EXPERIMENTAL AND CLINICAL TRANSPLANTATION

We report a case of recurrent tubulointerstitial nephritis without uveitis in a patient with previous tubulointerstitial nephritis and uveitis syndrome after transplant. A 26-year-old male patient who had been diagnosed with tubulointerstitial nephritis and uveitis syndrome at 8 years of age developed end-stage renal failure and subsequently underwent living-donor related renal transplant at 17 years old. The 1st recurrence of tubulointerstitial nephritis and uveitis occurred 36 months after transplant, which was treated with increased immunosuppressive drugs. Graft function worsened again to estimated glomerular filtration rate of 25 mL/min/1.73 m² at 76 months after transplant. Transplant ultrasonography was unremarkable. Virology tests (including cytomegalovirus, BK virus, and Epstein-Barr virus tests) were all negative, with negative donor-specific antibodies. Urine protein creatinine ratio was unremarkable. A biopsy showed chronic allograft rejection and graft sclerosis, and immunosuppressive medications were subsequently decreased. The patient’s renal function continued to decline over the next 3 months, with estimated glomerular filtration rate showing 18 mL/min/1.73 m², prompting a further renal biopsy that showed granulomatous interstitial nephritis and moderate interstitial fibrosis. This was consistent with a further relapse of tubulointerstitial nephritis but without uveitis. His renal function improved over the next few months after tacrolimus was reintroduced.

Key words : TINU, Transplant dysfunction

Tubulointerstitial nephritis and uveitis (TINU) syndrome, first described by Dobrin and associates in 1975,¹ is a rare and poorly understood condition, which is usually characterized by a tubulointerstitial nephritis with an acute self-limiting course and uveitis with a chronic, relapsing course. It usually affects young adults with a female preponderance.²

Here, we describe the clinical course of a 26-year-old renal transplant recipient whose primary renal disease was TINU syndrome but presenting with a flare-up of tubulointerstitial nephritis only after the immunosuppression agents were reduced 9 years after transplant.

It has previously been proposed that the presence of circulating autoantibodies may be responsible for the recurrence of TINU after transplant.³ We would like to also propose the role of immunosuppression medications as suppressors of the underlying autoimmune process associated with TINU syndrome and other autoimmune diseases.

A 26-year-old male patient who had been diagnosed with TINU syndrome at 8 years old was documented with declining renal function, resulting in end-stage renal failure and living-donor related renal transplant 9 years later at the age of 17 years (mismatch 0:1:1). Three years after transplant, the patient developed recurrence of TINU presenting as uveitis. With decline in renal function 3 years after transplant, a biopsy was performed that showed granulomatous interstitial nephritis.⁴

Immunosuppressive medications were thus increased. His estimated glomerular filtration rate (eGFR) had declined from 94 mL/min at 36 months after transplant to 32 mL/min at 52 months after transplant, despite the increase in immunosuppressive medications. The patient’s eGFR stabilized after administration of 3 doses of 1 g intravenous methylprednisolone to an eGFR of 40 mL/min/1.73 m² at 66 months after transplant.

At 76 months after transplant, the patient’s renal function subsequently worsened to eGFR of 25 mL/min/1.73 m². Transplant ultrasonography was unremarkable at 76 months after transplant with no features of obstruction. Virology tests, (cytomegalovirus, BK virus, and Epstein-Barr virus tests) were all negative. The patient did not have donor-specific antibodies. Urine protein creatinine ratio was 46 mg/mmol creatinine. The relevant laboratory investigations are listed in Table 1. The patient underwent a renal biopsy, which showed chronic allograft rejection and graft sclerosis associated with moderate to severe tubular atrophy and interstitial fibrosis. There was no evidence of granulomatous tubulointerstitial nephritis to suggest a relapse of TINU and no evidence of cellular rejection or positive C4d staining.

Tacrolimus was subsequently decreased and eventually stopped over the next few months in view of the risk of interstitial fibrosis and tubular atrophy associated with calcineurin inhibitors. Mycophenolate mofetil was consequently increased to 1 g twice daily. The dose of prednisolone remained unchanged at 5 mg daily. Cytomegalovirus titers came back mildly positive at a log of 2.96 (922 copies/mL) soon after this alteration in medication. The patient, however, remained asymptomatic of cytomegalovirus infection and did not receive treatment for this; however, mycophenolate mofetil dose, as a result, was reduced to 500 mg twice daily. Further cytomegalovirus testing was negative. The patient showed a further decline in renal function over the next 3 months to eGFR of 18 mL/min/1.73 m², prompting a further renal biopsy, which showed granulomatous interstitial nephritis and moderate interstitial fibrosis. This was consistent with a further relapse of tubulointerstitial nephritis without uveitis (Figure 1).

The patient’s renal function improved over the next few months after reintroduction of tacrolimus (4 mg twice daily, with trough levels between 5 and 8 μg/L) to reach eGFR of 30 mL/min. Figure 2 shows changes in eGFR since transplant.

Tubulointerstitial nephritis and uveitis syndrome is characterized by a reversible nephropathy that either resolves spontaneously or after treatment with steroids and a uveitis that can frequently relapse. The recurrence of tubulointerstitial nephritis, with the absence of uveitis, in this patient after reduction of immunosuppressive agents is a rare occurrence and has not previously been reported in this context.

Immunosuppressive therapy was justifiably reduced for this patient after a renal biopsy showed interstitial fibrosis and tubular atrophy and a moderate rise in cytomegalovirus polymerase chain reaction titers. As a result of this reduction, a flare-up of tubulointerstitial nephritis without uveitis was shown, leading to a decline in graft function. It is postulated that long-term immunosuppression may be required for some patients with TINU syndrome who have recurrent and progressive disease.^2,3,5

Despite the reporting of over 200 cases of this syndrome, its pathogenesis is still poorly understood.⁶ In this case, recurrence occurred 36 months after transplant with a biopsy at the time that showed TINU occurring during this episode, whereas the second relapse occurred 79 months after transplant but without uveitis. This increases the queries about the exact pathogenesis of this rare disease. Both the recurrence and the relapse were treated with increases in immunosuppressive therapy. Some studies allude to a T-cell-mediated immunity, whereas others suggest an autoantibody-mediated disease in TINU syndrome.

Renal biopsies of patients with TINU syndrome mainly show T-cell infiltration associated with the presence of monocytes and macrophages. It has been suggested that the pathogenesis involves mainly a T-cell-mediated immunity, leading to the formation of granuloma in organs, such as the kidneys, bone marrow, lymph nodes, and liver.⁷ Renal tubular epithelia and uveal epithelial cells share some common functions, particularly those related to electrolyte transporters sensitive to carbonic anhydrase inhibitors.^3,5,8 It is likely that they share a common antigen that may explain cross-reactivity.

Abed and associates demonstrated the presence of a circulating autoantibody that recognizes a common antigen present in both tubular and uveal epithelial cells. By indirect immunofluorescence, they demonstrated the presence of focal cytoplasmic immunoglobulin G deposits on proximal and distal tubular epithelial cells along with membranous immunoglobulin G deposits in uveal cells. This study alludes to the possible presence of concomitant antitubular and antiuveal antibodies.²

Because the exact pathogenesis of this disease still remains unclear, further research is required. The relapse of tubulointerstitial nephritis in our renal transplant recipient after reduction in immunosuppressive treatment certainly lays weight to the existence of a circulating autoantibody capable of causing disease recurrence but also underlies the importance of long-term immunosuppression in a select group of individuals.

Volume: 16 Issue: 2 April 2018

FULL TEXT