Successful Reversal of Tarak Srivastava, MD,a Shahryar Jafri,a William E. Truog, MD,b Judith Sebestyen Furosemide-InducedVanSickle, MD,a Winston M. Manimtim, MD,b Uri S. Alon, MDa Secondary Hyperparathyroidism With Cinacalcet abstract Secondary hyperparathyroidism (SHPT) is a rare complication of furosemide therapy that can occur in patients treated with the loop diuretic for a long period of time. We report a 6-month-old 28-weeks premature infant treated chronically with furosemide for his bronchopulmonary dysplasia, who developed hypocalcemia and severe SHPT, adversely affecting his bones. Discontinuation of the loop diuretic and the addition
of supplemental calcium and calcitriol only partially reversed the SHPT, aSections of Nephrology, Bone and Mineral Disorder Clinic, bringing serum parathyroid hormone level down from 553 to 238 pg/mL. and bNeonatology, The Children’s Mercy Hospitals and Clinics, University of Missouri at Kansas City, Kansas City, After introduction of the calcimimetic Cinacalcet, we observed a sustained Missouri normalization of parathyroid hormone concentration at 27 to 63 pg/mL and, with that correction, of all biochemical abnormalities and healing of the Drs Srivastava and Alon conceptualized and designed the study and drafted the initial bone disease. No adverse effects were noted. We conclude that in cases of manuscript; Drs Truog, Manimtim, Sebestyen SHPT due to furosemide in which traditional treatment fails, there may be VanSickle, and Mr Jafri carried out the initial room to consider the addition of a calcimimetic agent. analyses and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. DOI: https://doi.org/10.1542/peds.2016-3789 Furosemide therapy in the endocrinopathy may persist for a Accepted for publication Mar 10, 2017 neonatal/infantile period is well prolonged period. Address correspondence to Uri S. Alon, MD, Section known to be associated with of Nephrology, The Children’s Mercy Hospital, 2401 medullary nephrocalcinosis from In recent years, a calcimimetic agent, Gillham Rd, Kansas City, MO 64108. E-mail: ualon@ cmh.edu hypercalciuria1, 2caused by the Cinacalcet, which acts on the calcium- PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, loop diuretic. A less known sensing receptor 9has become available complication of chronic treatment to suppress PTH. The calcimimetic 1098-4275). with furosemide– is the development agent changes the configuration of Copyright © 2017 by the American Academy of Pediatrics of secondary3 6 hyperparathyroidism the calcium-sensing receptor in the (SHPT). The latter is attributed parathyroid glands, making them more FINANCIAL DISCLOSURE: The authors have to the hypercalciuria, leading to the sensitive to circulating serum calcium, indicated they have no financial relationships development of hypocalcemia, which resulting in decreased secretion of relevant to this article to disclose. FUNDING: Supported by the Sam and Helen Kaplan stimulates6, parathyroid7 hormone (PTH) PTH. Although originally created secretion, but recent literature for use in adults with SHPT, there Research Fund in Pediatric Nephrology and Eric McClure Research Fund in Pediatric Bone and also suggests an additional, direct have been now several reports of Mineral Disorders. stimulating effect of furosemide on the successful use of this agent in children 8 – POTENTIAL CONFLICT OF INTEREST: The authors parathyroid glands. It is expected that with SHPT from various10 13 genetic and have indicated they have no potential conflicts of discontinuation of the loop diuretic, at acquired etiologies. We report interest to disclose. times combined with supplementation our novel experience in a premature with calcium and active vitamin infant with severe bronchopulmonary To cite: Srivastava T, Jafri S, Truog WE, et al. D metabolites, will reverse the dysplasia (BPD) necessitating long- Successful Reversal of Furosemide-Induced Sec SHPT. However, if the parathyroid term treatment with furosemide who ondary Hyperparathyroidism With Cinacalcet. Pedi glands achieve a significant level of developed SHPT. After observing only atrics. 2017;140(6):e20163789 hyperplasia, the task of controlling partial response to traditional therapy SHPT will be difficult, and the with calcium and calcitriol, the SHPT Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 140, number 6, December 2017:e20163789 Case Report
Srivastava et al 2017 ROUGH GALLEY PROOF Successful Reversal of Furosemide-Induced https://doi.org/10.1542/peds.2016-3789 December 2017 Secondary Hyperparathyroidism With Cinacalcet 6 140 Pediatrics VDR tapered and discontinued next, and was successfully reversed with CASRwith inheritedPHEX CYP27B1 forms ofCYP2R1 rickets – Cinacalcet. DMP1and/orCLCN7 osteopetrosisSOST LRP4 (namelySNX10 , finally Cinacalcet was stopped (Table 1, , , , , weeks 11.5 16.5). The child was Case Report TMFSF11 TNFRSF11A OSTM1 , , , , , then able to maintain serum calcium , , and ) and PTH levels in their normal ’ were negative. A microarray did not ranges until discharge 8 weeks later. The child was born at 28 weeks identify any deletion or duplication. At follow-up a month later, serum gestation with a birth weight of Calcitriol was added to address calcium and PTH were normal at 830 g. He was transferred from his his hypocalcemia. Over the next 3 10.2 mg/dL and 78 pg/mL, respectively. weeks, his serum PTH decreased but The child tolerated therapy with birth hospital at 2 months of age − for ongoing needs of prematurity, remained elevated at 257 pg/mL Cinacalcet without any adverse severe BPD, and possible need for (Table 1, week 3.4). At this point, effects. Throughout this course, tracheostomy. On admission to our our team was consulted, and the his serum creatinine and urine institution, furosemide was added diagnosis of furosemide-induced calcium/creatinine ratio remained to his ongoing thiazide therapy SHPT was made. Furosemide was normal. The renal ultrasound to treat his respiratory condition. discontinued and the chlorothiazide on last follow-up showed no At age 5.5 months, he underwent dose doubled. In coming weeks, a nephrocalcinosis. Serum ALP, which tracheostomy and placement of further decrease in PTH levels was was originally elevated, gradually ventriculoperitoneal shunt for noted, but the dose of calcitriol and normalized. Follow-up radiographs hydrocephalus. MRI of the brain calcium supplementation had to be done at 1 year of age showed normal performed for evaluation of the decreased to avoid hypercalcemia. mineralization with resolution of ventriculoperitoneal shunt showed Nevertheless, despite sustained metaphyseal cupping and fraying severe demineralization of the normalization of serum calcium over (Fig 1). this 6-week period, his serum PTH bones (Fig 1). The skeletal survey Discussion conducted the next day showed remained elevated (Table 1, week 0). abnormal bony demineralization After discussion with the family, a concerning for a metabolic bone decision was made to initiate oral disorder. That day serum ionized Cinacalcet 3 mg/day (0.4 mg/kg/day) Furosemide is a potent loop diuretic – calcium (iCa) was 0.99 mmol/L in 2 divided doses. Over the next with action in the loop of Henle that (normal 1.13 1.37), and he was 2 weeks (Table 1: Cinacalcet Course A), results in decreased sodium and started on calcium supplementation. PTH normalized at 15 to 25 pg/mL. water reabsorption; it is often used − 14 Further detailed evaluation in the Due to hypocalcemia, calcium in infants with BPD. However, coming days (Table 1, week 7.0), supplementation was increased. its action also results in decreased when his chronological age was 6 With serum PTH and calcium levels calcium reabsorption because
months and weight 6.3 kg, detected within their normal range, Cinacalcet calcium and sodium15 reabsorption are decreased serum calcium (8.9 mg/dL); was subsequently discontinued coupled at this site. The increased iCa 1.09 mmol/L; elevated PTH (Table 1, week 2.0). Within the urinary calcium excretion may
(553 pg/mL), alkaline phosphatase next 2 weeks, the serum PTH result in formation of medullary1,2 (ALP; 420 U/L), and 1,25(OH) 2- rebounded to 151 to 234 pg/mL. nephrocalcinosis or stones. In vitamin D (689 pg/mL); and normal This suggested significant older patients, furosemide has also phosphorus (5.4 mg/dL), 25(OH)- hyperplasia of the parathyroid glands been reported to be associated with vitamin D (65 ng/mL), and urine requiring sustained pharmacological decreased bone– mineral density,
calcium/creatinine ratio (0.22 mg/mg). suppression of PTH. An attempt osteoporosis,16 18 and high risk for At that time, his treatment of BPD to image the parathyroid glands fractures. In addition, there have included furosemide (3 mg/kg/day), by using neck ultrasound failed been reports– about the association of
chlorothiazide (22.5 mg/kg/day), because of neck size and presence the loop 3diuretic8 with5 development and prednisone (0.5 mg/kg every of tracheostomy. At this point, of SHPT. Coe et al in 1973 48 hours). Renal ultrasound showed Cinacalcet was reinitiated (Table 1: demonstrated that adults treated no medullary nephrocalcinosis. Cinacalcet Course B) with with furosemide had elevated PTH
His nutritional formula provided concomitant calcitriol and calcium similar to adults with persistent 6 elemental calcium, phosphorus, supplementation. Serum PTH hypercalciuria. In 1985, Fujita et al and vitamin D of 603 mg/day, eventually normalized and stayed showed that adults treated for a 437 mg/day, and 260 U/day, within the normal range for the next week with oral furosemide had respectively. Genetic mutation 12 weeks. Calcitriol was discontinued elevated urine calcium (effect on analysis for conditions associated first, calcium supplementation was loop of Henle) and cyclic adenosine Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 Srivastava et al
Srivastava et al 2017 ROUGH GALLEY PROOF Successful Reversal of Furosemide-Induced https://doi.org/10.1542/peds.2016-3789 December 2017 Secondary Hyperparathyroidism With Cinacalcet 6 140 Pediatrics range (Table 1: Cinacalcet Course A). After Cinacalcet was stopped, PTH levels immediately rebounded and were brought back to normal with the reintroduction of the calcimimetic. We believe that the hormonal rebound provides a proof of concept that the suppression of PTH was the result of treatment with Cinacalcet and not coincidental.
5 Coe et al reported that SHPT associated with persistent hypercalciuria was secondary to hyperplasia of the glands and
would respond to calcium3 infusion. FIGURE 1 Venkataraman et al reported that MRI (left panel) at 6 months of age showing massive expansion of the calvarial vault suggestive autopsy in one of the premature of metabolic bone disease. Radiograph of the right wrist (right upper panel) performed the next infants who developed furosemide- day showing diffuse demineralization with widening and flaring of the metaphysis. The follow-up radiograph (right lower panel) done at 1 year of age, 4 months after initiation of Cinacalcet therapy, induced SHPT showed enlarged shows normalization of bone mineralization and metaphyseal anatomy. parathyroid glands. Our attempt to image the parathyroid glands was not successful due to presence of tracheostomy. However, on the basis monophosphate excretion (effect despite normal urine calcium of the course of events, we believe of elevated PTH). More recently, excretion, which could be explained that also in our case, the parathyroid cross-sectional analyses of large data by adjunctive thiazide therapy glands achieved a significant level sets from the United States, Brazil, or a calcium-depleted skeleton. of hyperplasia making the task of and Australia have shown the loop Another possible mechanism for controlling SHPT more difficult; diuretic to be associated with– SHPT the development of SHPT is based specifically, if left to conventional in adults with both normal4,7, 19 and21 on the new observation of a direct treatment, the state of SHPT would reduced renal function. 3 stimulatory effect of furosemide on have persisted for a prolonged Similarly, Venkataraman et al the parathyroid cells8 acting via the period. Cinacalcet, a calcimimetic communicated this complication NKCC1 receptor. that acts on the calcium-sensing in 1983 in 4 preterm infants receptor to suppress PTH secretion, who consequently developed In the present case, the infant, was previously shown to be effective hyperparathyroid bone disease, but with ventilator-dependent BPD, and safe in reversing– various types no additional pediatric cases have was treated with furosemide for of primary and10 SHPT13 in both adults since been reported. Although SHPT 4 months, when the brain MRI and children. Furthermore,8 as from furosemide has been reported followed by skeletal radiographs recently shown by Muller et al, in adults, it seems to be a rarity in the showed severe osteopenia (Fig it negates the direct effect of pediatric population. 1). The biochemical evaluation furosemide on the parathyroid that followed was consistent with glands. It thus seems to be the The mechanism of furosemide- furosemide-induced SHPT (Table ideal drug to use in a circumstance induced SHPT has been 1). After calcitriol and calcium such as in our patient for rapid conventionally attributed to supplementation decreased PTH and safe correction of SHPT. As – increased urinary calcium excretion, only partially, furosemide was with our previous experience with but that alone does not completely discontinued. Over the next 3 weeks, vitamin D resistant rickets and
explain the development of 22 serum PTH further decreased but pseudohypoparathyroidism type 1b, SHPT from calciuria. Riss et al remained elevated. It was realized and as was the case in our current showed that although thiazides that further suppression of PTH patient, bringing serum PTH back decrease urine calcium excretion secretion may come at the cost into the normal range resulted in
in primary hyperparathyroidism, of hypercalcemia. Cinacalcet was normalization of serum ALP10, and11 they do not affect serum PTH therefore added, and subsequently healing of the bone disease. level. Similarly, our case had SHPT PTH was decreased to its normal As previously observed in animals Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 140, number 6, December 2017 3
Srivastava et al 2017 ROUGH GALLEY PROOF Successful Reversal of Furosemide-Induced https://doi.org/10.1542/peds.2016-3789 December 2017 Secondary Hyperparathyroidism With Cinacalcet 6 140 Pediatrics TABLE 1 Effect of Therapy With Elemental Calcium, Calcitriol, and Cinacalcet Before and On and Off Cinacalcet on Serum Biochemical Variables in a Premature Infant With Furosemide-Induced SHPT Time, wk Elemental Calcitriol, µg/d Cinacalcet, mg/d iCa, mmol/L Serum P, mg/dL Serum PTH, Serum ALP, U/L Calcium, mg/d pg/mL Reference range — — — 1.13–1.37 4.2–7.0 10–89 110–320 Pre-cinacalcet −7.0 560 — 1.09 5.4 553 420 −6.1 560 0.15 — 1.21 4.9 531 419 −5.0 560 0.30 — 1.13 5.4 484 553 −3.4a 560 0.30 — 1.26 6.6 257 — −2.6 560 0.30 — 1.43 6.3 161 — −1.4b 280 0.15 — 1.27 5.9 157 336 0.0 280 0.15 — 1.30 5.6 238 335 Cinacalcet course A 0.6 280 0.15 6.9 1.17 5.4 137 — 1.0 280 0.15 7.8 1.33 5.7 25 — 1.6 280 0.15 6.0 1.01 6.0 15 — 2.0c 600 0.15 6.0 1.12 6.0 25 — Off cinacalcet 2.6 600 0.15 — 1.27 6.2 234 — 3.6 600 0.15 — 1.31 5.9 151 — Cinacalcet course B 4.6 600 0.15 3.5 1.26 5.1 117 216 6.6d 780 0.15 7.2 1.21 7.6 119 — 8.0 780 0.15 6.9 1.19 7.1 10 — 9.0 780 0.15 6.6 1.17 7.6 90 — 10.5 780 0.15 3.3 1.31 5.9 63 — 11.5 780 0.15 3.3 1.34 8.7 92 — 12.5 780 — 5.4 1.29 5.7 104 — 13.5 780 — 4.8 1.19 8.2 27 — 14.5 760 — 4.8 1.23 7.2 44 — 15.5 240 — 4.8 1.27 6.9 28 — 16.5 — — 2.4 1.28 7.6 55 — Off cinacalcet 18.0 — — — 1.38 7.3 63 190 20.5 — — — 1.32 5.8 35 — 24.5 — — — 1.37 5.9 45 — Serum creatinine ranged between 0.22 and 0.29 mg/dL throughout the study period (reference range 0.06–0.45 mg/dL). a Furosemide was discontinued and dose of chlorothiazide doubled. b Calcium and calcitriol supplementation were decreased due to hypercalcemia (iCa 1.43 at week −2.6). c Calcium supplementation was increased due to hypocalcemia (iCa 1.01 at week 1.6). d Calcium supplementation was increased due to hypocalcemia (iCa 1.06 at week 6).
’ Acknowledgments
and humans, Cinacalcet s main the loop diuretic, and if diuresis is adverse effect was the development still required, the use of a thiazide The off-label use of Cinacalcet in of hypocalcemia, requiring the diuretic is preferable. In case this furosemide-induced SHPT was adjustment of supplemental active maneuver does not help reverse extensively discussed with the vitamin D metabolite to sustain SHPT, calcium and active vitamin family. The family gave serum iCa concentration10,11, 23 within its D metabolites need to be added. If their consent for publication normal range. satisfactory suppression of PTH is of the case report. still not noted, we now have in our Abbreviations armamentarium the calcimimetic Several lessons can be learned ’ from the present case. In children agent. We recommend, on the basis chronically treated with a loop of others and our own experience, ALP: alkaline phosphatase diuretic, close attention should be continuing to monitor serum iCa BPD: bronchopulmonary paid to their mineral metabolism, and urine calcium closely because dysplasia specifically periodic assessment some patients under calcimimetic iCa: ionized calcium of serum iCa and PTH levels and treatment develop hypocalcemia PTH: parathyroid hormone urine calcium should be performed. responding to calcitriol and/ SHPT: secondary Once abnormalities are detected, all or hypercalciuria responding to hyperparathyroidism efforts should be made to discontinue thiazides. Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 Srivastava et al
Srivastava et al 2017 ROUGH GALLEY PROOF Successful Reversal of Furosemide-Induced https://doi.org/10.1542/peds.2016-3789 December 2017 Secondary Hyperparathyroidism With Cinacalcet 6 140 Pediatrics References hyperparathyroidism in the Chronic L. Loop diuretics increase bone Renal Insufficiency Cohort. Nephrol turnover and decrease BMD in 1. Hufnagle KG, Khan SN, Penn D, Dial Transplant. 2011;26(4):1258 1265 osteopenic postmenopausal women: Cacciarelli A, Williams P. Renal – results from a randomized controlled calcifications: a complication 8. Muller ME, Forni Ogna V, Maillard study with bumetanide. J Bone Miner of long-term furosemide therapy M, et al. Furosemide stimulation of Res. 2006;21(1):163 170 in preterm infants. Pediatrics. parathormone in humans: role of the – 1982;70(3):360–363 calcium-sensing receptor and the 17. Rejnmark L, Vestergaard P, Mosekilde renin-angiotensin system. Pflugers L. Fracture risk in patients treated 2. Saarela T, Lanning P, Koivisto M, Arch. 2015;467(12):2413 2421 with loop diuretics. J Intern Med. Paavilainen T. Nephrocalcinosis in – 2006;259(1):117 124 full-term infants receiving furosemide 9. Alon US. Diseases and clinical – treatment for congestive heart applications of the calcium sensing 18. Carbone LD, Johnson KC, Bush AJ, failure: a study of the incidence receptor. Pediatr Endocrinol Rev. et al. Loop diuretic use and fracture in and 2-year follow up. Eur J Pediatr. 2007;5(1):482–488 postmenopausal women: findings from the Women s Health Initiative. Arch 1999;158(8):668–672 10. Srivastava T, Krudys J, Mardis NJ, ’ Intern Med. 2009;169(2):132 140 3. Venkataraman PS, Han BK, Tsang Sebestyen-VanSickle J, Alon US. – RC, Daugherty CC. Secondary Cinacalcet as adjunctive therapy in 19. Vasco RF, Moyses RM, Zatz R, Elias hyperparathyroidism and bone pseudohypoparathyroidism type 1b. RM. Furosemide increases the risk disease in infants receiving long-term Pediatr Nephrol. 2016;31(5):795–800 of hyperparathyroidism in chronic furosemide therapy. Am J Dis Child. kidney disease. Am J Nephrol. 11. Srivastava T, Alon US. Cinacalcet as 1983;137(12):1157 1161 2016;43(6):421 430 – adjunctive therapy for hereditary – 4. Corapi KM, McMahon GM, Wenger JB, 1,25-dihydroxyvitamin D-resistant 20. Stein MS, Scherer SC, Walton SL, Seifter JL, Bhan I. Association of loop rickets. J Bone Miner Res. et al. Risk factors for secondary diuretic use with higher parathyroid 2013;28(5):992–996 hyperparathyroidism in a nursing hormone levels in patients with normal home population. Clin Endocrinol (Oxf). 12. Silverstein DM, Kher KK, Moudgil renal function. JAMA Intern Med. 1996;44(4):375 383 A, Khurana M, Wilcox J, Moylan K. – 2015;175(1):137 138 – Cinacalcet is efficacious in pediatric 21. Vaidya A, Curhan GC, Paik JM, 5. Coe FL, Canterbury JM, Firpo JJ, dialysis patients. Pediatr Nephrol. Kronenberg H, Taylor EN. Hypertension, Reiss E. Evidence for secondary 2008;23(10):1817–1822 antihypertensive medications, hyperparathyroidism in idiopathic and risk of incident primary 13. Alon US, VandeVoorde RG. Beneficial hypercalciuria. J Clin Invest. hyperparathyroidism. J Clin Endocrinol effect of cinacalcet in a child with 1973;52(1):134 142 Metab. 2015;100(6):2396 2404 – familial hypocalciuric hypercalcemia. – 6. Fujita T, Delea CS, Bartter FC. The Pediatr Nephrol. 2010;25(9):1747–1750 22. Riss P, Kammer M, Selberherr A, et al. effects of oral furosemide on the The influence of thiazide intake on 14. Najak ZD, Harris EM, Lazzara A Jr, Pruitt response of urinary excretion of calcium and parathyroid hormone AW. Pulmonary effects of furosemide in cyclic adenosine monophosphate levels in patients with primary preterm infants with lung disease. and phosphate to parathyroid hyperparathyroidism. Clin Endocrinol J Pediatr. 1983;102(5):758–763 extract in normal subjects. Nephron. (Oxf). 2016;85(2):196–201 1985;41(4):333–336 15. Brater DC. Update in diuretic therapy: 23. Pattaragarn A, Fox J, Alon US. Effect 7. Isakova T, Anderson CA, Leonard MB, clinical pharmacology. Semin Nephrol. of the calcimimetic NPS R-467 on et al; Chronic Renal Insufficiency 2011;31(6):483–494 furosemide-induced nephrocalcinosis Cohort (CRIC) Study Group. 16. Rejnmark L, Vestergaard P, in the young rat. Kidney Int. Diuretics, calciuria and secondary Heickendorff L, Andreasen F, Mosekilde 2004;65(5):1684–1689
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Srivastava et al 2017 ROUGH GALLEY PROOF Successful Reversal of Furosemide-Induced https://doi.org/10.1542/peds.2016-3789 December 2017 Secondary Hyperparathyroidism With Cinacalcet 6 140 Pediatrics Successful Reversal of Furosemide-Induced Secondary Hyperparathyroidism With Cinacalcet Tarak Srivastava, Shahryar Jafri, William E. Truog, Judith Sebestyen VanSickle, Winston M. Manimtim and Uri S. Alon Pediatrics originally published online November 30, 2017;
Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/11/28/peds.2 016-3789 References This article cites 23 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/11/28/peds.2 016-3789#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Nephrology http://www.aappublications.org/cgi/collection/nephrology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml
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