176:1 C Verdelli and S Corbetta Kidney disease in primary 176:1 R39–R52 Review hyperparathyroidism MECHANISMS IN ENDOCRINOLOGY Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects C Verdelli1 and S Corbetta1,2 Correspondence 1 2 Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy and Endocrinology should be addressed Service, Department of Biomedical Sciences for Health, University of Milan, IRCCS Istituto Ortopedico Galeazzi, to S Corbetta Milan, Italy Email [email protected] Abstract Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is European Journal European of Endocrinology likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow-up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed. European Journal of Endocrinology (2017) 176, R39–R52 Invited Author’s profile Prof Sabrina Corbetta graduated in Medicine and obtained a PhD at University of Milan in Italy. She is a professor of Endocrinology at the University of Milan, head of the Endocrine Service and of the Laboratory of Experimental Endocrinology at IRCCS Istituto Ortopedico Galeazzi in Milan. She is a member of the European Society of Endocrinology from 2007. Over the last 15 years, she has developed her scientific interest in the clinical aspects of primary hyperparathyroidism focusing on kidney involvement, and in the parathyroid tumorigenesis. She has published over 100 papers. In 2014, she collaborated on the development of the Italian Society of Endocrinology Guidelines for the diagnosis and management of the mild primary hyperparathyroidism. She is a member of the scientific committee of the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS) and of the board of the Italian Society of Endocrinology. www.eje-online.org © 2017 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-16-0430 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:13:15PM via free access 10.1530/EJE-16-0430 Review C Verdelli and S Corbetta Kidney disease in primary 176:1 R40 hyperparathyroidism Introduction Primary hyperparathyroidism (PHPT) is a common for the clinical setting, while ‘calcium sensing receptor’ endocrine disorder due to inappropriate parathormone and ‘calcium gene’, or ‘phosphate gene’, or ‘VDR’ were (PTH) release from tumour parathyroid glands. PTH used for the molecular aspects. The search retrieved mainly acts through the activation of the G-protein 50 records related to the clinical setting and 13 coupled receptor PTHR1. Kidney cells are targets of the records related to the molecular aspects. Both authors PTH biological activity, which regulates renal calcium working independently and reviewed all abstracts and phosphate handling. Clinical kidney injuries, namely and selected full-text manuscripts for eligibility. kidney stones and stone-related complications, such Discrepancies in data extraction were resolved by as urinary tract infections, hydronephrosis and kidney consensus. Non English language papers and studies failure, were considered expected complications in the only reported in conference abstracts were excluded. In era of symptomatic PHPT, while they have become rare addition, the bibliographies of relevant citations were in the currently prevalent asymptomatic presentation evaluated for any additional appropriate citation. of PHPT. Nonetheless, extensive screening of patients with asymptomatic PHPT revealed that a consistent proportion experiences hypercalciuria, asymptomatic Clinical aspects renal microlithiasis detected by ultrasound examination Kidney stones in PHPT patients and mild decreases in kidney function. In the recent past, the effort of the Kidney Disease: Symptomatic kidney stones occurred in PHPT series from Improving Global Outcomes (KDIGO), an international 1970s and 1980s in 40–60% of PHPT patients. In the kidney disease guideline development entity, that has last two decades, symptomatic kidney stones diagnosis produced guidelines on kidney diseases since 2008, dramatically dropped to 10–20% of PHPT patients. highlighted that mild kidney function impairment affects Indeed, imaging screening revealed that asymptomatic healthy (1). Because of the morbidity and mortality kidney stones occur more frequently. In asymptomatic associated with reduced kidney function, early diagnosis PHPT patients, stones are common with a prevalence is important and should be pursued in at-risk populations. ranging from 25% to 55% in different series (3, 4, 5), This burden of considerations pushed the Panel with stones being bilateral in 16.4% of PHPT patients (5). of the Forth Workshop on asymptomatic PHPT to Moreover, kidney stones occur with a similar prevalence European Journal European of Endocrinology extend the recommendations for parathyroid surgery in normocalcaemic (15%) and hypercalcaemic (19%) to the occurrence of hypercalciuria and/or lithogenic PHPT patients (6). Renal calcifications (kidney stones and biochemical urine, of asymptomatic kidney stones nephrocalcinosis) were associated with higher calcium/ detected by imaging and of a slightly reduced estimated creatinine excretion rate in a series of surgically proven glomerular filtration rate (2). Besides the attention to PHPT patients (4), while any difference could be detected mild injury of kidney function promoted by the KDIGO in another series (5). panel of experts, molecular insight about renal handling The precise pathogenesis of urinary stone formation of calcium, phosphate and other electrolytes have been in the general population, and also in PHPT patients, accumulated and some of them have been shown to is unknown: it is likely related to crystal formation, modulate the clinical presentation of PHPT. mainly in the early stages of nucleation, aggregation The aim of the present review was to provide a and agglomeration of crystals. The presence of multiple revision of the clinical and molecular aspects of kidney inorganic and organic constituents in urine, and involvement in the current asymptomatic PHPT patients. interactions between promoters and inhibitors further The main source of data acquisition included PubMed modulate the stone formation. Crystals retention is a search strategies. Papers published in the last 10 years, key factor. In PHPT patients with kidney stones, both from 2005 until now, were screened until April 30th, 2016. interstitial apatite plaques, also known as Randall plaques, Original studies and meta-analysis were included, while which are common in idiopathic calcium oxalate stone case reports were reported only when any other consistent formation, and intratubular crystal deposits, common evidence was available. Search strategies used the following in calcium phosphate stone formation, have been found as key words: ‘primary hyperparathyroidism’ and ‘kidney (7). Several factors may promote precipitation of crystals: stones’, or ‘kidney disease’, or ‘CKD’, or ‘nephrolithiasis’ increased renal calcium excretion and increased urine www.eje-online.org Downloaded from Bioscientifica.com at 09/30/2021 09:13:15PM via free access Review C Verdelli and S Corbetta Kidney disease in primary 176:1 R41 hyperparathyroidism phosphate, increased urine oxalate, increased urine with calcium phosphate and with calcium oxalate are sodium, decreased urine citrate concentrations and known risk factors for nephrolithiasis, while risk factors proteinuria. Hypercalciuria is the main risk factor for for nephrocalcinosis are not clearly defined (Fig. 1). kidney stone development in PHPT patients (8). Evidence, Hypercalciuria, defined as urine calcium excretion not confirmed by other studies, also suggested that >4 mg/kg body weight/24 h in the presence of conserved relative high urine oxalate excretion and low urine citrate kidney function, occurred in about two-thirds to three- levels contribute to kidney stone risk in PHPT patients (3), quarters of PHPT patients in recent series (3, 13). Obesity while the role of urine phosphate, magnesium, sodium has been indicated as a risk factor for hypercalciuria