Year : 2009 | Volume
: 20 | Issue : 5 | Page : 770--774
Modifying cyclosporine associated renal allograft dysfunction
N Mohapatra1, AV Vanikar1, RD Patel1, HL Trivedi2,
1 Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H.L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
2 Department of Nephrology and Transplantation Medicine G.R. Doshi and K.M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H.L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
A V Vanikar
Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R.. Doshi and K. M. Mehta Institute of Kidney Diseases & Research Centre (IKDRC)- Dr. H. L. Trivedi Institute of Transplantation Sciences (ITS) Civil Hospital Campus, Asarwa, Ahmedabad 380016, Gujarat
Transplantation is accepted therapy for chronic kidney disease. However the essential immunosuppressive agents for graft survival have their own side-effects. Renal biopsy is a reliable tool for diagnosing cyclosporine (CsA) nephrotoxicity. To present our observations on CsA toxicity in renal allograft biopsies, we studied prospectively 207 renal allograft biopsies performed for graft dysfunction as per Ahmedabad Tolerance Induction Protocol (ATIP) and compared them to 50 controls from January to October 2007. The ATIP comprised donor specific leucocyte infusions, low dose target specific irradiation; non-myeloablative conditioning with Anti-T ± B cell antibodies followed by intraportal administration of cultured donor bone marrow (BM) ± adipose tissue derived mesenchymal stem cells. Renal transplantation was performed following negative lymphocytotoxicity cross-matching. The post-transplant immunosuppressive agents included CsA 2.5 ± 0.5 mg/kg BW/day and prednisone 0.2 mg/kg BW/day. The controls were transplanted using standard triple immunosuppressive agents including CsA 5 ± 1 mg/Kg BW/day, prednisone 0.6 mg/kg BW/day, and MMF/ Azathioprine. The Institutional Review Board approved the ATIP. The biopsies were categorized into 2 groups; group A (N=97): performed < 6 months, group B (N= 160), > 6 months posttransplant. Acute CsA toxicity was observed in group A: 2.5% ATIP and 11.1% controls; group B: 16.2% ATIP and 8.8% controls. Chronic CsA toxicity was observed in group B: 10.8 % ATIP and 17.6 % controls. Acute toxicity was more in the ATIP, while chronic toxicity was more in the controls. CsA doses were reduced post-biopsy and resulted in improved graft function evaluated by serum creatinine. We conclude that CsA nephrotoxicity evaluated by allograft biopsy resulted in allograft function recovery by decreasing the cyclosporine dose, and the ATIP decreased the incidence of CsA nephrotoxicity.
|How to cite this article:|
Mohapatra N, Vanikar A V, Patel R D, Trivedi H L. Modifying cyclosporine associated renal allograft dysfunction.Saudi J Kidney Dis Transpl 2009;20:770-774
|How to cite this URL:|
Mohapatra N, Vanikar A V, Patel R D, Trivedi H L. Modifying cyclosporine associated renal allograft dysfunction. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Jul 9 ];20:770-774
Available from: http://www.sjkdt.org/text.asp?2009/20/5/770/55359
Discovery of cyclosporine (CsA) in 1971 by Jean Borel and human trials in 1976 ushered a new era in transplantation biology. Sir Roy Calne first noted its nephrotoxic effects, however, its use in combination with low dose steroids by Starzl et al saved it from disuse. , CsA toxicity can occur in acute and chronic forms and manifest in different forms such as functional toxicity, delayed recovery, acute tubular necrosis, toxic tubulopathy and vascular toxicity.  Acute phase CsA occurs with a median onset of six months post-transplantation, is usually reversible and associated with functional nephrotoxicity. Chronic nephrotoxicity that occurs at a median onset of 3 years is largely irreversible and accompanied by hyaline arteriopathy, striped interstitial fibrosis and tubular atrophy  .
We aim in this study to compare findings of CsA nephrotoxicity in the biopsies of renal transplant patients treated according to a modified protocol of immunosuppressive agents after transplantation with those treated according to the regular CsA-based regimen.
Patients and Methods
We performed in our center a prospective comparative study of 257 renal allograft biopsies performed because of graft dysfunction over a period of 10 months from January to October 2007. These biopsies belonged to two groups; 217 from patients treated as per Ahmedabad Tolerance Induction Protocol (ATIP) and 50 from patients treated according to the regular protocol (controls).
The ATIP included 2 donor specific leucocyte infusions, low dose target specific irradiation of 200 CGY × 5 days to sub-diaphragmatic lymphnodes, part of pelvic bones, lumbar and thoracic vertebrae; non-myeloablative conditioning with anti-T cell antibodies, 1.5 mg/kg BW/day ± AntiB cell antibodies (8 mg/kg BW/day), followed by intraportal administration of cultured bone marrow (BM) from donor posterior superior iliac crest ± cultured mesenchymal stem cells from donor adipose tissue. Renal transplantation was performed following negative lymphocytotoxicity cross-match test. Post-transplant immunosuppressive agents included CsA 2.5 ± 0.5 mg/kg BW/day and prednisone 0.2 mg/kg BW/day. The controls were transplanted using only standard triple drug immunosuppressive agents of CsA 5 ± 1 mg/kg BW/day, prednisone 0.6 mg/kg BW/day, and MMF/Azathioprine.
The biopsies were categorized into two groups: group A comprised biopsies with early graft dysfunction, which occurred before 6 months ( 180 days) post-transplant .
Group A biopsies were obtained from 87 patients subjected to the ATIP (66 males, 21 females) with a mean age of 34 years (range: 12-63 years) performed at a mean of 115 days (range: 36-180 days) post-transplant with a mean serum creatinine (SCr) of 3.1 mg/dL (range: 018.4 mg/dL); and 10 biopsies from patients served as controls (8 males, 2 females) with a mean age of 27 years (range: 8-56 years) performed at a mean of 147.9 days (range: 119-179 days) post-transplant with a mean SCr of 2 mg/dL (range: 1-3.97 mg/dL).
Group B biopsies were obtained from 120 patients subjected to the ATIP (107 males, 13 females) with a mean age of 33 years (range: 12-63 years) and performed at a mean of 854 days (range:182-3124 days) post-transplant with a mean SCr of 2.7 mg /dL (range: 0.8-7.9 mg/ dL), and 40 biopsies from patients served as controls (8 males, 2 females) with a mean age of 33 years (range: 11-59 years) and performed at a mean of 964.9 days (range: 183-5136 days) post-transplant with a mean SCr of 2.7 mg/dL (range: 1- 4.9 mg/dL).
The histopathological findings were evaluated according to the guidelines of modified Banff criteria by performing Hematoxylin and Eosin, Periodic Acid Schiff reagent, Jone's Methanamine Silver, Gomori Trichrome, and C4d (polyclonal- Biomedica Gruppe, Germany) staining on 3 µ thick paraffin sections.
Acute CsA toxicity was diagnosed if the following criteria in the biopsies were satisfied including toxic tubulopathy, toxic arteriolopathy, and toxic glomerulopathy (in the form of dilated capillaries filled with RBCs and hyalinosis in occasional glomerular afferent arterioles or in the form of acute thrombotic microangiopathy).
The CsA trough levels measured with Fluorescence Polarization Immunoassay (Abbott Lab, USA) were performed in all the patients with suspected CsA toxicity before performing biopsies.
In group A, CsA toxicity was observed in 9/85 (10.6%) biopsies from the ATIP treated patients and 1/10 (10%) biopsies from the controls [Figure 1]. The other interesting findings included 1.2% acute tubulointerstitial rejection (ATIR) in the ATIP treated patients versus 40% ATIR in the controls, 22.4 % acute vascular plus humoral rejection in ATIP treated patients versus 30% in the controls, and other findings were acute tubular necrosis, recurrent disease and others as mentioned in [Table 1].
In group B, acute plus chronic CsA toxicity was observed in 36/120 (29.9 %) biopsies from the ATIP treated patients versus 11/40 (27.5%) biopsies from the controls and other findings are mentioned in [Table 2]. accordingly, CsA toxicity was higher in the ATIP treated patients than the controls [Table 3].
The mean SCr in the ATIP treated patients and manifesting acute CsA toxicity was 2.5 mg/dL (range: 1.6-4.5 mg/dL) and it recovered to 1.37 mg /dL (range: 1.24-1.5 mg%) after decreasing CsA doses, which showed a mean trough CsA levels of 110.3 ng/mL (range: 72-169 ng/mL) at the time of biopsy. On the other hand, the controls had a mean SCr of 2.4 mg/dL (range: 1.53.4 mg%), which recovered to 1.9 mg/dL (range: 1.4-2.5 mg%) after decreasing CsA doses, which showed a mean trough CsA levels of 240.5 ng/mL (range: 182.6-289.2 ng/mL) at the time of biopsy [Table 4]. There were no significant changes in grafts' function in spite of decreasing/weaning off CsA in patients with chronic toxicity.
CsA is an epoch- making immunosuppressive agent with adverse effects of which acute and chronic nephrotoxicity are important. CsA prevents T-cell activation by inhibiting calcineurin (cytoplasmic phosphatase enzyme) required for transcription of interleukin-2 and cytokines, which are up-regulated when antigen is presented to T-cells. However its side effects were noted even at the therapeutic range, in the form of nephrotoxicity, hyperlipidemia, hypertension, glucose in-tolerance, hirsuitism and gum hyperplasia. 
The histological features indicative of acute toxicity are necrosis and dropout of myocytes, replacement of these myocytes by hyaline insudates in afferent arterioles, and isometric vacuolization in proximal tubules. We believe that toxic glomerulopathy we observed in the form of ectatically dilated capillaries was due to direct toxic effect of CsA on glomerular capillaries.
Toxic tubulopathy and acute arteriolopathy would require dose regulation with lowering of CsA dosage. However toxic changes such as delayed recovery from acute tubular necrosis and thrombotic microangiopathy would require prompt withdrawal of CsA. 
In our ATIP treated patients, acute toxicity was observed at low CsA levels (110.3 ng/mL) as compared with the controls at higher CsA levels (240.5 ng/mL). Long-term prospective trials for CsA levels and its toxic effects with body mass index may prove to be useful for ascertaining an effective "safe" dose, or even whether CsA should be continued in the longterm period following renal transplantation for better graft survival.  However circulating levels may not always correlate with tissue levels.
Both immunologic and non-immunologic factors participate in the pathogenesis of chronic allograft dysfunction with one of them being chronic CsA nephrotoxicity.  Our ATIP treated patients required very low dose CsA, in spite of which they were not protected from allograft injury.
We conclude that we found an interesting and unexplained observation in this study that acute CsA toxicity was higher in the ATIP treated renal transplantation patients after 6 months of transplantation even at a low dose and low trough levels of this drug. However, T-cell mediated rejection and chronic CsA toxicity were lower in the ATIP treated patients associated with low CsA trough levels.
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