Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in ...epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.
In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.
Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 80% with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (p
<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.
Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.
US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.
Until recently, most attention given to patients with macroalbuminuria has focused on their worse renal prognosis, while in contrast, patients with microalbuminuria were mostly considered to be at ...increased cardiovascular risk. In recent years, however, evidence has been accumulating that this distinction between the 2 -- either large or small quantities of albumin in the urine -- is not that clear. On the one hand, various studies have reported that macroalbuminuria also bears an increased cardiovascular risk. Interestingly, the extent to which albumin loss can be reduced in patients with macroalbuminuria is associated not only with a better renal prognosis, but also similarly with a better cardiovascular prognosis. On the other hand, patients with microalbuminuria not only have an impaired cardiovascular, but also an impaired renal, prognosis. These latter findings in microalbuminuria are especially of importance for the renal community, as screening for albuminuria is not carried out systematically even in patients with increased risk for microalbuminuria, such as those with diabetes and those with essential hypertension. When promoting routine screening for albuminuria, one should realize, moreover, that such projects will most likely be much more cost-effective when directed to preventing not only renal end points, but also CV end points.
Insulin resistance is considered to play an important role in the development of cardiovascular disease, which limits long-term renal transplant survival. Renal transplant recipients are more ...insulin-resistant compared with healthy controls. It is not known to date which factors relate to this excess insulin resistance. Therefore, we investigated which factors are related to insulin resistance long-term after renal transplantation.
All renal transplant recipients at our outpatient clinic with a functioning graft for more than one year were invited to participate. We excluded diabetic recipients. Recipient, donor, and transplant characteristics were collected as putative determinants. We used fasting insulin, homeostasis model assessment index, and McAuley's index as valid estimates of insulin resistance. Linear regression models were created to investigate independent determinants of all indexes.
A total of 483 recipients (57% male, 50+/-12 years) were analyzed at a median (interquartile range) time of 6.0 (2.6-11.6) years posttransplant. The most consistent determinants across all three indices were body mass index (P<0.001), waist-to-hip ratio (P<0.001), and prednisolone dose (P<0.05). Independent associations were present for total cholesterol (P<0.001), high-density lipoprotein cholesterol (P<0.001), creatinine clearance (P<0.05), recipient age (P<0.001), and gender (P< or =0.002). No independent associations were present for transplant-related factors such as acute rejection treatment or cytomegalovirus seropositivity.
Our results indicate that obesity, distribution of obesity, and prednisolone treatment are the predominant determinants of insulin resistance long term after transplantation. Insulin resistance after renal transplantation could be managed favorably by weight and prednisolone dose reduction, which may reduce cardiovascular disease.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Albuminuria has been proven to be associated with cardiovascular morbidity and mortality.
• Such an association has been found not only in subjects with ...diabetes and hypertension, but also in the general population.
• It could therefore be expected that especially subjects with higher albuminuria levels may benefit from blood pressure‐lowering agents to improve their cardiovascular outcome.
WHAT THIS STUDY ADDS
• This study indicates that the efficacy of blood pressure‐lowering agents to prevent cardiovascular events is dependent of the level of albuminuria before start of such treatment.
• The higher baseline albuminuria, the better the relative and absolute risk reduction for cardiovascular events with blood pressure‐lowering drugs.
• The data also suggest a possible better cardiovascular protective effect of renin–angiotensin intervening agents compared with other blood pressure‐lowering agents.
AIMS
Albuminuria has been proven to be associated with cardiovascular (CV) events in specific patient populations, but also in the general population. This study aimed to investigate whether the efficacy of blood pressure‐lowering agents in preventing CV events depends on baseline urinary albumin excretion (UAE) and, if so, whether this holds true for blood pressure‐lowering agents in general, or is limited to agents that interfere in the renin–angiotensin system.
METHODS
Data were used from a community‐based cohort study and pharmacy dispensing records. Included were subjects with hypertension (systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg), no cardiovascular disease history, and no previous use of blood pressure‐lowering agents.
RESULTS
During study follow‐up (7.1 ± 1.6 years), 122 CV events were observed in 1185 subjects included. Start of blood pressure‐lowering agents vs. non‐use was associated with a difference in absolute CV event risk of 0.7%, 6% and 12.6% for all subjects, those with UAE ≥ 15 mg day−1 and ≥30 mg day−1, respectively. Cox regression analysis showed that the relative risk for CV events after start of blood pressure‐lowering agents was significantly dependent (P < 0.05) on baseline UAE; with hazard ratios of 0.87 95% confidence interval (CI) 0.48, 1.60, P = NS, 0.58 (95% CI 0.36, 0.94, P < 0.05) and 0.37 (95% CI 0.20, 0.68, P < 0.05), for subjects with UAE < 15, ≥15 and ≥30 mg day−1, respectively. Results adjusted for covariates were essentially similar. The use of angiotensin converting enzyme inhibitor/angiotensin‐II receptor blocker (ACEi/ARB) treatment tended to be associated with a more favourable CV prognosis when compared with non‐ACEi/ARB treatment (difference P = 0.06).
CONCLUSIONS
Our results suggest that the efficacy of blood pressure‐lowering agents to prevent CV events is dependent on baseline albuminuria. The higher baseline albuminuria, the more absolute as well as relative risk reduction can be achieved. Our data suggest that this may especially be true for ACEi/ARBs. We caution that this is an observational study, and that these conclusions should therefore be regarded as hypothesis generating, rather than hypothesis testing.
Recently, prediction models for type 2 diabetes mellitus (T2DM) in older adults (aged ≥ 55 year) were developed in the KORA S4/F4 study, Augsburg, Germany. We aimed to externally validate the KORA ...models in a Dutch population. We used data on both older adults (n = 2,050; aged ≥ 55 year) and total non-diabetic population (n = 6,317; aged 28-75 year) for this validation. We assessed performance of base model (model 1: age, sex, BMI, smoking, parental diabetes and hypertension) and two clinical models: model 1 plus fasting glucose (model 2); and model 2 plus uric acid (model 3). For 7-year risk of T2DM, we calculated C-statistic, Hosmer-Lemeshow X² -statistic, and integrated discrimination improvement (IDI) as measures of discrimination, calibration and reclassification, respectively. After a median follow-up of 7.7 years, 199 (9.7%) and 374 (5.9%) incident cases of T2DM were ascertained in the older and total population, respectively. In the older adults, C-statistic was 0.66 for model 1. This was improved for model 2 and model 3 (C-statistic = 0.81) with significant IDI. In the total population, these respective C-statistics were 0.77, 0.85 and 0.85. All models showed poor calibration (P < 0.001). After adjustment for the intercept and slope of each model, we observed good calibration for most models in both older and total populations. We validated the KORA clinical models for prediction of T2DM in an older Dutch population, with discrimination similar to the development cohort. However, the models need to be corrected for intercept and slope to acquire good calibration for application in a different setting.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis ...for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Display omitted
Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10−10 to 10−15). Of these, rs10206899 ...(near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10−5 and P = 3.6 × 10−4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
PDF
