Anuria after kidney transplantation diagnosed as early recurrence of focal segmental glomerulosclerosis combined with acute calcineurin inhibitor nephrotoxicity: a case report and literature review

Primary focal segmental glomerulosclerosis (FSGS) is a common glomerular disease that can lead to end-stage kidney disease [1]. FSGS has a high risk of recurrence after kidney transplantation (KT), with an incidence ranging from 30% after the first KT to 80% after the second KT, if the previous graft was lost due to recurrence of FSGS [2]. In addition, recurrent FSGS can cause poor graft prognosis, such as a rapid decline in graft function and an increase in the risk of graft failure [2].

Podocytes are the major sites of damage in FSGS. They consist of a cell body and multiple foot processes that contact the glomerular basement membrane and form a glomerular filtration barrier to prevent proteinuria [3]. The pathogenesis of FSGS has not yet been clearly elucidated. However, since FSGS mainly recurs early after KT, pre-existing circulating factors, such as soluble urokinase plasminogen activator receptor, cardiotrophin-like cytokine factor-1, apolipoprotein A-lb, and anti-CD40 antibodies, are considered to play important roles in recurrent FSGS [3]. Circulating permeability factors increase glomerular capillary permeability to albumin, which impairs the glomerular filtration barrier and results in persistent proteinuria.

Calcineurin inhibitors (CNIs) are immunosuppressive agents that are commonly used after KT, and they effectively prevent rejection. However, acute CNI nephrotoxicity can occur early after KT. Many studies have demonstrated acute graft dysfunction combined with decreased urine volume related to high serum CNI levels [4, 5]. CNIs are known to cause vasoconstriction of the afferent glomerular arterioles, a reduction in vascular flow, and a decrease in the diameter of afferent arterioles, resulting in nephrotoxicity [6].

Herein, we report a patient who experienced early recurrence of FSGS concurrent with CNI toxicity presenting with anuria after KT. Although several cases of early recurrence of FSGS after KT have been reported, the distinctive feature of this case is the difficult diagnosis of recurrent FSGS with anuria caused by combined acute CNI toxicity.

A 55-year-old Asian man with end-stage kidney disease caused by primary FSGS, underwent deceased donor KT. At the age of 35, he was diagnosed with primary FSGS and treated with immunosuppressants, including corticosteroids and cyclophosphamide, and later cyclosporin and mycophenolic acid. However, despite treatment, the patient failed to achieve remission. His renal function gradually declined, leading to initiation of hemodialysis by age 44, 9 years after primary FSGS diagnosis. Eleven years after hemodialysis, he was assigned to receive a kidney from a deceased donor. He was in an anuric state and had comorbid hypertension and diabetes. The pretransplant T cell and B cell crossmatch via flow cytometry was negative, respectively without the presence of donor-specific anti-HLA antibodies. The pretransplant panel-reactive antibody values (class I and class II) were 0%. The donor was a 25-year-old woman (height: 161 cm, weight: 70 kg) who was brain-dead and with no comorbidities. The donor had stable vital signs without using vasopressors and had a final serum creatinine level of 0.44 mg/dL, which remained consistently in the normal range throughout the donor management. The kidney donor profile index score was low at 4.

During the operation, there were no complications and the patient’s vital signs were maintained within the reference range. The cold ischemic time was 139 min, whereas the warm ischemic time was 41 min. Basiliximab was initially used for induction immunosuppression, and tacrolimus, mycophenolate, and methylprednisolone were used for maintenance immunosuppression. The initial urine volume was good during the first 24 h following KT (6 L/day; Fig. 1). During the 48 h postoperative period, a graft diethylenetriamine pentaacetate (DTPA) scan showed no specific abnormalities, but the urine volume decreased to 1 L/day. Gross hematuria and proteinuria were confirmed with an increase in urine turbidity. Urine analysis revealed the following findings: protein 2+; red blood cells, many/high power field; white blood cells, 3–5/high power field without a urine culture being performed; and increased tacrolimus trough level, 16.8 ng/mL. Subsequently, during the 72-h postoperative period, the urine volume decreased to less than 100 mL/day, and the tacrolimus trough level was still high at 19.6 ng/mL even after a reduced dose of tacrolimus. Moreover, the serum creatinine level gradually increased, and the patient developed a mild tremor in both hands. Based on these findings including clinical course, we considered tacrolimus-induced nephrotoxicity. The graft doppler ultrasound of the graft revealed normal echogenicity without hydronephrosis. The perfusion throughout the graft renal artery, vein, and intragraft was good, and the resistive index was within the normal range. Considering acute tacrolimus nephrotoxicity, tacrolimus was discontinued and antithymocyte globulin was administered. Despite the intervention, anuria continued and the tacrolimus trough level remained elevated at 16.1 ng/mL the next day. Hemodialysis was started on POD 4. The patient’s anuric status did not improve, and a graft biopsy was performed on POD 7. On light microscopy (LM), the glomeruli appeared normal (Fig. 2A), but isometric vacuolization in the tubular cytoplasm was observed, suggesting acute CNI toxicity (Fig. 2B). We found no features of acute tubular necrosis resulting from ischemia, such as tubular epithelial degeneration or detachment from the basement membrane or changes in rejection, either acute T cell-mediated rejection or antibody-mediated rejection. C4d staining confirmed via immunohistochemistry was negative. The Banff scores were all zero. We discontinued tacrolimus, but the anuria persisted. The results of electron microscopy (EM) revealed diffuse foot process effacement suggesting recurrence of FSGS (Fig. 2C). Plasmapheresis for recurrent FSGS was performed for three consecutive days and then once every two days, and the urine volume gradually increased after plasmapheresis initiation. Hemodialysis was discontinued after six sessions of plasmapheresis. The patient was discharged on POD 54 after eight sessions of plasmapheresis. The serum creatinine level was 1.4 mg/dL, but proteinuria did not decrease (15.3 g/g creatinine). After 2 weeks, pitting edema worsened, and the serum creatinine level rose to 2.3 mg/dL. Thus, a second graft biopsy was performed on POD 68. On LM, only one glomerulus had segmental sclerosis out of the 22 glomeruli (Fig. 3A); sclerosis with vacuolization of the overlying podocyte was observed. Lining tubular epithelium of the surrounding tubules were somewhat attenuated, but no epithelial necrosis was noted. No inflammatory cell infiltration along the interstitium; no evidence of rejections. Diffuse foot process effacement on the glomerular basement membrane was seen on EM (Fig. 3B), which were one of the characteristic findings of FSGS. Five additional sessions of plasmapheresis were performed (the patient received a total of 13 sessions of plasmapheresis), and then, rituximab (375 mg/m²) was administered twice. The patient remained in partial remission at 5 months after KT, with a serum creatinine level of 1.15 mg/dL and a UPCR of 4.1 g/g creatinine.