Kidney Damage Biomarkers and Incident Chronic Kidney Disease During Blood Pressure Reduction: A Case-Control Study

Abstract

Background: Whether the increased incidence of chronic kidney disease (CKD) during intensive systolic blood pressure (SBP) lowering is accompanied by intrinsic kidney injury is unknown.

Objective: To compare changes in kidney damage biomarkers between incident CKD case participants and matched control participants as well as between case participants in the intensive (<120 mm Hg) versus the standard (<140 mm Hg) SBP management groups of SPRINT (Systolic Blood Pressure Intervention Trial).

Design: Nested case-control study within SPRINT.

Setting: Adults with hypertension without baseline kidney disease.

Participants: Case participants (n = 162), who developed incident CKD during trial follow-up (128 in the intensive and 34 in the standard group), and control participants (n = 162) without incident CKD, who were matched on age, sex, race, baseline estimated glomerular filtration rate, and randomization group.

Measurements: 9 urinary biomarkers of kidney damage were measured at baseline and at 1 year. Linear mixed-effects models were used to estimate 1-year biomarker changes.

Results: Higher concentrations of urinary albumin, kidney injury molecule-1, and monocyte chemoattractant protein-1 at baseline were significantly associated with greater odds of incident CKD (adjusted odds ratio per doubling: 1.50 [95% CI, 1.14 to 1.98], 1.51 [CI, 1.05 to 2.17], and 1.70 [CI, 1.13 to 2.56], respectively). After 1 year of blood pressure intervention, incident CKD case participants in the intensive group had significantly greater decreases in albumin-creatinine ratio (ACR), interleukin-18, anti-chitinase-3-like protein 1 (YKL-40), and uromodulin than the matched control participants. Compared with case participants in the standard group, those in the intensive group had significantly greater decreases in ACR, β2-microglobulin, α1-microglobulin, YKL-40, and uromodulin.

Limitation: Biomarker measurements were available only at baseline and 1 year.

Conclusion: Incident CKD in the setting of intensive SBP lowering was accompanied by decreases, rather than elevations, in levels of kidney damage biomarkers and thus may reflect benign changes in renal blood flow rather than intrinsic injury.

Primary funding source: National Institute for Diabetes and Digestive and Kidney Diseases.

Figure 1.

The 1-year percent changes of nine urinary biomarkers among incident CKD cases and matched controls, stratified by randomization arm, in SPRINT. The black bars denote incident CKD cases, and the gray bars denote matched controls without CKD. There were 128 cases in the intensive arm and 34 in the standard arm; one control was matched per case within each intervention arm on age (within 5 years), sex, race, and baseline eGFR (within 5 ml/min/1.73m2). The 1-year changes were estimated from separate linear mixed models for each biomarker, adjusting for log2-transformed urine creatinine and systolic blood pressure. Error bars denote the 95% confidence intervals (CIs). The y-axes are truncated at +/− 80%. The 95% CI upper bounds for several biomarkers among cases in the standard arm were truncated: the 95% CI upper bounds of 1-year changes in KIM-1, MCP-1, β2M, and α1M extend to 97%, 89%, 114%, and 163%, respectively. Brackets with p-values represent comparisons of 1-year changes between respective groups at bracket tails. P-values <0.05 were considered statistically significant and have been bolded. The numerical values of the 1-year change and 95% CIs are presented in Appendix Table 6. Full names for each urinary biomarker are as follows: albumin-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), anti-chitinase-3-like protein 1 (YKL-40), beta-2 microglobulin (β2M), α1microglobulin (α1M), and uromodulin (UMOD).