Hypocitraturia Is an Untoward Side Effect of Human Parathyroid Hormone (hPTH) 1-34 Therapy in Hypoparathyroidism That May Increase Renal Calcifications
Presentation Number: OR06-1
Date of Presentation: April 4th, 2017
Rachel I Gafni*1, Craig B Langman2, Lori C. Guthrie3, Beth Brillante1, Robert James4, Nancy A Yovetich4, Alison M Boyce3 and Michael T. Collins3
1National Institutes of Health, 2Feinberg School of Medicine, Northwestern University, Chicago, IL, 3Section on Skeletal Disorders and Mineral Homeostasis, Bethesda, MD, 4Rho, Inc, Chapel Hill, NC
Background: Subcutaneous hPTH therapy can effectively manage hypocalcemia in patients with hypoparathyroidism (hypoPTH), with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal co-morbidities of hypoPTH: nephrocalcinosis (NC) and nephrolithiasis (NL). Urinary citrate promotes the solubility of urinary calcium; hypocitraturia is a known risk factor for NC/NL. The prevalence of hypocitraturia in hPTH-treated patients is unknown.
Methods: Thirty patients with hypoPTH were treated with hPTH 1-34 for up to 5 years, to maintain blood calcium at 7.6-9 mg/dL. Twenty-four-hour urinary calcium (Ca), citrate (cit), and Ca/cit ratios were measured at baseline (BL), every 6 months on hPTH, and at follow-up after stopping hPTH. Renal ultrasound and CT were performed annually.
Results: At BL, the geometric mean (95% CL) for Ca was 349 mg/d (292,418; nl<250) and for cit was 568 mg/d, (415, 777; nl 250-1190), with a Ca/cit of 0.61 mg/mg, (0.465, 0.794; target<0.7). After 6 mos of hPTH, Ca and cit had decreased (245 mg/d, p<0.01 and 316 mg/d, p<0.01, respectively), resulting in an increased Ca/cit (0.81mg/mg (0.499,1.311), p=NS) that continued to increase (Ca/cit 1.03 mg/mg at last visit on hPTH, p<0.05). In 14 subjects, K-citrate (30-60 meq/d) was supplemented with varying responses. Overall, compared to BL, cit levels remained low (p<0.01) and Ca/cit remained elevated (p<0.02) while on hPTH. At follow-up, compared to the last measures on hPTH, cit rose to 601 mg/d (p<0.01), reducing the Ca/cit to 0.49 mg/mg; (0.392, 0.579; p<0.01). Ca rose to 270 mg/d (203, 359), which was higher than the last measure on hPTH (203 mg/d, p<0.05), but still lower than BL (p<0.05). Serum bicarbonate was decreased at the last measure on hPTH compared to BL (25.6 vs 27.5 mmol/L, p<0.01), and remained lower than BL at follow-up (26 mmol/L, p=0.04). eGFR increased on hPTH (86 vs. 95 mL/min, p<0.001) and returned to baseline at follow-up. Urine pH was unchanged throughout. Total daily hPTH 1-34 dose was negatively correlated with cit (r=-0.46; p<0.001) and positively correlated with Ca/cit (r= 0.37; p<0.001). On serial imaging, 6 subjects never showed NC/NL; 8 had NC/NL prior to hPTH that did not progress, and 16 developed new or progressive NC/NL after starting hPTH.
Conclusions: Proximal renal tubular acidosis is a known effect of excess PTH, both experimentally and in primary hyperparathyroidism. Metabolic acidosis reduces tubular secretion of citrate, which may lead to hypocitraturia and increased NC/NL. Our data demonstrate that, while hPTH 1-34 therapy might be promising for hypocalcemia management in hypoparathyroidism, hypocitraturia is an untoward effect that may result in an increased risk of renal calcifications. Thus, with increasing use of hPTH in hypoPTH, close monitoring and treatment for hypocitraturia may be indicated to prevent new-onset or progression of NC/NL.
Disclosure: RIG: Coinvestigator, Shire. LCG: Coinvestigator, Shire. BB: Coinvestigator, Shire. MTC: Investigator, Shire. Nothing to Disclose: CBL, RJ, NAY, AMB