Quiz Page May 2010: Debilitating Pain of the Hands and Feet Following Kidney Transplant

Vadivel, Nidyanandh; Surana, Sikander P.; Galvez-Trevino, Raul; Chandraker, Anil K.

doi:10.1053/j.ajkd.2009.11.027

« Previous Next »American Journal of Kidney Diseases
Volume 55, Issue 5 , Pages A33-A35, May 2010

Quiz Page May 2010:

Debilitating Pain of the Hands and Feet Following Kidney Transplant

Nidyanandh Vadivel, MB, MRCP(UK)
- Transplantation Research Center and Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston, MA
- Address correspondence to Nidyanandh Vadivel, MB, MRCP(UK), Renal Division, Brigham and Women's Hospital, MRB4, 45 Francis St, Boston, MA 02115
Sikander P. Surana, MD
- Transplantation Research Center and Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston, MA
Raul Galvez-Trevino, MD
- Department of Radiology, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston, MA
Anil K. Chandraker, MB, FRCP(UK)
- Transplantation Research Center and Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston, MA

Back to Article Outline

Clinical Presentation

A 52-year-old woman with end-stage renal disease secondary to polycystic kidney disease received a preemptive 1-haplotype–matched living kidney transplant from her brother. The immunosuppressive regimen consisted of basiliximab induction, early steroid withdrawal (5 days), and maintenance tacrolimus and mycophenolate mofetil therapy, as well as valganciclovir, trimethoprim/sulfamethoxazole, metoprolol, hydralazine, famotidine, and simvastatin. The patient had an uneventful early posttransplant course. A month posttransplant, she developed severe throbbing pain in her hands and feet. The pain was worse on weight bearing and exertion. Examination did not show focal muscle, bone, or joint tenderness. Laboratory tests showed a normal basic metabolic profile with a serum creatinine level of 0.8 mg/dL (70.7 μmol/L; estimated glomerular filtration rate of 80 mL/min/1.73 m² [1.3 mL/s/1.73 m²] calculated using the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation), and a tacrolimus level of 8 ng/mL. The bone profile showed the following values: corrected calcium, 10.6 mg/dL (2.7 mmol/L); phosphate, 2.9 mg/dL; serum alkaline phosphatase, 120 U/L (reference range, 36-118 U/L), and parathyroid hormone, 70 pg/mL (70 ng/L; reference range, 10-65 pg/mL [10-65 ng/L]). Oral hydromorphone therapy resulted in partial pain relief. Magnetic resonance imaging (MRI) of her feet was performed (Fig 1).

- View Large Image
- Download to PowerPoint
Figure 1.
(A, B) Sagittal 1.5-Tesla magnetic resonance images acquired using a short tau inversion recovery sequence at the time of diagnosis.

■ How would you approach the diagnosis?

■ What are the radiologic findings on Fig 1?

■ How would you manage this condition?

Back to Article Outline

Discussion

How would you approach the diagnosis?

Bone pain after kidney transplant can be secondary to preexisting bone disease, persistent severe hyperparathyroidism, osteomalacia caused by severe vitamin D deficiency or resistance, osteonecrosis or rapid osteopenia from high-dose corticosteroid therapy, and immunosuppression-related bone marrow edema syndrome (also known as posttransplant bone marrow edema syndrome and calcineurin inhibitor pain syndrome). Our patient had treated hyperparathyroidism with a mildly increased alkaline phosphatase level of 120 U/L (reference range, 36-118 U/L). Vitamin D level also was normal, and she did not have symptoms or signs of trauma, infection, or inflammatory arthritis. Symmetrical lower-limb pain in the post-transplant period, often associated with a mildly increased alkaline phosphatase level, should raise the suspicion of bone marrow edema syndrome. MRI of the feet can confirm the diagnosis.

What are the radiologic findings on Fig 1?

MRI of our patient (Fig 1) showed mild bone marrow and subcutaneous fat edema involving the posterior calcaneus and heels bilaterally. In her case, bone marrow and periarticular soft-tissue edema clinched the diagnosis. However, bone marrow edema on MRI is a nonspecific finding. It may be secondary to trauma/stress injury, disuse osteopenia, reflex sympathetic dystrophy, or inflammatory arthritis. Clinical correlation is crucial to establish this diagnosis. Bone scintigraphy may show increased tracer uptake (a sign of hypervascularization, hyperperfusion, and hypermetabolism) in the affected bones and joints. X-Rays often are not helpful, showing only some degree of osteoporosis.

How would you manage this condition?

Bone marrow edema is a poorly understood and potentially incapacitating condition after transplant. Calcineurin inhibitors often have been implicated in its pathogenesis, possibly through intraosseous vasoconstriction disturbing bone perfusion and permeability, and resulting in bone marrow edema.¹, ² This phenomenon is seen more often in the lower limbs, possibly related to greater venous blood pressure. Sirolimus therapy also has been associated with this condition in one case series,³ as well as in our own experience. In the modern era of transplantation, onset of this condition coincides with the period of maximum immunosuppression in the early posttransplant period.

Decreases in doses of immunosuppressive medications, particularly calcineurin inhibitors, appear to be the most reasonable approach, but may take weeks to be fully effective. Other therapeutic modalities, including clodronate and calcitonin (through osteolysis inhibition), calcium channel blockers (notably nifedipine, through a decrease in intraosseous hypertension), and iloprost (a vasodilating prostanoid), have been used with variable success.

Our patient had an aggressive disabling form of the disease that did not respond to withdrawal of tacrolimus therapy. Symptoms and radiologic findings were exacerbated after substitution of sirolimus, suggesting that the condition is caused by the degree of overall immunosuppression, rather than the specific immunosuppressive agents (Fig 2A and B). Figure 2A shows a new area of edema at the fourth metatarsal head with irregular linear lesions, concerning for stress fracture (* in Fig 2A) and significant interval progression of the bone marrow edema (+ in Fig 2B). Sirolimus dose was decreased gradually, then discontinued, and mycophenolate mofetil dose was tapered. By 5 months posttransplant, maintenance immunosuppression consisted of only monotherapy with 500 mg twice daily of mycophenolate mofetil.

- View Large Image
- Download to PowerPoint
Figure 2.
Magnetic resonance imaging findings (A,B) during follow up and (C, D) after clinical improvement.

The patient had gradual but complete resolution of her symptoms and radiologic signs (Fig 2C and D shows complete resolution of bone marrow edema at both calcaneus bones and a healed fourth metatarsal fracture on the left foot). Her transplant function has been very stable for 3 years on mycophenolate mofetil monotherapy.

Back to Article Outline

Final Diagnosis

Bone marrow edema associated with immunosuppressive medications.

Back to Article Outline

References

Grotz WH, Breitenfeldt MK, Braune SW, et al. Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation. Transpl Int. 2001;14(1):16–23

Villaverde V, Cantalejo M, Balsa A, Mola EM. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506). Ann Rheum Dis. 1999;58(10):653–654

Rike AH, Alloway RR, Flaspohler L, et al. Single-center retrospective review of sirolimus-induced bone pain in renal transplant recipients. Am J Transplant. 2006;6(8 Suppl):161