Dinanda J. de Jager

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.

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 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.

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.

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.

Senescence rates in patients with end‐stage renal disease: a critical appraisal of the Gompertz model

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end‐stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age‐specific mortality rates for European patients on dialysis (n = 274 221; follow‐up = 594 767 person‐years), for European patients with a functioning kidney transplant (n = 61 286; follow‐up = 345 024 person‐years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P < 0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.

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.

BackgroundTo 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.MethodsIn 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.ResultsA 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.ConclusionsIn 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.

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.

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.