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

Abstract

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.

Figure 1. Hazard ratios of all-cause and cardiovascular mortality according to eGFR in non-hypertensives (black-line) versus hypertensives (red-line)

Panels A through D represents results of all-cause (A and B) and cardiovascular (C and D) mortality in the combined general and high-risk populations. Panels A and C use eGFR of 95 mL/min/1.73m² among non-hypertensive as a single reference point (diamond) for both hypertensive and non-hypertensive individuals to visualize the main effect of hypertension on risk. Panels B and D use eGFR of 95 mL/min/1.73m² among hypertensives and non-hypertensives as the reference point (diamond) for hypertensives and non-hypertensives to visualize interaction between eGFR and hypertensive status, respectively.. Significant interaction between hypertension and eGFR is represented by “x” signs on the bottom of the right panels. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index, and albuminuria (log-ACR, log-PCR or categorical dipstick proteinuria [negative, trace, 1+, ≥2+])

Figure 2. Hazard ratios of all-cause and cardiovascular mortality according to ACR in non-hypertensives (black-line) versus hypertensives (red-line)

Panels A through D represents results of all-cause (A and B) and cardiovascular (C and D) mortality in the combined general and high-risk populations. Panels A and C use ACR of 5 mg/g among non-hypertensive as a single reference point (diamond) for both hypertensive and non-hypertensive individuals to visualize the main effect of hypertension on risk. Panels B and D use ACR of 5 mg/g among hypertensives and non-hypertensives as the reference point (diamond) for hypertensives and non-hypertensives to visualize interaction between ACR and hypertensive status, respectively. Significant interaction between hypertension and ACR is represented by “x” signs in the right panels. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index, and eGFR splines.

Figure 3. Hazard ratios of ESRD according to eGFR and ACR in non-hypertensives (black-line) versus hypertensives (red-line)

Panels A and B shows eGFR association with ESRD and panels C and D shows ACR association with ESRD in CKD cohorts. Left panels use eGFR of 50 mL/min/1.73m² (B) and ACR of 5 mg/g (C) among non-hypertensive as a single reference point (diamond) for both hypertensive and non-hypertensive individuals. Right panels use eGFR of 50 mL/min/1.73m² (A) and ACR of 100 mg/g (C) as the reference points (diamond) in each hypertensive and non-hypertensive groups, respectively. Because there were few participants with eGFR >60 mL/min/1.73m² in the CKD cohorts by definition, the associations were only shown below 60. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index, and albuminuria (log-ACR, log-PCR or categorical dipstick proteinuria [negative, trace, 1+, ≥2+]) or eGFR splines, as appropriate.

Figure 4. Hazard ratios of all-cause mortality for eGFR in non-hypertensives (black-line) versus hypertensives (red-line) according to diabetes status

Panels A through D show eGFR association with all-cause mortality in non-diabetics (panel A and B) versus diabetics (panel C and D) in the combined general and high-risk populations. Significant interaction between hypertension and eGFR is represented by “x” signs. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body mass index, and albuminuria (log-ACR, log-PCR or categorical dipstick proteinuria [negative, trace, 1+, ≥2+]).