Chronic Kidney Disease Ups Mortality, ESRD--Both With, Without HTN or Diabetes

October 02, 2012

October 1, 2012 (Baltimore, Maryland) — Kidney disease is a significant predictor of all-cause mortality and end-stage renal disease (ESRD) in patients with and without hypertension or diabetes, according to two large meta-analyses by the Chronic Kidney Disease Prognosis Consortium (CKD-PC) [1,2].

In the first meta-analysis, the association between low estimated glomerular filtration rate (eGFR) and high albuminuria with mortality was somewhat stronger in individuals without than those with hypertension but was still sharply elevated for both groups. Based on the results, investigators say that CKD "warrants attention and management, irrespective of hypertension status."

Similarly, data from a second meta-analysis showed that, although individuals with diabetes had a higher risk of all-cause and cardiovascular mortality than those without diabetes across a range of eGFRs and albumin-to-creatinine ratios (ACRs), the relative risks according to measures of kidney disease are "much the same in individuals with and without diabetes."

Irrespective of whether or not patients had diabetes, cardiovascular disease was an important source of mortality in patients, "underscoring the importance of identifying and treating risk factors for cardiovascular disease in all patients with CKD," according to the lead researcher of the CKD-PC diabetes analysis, Dr Caroline Fox (Brigham and Women's Hospital, Boston, MA), and colleagues.

Two Large Meta-Analyses

Published online September 21, 2012 in Lancet, Dr Bakhtawar Mahmoodi (Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD), lead investigator of the hypertension analysis, noted that decreased eGFR and increased albuminuria, which are used to define CKD, frequently coexist alongside traditional cardiovascular risk factors, including hypertension. The prevalence of hypertension in patients with CKD ranges from 22% for stage 1 disease to more than 80% in patients with stage 4 disease.

Researchers analyzed data from 45 cohorts, including 25 cohorts of the general population, seven cohorts of high-risk patients, and 13 CKD trials, with 1 127 656 participants, including 364 344 with hypertension. In the general-population and high-risk cohorts, all-cause mortality risk was approximately 1.1- to 1.2-times higher in individuals with hypertension than those with normal blood pressure with preserved eGFR.

Using a reference eGFR of 95 mL/min/1.73 m2 for individuals without hypertension, those with high blood pressure had a higher risk of death for an eGFR >55 mL/min/1.73 m2 for all-cause mortality and >45 mL/min/1.73 m2 for cardiovascular mortality. Individuals with hypertension had a steeper relative risk for the eGFR range of 45–75 mL/min/1.73 m2 for cardiovascular mortality, but the risk of death was the same or higher--depending on the cause--for individuals without hypertension. Overall, the risk of all-cause and cardiovascular mortality increased with lower eGFR and higher albuminuria categories for normo- and hypertensive subjects.

"We also identified dose-dependent associations of low eGFR and high ACR in the 13 CKD cohorts with more than 38 000 participants," state Mahmoodi and colleagues. "In these cohorts, however, neither the associations with mortality nor with ESRD differed by hypertensive status."

CKD-PC Diabetes Analysis

In the diabetes analysis, CKD-PC researchers analyzed data from 1 024 977 subjects, including 128 505 with diabetes, from 30 general-population and high-risk cohorts and 13 CKD cohorts.  For all-cause mortality, there were 75 306 deaths over 8.5 years of follow-up; for cardiovascular mortality, there were 21 237 deaths from cardiovascular causes over a mean follow-up of 9.2 years. In the general-population and high-risk cohorts, the risk of death was 1.2- to 1.9-times higher for individuals with diabetes than those without across different eGFR and ACR ranges.

However, using a fixed eGFR and ACR reference point (for example, comparing all-cause mortality at eGFR 45 mL/min/1.73 m2 vs 95 ml/min/1.73 m2), the hazard ratios for mortality outcomes according to lower eGFR and higher ACR were similar in patients with and without diabetes.

"Individuals with diabetes have a higher risk of all-cause and cardiovascular mortality than do those without diabetes across the range of eGFR and ACR," write the CKD-PC researchers. "However, relative risks of these health outcomes according to measures of kidney disease are much the same in individuals with and without diabetes. The use of clinically relevant cutoff points showed the importance of both eGFR and ACR with respect to each of these outcomes."

We Think We Know, But We Don't

In an editorial [3], Drs Paul Stevens and Christopher Farmer (University National Health Service Foundation Trust, Canterbury, UK) point out that there is controversy in the management, diagnosis, and treatment of patients with an isolated finding of eGFR between 45 to 60 mL/min/1.73 m2 or >60 mL/min/1.73 m2 and a urine ACR between 30 to 300 mg/g. In these CKD patients, even without hypertension and diabetes, the risks of cardiovascular mortality were significantly elevated.

"These two studies underline the association of adverse outcomes with moderate reduction in kidney function and low levels of proteinuria, but we still need to know why this association occurs," write the editorialists. "We think we know some of the factors in progression amenable to to prevent associated adverse outcomes, such as control of diabetes and hypertension, but the two accompanying studies of effect modification by hypertension and diabetes disease status show us we still have a lot to learn."