Tacrolimus-Associated Acute Calcium Pyrophosphate Crystal Arthropathy in a Kidney Transplant Recipient

Summary: Background: Chronic hypomagnesemia is a known risk factor for calcium pyrophosphate (CPP) crystal deposition, in which Tacrolimus is known to have the adverse effect of hypomagnesemia. There have been case reports that describe CPPD flares in liver and allogenic bone marrow transplant patients associated with tacrolimus use and resultant hypomagnesemia. Surprisingly, despite being the most common transplant, there have been no case reports of renal transplant recipients with tacrolimus-associated CPPD, possibly due to the protective effect of hypocalcemia associated with end-stage renal disease. Our report describes the first known case of CPPD disease associated with tacrolimus use in a renal transplant recipient. Case Presentation: Our patient is a 78-year-old male with history of kidney transplant 30 years ago, chronic hypomagnesemia, and heart failure with reduced ejection fraction who was admitted with bilateral lower extremity swelling for 2 weeks and right lower extremity pain and erythema for 1 day. He was treated for presumed cellulitis and heart failure exacerbation with empiric antibiotics and intravenous furosemide. Tacrolimus 2.5mg twice daily (BID) was started on admission. CRP and ESR were elevated on admission at 21.0 and 80, respectively. Over the following 4 days, the patient developed worsening pain, swelling, and erythema of both knees and left wrist, elbow, and shoulder. He also developed low grade fevers, bilateral extremity tremors, and altered mental status. Magnesium levels were low at 1.3 and CRP/ESR rose to 30/120. Left shoulder, left wrist, and bilateral knee X-rays showed chondrocalcinosis and degenerative changes consistent with CPPD. Arthrocentesis demonstrated sterile synovial fluid, a non-septic white cell count (< 50 000), and was positive for CPP crystals. On admission Day 5 (D5), Tacrolimus was held due to a supratherapeutic 17-hour tacrolimus trough of >30 ng/mL and the patient was started on 24mg oral methylprednisolone to taper. Patients joint pain, low grade fevers and altered mental status resolved over 2 days. On D12, the patient completed 7 days of methylprednisolone and was switched to his maintenance dose of prednisone. Tacrolimus was reintroduced at a dose of 2.5mg BID. On D13, the patient developed recurrence of altered mental status and tremor. Tacrolimus level was 6.1 and the drug was held. Magnesium was 1.9 from 2.2 the prior day. On D14, the patient developed recurrence of right knee, left wrist and shoulder arthritis, and low grade fever. Methylprednisolone was restarted at 16mg oral daily to taper over 14 days, and the patient had improvement in mental status and resolution of pain. Patient was discharged on Tacrolimus 1mg bid with outpatient follow-up. Discussion: Magnesium is known to stimulate pyrophosphate catabolism by being a co-factor to the enzyme pyrophosphatase which catalyses Adenosine triphosphate (ATP) in adenosine diphosphate (ADP)+PPi. Therefore, in the setting of hypomagnesemia, there is decreased hydrolysis activity which leads to elevated pyrophosphate levels and decreased solubility of pyrophosphate in the synovial fluid. It is known that hypomagnesemia can be induced by tacrolimus through a renal loss mechanism in the distal part of the nephron, which can lead to a tacrolimus-induced hypomagnesemia associated to CPPD events. Genetic etiologies such as Gitelman’s syndrome and Bartter syndrome are associated with CPPD due to induced magnesium deficiency. Hypercalcemia in primary hyperparathyroidism is associated with CPPD, therefore Cadiou et al. hypothesize that hypocalcemia can be a protective factor in development of CPPD in patients with chronic kidney failure. In renal transplants NSAIDs are avoided, similar studies with other transplanted organs use colchicine for disease flares and prevention. Colchicine and tacrolimus can be a harmful combination as their metabolism is via CYP3A4 for both drugs, which may increase its concentrations; therefore, some experts prefer to use steroids for acute flairs. On a case reported by Cadiou et al., patient was using tacrolimus, and was changed for everolimus and with magnesium repletion for which after an 8 months slow prednisone taper patient did not experience relapse symptoms. Conclusion: To our knowledge, this is the first case of CPP crystal arthropathy in patients with tacrolimus after kidney transplant. Providers who care for solid-organ transplant recipients and patients on long-term systemic tacrolimus should be aware of tacrolimus-associated CPPD.