Numerous studies have documented the benefits of treatment of hypertension in lowering the risk for cardiovascular disease and all-cause mortality. However, according to Rakesh Malhotra, MD, MPH, and colleagues, the effects of lowering blood pressure on the progression of chronic kidney disease (CKD) are less certain, due to the higher risk for acute kidney injury (AKI) and increased rapid loss of estimated glomerular filtration rate (eGFR) associated with treating to lower blood pressure targets.
In patients with prevalent CKD, the risks for AKI and loss of eGFR are particularly concerning because those patients have lower eGFRs at baseline and are likely less able to tolerate additional kidney risks. The optimal balance of the risks and benefits of hypertension treatment in patients with CKD is not well defined.
The SPRINT (Systolic Blood Pressure Intervention Trial) compared the effects of lowering systolic blood pressure to a target of <120 mm Hg with standard blood pressure control (systolic blood pressure, <140 mm Hg) on the risks for cardiovascular events. The SPRINT cohort included patients with hypertension but without diabetes or prior stroke at high risk for cardiovascular disease. Of the total cohort, 2646 (~30%) had CKD at baseline.
The effect of intensive blood pressure lowering on eGFR was most pronounced during the first 6 months of treatment, suggesting that the change may have represented hemodynamic effects rather than intrinsic kidney damage. Dr. Malhotra et al. conducted a longitudinal analysis of a subgroup of SPRINT participants to test the hypothesis that the predominant cause for the greater change in eGFR in the intensive arm of SPRINT reflected hemodynamic changes by examining changes in eight markers of kidney tubule health by treatment arm assignment. Results of the analysis were reported in the American Journal of Kidney Diseases [2019;73(1):21-30].
The urine biomarkers of tubule function measured were b2-microglobulin (B2M), a1-microglobulin (A1M), and uromodulin; measured biomarkers of kidney injury were interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL); measured biomarker of kidney inflammation was monocyte chemoattractant protein 1 (MCP-1); and measured biomarker of repair was human cartilage glycoprotein 39 (YKL-40).
Of the 2646 SPRINT participants with CKD at baseline (eGFR <60 mL/min/1.73 m2 by the CKD Epidemiology Collaboration creatinine-cystatin C equation), 1000 were selected using simple random sampling. Of those, 22 were excluded due to missing data on urine specimens, resulting in a final sample for the current analysis of 978 participants.
Mean age of the total cohort was 72 years, 60% were men, 66% were non-Hispanic white, and 39% had a history of cardiovascular disease. At baseline, median eGFR was 48 mL/min/1.73 m2, median urinary albumin-creatinine ratio (ACR) was 15 mg/g, mean systolic blood pressure was 139 mm Hg, and mean diastolic blood pressure was 75 mm Hg. The mean number of antihypertensive medications was 2.0. Of the 978 participants, 519 were randomly assigned to the intensive blood pressure arm and 459 to the standard blood pressure arm. With the exception of serum triglyceride levels, which were lower in the intensive blood pressure arm (124 vs 135 mg/dL; P=.04), distribution of all measurements were similar in the two arms.
At baseline, concentrations of the eight urinary tubule biomarkers were similar across the two arms. At year 1, eGFR was 7% lower and ACR was 32% lower among participants in the intensive arm compared with those in the standard arm in this subset analysis. There were no differences in any of the eight urinary tubular marker levels in the intensive versus standard arm at year 1.
Using an omnibus test to compare differences in urinary biomarker levels across baseline, year 1, and year 4, there were statistically significant differences detected for two biomarkers: B2M (P=.03) and A1M (P=.01) across study years. At year 1, B2M level was 29% lower and A1M level was 24% lower in the intensive arm compared with the standard arm. There was a similar difference seen across study years for urinary IL-18 level; however, the omnibus P value did not reach statistical significance. At year 4, differences in eGFRs and urinary ACRs across the two arms were similar to year 1 (7% and 31% lower in the intensive vs the standard arm, respectively). There were no statistically significant differences in any urinary tubule marker levels across the two arms at year 4.
In the intensive arm, the largest reductions in urinary ACR, B2M, A1M, and IL-18 levels at year 1 were seen in those who experienced decreases in eGFR among the highest quintile. Evaluation of heterogeneity across categories of eGFR was statistically significant for ACR, A1M, and IL-18 (P<.001 for all), and neared statistical significance for B2M (P=.07). There was no relation to the magnitude of change in eGFR in either treatment arm with changes in urine biomarker levels at year 4.
When the sample was limited to participants in the intensive arm in a comparison of the magnitude of achieved change in systolic blood pressure during the trial with concurrent changes in urinary tubule marker levels, at year 1, participants who achieved the largest reductions in systolic blood pressure (decline >30 mm Hg from baseline) also had the greatest reductions in eGFRs (of 11%) and ACRs (of 40%). Participants with the smallest changes in systolic blood pressure had the least changes or improvements in eGFRs and urinary ACRs during follow-up (P<.001).
Citing limitations to the analysis, the researchers included the exclusion of individuals with diabetes, stroke, or proteinuria with protein excretion >1 g/d, and the inclusion of some patients with advanced CKD that may have limited the generalizability of the findings to other settings.
“In conclusion, although intensive systolic blood pressure lowering resulted in reductions in eGFR, we found no evidence that it induced kidney tubule cell damage based on evaluation of eight distinct kidney tubule biomarkers. Intensive blood pressure lowering was associated with lower concentrations of two urinary biomarkers that are filtered at the glomerulus and reabsorbed at the proximal tubule. These findings support the hypothesis that reductions in eGFR observed with intensive blood pressure lowering reflect hemodynamic changes rather than intrinsic kidney cell damage in persons with CKD,” the researchers said.
- Researchers conducted an analysis on a subset of patients with chronic kidney disease (CKD) in the SPRINT study to determine whether changes in kidney function following intensive systolic blood pressure reduction reflected hemodynamic effects or accelerated intrinsic kidney damage.
- The analysis measured eight urine biomarkers of tubule function: B2M, A1M,UMOD, IL-18, KIM-1, NGAL, MCP-1, and YKL-40.
- At years 1 and 4, none of the tubule markers were higher in the intensive arm compared with the standard arm; B2M and A1M were 29% and 24% lower at year 1 in the intensive arm versus the standard arm.