 m² (hazard ratio [HR], 0.58; 95% CI, 0.44 to 0.77) and 30–44 ml/min per 1.73 m² (HR, 0.65; 95% CI, 0.50 to 0.85), but not among those with eGFRs<30 ml/min per 1.73 m² (HR, 0.98; 95% CI, 0.71 to 1.35).

Conclusions

Transvenous ICDs placed for primary prevention are associated with a survival benefit in those with stage 3 CKD, but not in those with stage 4 CKD.     

CKD and Hypertension during Long-Term Follow-Up in Children and Adolescents Previously Treated with Extracorporeal Membrane Oxygenation

Background and objectives

Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined.

Design, setting, participants, & measurements

Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m² or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membrane oxygenation without preemptive hemofiltration.

Results

Median follow-up of 169 screened participants was 8.2 years (interquartile range=5.2–12.1 years). Nine children had a lower eGFR, but all rates were >60 ml/min per 1.73 m². Proteinuria was observed in 20 children (median=0.26 mg protein/mg creatinine; interquartile range=0.23–0.32 mg protein/mg creatinine), and 32 children had hypertension. Only history of AKI was associated with CKD (P=0.004). Children with RIFLE scores injury and failure had 4.3 times higher odds of CKD signs or hypertension than those without AKI (95% confidence interval, 1.6 to 12.1; P=0.004).

Conclusions

Altogether, 54 participants (32%) had at least one sign of CKD and/or hypertension. However, most values were marginally abnormal, with no immediate consequences for clinical care. Nevertheless, a prevalence of 32% clearly indicates that survivors of neonatal extracorporeal membrane oxygenation, especially those with AKI, are at risk of a more rapid decline of kidney function with increasing age. Therefore, screening for CKD development in adulthood is recommended.     

Outcomes After Post-Traumatic AKI Requiring RRT in United States Military Service Members

Background and objectives

Mortality and CKD risk have not been described in military casualties with post-traumatic AKI requiring RRT suffered in the Iraq and Afghanistan wars.

Design, setting, participants, & measurements

This is a retrospective case series of post-traumatic AKI requiring RRT in 51 military health care beneficiaries (October 7, 2001–December 1, 2013), evacuated to the National Capital Region, documenting in-hospital mortality and subsequent CKD. Participants were identified using electronic medical and procedure records.

Results

Age at injury was 26±6 years; of the participants, 50 were men, 16% were black, 67% were white, and 88% of injuries were caused by blast or projectiles. Presumed AKI cause was acute tubular necrosis in 98%, with rhabdomyolysis in 72%. Sixty-day all-cause mortality was 22% (95% confidence interval [95% CI], 12% to 35%), significantly less than the 50% predicted historical mortality (P<0.001). The VA/NIH Acute Renal Failure Trial Network AKI integer score predicted 60-day mortality risk was 33% (range, 6%–96%) (n=49). Of these, nine died (mortality, 18%; 95% CI, 10% to 32%), with predicted risks significantly miscalibrated (P<0.001). The area under the receiver operator characteristic curve for the AKI integer score was 0.72 (95% CI, 0.56 to 0.88), not significantly different than the AKI integer score model cohort (P=0.27). Of the 40 survivors, one had ESRD caused by cortical necrosis. Of the remaining 39, median time to last follow-up serum creatinine was 1158 days (range, 99–3316 days), serum creatinine was 0.85±0.24 mg/dl, and eGFR was 118±23 ml/min per 1.73 m². No eGFR was <60 ml/min per 1.73 m², but it may be overestimated because of large/medium amputations in 54%. Twenty-five percent (n=36) had proteinuria; one was diagnosed with CKD stage 2.

Conclusions

Despite severe injuries, participants had better in-hospital survival than predicted historically and by AKI integer score. No patient who recovered renal function had an eGFR<60 ml/min per 1.73 m² at last follow-up, but 23% had proteinuria, suggesting CKD burden.     

Arterial Stiffness and Decline in Kidney Function

Background and objectives

The independent link between arterial stiffness and CKD remains unknown. We investigated the association of indicators of arterial stiffness with decline in kidney function.

Design, setting, participants, & measurements

We studied 3666 participants (mean age =65 years old; 58% women) from the Rotterdam Study. Pulse pressure (PP), carotid stiffness, and pulse wave velocity (PWV) were measured. We created genetic risk scores for PP and PWV. Annual declines in kidney function and incident CKD were assessed using eGFR. To put our findings in context of the literature, we performed a meta-analysis of the available population–based studies.

Results

After a median (interquartile range) follow–up time of 11 (10.7–11.3) years, 601 participants with incident CKD were recognized. In the model adjusted for age, sex, mean arterial pressure, heart rate, and baseline GFR, each SD higher PP was associated with 0.15-ml/min per 1.73 m² steeper annual eGFR decline (95% confidence interval [95% CI], 0.10 to 0.20) and 11% higher risk of incident CKD (95% CI, 1.05 to 1.18). Each SD greater carotid stiffness was associated with 0.08-ml/min per 1.73 m² steeper annual eGFR decline (95% CI, 0.04 to 0.13) and 13% higher risk of incident CKD (95% CI, 1.05 to 1.22). Each SD higher PWV was associated with 7% higher risk of incident CKD (95% CI, 1.00 to 1.14). Incorporating our findings in a meta-analysis, each SD higher PP and PWV were associated with 16% (95% CI, 1.12 to 1.21) and 8% (95% CI, 1.03 to 1.14) higher risks of incident CKD. Each SD higher PP genetic risk score was associated with 0.06-ml/min per 1.73 m² steeper annual eGFR decline (95% CI, 0.01 to 0.10) and 8% higher risk of incident CKD (95% CI, 1.03 to 1.14). There was no association between PWV genetic risk score and kidney function decline.

Conclusions

Higher indices of arterial stiffness are associated with steeper decline in kidney function. This suggests that vascular stiffness could be considered as a target for delaying decline in kidney function.