Calcineurin inhibitors (CNI) are potent immunosuppressive agents in prophylaxis against graft rejection viz. human kidney, liver and heart transplantation [1] . Moreover, due to their inhibition of T cell activation, they are often used off label in multiple autoimmune disorders including nephrotic syndrome [2] . Initially, Cyclosporine A was introduced in 1970 followed by Tacolimus in 1984 [3] . The latter did not have the adverse effects of hypertrichosis and gingival hyperplasia, and was associated with lower graft failure rates in kidney transplant patients when compared to Cyclosporine A [4] . Despite their structural differences; both drugs have similar mechanism of action and unfortunately acute and chronic nephrotoxicity [5] . Previous research had shown that acute CNI-nephrotoxicity is reversible and is due to afferent arteriolar vasoconstriction. On the other hand; chronic CNI-toxicity was irreversible and characterize by interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, as well as glomerulosclerosis [5] . Moreover, recent register studies have demonstrated that virtually all kidney transplanted patients develop signs of chronic CNI-toxicity within 10 years after kidney transplantation [6] . In this case report, we expand the spectrum of such toxicity with the addition of reversible chronic interstitial nephritis.

A 17-year-old man presented with relapse of his nephrotic syndrome in June 2020. His disease was diagnosed at the age of 2 years. He used to respond completely to Prednisone 1 mg/kg for 1 months followed by gradual tapering till discontinuation by 3^rd month. Subsequently, he had 1 relapse/year and had responded to corticosteroid therapy. Ten years later, he relapses were more frequent (up to 4/year) and had received 3-months course of oral Cyclophosphamide yet without benefit. Kidney biopsy showed minimal change disease on light microscopy and lacked any immune deposits on immunoperoxidase stain. Initially, he was started on Tacrolimus 2 mg twice daily. However, as seen in Figure 1, his serum creatinine had increased from normal to 270 umol/L and serum albumin had decreased further from 29 to 17 g/L. At that time, 13-hour Tacolimustrough level was within therapeutic range at 2.9 ug/L (Normal: up to 7). The dose of Tacrolimus was reduced to 1 mg twice daily and Prednisone 20 mg daily was added. Moreover, Rituximab 1 g infusion followed by another one 2 weeks later was given in an attempt avoid future use of Prednisone and Tacrolimus. One month later, serum albumin had increased to 35 g/L yet serum creatinine that had decreased initially to 100 umol/L had increased gradually to 150 umol/L. Hence, Prednisone and Tacrolimus were discontinued to assess the efficacy of isolated Rituximab therapy. Unfortunately, 1 month later, he relapsed again with serum albumin at 13 g/L and serum creatinine remained high at 150 umol/L. Subsequently, Prograf 1 mg twice daily was added, as a synergetic agent, to his inefficient Rituximab therapy. Unfortunately, 1 months later, on such re-chalange and despite low serum level of Prograf, his serum creatinine had increased to 537 umol/L. Moreover, he remained edematous with serum albumin at 13 g/L. At this stage, kidney biopsy was done and had shown normal glomeruli with features

of active interstitial with chronic elements and fibrosis (Figure 2). Tacrolimus was discontinued and Prednisone 60 mg daily was added in addition to MMF 1 g twice daily. One month later, serum creatinine had decreased to normal and serum albumin had increased to 27 g/L with resolution of his nephrotic state and 5-kg weight loss. One month later, his serum creatinine remained normal and serum albumin had improved further to normal. The dose of Prednisone was reduced gradually after the first month and had reached 5 mg daily by the 3^rd month. Since the patient was stable, the dose of MMF was also reduced after 3 months to 500 mg twice daily. By now, and after 1 year of the latter dose decrement, he remained stable clinically and without hypertension, proteinuria and hematuria.

This case report reveals 2 important issues viz. a) Induction of interstitial nephritis, by Tacrolimus, that is reversible with Corticosteroids and MMF and b) safety and efficacy of MMF in management of frequently relapsing minimal change disease refractory to Cyclophosphamide and even Rituximab. The induction of chronic interstitial nephritis as a CNI-toxicityis a new phenomenon that has valuable future implications. It is different from; a) the vasculopathic acute toxicity sinceit will not improve with dose-decrement or drug-discontinuation, and b) the irreversible chronic interstitial fibrosis. It should be included in the differential diagnosis of chronic renal disease in native or transplanted ones in patients on CNI and diagnosis can be established by kidney biopsy [7] . In suspected cases that lacked overt etiology of graft-dysfunction; a) discontinuation of CNI, and b) therapeutic trial of Corticosteroids and MMF, may be rewarding. In our patient; MMF was a valuable tool in management of drug-refractory NS and limited long-term and high-dose exposure to Corticosteroids [8] . After its 3-months induction phase; its immunosuppression remained adequate at lower dosage. Moreover, in addition to its potent immunosuppression, it has a potent antiproliferative action via suppression of both B and T cells via stimulation of CD3/CD28 that inhibits T cell IL-17, IFN-γ and TNF-α production [9] . The

latter has been shown in steroid-resistant MCD and nephritis associated with Henoch-Schönlein Purpura [10] [11] .

Interstitial nephritis should be considered in patients with renal impairment following CNI-therapy. Kidney biopsy is essential for diagnosis and prognosis is favorable with proper management.

Written informed consent was obtained from the patient for the publication of this clinical case, there are no images of the patient in this manuscript

The authors declare that they have no potential conflict of interest related to the contents of this article.

El-Reshaid, K. and Al-Bader, S. (2023) Reversible Chronic Interstitial Nephritis Induced by Tacrolimus. Open Journal of Nephrology, 13, 1-5. https://doi.org/10.4236/ojneph.2023.131001