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.

Re: comment from Ladak et al. to JH-D-23-00692, entitled ‘Analyzing eGFR-Dip after medical target therapy in primary aldosteronism’

“…Regarding their suggestion for a more robust ANOVA analysis, via including patient age stratification, we are in full agreement [3]. Stratifying eGFR-dip cohorts by age promises to offer a refined perspective on risk assessment.…”

“…Robertson et al [2] demonstrated that acute caffeine consumption increased serum renin levels significantly, which would cause an increase in downstream plasma aldosterone concentrations. In addition, a large body of research demonstrated that salt intake has an inverse relationship with renin production/RAAS activation, though the exact mechanism remains unknown [3].…”

Challenges in Diagnosing and Managing the Spectrum of Primary Aldosteronism

“…In Australia and most other countries, spironolactone is commonly used as first-line therapy. An initial decline in renal function, as reflected by creatinine-based eGFR, can be observed following MRA or surgical treatment of PA because of correction of aldosterone-mediated glomerular hyperfiltration, which unmasks underlying renal dysfunction [ 55 ]. Reassuringly, the drop in eGFR does not reflect intrinsic damage to the renal tubules as biomarkers of renal tubular health are restored following targeted treatment [ 55 ] and a larger acute fall in eGFR in this setting has been associated with less decline in the longer term [ 56 ].…”

The problem of timely diagnosis of primary hyperaldosteronism. Clinical case

“…Підозра на ПГА виникає у випадку стійкого поєднання АГ із зумовленим гіпокаліємією різного ступеня вираженості специфічним нейром'язовим синдромом (оніміння, слабкість у м'язах кінцівок, втомлюваність, судоми, парестезії), а також не властивим для банальної АГ високим ризиком швидкого погіршення ниркової функції та розвитку хронічної хвороби нирок [4]. Окрім того, імовірність ПГА підвищує незадовільній контроль АТ стандартною комбінацією засобів фармакотерапії, неочікуваний позитивний терапевтичний ефект антагоністів мінералокортикоїдних рецепторів, АГ у молодих, а також сімейний анамнез ранньої АГ або інсульту у молодому віці, пароксизмальний перебіг АГ [5].…”

“…Більшість авторів відзначають наявність неспецифічних змін, характерних для АГ (артеріолосклеротичний нефросклероз) [17]. Описують специфічні для ПГА зміни -«гіпокаліємічну нирку» (пошкодження епітелію канальців нирки внаслідок гіпокаліємії та метаболічного алкалозу, що призводить до запалення з імунним компонентом і склерозом інтерстицію) [4]. Треба зазначити, що ураження нирок при ПГА, а по суті, розвиток вторинної нефрогенної АГ розглядається як одна з причин збереження АГ після видалення АПА.…”