Immunosuppressants

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

A 2-year-old girl developed BK viraemia, coronavirus infection, parainfluenza infection, BK virus-associated nephropathy and urinary tract infections during treatment with antithymocyte-globulin, leflunomide, methylprednisolone, mycophenolate-mofetil, prednisolone or tacrolimus for renal transplant (RT) [routes and durations of treatments to reactions onsets not stated; not all dosages and outcomes stated].

The girl had a history of end-stage renal disease secondary to hypoxic-ischaemic injury at birth. She had received peritoneal dialysis (PD) as renal replacement therapy from 2 weeks until 4 months of age. However, recurrent fungal peritonitis had developed and her PD was discontinued. At the age of 2 years, she received a deceased donor kidney transplant from an adult donor. Allograft was placed intra-abdominally. The donor renal artery and vein was anastomosed with her aorta and inferior vena cava via end-to-side anastomosis using prolene suture, respectively. She was polyuric before to the transplant and to prevent dehydration episodes post-RT, bilateral native nephrectomies were performed during transplant without any adverse event. Thereafter, abdominal fascia and skin were closed with suture. Induction of immunosuppression was performed with antithymocyte globulin [thymoglobulin] 4.5 mg/kg and methylprednisolone. After anastomosis, she showed excellent graft perfusion. However, after one hour, she progressively became oligoanuric and thereafter anuric by 4 hours. Doppler ultrasonogram (US) revealed poor blood flow which led to emergency abdominal re-exploration 6 hours post-RT. Further study showed an early thrombus at the renal artery tip for which she underwent thrombectomy and her kidney was kept cold at backbench. Thereafter, re-anastomosis of the renal artery with the right common iliac artery was performed using prolene suture. After thrombectomy, heparin infusion and baby aspirin was given to her. However, her renal function remained deteriorated with elevated serum creatinine that required haemodialysis. On postoperative day 1, she started receiving mycophenolate-mofetil without tacrolimus due to delayed graft function. An open transplant kidney biopsy revealed features of acute tubular necrosis [aetiology unknown] without any rejection on postoperative day 3. Subsequently, improvement in her urine output was noted and postoperative day 14, her PD was discontinued. On postoperative day 19, her Gore-Tex patch was removed, and fascia and skin were closed. On postoperative day 21, she was discharged from the hospital with tacrolimus, mycophenolate-mofetil, unspecified steroid and aspirin. She also received anti-infective prophylaxis with cotrimoxazole [trimethoprim-sulfamethoxazole], valganciclovir and nystatin. One month post-RT, she started receiving amlodipine for mild asymptomatic hypertension. After 6 weeks, her ureteral stent was removed. For maintenance of serum trough tacrolimus levels, dose reduction was required. Thereafter, she developed viral respiratory illness, urinary tract infection and febrile neutropenia for which she required multiple hospitalisation.

These multiple episodes were managed with appropriate unspecified antibiotics, reduced immunosuppression, granulocyte colony-stimulating factor and supportive measures. The girl developed spontaneous bruising [aetiology unknown] and her aspirin treatment was discontinued at 2 months. Two months post-RT, she developed severe neutropenia and BK viraemia. Her mycophenolate-mofetil treatment was stopped. At 2 months post-RT, she started receiving leflunomide 20mg daily. Two months later, she again started receiving mycophenolate-mofetil. Thereafter, her renal function remained stable with baseline serum creatinine. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA PCR found to be negative throughout. At 5 months post-RT, she presented with hypertensive emergency and posterior reversible encephalopathy syndrome (PRES) [aetiology unknown] following another episode of respiratory illness. The respiratory illness was later found to be secondary to coronavirus and parainfluenza infection. At that presentation, her medications included tacrolimus, prednisolone, cotrimoxazole, amlodipine, valganciclovir and leflunomide. Laboratory study showed her systolic BP ranged from 160 to 180mm Hg, in spite of multiple antihypertensives with continuous infusion of nicardipine. On day 2 of hospitalisation, she developed generalised tonic-clonic seizure [aetiology unknown] and had a BP of 190/100mm Hg. Brain MRI revealed changes consistent with PRES. Therefore, her antihypertensive therapy was increased with the combination of nicardipine infusion, hydralazine, carvedilol, clonidine, furosemide, amlodipine, losartan and minoxidil. ECG showed mild-to-moderate left ventricular hypertrophy(LVH) with left ventricular mass index (LVMI) of 178.85 g/m^2.7. Doppler US of the allograft revealed decreased resistive indices (0.4-0.5) with tardus parvus waveforms and no hydronephrosis. Duplex study of renal artery demonstrated extremely increased velocities at the proximal renal artery which confirmed proximal transplant renal artery stenosis (TRAS). Thereafter, her renal function continuously worsened with elevated serum creatinine. Her losartan treatment was stopped. PCR study found serum BK virus load 2510 copies/mL and urine BK virus load 3.1 million copies/mL with negative CMV and EBV. Percutaneous transplant kidney biopsy revealed mild but diffused interstitial inflammation, heavier in the medulla, with CD3-positive lymphocytes and CD68 mononuclear cells associated with mild lymphocytic tubulitis and moderate interstitial fibrosis and tubular atrophy (IF/TA). The immunohistochemical stain for SV40 was positive in the epithelial cells of distal and proximal tubules. The haemorrhage, oedema or endotheliitis was not found. Peritubular C4d staining was negative and with no definitive intranuclear inclusion. These findings were consistent with BK virus-associated nephropathy. Therefore, she was treated with immune-globulin [IVIG], and leflunomide dose was increased to 30mg daily and tacrolimus was stopped. However, she developed oliguria and pulmonary oedema. Eventually, she required haemodialysis and mechanical ventilation. A few days later, her haemodialysis was discontinued without improvement in pulmonary function. Her hypertension persisted in spite of multiple antihypertensive drugs. A conventional digital subtraction angiogram was performed which showed a severe anastomotic stenosis of the renal artery with a preprocedural gradient of 50mm Hg across the stenosis. Therefore, percutaneous transluminal angioplasty (PTA) with stenting of the transplant renal artery was performed. Eventually, improvement in blood flow was noted with gradient reduction to 18mm Hg. Within few hours, her BP was within normal range with intermittent elevation. Repeat doppler US revealed normalisation of resistive indices and normal-appearing vascular waveforms. She continued to receive maintenance therapy with aspirin following stenting of the transplant renal artery. At the time of discharge, her creatinine was at baseline and BP was controlled. She was discharged with amlodipine, clonidine, aspirin, prednisone and low-dose tacrolimus. Repeated ECG showed decrease in LVMI up to to 105.86 g/m^2.7. Follow up after ten months showed stabilised baseline serum creatinine, controlled BP and normal waveforms in doppler renal transplant sonograms. At 7 months post-RT, her BK viraemia had resolved. Her leflunomide treatment was discontinued and she again started receiving mycophenolate-mofetil.