Markers of Kidney Tubular Function Deteriorate While Those of Kidney Tubule Health Improve in Primary Aldosteronism After Targeted Treatments

Abstract

Background Targeted treatment with mineralocorticoid receptor antagonists (MRAs) or adrenalectomy in patients with primary aldosteronism (PA) causes a decline in estimated glomerular filtration rate; however, the associated simultaneous changes in biomarkers of kidney tubule health still remain unclear. Methods and Results We matched 104 patients with newly diagnosed unilateral PA who underwent adrenalectomy with 104 patients with unilateral PA who were treated with MRAs, 104 patients with bilateral PA treated with MRAs, and 104 patients with essential hypertension who served as controls. Functional biomarkers were measured before the targeted treatment and 1 year after treatment, including serum markers of kidney function (cystatin C, creatinine), urinary markers of proximal renal tubular damage (L-FABP [liver-type fatty-acid binding protein], KIM-1 [kidney injury molecule-1]), serum markers of kidney tubular reserve and mineral metabolism (intact parathyroid hormone), and proteinuria. Compared with the patients with essential hypertension, the patients with PA had higher pretreatment serum intact parathyroid hormone and urinary creatinine-corrected parameters, including L-FABP, KIM-1, and albumin. The patients with essential hypertension and with PA had similar cystatin C levels. After treatment with MRAs or adrenalectomy of unilateral PA and MRAs of bilateral PA, the patients with PA had increased serum cystatin C and decreased urinary L-FABP/creatinine, KIM-1/creatinine, creatinine-based estimated glomerular filtration rate, intact parathyroid hormone, and proteinuria (all P<0.05). In multivariable regression models, a higher urinary L-FABP/creatinine ratio and older age were significantly correlated with the occurrence of kidney failure (estimated glomerular filtration rate dip ≥30%) in the patients with PA after targeted treatment. Conclusions Compared with the matched patients with essential hypertension, the incident patients with PA at diagnosis had higher levels of several biomarkers, including markers of kidney damage, tubular reserve/mineral metabolism, and proteinuria. Functional kidney failure in the patients with PA after treatment could be predicted by a higher baseline urinary L-FABP/creatinine ratio and older age. After targeted treatments in the patients with bilateral or unilateral PA, these biomarkers of kidney tubule health were restored, but creatinine-based estimated glomerular filtration rate declined, which may therefore reflect hemodynamic changes rather than intrinsic damage to kidney tubular cells.

Keywords: KIM‐1; L‐FABP; TAIPAI; cystatin C; iPTH; kidney failure; proteinuria.

Figure 1. A scheme depicting experimental design*.

EH indicates essential hypertension; and PA, primary aldosteronism.

Figure 2. Differences in baseline biochemistry data in patients with PA, essential hypertension, with temporal change of kidney profiles § after treatments in uPA (A) and biPA patients (B). Bar plots show the differences in eGFR, plasma cystatin C, proteinuria, urinary L‐FABP, and urinary KIM‐1. After targeted therapy in the PA patients, these biomarkers of kidney tubule health were restored, but creatinine‐based eGFR declined.

*Expression units of the y axis: eGFR (ml/min/1.73²), proteinuria (μg/mg) multiplied by 10, cystatin C (mg/L) multiplied by 100, L‐FABP/creatinine (μg/g) multiplied by 10, KIM‐1/creatinine (μg/g) multiplied by 100. The analysis consisted of paired t tests and expressed as mean±SEM. Proteinuria defined as microalbuminuria adjusted with urine creatinine. BiPA indicates bilateral primary aldosteronism; eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone; KIM‐1, Kidney injury molecule‐1; L‐FABP, liver‐type fatty acid binding protein; MRA, mineralocorticoid receptor antagonist; OP, operation; PA, primary aldosteronism; and uPA, unilateral primary aldosteronism. *P<0.05; **P<0.01.

Figure 3. Correlation network to visualize the correlation between levels of biomarkers and baseline characteristics in patients with all primary aldosteronism (A), unilateral PA (B), and bilateral PA (C).

Correlation matrix between levels of biomarkers and baseline characteristics in patients with primary aldosteronism. The correlations between blood pressure, SBP, DBP, BMI, and levels of kidney biomarkers at index enrollment when holding drugs that interfere with RAAS were examined. On the contents of the diagonal are the value (logit) of the correlation. Blue color depicts negative correlation, and red color depicts positive correlation. * Correlation matrix analysis is used to study dependences or associations between variables. BMI indicates body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone; K, potassium; KIM‐1, kidney injury molecule‐1; L‐FABP, liver‐type fatty acid binding protein; PA, primary aldosteronism; PRA, plasma renin activity; RAAS, renin–angiotensin–aldosterone system; and SBP, systolic blood pressure.

Figure 4. An illustrative diagram depicting the temporal change of levels of biomarkers regarding kidney tubule health and kidney failure after targeted treatments in patients with primary aldosteronism.

It showed both surgery (unilateral adrenalectomy) or medical (with MRA) treatments could improve kidney tubular biomarkers of injury/repair, injury/fibrosis, tubular reserve, and mineral metabolism in patients with PA. EH indicates essential hypertension; eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone; KIM‐1, kidney injury molecule‐1; L‐FABP, liver‐type fatty acid binding protein; MRA, mineralocorticoid receptor antagonist; OP, operation; OR, odds ratio; PA, primary aldosteronism; and u, urinary.