Signification of distal urinary acidification defects in hypocitraturic patients

Abstract

Background and objectivesHypocitraturia has been associated with metabolic acidosis and mineral disorders. The aim of this study was to investigate the occurrence of urinary acidification defects underlying hypocitraturia.Materials and methodsThis retrospective observational study included 67 patients (32 men), aged 40.7±15.1 years with hypocitraturia (<1.67 mmol/24-h) and nephrolithiasis, nephrocalcinosis, and/or bone demineralization, referred to our center from 2000 to 2015. We aimed to assess renal distal acidification capacity, prevalence and mechanisms of urinary acidification defects. Patients with low baseline plasma HCO3- (<22 mmol/L) were studied by bicarbonate loading or furosemide/fludrocortisone tests. Patients with normal baseline plasma HCO3- had an ammonium-chloride challenge test. A normal response was a decrease in urinary pH <5.3 and an increase in urinary NH4+ ≥33 μmol/min and defined idiopathic hypocitraturia.ResultsEleven patients (16.4%) had low HCO3- and overt distal acidification defect. Three had a mutation in the gene encoding AE1, 4 had Gougerot-Sjögren syndrome and no cause was found in the remaining 4 cases. Fifty-six patients (83.6%) had normal HCO3-; of those, 33 (58.9%) had idiopathic hypocitraturia. Among the 23 (41%) remaining patients, 12 were unable to increase urinary NH4+ excretion (among them, 8 were able to decrease urinary pH and 4 were not) whereas 11 were able to increase urinary NH4+ excretion but unable to decrease urinary pH. These 11 patients had higher fasting urinary calcium, reflecting bone resorption, than the other 12 patients: median 0.41 [0.24–0.47] vs. 0.22 [0.08–0.37] mmol/mmol creatinine (P = 0.04).ConclusionsPatients with hypocitraturia and normal plasma HCO3- frequently show a latent acidification defect that can be further dissected into one of several subtypes based on urinary pH and NH4+ response to the acid load. Those patients with impaired urine acidification capacity but preserved NH4+ excretion exhibit particularly high calciuria and should be identified to optimize nephrolithiasis prevention.

Incomplete distal renal tubular acidosis in children

“…In addition, subjects with iDRTA do not have chronic extrarenal acidosis, which stimulates NH4 excretion. Moreover, it is known that the urine pH does not necessarily reflect the rate of NH4 + excretion 32,33 . A decreased ability to concentrate the urine may likely be present in entities associated with iDRTA such as interstitial kidney diseases, nephrocalcinosis and urolithiasis.…”

“…Although recurrent stone formers have a risk of vertebral fracture 4 times higher than non‐stone formers, the association of osteopenia and iDRTA is controversial and not clearly demonstrated 21,37,38 . The association of iDRTA with hypocitraturia and preserved NH4+ excretion has been suggested to define a subpopulation of patients with high risk of hypercalciuria 33 . The mechanism of hypocitraturia in iDRTA remains to be clarified.…”

Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes

“…Following ammonium chloride loading or furosemide/fludrocortisone administration, patients with incomplete distal RTA are unable to lower the urine pH to < 5.3 (159,196). More recently it has been shown the patients fall into 3 categories based on their urine pH and ammonia excretion during a furosemide/fludrocortisone test (166). The group with normal urine acidification and defective urine ammonia excretion may involve abnormalities in NHE4, RhBG/RhCG, and cerebroside sulfotransferases that are known to play an important role in ammonia transfer from the thick ascending limb to the collecting duct in the mouse.…”

“…More recently Forni Ogna et al reported that patients can be divided into three separate groups based on the urinary pH and ammonia excretion in response to a urine acidification challenge (Fig. 4) (166). 65% of the total patients were unable to lower their urine pH < 5.3.…”

Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real‐world Data Results from the AlcalUN Study

“…Moreover, metabolic acidosis can also coexist with a blood bicarbonate concentration within the normal range in patients with 3 or without CKD. 4 Overt metabolic acidosis (as well as acid retention) has been shown to be a key independent factor for worsening CKD progression 5 and overall survival. 6 Experimental and clinical studies have also reported close relationships with hyperkalemia, muscle waste, osteopenia, clinical outcomes (such as asthenia), and quality of life.…”