Screening for elevated albuminuria and subsequently hypertension identifies subjects in which treatment may be warranted to prevent renal function decline.

Background: We investigated whether initial population screening for elevated albuminuria with subsequent screening for hypertension in case albuminuria is elevated may be of help to identify subjects at risk for accelerated decline in kidney function. Methods: We included subjects who participate in the PREVEND observational, general population-based cohort study and had two or more glomerular filtration rate (eGFR) measurements available during follow-up. Elevated albuminuria was defined as an albumin concentration ≥20 mg/L in a first morning urine sample confirmed by an albumin excretion ≥30 mg/day in two 24-h urines. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or use of blood pressure-lowering drugs. eGFR was estimated with the CKD-EPI creatinine-cystatin C equation. Results: Overall, 6471 subjects were included with a median of 4 [95% confidence interval (CI) 2-5] eGFR measurements during a follow-up of 11.3 (95% CI 4.0-13.7) years. Decline in eGFR was greater in the subgroups with elevated albuminuria. This held true, not only in subjects with known hypertension (-1.84 ± 2.27 versus -1.16 ± 1.45 mL/min/1.73 m 2 per year, P < 0.05), but also in subjects with newly diagnosed hypertension (-1.59 ± 1.55 versus -1.14 ± 1.38 mL/min/1.73 m 2 per year, P < 0.05) and in subjects with normal blood pressure (-1.18 ± 1.85 versus -0.81 ± 1.02 mL/min/1.73 m 2 per year in subjects, P < 0.05). This effect was most pronounced in the population ≥55 years of age and male subjects. In addition, subjects with elevated albuminuria had higher blood pressure than subjects with normoalbuminuria, and in subjects with elevated albuminuria as yet undiagnosed hypertension was twice as prevalent as diagnosed hypertension. Conclusions: Initial screening for elevated albuminuria followed by screening for hypertension may help to detect subjects with increased risk for a steeper decline in kidney function.

Past Decline Versus Current eGFR and Subsequent Mortality Risk.

A single determination of eGFR associates with subsequent mortality risk. Prior decline in eGFR indicates loss of kidney function, but the relationship to mortality risk is uncertain. We conducted an individual-level meta-analysis of the risk of mortality associated with antecedent eGFR slope, adjusting for established risk factors, including last eGFR, among 1.2 million subjects from 12 CKD and 22 other cohorts within the CKD Prognosis Consortium. Over a 3-year antecedent period, 12% of participants in the CKD cohorts and 11% in the other cohorts had an eGFR slope <-5 ml/min per 1.73 m(2) per year, whereas 7% and 4% had a slope >5 ml/min per 1.73 m(2) per year, respectively. Compared with a slope of 0 ml/min per 1.73 m(2) per year, a slope of -6 ml/min per 1.73 m(2) per year associated with adjusted hazard ratios for all-cause mortality of 1.25 (95% confidence interval [95% CI], 1.09 to 1.44) among CKD cohorts and 1.15 (95% CI, 1.01 to 1.31) among other cohorts during a follow-up of 3.2 years. A slope of +6 ml/min per 1.73 m(2) per year also associated with higher all-cause mortality risk, with adjusted hazard ratios of 1.58 (95% CI, 1.29 to 1.95) among CKD cohorts and 1.43 (95% CI, 1.11 to 1.84) among other cohorts. Results were similar for cardiovascular and noncardiovascular causes of death and stronger for longer antecedent periods (3 versus <3 years). We conclude that prior decline or rise in eGFR associates with an increased risk of mortality, independent of current eGFR.

Urine Albumin-Creatinine Ratio Versus Albumin Excretion for Albuminuria Staging: A Prospective Longitudinal Cohort Study.

BACKGROUND: New guidelines advocate the use of albumin-creatinine ratio (ACR) in a urine sample instead of 24-hour urinary albumin excretion (UAE) for staging albuminuria. Concern has been expressed that this may result in misclassification for reasons including interindividual differences in urinary creatinine excretion. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: We examined 7,623 participants of the PREVEND and RENAAL studies for reclassified when using ACR instead of 24-hour UAE, the characteristics of reclassified participants, and their outcomes. Albuminuria was categorized into 3 ACR and UAE categories: <30, 30 to 300, and >300mg/g or mg/24 h, respectively. PREDICTORS: Baseline ACR and 24-hour UAE. OUTCOMES: Cardiovascular (CV) morbidity and mortality and all-cause mortality. RESULTS: When using ACR in the early morning void instead of 24-hour UAE, 88% of participants were classified in corresponding albuminuria categories. 307 (4.0%) participants were reclassified to a higher, and 603 (7.9%), to a lower category. Participants who were reclassified to a higher ACR category in general had a worse CV risk profile compared with nonreclassified participants, whereas the reverse was true for participants reclassified to a lower ACR category. Similarly, Cox proportional hazards regression analyses showed that reclassification to a higher ACR category was associated with a tendency for increased risk for CV morbidity and mortality and all-cause mortality, whereas reclassification to a lower ACR category was associated with a tendency for lower risk. Net reclassification improvement, adjusted for age, sex, and duration of follow-up, was 0.107 (P=0.002) for CV events and 0.089 (P<0.001) for all-cause mortality. LIMITATIONS: Early morning void urine collection instead of spot urine collection. CONCLUSIONS: Our results indicate that there is high agreement between early morning void ACR and 24-hour UAE categories. Reclassification is therefore limited, but when present, is generally indicative of the presence of CV risk factors and prognosis.

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function.

BACKGROUND: A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN: Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS: Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION: Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES: Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS: GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS: In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS: Limited sample size, no control group. CONCLUSIONS: In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.

Hemodialysis-induced regional left ventricular systolic dysfunction and inflammation: a cross-sectional study.

BACKGROUND: Hemodialysis may acutely induce regional left ventricular (LV) systolic dysfunction, which is associated with increased mortality and progressive heart failure. We tested the hypothesis that hemodialysis-induced regional LV systolic dysfunction is associated with inflammation and endothelial injury. Additionally, we studied whether hemodialysis-induced LV systolic dysfunction is associated with an exaggerated bioincompatibility reaction to hemodialysis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 105 hemodialysis patients on a thrice-weekly dialysis schedule were studied between March 2009 and March 2010. PREDICTORS: Plasma indexes of inflammation (high-sensitivity C-reactive protein, pentraxin 3 [PTX3], interleukin 6 [IL-6], and IL-6:IL-10 ratio), bioincompatibility (leukocytes, neutrophils, complement C3, and myeloperoxidase), and endothelial function (soluble intercellular adhesion molecule 1 [ICAM-1], von Willebrand factor, proendothelin, and endothelin) were measured just before dialysis and at 60, 180, and 240 minutes intradialysis. OUTCOMES: Hemodialysis-induced regional LV systolic function. Wall motion score was measured by echocardiography at 30 minutes predialysis, 60 and 180 minutes intradialysis, and 30 minutes postdialysis. We defined hemodialysis-induced regional LV systolic dysfunction as an increase in wall motion score in 2 or more segments. RESULTS: Patients with hemodialysis-induced regional LV systolic dysfunction (n=29 [27%]) had significantly higher predialysis high-sensitivity C-reactive protein, PTX3, IL-6, and lL-6:IL-10 ratio values. Predialysis levels of bioincompatibility and endothelial markers did not differ between groups. Intradialysis courses of markers of inflammation, bioincompatibility, and endothelial function did not differ in patients with versus without hemodialysis-induced regional LV systolic dysfunction. LIMITATIONS: Coronary angiography or computed tomography for quantification of coronary calcifications in our patients was not performed; therefore, we could not relate markers of inflammation to the extent of atherosclerosis. CONCLUSIONS: Patients with hemodialysis-induced regional LV systolic dysfunction have a proinflammatory cytokine profile. There was no indication of an association with an exaggerated bioincompatibility reaction to hemodialysis.

Dialysis hypotension: a role for inadequate increase in arginine vasopressin levels? A systematic literature review and meta-analysis.

BACKGROUND: Intradialytic hypotension is a common complication of hemodialysis (HD). Some studies have suggested that inadequate arginine vasopressin (AVP) increase could play a role in the pathogenesis of intradialytic hypotension. However, AVP levels during HD and its relation to hypotension has never been systematically studied. SUMMARY: PubMed and Embase were searched (1970-2013, search terms 'vasopressin' and 'hemodialysis') for studies reporting on AVP levels during standard HD or other dialysis techniques. Observational studies reporting on AVP levels pre- and postdialysis were additionally included in a meta-analysis. Thirty-seven studies were included in the systematic literature review, of which 26 studies were eligible for meta-analysis. The main findings were that pretreatment AVP levels were higher in dialysis patients compared with healthy controls (6.4 ± 3.5 vs. 2.5 ± 1.3 pg/ml, p = 0.003) and that plasma AVP levels showed little or no increase during HD (from 7.0 ± 4.9 to 8.8 ± 9.3, p = 0.433). Significant heterogeneity was found between studies. Meta-regression analysis revealed no significant associations between AVP and patient or study characteristics. Studies on other dialysis techniques showed mixed results regarding the AVP course. The eight studies that addressed the relation between intradialytic hypotension and AVP also showed inconsistent results. KEY MESSAGES: Plasma AVP levels are higher in dialysis patients compared with healthy controls, but show little or no increase during HD. The lack of a rise in AVP levels during HD may be pathophysiologically involved in the onset of intradialytic hypotension, but firm conclusions are not possible from our review of the literature.

Effect of nocturnal haemodialysis on body composition.

BACKGROUND: Haemodialysis patients have a high risk of malnutrition which is associated with increased mortality. Nocturnal haemodialysis (NHD) is associated with a significant increase in protein intake compared with conventional haemodialysis (CHD). It is unclear whether this leads to improved nutritional status. Therefore, we studied whether 1 year of NHD is associated with a change in body composition. METHODS: Whole-body composition using dual-energy X-ray absorptiometry (DEXA) and normalised protein catabolic rate (nPCR) were measured in 11 adult patients before and 1 year after the transition from CHD (12 h dialysis/week) to NHD (28-48 h dialysis/week). Similar measurements were performed in a matched control group of 13 patients who stayed on CHD. Differences between groups were analysed with linear mixed models. RESULTS: At baseline, nPCR, total mass, fat-free mass, and fat mass did not differ significantly between the CHD and NHD groups. nPCR increased in the NHD group (from 0.96 ± 0.23 to 1.12 ± 0.20 g/kg/day; p = 0.027) whereas it was stable in the CHD group (0.93 ± 0.21 at baseline and 0.87 ± 0.09 g/kg/day at 1 year, n.s.). The change in nPCR differed significantly between the two groups (p = 0.027). We observed no significant differences in the course of total mass, fat-free mass, and fat mass during the 1-year observation period between the NHD and CHD groups. CONCLUSIONS: One year of NHD had no significant effect on body composition in comparison with CHD, despite a significantly higher protein intake in patients on NHD.

Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

Association between sodium intake and change in uric acid, urine albumin excretion, and the risk of developing hypertension.

BACKGROUND: A high-sodium diet has little short-term effect on blood pressure in nonhypertensive individuals but, for unclear reasons, is associated with hypertension if consumed long term. We hypothesized that a chronically high sodium intake would be associated with increases in biomarkers of endothelial dysfunction, specifically serum uric acid (SUA) and urine albumin excretion (UAE), and that high sodium intake would be associated with incident hypertension among those with higher SUA and UAE. METHODS AND RESULTS: We prospectively analyzed the associations between sodium intake and the change in SUA (n=4062) and UAE (n=4146) among participants of the Prevention of Renal and Vascular End Stage Disease (PREVEND) study who were not taking antihypertensive medications. We also examined the association of sodium intake with the incidence of hypertension (n=5556) among nonhypertensive participants. After adjustment for confounders, each 1-g-higher sodium intake was associated with a 1.2-µmol/L increase in SUA (P=0.01) and a 4.6-mg/d increase in UAE (P<0.001). The relation between sodium intake and incident hypertension varied according to SUA and UAE. For each 1-g-higher sodium intake, the adjusted hazard ratio for developing hypertension was 0.98 (95% confidence interval, 0.89-1.08) among those in the lowest tertile of SUA and 1.09 (1.02-1.16) among those in the highest tertile. Corresponding hazard ratios were 0.99 (confidence interval, 0.93-1.06) among participants whose UAE was <10 mg/d and 1.18 (confidence interval, 1.07-1.29) among those whose UAE was >15 mg/d. CONCLUSIONS: Over time, higher sodium intake is associated with increases in SUA and UAE. Among individuals with higher SUA and urine UAE, a higher sodium intake is an independent risk factor for developing hypertension.

Change in the estimated glomerular filtration rate over time and risk of all-cause mortality.

Using a community-based cohort we studied the association between changes in the estimated glomerular filtration rate (eGFR) over time and the risk of all-cause mortality. We identified 529,312 adults who had at least three outpatient eGFR measurements over a 4-year period from a provincial laboratory repository in Alberta, Canada. Two indices of change in eGFR were evaluated: the absolute annual rate of change (in ml/min per 1.73 m(2) per year) and the annual percentage change (percent/year). The adjusted mortality risk associated with each category of change in eGFR was assessed, using stable eGFR (no change) as the reference. Over a median follow-up of 2.5 years there were 32,372 deaths. Compared to the reference participants, those with the greatest absolute annual decline less than or equal to 5 ml/min per 1.73 m(2) per year had significantly increased mortality (hazard ratio of 1.52) adjusted for covariates and kidney function at baseline (last eGFR measurement). Participants with the greatest increase in eGFR of 5 ml/min per 1.73 m(2) per year or more also had significantly increased mortality (adjusted hazard ratio of 2.20). A similar pattern was found when change in eGFR was quantified as an annual percentage change. Thus, both declining and increasing eGFR were independently associated with mortality and underscore the importance of identifying change in eGFR over time to improve mortality risk prediction.

Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease.

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: <30 ml/min per 1.73 m(2). Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30 mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR ((125)I-iothalamate clearance) was found that reached significance in groups A and B: -7.8 (interquartile range -13.7 to -1.3) and -4.3 (-9.7 to -0.9) ml/min per 1.73 m(2), respectively, but not in group C (GFR decrease -0.7 (-1.1 to 1.5) ml/min/1.73 m(2)). The percentage change in GFR, ERPF ((131)I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.

BACKGROUND: Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease. However, whether the association of the kidney disease measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status is unknown. METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and ESRD associated with eGFR and albuminuria in individuals with and without hypertension. FINDINGS: We analysed data for 45 cohorts (25 general population, seven high-risk, and 13 chronic kidney disease) with 1,127,656 participants, 364,344 of whom had hypertension. Low eGFR and high albuminuria were associated with mortality irrespective of hypertensive status in the general population and high-risk cohorts. All-cause mortality risk was 1·1-1·2 times higher in individuals with hypertension than in those without hypertension at preserved eGFR. A steeper relative risk gradient in individuals without hypertension than in those with hypertension at eGFR range 45-75 mL/min per 1·73 m(2) led to much the same mortality risk at lower eGFR. With a reference eGFR of 95 mL/min per 1·73 m(2) in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) was 1·77 (95% CI 1·57-1·99) in individuals without hypertension versus 1·24 (1·11-1·39) in those with hypertension (p for overall interaction=0·0003). Similarly, for albumin-creatinine ratio of 300 mg/g (vs 5 mg/g), HR was 2·30 (1·98-2·68) in individuals without hypertension versus 2·08 (1·84-2·35) in those with hypertension (p for overall interaction=0·019). We recorded much the same results for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results for chronic kidney disease cohorts were similar to those for general and high-risk population cohorts. INTERPRETATION: Chronic kidney disease should be regarded as at least an equally relevant risk factor for mortality and ESRD in individuals without hypertension as it is in those with hypertension. FUNDING: US National Kidney Foundation.

Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.

BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown. METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes. FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts. INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes. FUNDING: US National Kidney Foundation.

Tubular secretion of creatinine in autosomal dominant polycystic kidney disease: consequences for cross-sectional and longitudinal performance of kidney function estimating equations.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal tubular cell proliferation and dedifferentiation, which may influence tubular secretion of creatinine (CCr[TS]). STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: We therefore investigated CCr(TS) in patients with ADPKD and controls and studied consequences for the performance of glomerular filtration rate (GFR) estimating equations. INDEX & REFERENCE TESTS: In patients with ADPKD and healthy controls, we measured GFR as (125)I-iothalamate clearance while simultaneously determining creatinine clearance. OTHER MEASUREMENTS: 24-hour urinary albumin excretion. RESULTS: In 121 patients with ADPKD (56% men; mean age, 40 ± 11 [SD] years) and 215 controls (48% men; mean age, 53 ± 10 years), measured GFR (mGFR) was 78 ± 30 and 98 ± 17 mL/min/1.73 m(2), respectively, and CCr(TS) was 15.9 ± 10.8 and 10.9 ± 10.6 mL/min/1.73 m(2), respectively (P < 0.001). The higher CCr(TS) in patients with ADPKD remained significant after adjustment for covariates and appeared to be dependent on mGFR. Correlation and accuracy between mGFR and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) estimated GFR (eGFR) were 0.95 and 99%, respectively; between mGFR and MDRD (Modification of Diet in Renal Disease) Study eGFR, they were 0.93 and 97%, respectively. Values for bias, precision, and accuracy were similar or slightly better than in controls. In addition, change in mGFR during 3 years of follow-up in 45 patients with ADPKD correlated well with change in eGFR. LIMITATIONS: Cross-sectional, single center. CONCLUSIONS: CCr(TS) in patients with ADPKD is higher than that in controls, but this effect is limited and observed at only high-normal mGFR. Consequently, the CKD-EPI and MDRD Study equations perform relatively well in estimating GFR and change in GFR in patients with ADPKD.

Changes in left ventricular diastolic function during hemodialysis sessions.

BACKGROUND: Left ventricular diastolic dysfunction is common in hemodialysis patients and is associated with worse outcome. Previous studies have shown that diastolic function worsens from pre- to post-dialysis session, but this has not been studied during hemodialysis. We studied the evolution of diastolic function parameters early and late during hemodialysis. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 109 hemodialysis patients on a thrice-weekly dialysis schedule with a mean age of 62.5 ± 15.6 (SD) years were studied between March 2009 and March 2010. PREDICTOR: Hemodialysis with constant ultrafiltration rate and dialysate conductivity. OUTCOMES: Changes in diastolic function parameters. MEASUREMENTS: Mitral early inflow (E) and tissue Doppler early diastolic velocity (mean e') were evaluated by echocardiography predialysis, at 60 and 180 minutes intradialysis, and postdialysis. Relative blood volume changes were calculated from changes in hematocrit. RESULTS: Predialysis E and mean e' were 0.93 ± 0.24 m/s and 6.6 ± 2.1 cm/s, respectively. E and mean e' values decreased significantly during hemodialysis (P < 0.001). The steepest change occurred at 60 minutes intradialysis (E, -21.4% ± 17.6% and -30.5% ± 19.2% at 60 and 180 minutes, respectively; mean e', -16.0% ± 18.6% and -19.5% ± 21.8% at 60 and 180 minutes, respectively). At 60 minutes intradialysis, changes in relative blood volume and brain natriuretic peptide level were associated significantly with the change in E but not with the change in mean e'. LIMITATIONS: Changes in relative blood volume may not fully reflect central blood volume changes and do not capture the effect of blood loss to the extracorporal circuit. Left atrial volume was not measured. CONCLUSIONS: Left ventricular diastolic function worsens early during a hemodialysis session. The decrease in mean e' at 60 minutes intradialysis was unrelated to changes in relative blood volume. Although this finding does not exclude a role of hypovolemia because of the limitations of the measurement of relative blood volume, it raises the possibility that non-volume-related mechanisms are involved in the early decrease in mean e' during hemodialysis.

Variability of predialytic, intradialytic, and postdialytic blood pressures in the course of a week: a study of Dutch and US maintenance hemodialysis patients.

BACKGROUND: Patients with thrice-weekly hemodialysis have higher predialysis weights and ultrafiltration rates at the first compared with subsequent dialysis sessions of the week. We hypothesized that these variations in weight and ultrafiltration rate are associated with a systematic difference in blood pressure. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: During 3 months, we prospectively collected hemodynamic data for 4,007 hemodialysis sessions involving 124 Dutch patients. A similar analysis was performed with 789 US patients, comprising 6,060 hemodialysis sessions. FACTOR: First versus subsequent hemodialysis sessions of the week. OUTCOMES: Blood pressure. MEASUREMENTS: Blood pressure, weight, and ultrafiltration rate were analyzed separately for the first, second, and third dialysis sessions of the week. Comparisons were made with linear mixed models. RESULTS: In Dutch patients, predialysis weight and ultrafiltration rate were significantly greater at the first compared with subsequent hemodialysis sessions of the week (P < 0.001). Predialysis systolic and diastolic blood pressures were higher at the first than at subsequent sessions of the week (P < 0.001). Predialysis blood pressure differences persisted throughout the session: systolic and diastolic blood pressures were on average 5.0 and 2.5 mm Hg higher during the first compared to the third session of the week. Postdialysis blood pressures followed a similar pattern (P < 0.001). Blood pressure differences between the first and subsequent days of the week persisted after adjustment for possible confounders. Results in the US cohort were materially identical despite differences in patient characteristics and treatment practice between the 2 cohorts. LIMITATIONS: Dry weight was not assessed by objective methods. CONCLUSIONS: Blood pressure of patients on a thrice-weekly dialysis schedule varies systematically over the week. Predialysis blood pressure is highest at the first hemodialysis session of the week, most likely due to greater interdialytic weight gain. Intra- and postdialytic blood pressures also are highest at the first session of the week despite higher ultrafiltration rates.

Screening for albuminuria with subsequent screening for hypertension and hypercholesterolaemia identifies subjects in whom treatment is warranted to prevent cardiovascular events.

BACKGROUND: In the general population, many subjects have yet unrecognized hypertension and hypercholesterolaemia, and are thus not treated. We investigated whether population screening for elevated albuminuria can identify subjects with previously unrecognized hypertension and/or hypercholesterolaemia at high risk for cardiovascular (CV) disease. METHODS: Included were 8143 subjects (28-75 years) that participate in the PREVEND study, a general population-based, observational cohort study. Elevated albuminuria was defined as an albumin concentration ≥ 20 mg/L in a first morning urine sample confirmed by an albumin excretion ≥ 30 mg/day in two 24-h urine samples. Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, and hypercholesterolaemia as serum total cholesterol ≥ 6.2 mmol/L, or as HDL cholesterol < 0.9 mmol/L and a total/HDL cholesterol ratio of ≥ 6. Combined CV morbidity and mortality during follow-up was adopted as outcome. RESULTS: In the group with, as well as in the group without elevated albuminuria, the number of subjects with yet unrecognized hypertension and hypercholesterolaemia was at least 2-fold higher than the number of subjects known with these CV risk factors. Mean follow-up was 7.1 ± 1.5 years, during which 445 CV events occurred. The hazard ratio for CV events was significantly elevated in the subjects with, compared with those without elevated albuminuria, independent of whether they had no CV risk factor present, a CV risk factor known or a CV risk factor newly discovered. The CV event rate in those with an elevated albuminuria crossed the recommended threshold to start antihypertensive or anticholesterolaemic treatment, not only when the CV risk factor was known, but also in the subgroup with newly diagnosed CV risk factor. In subjects with a newly discovered CV risk factor without albuminuria, absolute CV risk was significantly lower. CONCLUSIONS: Screening for elevated albuminuria and subsequent screening for CV risk factors identify subjects with yet unknown CV risk factors at high risk for CV disease that are likely to benefit from early preventive treatment.

Isolated microalbuminuria indicates a poor medical prognosis.

BACKGROUND: Microalbuminuria is often regarded as a sign of end-organ damage due to diabetes and/or hypertension, and as such to be associated with an increased risk for cardiovascular events. It has been questioned whether isolated microalbuminuria, that is microalbuminuria in the absence of a cardiovascular disease (CVD) history, hypertension and diabetes has clinical relevance. METHODS: Included were 8356 subjects who participated in the first four screening rounds of the PREVEND study, a prospective, community-based, observational cohort study. Isolated microalbuminuria was defined as microalbuminuria (30-300 mg/24 h), in the absence of a CVD history, hypertension (blood pressure<140/90 mmHg, not using blood pressure-lowering drugs) and diabetes (fasting glucose<7.0 mmol/L, not using glucose-lowering drugs). RESULTS: Three hundred subjects met the definition of isolated microalbuminuria, in which 2250 person-years of follow-up were available. In subjects with isolated microalbuminuria, the incidence rates of cardiovascular events and mortality, hypertension and diabetes were 15.3, 28.9 and 8.9 per 1000 person-year follow-up, respectively. Subjects with isolated microalbuminuria had an increased risk for cardiovascular events and mortality [crude HR 2.23 (1.63-3.07); P<0.001], hypertension [OR 1.95 (1.47-2.59); P<0.001] and diabetes [OR 4.69 (2.92-7.51); P<0.001] compared with subjects without microalbuminuria, CVD history, hypertension and/or diabetes. This increased risk remained significant after adjustment for age and gender. The relative risk held by isolated microalbuminuria was similar to the relative risk held by microalbuminuria in subjects that did have a CVD history, hypertension and/or diabetes. CONCLUSIONS: Isolated microalbuminuria indicates a poor prognosis and warrants medical attention.

High-sensitive troponin T and N-terminal pro-B type natriuretic peptide are associated with cardiovascular events despite the cross-sectional association with albuminuria and glomerular filtration rate.

AIMS: It has been suggested that troponins and natriuretic peptides can be falsely elevated in subjects with impaired kidney function because of decreased renal clearance. The value of these biomarkers in subjects with impaired kidney function has therefore been debated. We tested in a population-based cohort study, first, whether high-sensitive troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels are cross-sectionally associated with the estimated glomerular filtration rate (eGFR) and albuminuria, and secondly, whether these markers are associated with cardiovascular outcome, independent of eGFR, albuminuria and conventional cardiovascular risk factors. METHODS AND RESULTS: We included 8121 subjects from the PREVEND study with both values of hsTnT and NT-pro-BNP available. High-sensitive troponin T >0.01 µg/L and NT-pro-BNP >125 ng/L were defined as elevated. We first performed linear regression analyses with hsTnT and NT-pro-BNP as dependent variables. Next, we performed Cox-regression analyses, studying the associations of hsTnT and NT-pro-BNP with incident cardiovascular events. Of our cohort, 6.7% had an elevated hsTnT and 12.2% an elevated NT-pro-BNP. Also, the estimated glomerular filtration rate, albuminuria, and ECG-assessed ischaemia and left ventricular hypertrophy were all significantly associated with hsTnT and NT-pro-BNP in the linear regression analyses. Both hsTnT and NT-pro-BNP appeared associated with cardiovascular events, and these associations remained significant after adjustment for eGFR, albuminuria, age, gender and conventional cardiovascular risk factors (P= 0.03 and P< 0.001, respectively). Only a few subjects with markedly reduced renal function were included. The results presented are therefore mainly valid for a population with mildly impaired renal function. CONCLUSION: These data indicate that a finding of an increased hsTnT or NT-pro-BNP in subjects with chronic kidney disease stages 1/3 should be taken seriously as a prognostic marker for a worse cardiovascular outcome and not be discarded as merely a reflection of decreased renal clearance.

Comparison of midregional pro-A-type natriuretic peptide and the N-terminal pro-B-type natriuretic peptide for predicting mortality and cardiovascular events.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) provides prognostic information on mortality and future cardiovascular events for individuals from the general population. A novel immunoassay was recently developed that measures a midregional fragment of pro-A-type natriuretic peptide (MR-proANP). We compared the capabilities of MR-proANP and NT-proBNP for predicting mortality and cardiovascular events in a population-based study. METHODS: A total of 7819 patients participated in the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective observational study. Three clinical end points were studied: all-cause mortality, cardiovascular mortality, and cardiovascular events. After a median follow-up of 10.5 years, we used a Cox proportional hazards model to investigate the relationship between the 2 natriuretic peptides and the clinical end points. The Harrell C statistic and the integrated discrimination improvement (IDI) were used to compare MR-proANP and NT-proBNP. RESULTS: Increased plasma concentrations of both natriuretic peptides were associated with an increased risk of all-cause mortality and cardiovascular events, after adjustment for age, sex, and other cardiovascular risk factors. According to the Harrell C statistic analysis, the models with MR-proANP and NT-proBNP were comparable in predicting all-cause mortality, cardiovascular mortality, and cardiovascular events. In contrast to NT-proBNP, MR-proANP was not independently related to cardiovascular mortality. In all models, the IDI was higher for NT-proBNP than for MR-proANP. CONCLUSIONS: MR-proANP was as efficient as NT-proBNP in predicting all-cause mortality, cardiovascular mortality, and cardiovascular events; however, its association with cardiovascular mortality was not independent from other confounders.