Lipid levels and renal function decline in pre-dialysis patients.

BACKGROUND: Little is known about the effect of low-density lipoprotein (LDL) cholesterol, triglyceride (TG), and high-density lipoprotein (HDL) cholesterol levels on renal function decline in patients receiving specialized pre-dialysis care. METHODS: In the prospective PREPARE-2 study, incident patients starting pre-dialysis care were included when referred to one of the 25 participating Dutch specialized pre-dialysis outpatient clinics (2004-2011). Clinical and laboratory data were collected every 6 months. A linear mixed model was used to compare renal function decline between patients with LDL cholesterol, TG, or HDL cholesterol levels above and below the target goals (LDL cholesterol: <2.50 mmol/l, TG: <2.25 mmol/l, and HDL cholesterol: ≥1.00 mmol/l). Additionally the HDL/LDL cholesterol ratio was investigated (≥0.4). RESULTS: In our study population (n = 306), the median age was 69 years and 70% were male. Patients with LDL cholesterol levels above the target of 2.50 mmol/l experienced an accelerated renal function decline compared to patients with levels below the target (crude additional decline: 0.10 ml/min/1.73 m(2)/month, 95% CI 0.00-0.20; p < 0.05). A similar trend was found for TG levels above the target of 2.25 mmol/l (0.05 ml/min/1.73 m(2)/month, 95% CI -0.06 to 0.16) and for a HDL/LDL cholesterol ratio below 0.4 (0.06 ml/min/1.73 m(2)/month, 95% CI -0.05 to 0.18). Adjustment for potential confounders resulted in similar results, and the exclusion of patients who were prescribed lipid-lowering medication (statin, fibrate, or cholesterol absorption inhibitor) resulted in a slightly larger estimated effect. CONCLUSION: High levels of LDL cholesterol were associated with an accelerated renal function decline, independent of the prescription of lipid-lowering medication.

Noncardiovascular mortality in CKD: an epidemiological perspective.

Patients with chronic kidney disease (CKD) have increased risk of all-cause mortality; the elevated cardiovascular mortality in patients with end-stage renal disease is particularly well documented. Lately, the increased noncardiovascular mortality in these patients has gained particular attention. In this article, both cardiovascular and noncardiovascular mortality in CKD are discussed, with specific attention paid to studies that provide details of noncardiovascular causes of death. Examples are provided of several cardiovascular risk factors that also seem to be associated with noncardiovascular mortality, including levels of fetuin-A, troponin T, and C-reactive protein, as well as vitamin D deficiency and proteinuria. Potential pathophysiological mechanisms (such as inflammatory reactions and the uraemic milieu) that might explain the increased cardiovascular and noncardiovascular mortality in CKD are also discussed. Future research should not only focus on preventing cardiovascular mortality, but also on studying noncardiovascular mortality and the potential link between causal pathways of cardiovascular mortality and noncardiovascular mortality in CKD.

Is the decline of renal function different before and after the start of dialysis?

BACKGROUND: The presence of glomerular filtration in dialysis patients is associated with improved survival and quality of life. This study explores the time course of the glomerular filtration rate (GFR) between 1 year before and 1 year after the start of haemodialysis (HD) and peritoneal dialysis (PD). METHODS: This study included 1861 incident dialysis patients (NECOSAD cohort; 62% male, 60 ± 15 years, 61% HD, GFR 5.2 ± 3.6 mL/min/1.73 m(2)). A decline of the GFR was estimated using linear mixed-effects models adjusted for age, sex, primary kidney disease, cardiovascular disease and diabetes. The rate of decline was allowed to change at a certain point in time. RESULTS: The decline of the GFR attenuated from -0.53 mL/min/1.73 m(2)/month (95% CI: -0.58, -0.48) in the period before the start of dialysis to -0.12 (95% CI: -0.20, -0.04) at 2-4 months of dialysis in all patients. In HD, decline attenuated from -0.51 (95% CI: -0.57, -0.44) to -0.14 (95% CI: -0.26, -0.02); in PD from -0.55 (95% CI: -0.62, -0.48) to -0.11 (95% CI: -0.23, 0.01). In patients who started dialysis with a GFR equal/above median GFR at dialysis start, the decline attenuated (at 3 months) from -0.70 (95% CI: -0.78; -0.62) to -0.21 (95% CI: -0.36; -0.05). In patients who started dialysis with a GFR below median GFR at dialysis start, the decline attenuated (at 1 month) from -0.73 (95% CI: -0.88; -0.58) to -0.04 (95% CI: -0.27 , 0.19). CONCLUSIONS: The apparent decline of the GFR slows down after 2-4 months of dialysis. This decline was similar in HD and PD patients, although at a different level of GFR. Further studies are needed to examine explanations for this phenomenon.

Proteinuria as a risk marker for the progression of chronic kidney disease in patients on predialysis care and the role of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment.

BACKGROUND/AIMS: Proteinuria is a risk marker for progression of chronic kidney disease (CKD) and treatment with an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEi/ARB) is beneficial in these patients. However, little is known about proteinuria and ACEi/ARB treatment in patients on specialized predialysis care. Therefore, we investigated the association of urinary protein excretion (UPE) and ACEi/ARB treatment with renal function decline (RFD) and/or the start of renal replacement therapy (RRT) in patients on predialysis care. METHODS: In the PREPARE-1 cohort, 547 incident predialysis patients (CKD stages IV-V), referred as part of the usual care to outpatient clinics of eight Dutch hospitals, were included (1999-2001) and followed until the start of RRT, mortality, or January 1, 2008. The main outcomes were rate of RFD, estimated as the slope of available eGFR measurements, and the start of RRT. RESULTS: Patients with mild proteinuria (>0.3 to ≤1.0 g/24 h) had an adjusted additional RFD of 0.35 ml/min/1.73 m(2)/month (95% CI: 0.01; 0.68) and a higher rate of starting RRT [adjusted HR: 1.70 (1.05; 2.77)] compared with patients without proteinuria (≤0.3 g/24 h). With every consecutive UPE category (>1.0 to ≤3.0, >3.0 to ≤6.0, and >6.0 g/24 h), RFD accelerated and the start of RRT was earlier. Furthermore, patients starting (n = 16) or continuing (n = 133) treatment with ACEi/ARBs during predialysis care had a lower rate of starting RRT compared with patients not using treatment [n = 152, adjusted HR: 0.56 (0.29; 1.08) and 0.90 (0.68; 1.20), respectively]. CONCLUSION: In patients on predialysis care, we confirmed that proteinuria is a risk marker for the progression of CKD. Furthermore, no evidence was present that the use of ACEi/ARBs is deleterious.

Association of blood pressure with the start of renal replacement therapy in elderly compared with young patients receiving predialysis care.

BACKGROUND: In the growing elderly predialysis population, little is known about the effect of identified risk factors on the progression to end-stage renal disease. Therefore, we investigated the association of systolic (SBP) and diastolic blood pressure (DBP) with the start of renal replacement therapy (RRT), in elderly (≥65 years) compared with young (<65 years) predialysis patients. METHODS: In the PREPARE-1 cohort, 547 incident predialysis patients, referred as part of the usual care to eight Dutch predialysis care outpatient clinics, were included (1999-2001) and followed until the start of dialysis, transplantation, death, or until 1 January 2008. The outcome was the start of RRT. All analyses were stratified for age; <65 years (young) and ≥65 years (elderly). RESULTS: In young predialysis patients (n = 268) higher SBP (every 20 mm Hg increase) and high DBP (DBP ≥100 mm Hg compared with 80-89 mm Hg) were associated with a higher rate of starting RRT (adjusted hazard ratio (HR) (95% confidence interval) 1.21 (1.09;1.34) and 1.74 (1.16;2.62), respectively). However, in elderly predialysis patients (n = 240) only patients with SBP ≥180 mm Hg had an increased rate compared with patients with 140-159 mm Hg (adjusted HR 2.33 (1.41;3.87)). Furthermore, patients with DBP <70 or ≥100 mm Hg had an increased rate of starting RRT, independent of SBP, compared with patients with 80-89 mm Hg (fully adjusted HR 1.72 (1.01;2.94) and 2.05 (1.13;3.73), respectively). CONCLUSIONS: The association of SBP and DBP with the start of RRT is different between elderly and young predialysis patients.

Association of blood pressure with decline in renal function and time until the start of renal replacement therapy in pre-dialysis patients: a cohort study.

BACKGROUND: To investigate whether high blood pressure accelerates renal function decline in patients with advanced chronic kidney disease (CKD), we studied the association of systolic (SBP) and diastolic blood pressure (DBP) with decline in renal function and time until the start of renal replacement therapy (RRT) in patients with CKD stages IV-V on pre-dialysis care. METHODS: In the PREPARE-1 cohort 547 incident pre-dialysis patients, referred as part of the usual care to outpatient clinics of eight Dutch hospitals, were included between 1999 and 2001 and followed until the start of RRT, mortality, or end of follow-up (January 1st 2008). Main outcomes were rate of decline in renal function, estimated as the slope of available eGFR measurements, and time until the start of RRT. RESULTS: A total of 508 patients, 57% men and median (IQR) age of 63 (50-73) years, were available for analyses. Mean (SD) decline in renal function was 0.35 (0.75) ml/min/1.73 m2/month. Every 10 mmHg increase in SBP or DBP resulted in an accelerated decline in renal function (adjusted additional decline 0.04 (0.02;0.07) and 0.05 (0.00;0.11) ml/min/1.73 m2/month respectively) and an earlier start of RRT (adjusted HR 1.09 (1.04;1.14) and 1.16 (1.05;1.28) respectively). Furthermore, patients with SBP and DBP above the BP target goal of < 130/80 mmHg experienced a faster decline in renal function (adjusted additional decline 0.31 (0.08;0.53) ml/min/1.73 m2/month) and an earlier start of RRT (adjusted HR 2.08 (1.25;3.44)), compared to patients who achieved the target goal (11%). Comparing the decline in renal function and risk of starting RRT between patients with only SBP above the target (≥ 130 mmHg) and patients with both SBP and DBP below the target (< 130/80 mmHg), showed that the results were almost similar as compared to patients with both SBP and DBP above the target (adjusted additional decline 0.31 (0.04;0.58) ml/min/1.73 m2/month and adjusted HR 2.24 (1.26;3.97)). Therefore, it seems that especially having SBP above the target is harmful. CONCLUSIONS: In pre-dialysis patients with CKD stages IV-V, having blood pressure (especially SBP) above the target goal for CKD patients (< 130/80 mmHg) was associated with a faster decline in renal function and a later start of RRT.

Cardiovascular and noncardiovascular mortality among men and women starting dialysis.

BACKGROUND AND OBJECTIVES: Although women have a survival advantage in the general population, women on dialysis have similar mortality to men. We hypothesized that this paired mortality risk during dialysis may be explained by a relative excess of cardiovascular-related mortality in women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared 5-year age-stratified cardiovascular and noncardiovascular mortality rates, relative risks, and hazard ratios in a European cohort of incident adult dialysis patients (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry) with the European general population (Eurostat). Cause of death was recorded by ERA-EDTA codes in dialysis patients and by International Statistical Classification of Diseases codes in the general population. RESULTS: Overall, sex did not have a predictive effect on outcome in dialysis. Stratification into age categories and causes of death showed greater noncardiovascular mortality in young women (<45 years). In other age categories (45 to 55 and >55 years), women presented lower cardiovascular mortality. This cardiovascular benefit was, however, smaller than in the general population. Stratification by diabetic nephropathy showed that diabetic women in all age categories remained at increased mortality risk compared with men, an effect mainly attributed to the noncardiovascular component. CONCLUSIONS: Mortality rates and causes of death in men and women on dialysis vary with age. Increased noncardiovascular mortality may explain the loss of the survival advantage of women on dialysis. Both young and diabetic women starting dialysis are at a higher mortality risk than equal men.

Interaction on an additive scale.

Many clinical epidemiological studies investigate whether a certain exposure, or risk factor, is associated with the incidence of disease or mortality. It may be of interest to study whether this association is different in different types of patients, or to study joint effects. To investigate whether the effect of one risk factor differs across the strata of another risk factor, the presence of interaction among two risk factors can be examined. In statistics, interaction refers to the inclusion of a product term of two risk factors in a statistical model. Statistical interaction thereby evaluates whether the association deviates from either additivity or multiplicativity, depending on the scale of the model. From a public health perspective, the assessment of interaction on an additive scale may be most relevant. For a transparent presentation of interaction effects, it is recommended to report the separate effect of each exposure as well as the joint effect compared to the unexposed group as a joint reference category to permit evaluation of interaction on both an additive and multiplicative scale.

Reporting of interaction.

Interaction is the situation whereby the association of one risk factor with a certain outcome variable differs across strata of another risk factor. From a public health perspective, the assessment of interaction on an additive scale may be most relevant. Although additive models exist, logistic and Cox regression models are the most commonly used models in epidemiology. The resulting relative risks can be translated to an additive scale. The present paper presents surrogate measures to evaluate the presence of additive interaction when dealing with data on a multiplicative scale (relative risks). For a transparent presentation of interaction effects it is recommended to report the separate effect of each exposure as well as their joint effect compared to the unexposed group as joint reference category to permit evaluation of interaction on both an additive and multiplicative scale.

Association between time of referral and survival in the first year of dialysis in diabetics and the elderly.

OBJECTIVE: The objective of the study was to estimate the association between time of referral and survival during dialysis in diabetics and patients aged≥70 years. DESIGN, SETTING AND SUBJECTS: This study was a prospective follow-up study in 1438 incident dialysis patients (1996-2004, 62% male, 60±15 years) in The Netherlands. Main outcome measures. Referral (time between first pre-dialysis visit to a nephrologist and dialysis initiation) was classified as: late (<3 months), early (3-12 months) or very early (≥12 months). All-cause mortality risk within the first year of dialysis was calculated [HR (95% confidence interval, CI), adjusted for age, sex and primary kidney disease (PKD)]. Additive interaction between time of referral and diabetes mellitus (adjusted for age and sex) or age (adjusted for sex and PKD) was assessed by synergy index [S (95% CI)]. RESULTS: Thirty-two percent were late referred, 12% early and 56% very early; 21% had diabetes; and 30% were ≥70 years. Early and late referrals were associated with increased mortality compared with very early referral [HRadjearly: 1.5 (1.0, 2.4), late: 1.8 (1.3, 2.5)]. A similar trend was observed in diabetics and non-diabetics. However, no interaction between time of referral and diabetes was present [Slate 0.8 (0.4, 1.9), Searly 1.2 (0.4, 3.6)]. Likewise, in patients aged<70 and ≥70 years, time of referral was associated with increased mortality, without interaction [Slate 0.9 (0.4, 1.8), Searly 0.8 (0.3, 2.0)]. CONCLUSION: Late referral is associated with increased mortality in the first year of dialysis. Diabetes or high age does not have an additional worsening effect, implying that timely referral is important in future dialysis patients irrespective of diabetes or high age.

Benefit of kidney transplantation beyond 70 years of age.

BACKGROUND: Kidney transplantation generally improves long-term survival in patients with end-stage renal disease. However, in patients older than 70 years of age, only limited data are available that directly compare the potential survival benefit of transplantation versus dialysis. METHODS: All patients aged above 70 years who started dialysis between 1990 and 2005 and were waitlisted for kidney transplantation were included in the study. They were categorized according to time periods of inclusion (1990-99 vs 2000-05). Survival rates of altogether 286 dialysis patients were analyzed with a Kaplan-Meier model, as well as with a time-dependent Cox model. Comparisons were made between those who received a transplant and those who did not, and further between the two time periods. RESULTS: Median age at inclusion was 73.6 years (interquartile range 72.3-75.6). Two hundred and thirty-three patients (81%) received a kidney transplant during follow-up. Transplant recipients experienced an increased mortality in the first year after transplantation when compared to waitlisted patients. Patients starting dialysis between 1990 and 1999 had no significant long-term benefit of transplantation; HR for death 1.01 (0.58-1.75). In contrast, there was a substantial long-term benefit of transplantation among those starting dialysis after 2000; HR for death 0.40 (0.19-0.83), P = 0.014. CONCLUSIONS: Survival after kidney transplantation in patients over 70 years has improved during the last decade and offers a survival advantage over dialysis treatment. Our experience supports the use of kidney transplantation in this age group if an increased early post-operative risk is accepted. This transplant policy may be challenged for priority reasons.

Cardiovascular and noncardiovascular mortality among patients starting dialysis.

CONTEXT: Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE: To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS: Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES: Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS: Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCLUSION: Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.

Excellent agreement between C-reactive protein measurement methods in end-stage renal disease patients--no additional power for mortality prediction with high-sensitivity CRP.

BACKGROUND: The conventional method for C-reactive protein (CRP) measurement is an immunoturbidimetric assay (imCRP, detection limit > or =3 mg/l). However, high-sensitivity CRP (hsCRP, detection limit >0.1 mg/l) has been advocated as preferable biomarker for cardiovascular risk assessment. The aim of this study was to determine agreement between imCRP and hsCRP in end-stage renal disease (ESRD) patients, and to examine whether the association between CRP and mortality is comparable when using imCRP or hsCRP. METHODS: Patients from a prospective follow-up study among incident ESRD patients (NECOSAD) with serum CRP available at 3 months of follow-up were included [n = 840, 60% male, mean (SD) age 59 (15) years]. Agreement between imCRP and hsCRP was determined by intraclass correlation coefficient (ICC) and by Cohen's kappa (kappa) for CRP dichotomized to the presence (CRP >10 mg/l) or absence of systemic inflammation. The association between CRP and mortality was determined by Cox regression analysis and c-statistic. RESULTS: ICC between imCRP and hsCRP was 0.78, which improved to 0.86 after correction for systematic differences between measurement methods. Systemic inflammation was present in 28.2% and absent in 67.6% of patients according to both methods (discordant in 4.2%), resulting in good agreement between the two methods (kappa = 0.90). Patients with systemic inflammation had a significantly increased mortality risk compared with patients without systemic inflammation [HR(im,adj) = 1.49 (95%CI 1.14-1.93) and HR(hs,adj) = 1.53 (1.18-2.0)]. Predictive capacity of mortality was similar for both CRP methods [c-statistic(adj) 0.83 (0.79-0.86)]. CONCLUSION: The agreement between imCRP and hsCRP in patients with ESRD is very good. Furthermore, the association between CRP and mortality in ESRD patients is similar when using imCRP and hsCRP. These data suggest that there is no need to use a high-sensitivity method for the determination of inflammatory status in ESRD patients.