Primary Aldosteronism and Kidney Hemodynamics: Adding Another Piece to the Puzzle

Primary aldosteronism (PA) is increasingly recognized as the most common and modifiable form of secondary hypertension.1 While historically considered a rare disease, contemporary prevalence studies show that 4%–7% of cases of newly diagnosed hypertension in the primary care setting are attributable to PA. When considering more severe cases of hypertension such as resistant hypertension, PA prevalence increases to upwards of 20%.2 PA is characterized by autonomous (renin-/angiotensin II-independent) secretion of aldosterone from one or both adrenal glands and often in spite of concurrent hypokalemia and intravascular volume expansion. The primary site of action of aldosterone is the kidney where it binds the mineralocorticoid receptor (MR) located in the distal nephron.3 Activation of the MR induces potent sodium reabsorption via the epithelial sodium channel (ENaC) along with a commensurate excretion of potassium and hydrogen ions. Water reabsorption consequent to the ENaC-mediated sodium reabsorption results in suppression of both renin and angiotensin II. Suppression of angiotensin II leads to enhanced sodium delivery to the distal nephron resulting in a vicious cycle of further ENaC-mediated sodium reabsorption, intravascular volume expansion, and the classic clinical triad of hypertension, hypokalemia, and metabolic alkalosis. While the bulk of the existing literature on the clinical impact of PA focuses on its disproportionately high cardiovascular risk,4,5 PA also has important clinical implications on kidney health. Prior to targeted treatment, patients with PA develop glomerular hyperfiltration (i.e., a supraphysiologic elevation in the glomerular filtration rate [GFR]).6 Glomerular hyperfiltration (a hallmark of kidney dysfunction shared by other disease states such as diabetes mellitus and obesity) can be caused by intravascular volume expansion, afferent arteriolar vasodilation, and/or efferent arteriolar vasoconstriction.7 Over time, the resultant glomerular hypertension damages the glomeruli leading to increased proteinuria, a steeper longitudinal decline in GFR, and a corresponding higher incidence of chronic kidney disease.1,8,9 Importantly, targeted treatments such as MR antagonists and surgical adrenalectomy are effective in reversing the maladaptive glomerular hyperfiltration inherent to PA.6,8,10–12 In fact, these studies highlight that chronic kidney disease is often “unmasked” in patients with PA after targeted treatment is started as an initial decline in GFR is typical and should, in fact, be expected. While at first glance this may seem like a negative outcome, it should not be viewed in this manner. Reversal of glomerular hyperfiltration ultimately leads to a reduction in proteinuria, a less steep decline in GFR over time, and overall improved kidney outcomes. In fact, the patients with PA who experience the largest initial estimated GFR (eGFR) decline following initiation of MR antagonist medications experience the best long-term eGFR trajectory (i.e., the least steep eGFR slope).11 Furthermore, escalation of MR antagonist therapy in PA to target renin “unsuppression” (an increasingly utilized clinical biomarker of relative intravascular volume contraction and reversal of glomerular hyperfiltration in PA)13 has been shown to further reduce proteinuria and longitudinal eGFR decline.10,14 What is known about the effects of PA on kidney hemodynamics at the glomerular level that result in hyperfiltration? Ribstein et al. studied the glomerular hemodynamics of 25 patients with PA compared with a control group of patients with essential hypertension.6 Despite similar blood pressure control, the PA group tended to have higher glomerular hydrostatic pressure and lower afferent arteriolar resistance compared with the essential hypertension group. No significant difference in efferent arteriolar resistance was reported. Similar findings were demonstrated in a small study of 6 patients with PA where a reduction in afferent arteriolar resistance was seen with no significant change in efferent arteriolar resistance.15 In this issue of the American Journal of Hypertension, Uedono et al. provide the next piece of the puzzle in how PA impacts intraglomerular hemodynamics.16 In this observational study, 17 patients with PA underwent comprehensive kidney testing using a variety of approaches. Kidney function was assessed using several different methods including measured GFR (via plasma inulin clearance), eGFR (using both creatinine- and cystatin C-based equations), and 24-hour creatinine clearance. Twenty-four-hour proteinuria was also quantified. Renal plasma flow was assessed using para-aminohippurate clearance. Intraglomerular hemodynamics (intraglomerular hydrostatic pressure, afferent arteriolar resistance, and efferent arteriolar resistance) were calculated using plasma inulin and para-aminohippurate clearance within the Gomez formula.17 The study assessed how plasma aldosterone concentration correlated with these parameters. The main take-home findings from this study are displayed in Figure 1.16 Among patients with PA, higher aldosterone concentrations were associated with glomerular hyperfiltration, as evidenced by an increase in measured GFR via inulin clearance, along with a corresponding increase in proteinuria. In regard to intraglomerular hemodynamics, higher aldosterone concentrations were associated with increased intraglomerular hydrostatic pressure as consistent with prior work.6,15 However, in contrast to these prior studies, higher aldosterone concentrations were associated with an increase in efferent arteriolar resistance whereas there was no association identified with afferent arteriolar resistance (though this has been reported in prior studies).6,15 These findings were more pronounced among PA cases due to an aldosterone-producing adenoma, which also typically produces a more severe clinical and biochemical phenotype. Intraglomerular hemodynamic changes associated with primary aldosteronism. Abbreviations: GFR, glomerular filtration rate; Na+, sodium. Another interesting finding from this study relates to the various measures of kidney function that were concurrently assessed: measured GFR, eGFR (using both creatinine and cystatin C), and 24-hour creatinine clearance.16 Higher aldosterone concentrations were associated with measured GFR (the truest measure of kidney function) and cystatin C-based eGFR but not with either of the creatinine-based measures (creatinine-based eGFR and 24-hour creatinine clearance). It is well known to nephrologists that creatinine is an imperfect endogenous of GFR as its clearance from the blood relies not only on glomerular filtration but also on renal tubular secretion.18 To this end, this study assessed the relationship between aldosterone concentrations and the secretory component of creatinine clearance and found that higher aldosterone levels may trigger a decrease in tubular creatinine excretion. In turn, this may result in creatinine-based estimations of kidney function that are inaccurate in fully reflecting the glomerular hyperfiltration inherent to PA. While it is infeasible to routinely measure inulin clearance to measure GFR, these results may suggest moving away from creatinine-based GFR estimation and toward alternate assessments of kidney function such as cystatin C-based eGFR equations for patients with PA. Ultimately, this aspect of the study will require validation in a larger population of PA patients before altering clinical practice. In conclusion, PA leads to adverse kidney outcomes which can be traced to its deleterious impact on intraglomerular hemodynamics. Because of this, early diagnosis and treatment of PA are essential to improve kidney health. Targeted therapies such as MR antagonists and adrenalectomy are effective in reversing the maladaptive kidney hemodynamic changes seen with PA. Future studies should focus on strategies to optimize PA treatment approaches to enhance kidney outcomes and better monitor kidney health within this population. Furthermore, an increasing number of recent studies have clearly demonstrated that PA pathophysiology extends well beyond the historical biochemical and diagnostic confines used to define PA thereby impacting a much broader patient population.19,20 Bearing this in mind, it will be important going forward to develop an understanding of the kidney impact of these currently under-recognized “subclinical” forms of PA. Figure 1 was drawn in part using images from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Dr Hundemer is supported by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (Grant # PJT-175027), the Kidney Foundation of Canada (Grant # 851937-21KHRG and 24KHRG-1251453), and the Lorna Jocelyn Wood Chair for Kidney Research. The authors declared no conflict of interest.

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