Primary aldosteronism (PA) has been associated with cardiovascular hypertrophy and fibrosis, in part independent of the blood pressure level, but deleterious effects on the kidneys are less clear. Likewise, it remains unknown if the kidney can be diversely involved in PA caused by aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hence, in the Primary Aldosteronism Prevalence in Italy (PAPY) Study, a prospective survey of newly diagnosed consecutive patients referred to hypertension centers nationwide, we sought signs of renal damage in patients with PA and in comparable patients with primary hypertension (PH). Patients (n=1180) underwent a predefined screening protocol followed by tests for confirming PA and identifying the underlying adrenocortical pathology. Renal damage was assessed by 24-hour urine albumin excretion (UAE) rate and glomerular filtration rate (GFR). UAE rate was measured in 490 patients; all had a normal GFR. Of them, 31 (6.4%) had APA, 33 (6.7%) had IHA, and the rest (86.9%) had PH. UAE rate was predicted ( P <0.001) by body mass index, age, urinary Na ⁺ excretion, serum K ⁺ , and mean blood pressure. Covariate-adjusted UAE rate was significantly higher in APA and IHA than in PH patients; there were more patients with microalbuminuria in the APA and IHA than in the PH group ( P =0.007). Among the hypertensive patients with a preserved GFR, those with APA or IHA have a higher UAE rate than comparable PH patients. Thus, hypertension because of excess autonomous aldosterone secretion features an early and more prominent renal damage than PH.

Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P <10 ⁻³ ) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P <10 ⁻³ ) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P =0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism.

Purpose: The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. Design: We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. Results: Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). Conclusions: The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

Due to selection biases and inadequate statistical power, individual studies may fail to identify the clinical features of patients with an aldosterone-producing adenoma (APA) harboring KCNJ5 mutations. When this failure occurs, meta-analysis can provide significant outcome data. The objective was to determine the clinical features of these APA patients. We systematically searched the PubMed, Scopus, Web of Science, and Cochrane databases library in January 2015 applying the Population, Intervention, Comparison, and Outcome (PICO) strategy. The standardized differences in mean and corresponding 95% confidence interval of continuous variables were computed by random-effects modeling. We performed a meta-analysis of all available studies on somatic KCNJ5 mutations in APA. We could identify 13 studies that recruited 1636 patients (age 49 ± 4 years; 55% females). Differences between APA with and without KCNJ5 mutations in gender, plasma renin activity, plasma aldosterone, tumor size, serum potassium, and blood pressure were investigated. The overall prevalence of KCNJ5 mutations was 43% (range = 12-80%). Their rate was lower (P < .003) in the studies done in Europe, the United States, and Australia (35%) than in Japan and China (63%); it correlated (r = 0.60, P = .029) with the mean daily urinary sodium excretion. Compared with the wild-type, the mutated APA patients were younger (45 ± 3 vs 52 ± 5 yrs), had higher plasma aldosterone (42 ± 8 vs 33 ± 8 ng/dl), larger tumors (16.1 ± 6.4 versus 14.9 ± 7.4 mm), and were more often females (67% vs 44%) (all P < .05). Meta-analysis showed that more pronounced hyperaldosteronism, young age, female gender, and larger tumors are the phenotypic features of APA patients with KCNJ5 mutations. No significant differences in blood pressure and serum K(+) was found, which suggests that these clinical features do not help in identifying mutated APA patients.