Key words : Biopsy, Kidney transplant, Microcalcinosis, Mineral and bone disorder, Parathyroid hormone

Introduction

Kidney transplant (KT) is considered as the treat-ment of choice for patients with end-stage renal disease. Successful transplant corrects chronic kidney disease-mineral and bone disorder (CKD-MBD) to a large extent; however, CKD-MBD persists in 80% of the recipients in the first year after transplant.¹ After KT, CKD-MBD can manifest as persistent secondary hyperparathyroidism (pHPT) or de novo CKD-MBD, depending on the bone damage that occurred previously, and from immunosuppression.²

Graft dysfunction because of allograft calcification as a result of pHPT has been described in patients at least 3 to 6 months after transplant. We report a case of pHPT with normocalcemia leading to rapid graft dysfunction in the early transplant period, which showed evidence of metastatic calcification in biopsy.

Case Report

A 48-year-old renal allograft recipient was admitted with asymptomatic graft dysfunction 3 weeks after KT. He had received an ABO-compatible transplant from his father. Human leukocyte antigen (HLA) mismatch was 6/12. Cytomegalovirus immunog-lobulin G status was donor positive/recipient positive. The patient’s induction regimen included rabbit antithymocyte globulin, with cumulative dose of 3mg/kg. The patient had an uneventful posto-perative course and was discharged on prednisolone, mycophenolate mofetil, and tacrolimus with a nadir creatinine of 1.31 mg/dL after 10 days. Discharge tacrolimus level was 7.96 ng/mL by chemilumi-nescent microparticle immunoassay method.

History showed that, at aged 36 years, the patient underwent renal biopsy indicated for proteinuria and renal dysfunction (serum creatinine level of 1.61 mg/dL). Light microscopy revealed focal segmental glomerular sclerosis. Direct immunof-luorescence was 1+ positive only for C3. Interstitial fibrosis and tubular atrophy were mild (around 8%-10%). Electron microscopy was not done. Autoim-mune markers including antinuclear antibody, antineutrophil cytoplasmic antibodies, and comple-ments, were normal. The patient received prednisolone 50 mg once per day and mycophenolate mofetil 360 mg 3 times per day, and he gained complete remission after 3 months of treatment. However, the patient relapsed soon thereafter and was in partial remission for the next 2 years. The patient was treated with tacrolimus 2.5mg twice per day for 6 months before stopping all immunosup-pression as he did not respond; he was then treated conser-vatively with medical management of CKD stage 2 for another 3 years without any major events.

After this period, the patient shifted to alternative medicines but developed rapid progression of underlying kidney disease and developed uremic symptoms. He was started on maintenance hemodialysis in 2019. He was referred to our center for feasibility of renal transplant with his father as donor after being on maintenance hemodialysis for 3.5 years. During evaluation, he was found to have severe secondary hyperparathyroidism. Serum calcium was 8.0 mg/dL, serum phosphate was 7.5 mg/dL, and intact parathyroid hormone (PTH) was >2000 pg/mL with vascular calcifications (Figure 1). Ultraso-nography showed hyperplasia of bilateral inferior parathyroid glands. Parathyroid adenoma was ruled out on technetium Tc 99m Sestamibi scan.

The patient received phosphate binders, vitamin D, activated vitamin D (calcitriol), and calcimimetic (cinacalcet) sequentially, with regular monitoring of MBD parameters. Secondary hyperparathyroidism improved gradually over a period of 6 months and was well controlled before KT. Serial investigations are listed in Table 1. Serum creatinine was 1.57 mg/dL on readmission and showed a rising trend. Prerenal causes, tacrolimus toxicity, and infections were ruled out. On admission, 24-hour urine protein was 896 mg/dL and intact PTH was 970 pg/mL; cytome-galovirus and BK virus were not detected on quantitative polymerase chain reaction. The patient had normal graft Doppler ultrasonography and normal chest and whole body radiography. Levels of 24-hour urine calcium, phosphorus, oxalate, and uric acid were also normal.

Graft biopsy revealed normal nonproliferative glomeruli. Tubular atrophy and interstitial fibrosis involved about 8% to 10% of sampled cortex. Tubules showed prominent cytoplasmic vacuolar change and patchy acute injury with epithelial simplification and loss of brush borders. Several foci of tubular and parenchyma calcific deposits (microcalcinosis) were observed (Figure 2). There was no glomerulitis, peri-tubular capillaritis, crescent formation, intraca-pillary thrombi, interstitial inflammation, tubulitis, inclusion bodies, or viral cytopathic changes. Im-munofluorescence and C4d results were negative.

In view of biopsy findings and high intact PTH levels, Sestamibi scan was repeated; scan results suggested inferior parathyroid hyperplasia. He was treated with vitamin D3 cholecalciferol (60?000 U twice weekly), activated vitamin D (calcitriol; 0.25 ?g/day), and calcimimetic (cinacalcet; 30 mg/day). Secondary hyperparathyroidism gradually improved over 6 weeks along with creatinine returning to nadir value of 1.31 mg/dL. Intact PTH trends are illustrated in Figure 3.

Discussion

Recipients with pHPT have increased risk of graft loss, bone fractures, and mortality and worse cardiovascular outcomes, as reported by Pihlstrom and colleagues in 1840 patients.³ Studies from the 1980s have suggested that prevalence of pHPT was 10% to 60%, whereas current research has reported prevalence as high as 80%.4-6 A uniform cutoff does not exist for PTH level to clearly diagnose pHPT. A 12-month period is allowed posttransplant for normalization of PTH after which a PTH value of more than 2 times the upper limit (>130 pg/mL) is diagnosed as pHPT.7

Long dialysis vintage, severe preexisting secon-dary hyperparathyroidism, biochemical parameters, vitamin D deficiency, and graft function are factors that can predict development of pHPT.^1,8 Persistent hyper-parathyroid is characterized by an autonomous pattern of PTH secretion, leading to hypercalcemia and hypop-hosphatemia, unlike pretransplant CKD-MBD patients who have hypocalcemia and hyperp-hosphatemia predominantly. This is why transplant recipients resemble those with primary hyperparathyroidism.

Symptoms such as bone pain and pruritus are not generally observed in KT recipients with CKD-MBD because of less severity and different phenotype. Metastatic intratubular calcification due to pHPT leading to graft dysfunction in the early post-transplant period is rare. It was previously described in 2 case reports where it was attributed to uncontrolled secondary hyperparathyroidism at the time of transplant aggravated by tacrolimus toxicity in the first case9 and to overt hypercalcemia requiring emergency parathyroidectomy on day 7 in the second case.¹⁰ Our patient never had hypercalcemia (calcium levels corrected to albumin) or hypercalciuria. Concomitant vitamin D deficiency in our case might have led to a lower level of serum calcium and phosphate.

Other causes of intratubular calcification, inclu-ding primary hyperoxaluria, and acquired causes, such as excess dietary intake of oxalate, enteric hyperoxaluria, toxic exposures, hyperphosphatemia, and calcineurin inhibitor toxicity, were ruled out in our patient. Our patient did not have delayed graft function, which has been previously reported as a risk factor of pHPT, with nephrocalcinosis found within first week post-KT in 17% of patients with delayed graft function.11

Management of pHPT is based on clinical pre-sentation. Patients can be categorized as either presenting with typical features of hypercalcemia or hypophosphatemia or an atypical presentation, where there is an increased level of PTH without hypercalcemia, as in our case. Patients with pHPT with mild to moderate hypercalcemia are treated with cinacalcet (30 mg/day) with dose adjustment at monthly intervals. Parathyroidectomy is planned if there is no response after 6 to 12 months of cinacalcet use.¹² In patients with pHPT with severe hype-rcalcemia, parathyroid surgery is the preferred treatment.¹³ In a randomized controlled trial that compared subtotal parathyroidectomy to cinacalcet , all patients with parathyroidectomy and only 67% with cinacalcet achieved normocalcemia.¹⁴ For patients with hypophosphatemia, management revol-ves around treating secondary hyperparathyroidism itself unless severe hypophosphatemia is present (<1 mg/dL), in which case oral phosphate sup-plements are used. If patients are not hypercalcemic, vitamin D derivatives can be used to increase phosphorus levels. In cases of severe hypophosp-hatemia, parathyroidectomy is preferred.

In patients with pHPT without hypercalcemia, as in our case, the treatment is based on 25-hydroxyvitamin D concentration. If Vitamin D is below 20 ng/mL, cholecalciferol is the recommended initial treatment. If iPTH levels remain elevated despite normalization of 25-hydroxyvitamin D levels, an activated vitamin D derivative, such as calcitriol, should be used at a low dose (0.25 ?g/day). Dose titration should be conducted with calcium monitoring up to a maximum of 0.5 ?g/day. Renal function and vitamin D deficiency are predictors of iPTH levels in KT recipients. In a previous report, iPTH levels returned to normal in 7 of 8 patients who had vitamin D deficiency and were 6 months post-KT.15 Our patient had rapidly worsening graft dysfunction; therefore, along with calcitriol, we used cinacalcet simultaneously instead of sequentially to avoid the deleterious effects of parathyroidectomy in the immediate posttransplant period. Moreover, there was no evidence of adenoma and hypercalcemia, so we tried medical management. Over 6 weeks, we were able to control hyperparathyroidism; the patient continues regular follow-up with monitoring.

Conclusions

Vascular and graft calcification findings are inde-pendent predictors of long-term graft function and overall mortality, making it vital to treat CKD-MBD aggressively before KT. Patients with severe secondary hyperparathyroidism and long dialysis duration before KT require close surveillance. Posttransplant parathyroidectomy should be reserved for patients who do not respond to medical management.

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