CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

T. Herrler¹, T. Herrler¹, C. Arszol², S. Nowak², A. Haug², S. Huber¹, P. Bartenstein², K. Jauch¹, M. Hacker², M. Guba^1
1Department Of Surgery, University of Munich, Munich/GERMANY, ²Department Of Nuclear Medicine, University of Munich, Munich/GERMANY

Body: Introduction: Ischemia-reperfusion (I/R) injury after kidney transplantation has not only acute effects on renal function, but may also determine long-term outcomes after transplantation. This study differentially investigates acute functional consequences of commonly used immunosuppressive agents on renal function of kidneys after I/R and non-ischemic control kidneys. Methods: In Balb/C wt mice unilateral warm ischemia was induced by vascular clamping of the kidney hilum for 45 min. Immunosuppressive doses of cyclosporine A (CsA,40mg/kg b.w./d), sirolimus (SRL,1.5mg/kg b.w./d) and dexamethasone (DEX,10mg/kg b.w./d) were administered beginning 2 h before surgery. Tubular excretion function characterized by renal function peak and tubular excretion rate was examined using ^99mTc-MAG3 scintigraphy 48 h post ischemia. Tubular function was simultanously and separately recorded in both the ischemic and the contralateral non-ischemic kidney. Results: Without treatment tubular function was severely compromised after I/R compared to contralateral control kidneys. A significant reduction of renal function peak (85.9%±3.8%;p<0.01) indicating maximum uptake of the radioactive compound and tubular excretion rate (35.1%±5.2%;p<0.01) indicating the elimination capacity was found. Renal function in postischemic kidneys decreased even further with immunosuppressive doses of CsA (peak 52.1%±8.0%,p<0.01; tubular excretion rate 7.2%±1.0%), SRL (peak 78.6%±2.4%,n.s.; tubular excretion rate 11.1%±3.4%,p<0.01), and DEX (peak 61.69%±1.24%,p<0.01); tubular excretion rate 6.1%±1.9%,p<0.01) However, in contralateral control kidneys, immunosuppressive agents elicited a more differential effect on renal function. A compensatory increase in peak was seen without treatment (145.6%±8.5%) and when treated with DEX (114.0%±15.1%) and SRL (115.7%±7.5%), respectively. SRL was found to protect renal function and showed no significant change in tubular excretion rate (86.6%±15.4%,n.s.) compared to non-treated kidneys subjected to I/R (86.3%±12.1%). DEX led to a moderate decrease in tubular excretion function (32.3%±12.3%;p<0.05). In contrast, CsA did significantly impair renal function, as seen in marked reduction of peak level (42.8%±4.3%,p<0.01) and tubular excretion rate (5.8%±0.8%,p<0.01). Conclusions: This model using ^99mTc-MAG3 imaging measures and simulates renal function in both severely injured and healthy nephrons. While in reality both entities will coexsist after I/R injury and transplantation and commonly used parameters will only detect the net effect (e.g.s-creatinine), this technique allows for differential observation of these effects. Reflecting clinical experience CsA significantly impaired renal function of the healthy kidney. This was not the case for SRL. Both CsA and DEX affected recovery of renal function of kidneys after I/R injury, whereas SRL was unexpectedly inert. The results of this study suggest that delayed CsA strategies may help both renal recovery and the protection of not or lightly injured nephrons. In contrast, our data does not provide any rationale to withhold SRL immediately after transplantation in order to facilitate renal recovery.

Disclosure: All authors have declared no conflicts of interest.