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. 2022 Dec 8;35(12):1006-1013.
doi: 10.1093/ajh/hpac102.

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial

Jesse C Ikeme  1 , Ronit Katz  2 , Anthony N Muiru  1 , Michelle M Estrella  1 , Rebecca Scherzer  1 , Pranav S Garimella  3 , Stein I Hallan  4   5 , Carmen A Peralta  1   6 , Joachim H Ix  3   7   8 , Michael G Shlipak  1
Affiliations

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial

Jesse C Ikeme et al. Am J Hypertens. .

Abstract

Background: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail.

Methods: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables.

Results: Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function.

Conclusions: Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.

Keywords: biomarkers; blood pressure; chronic; cross-sectional studies; hypertension; kidney tubules; renal insufficiency.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Simultaneous associations of clinical and demographic risk factors with urine biomarkers and eGFR among SPRINT participants with eGFR <60 ml/min/1.73 m2 at enrollment. Estimates from a simultaneous multivariate linear regression of urine biomarker levels using characteristics selected by MSG-LASSO. Numbers depict standardized beta coefficients for estimates of urine biomarkers per increment change in clinical or demographic characteristics (1 SD for continuous variables). Cells are colored according to the scheme depicted on the right. Coefficients with P-values < 0.05 and characteristic-biomarker pairs not selected by MSG-LASSO are omitted and depicted as blank squares. *Color scheme is reversed for UMOD and eGFR due to clinically favorable implications of higher values, in contrast to the remaining urine biomarkers. Abbreviations: eGFR, estimated glomerular filtration rate; SPRINT, systolic blood pressure intervention trial; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; MCP-1, monocyte chemoattractant protein-1; YKL-40, chitinase-3-like protein-1, B2M, beta-2 microglobulin; A1M, alpha-1 microglobulin; UMOD, uromodulin; uAlb, urine albumin; SBP, systolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body-mass index; HF, heart failure; CVD, cardiovascular disease; RAAS-I, renin-angiotensin-aldosterone system inhibitors.
Figure 2.
Figure 2.
Select urine biomarker concentrations and baseline systolic blood pressure among SPRINT participants with eGFR <60 ml/min/1.73 m2 at study enrollment. Splines depicting urine alpha-1 microglobulin (A), beta-2 microglobulin (B) and albumin (C) levels based on an ordinary least squares model using restricted cubic splines with knots placed at the quartiles of SBP. Abbreviations: SPRINT, Systolic Blood Pressure Intervention Trial; A1m, alpha-1 microglobulin; B2m, beta-2 microglobulin; SBP, systolic blood pressure.
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