Joo Hyun Park

Pharmacological preconditioning with low-dose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney.

BACKGROUNDnIschemia/reperfusion (I/R) injury in the early posttransplant period is closely associated with delayed recovery of graft function, increased acute rejection, and late allograft dysfunction. Pharmacological preconditioning with low-dose cyclosporine (CsA) or FK506 was performed to induce ischemic tolerance in rat kidney with I/R injury.nnnMETHODSnLow-dose CsA (3 mg/kg, administered i.v.) or FK506 (0.3 mg/kg i.v.) were used to induce ischemic tolerance in Sprague-Dawley rats, and the induction of heat shock protein (hsp) 70 by CsA or FK506 was evaluated overtime. Rats were pretreated with CsA or FK506 6 hr before I/R injury when hsp70 was maximally expressed, and were killed 24 hr later. The effect of pharmacological preconditioning on subsequent I/R injury was evaluated in terms of renal function, histopathology score, assays for apoptosis (DNA fragmentation analysis, TUNEL staining, expressions of pro-apoptotic genes, and caspase activity), and the expression of inflammatory cytokine genes (interleukin-1 and tumor necrosis factor-alpha).nnnRESULTSnPreconditioning with low-dose CsA or FK506 significantly improved renal function and renal histology, compared to rats with I/R injury. Apoptotic cell death (typical DNA laddering and increased TUNEL-positive cells) in rat kidneys with I/R injury, was decreased by pretreatment with low-dose CsA or FK506. Increased expression of pro-apoptotic genes (Fas, Fas-ligand, caspase 1 and 3) and activated caspases in ischemic rat kidneys were decreased after CsA or FK506 pretreatment.nnnCONCLUSIONSnPretreatment with low-dose CsA or FK506 prevents subsequent I/R injury, and this effect may be related to the induction of hsp70. Pretreatment of renal donors with low-dose CsA or FK506 may result in an improvement in immediate posttransplant function.

Colchicine Suppresses Osteopontin Expression and Inflammatory Cell Infiltration in Chronic Cyclosporine Nephrotoxicity

Background: Colchicine (Col) is beneficial to renal injury because of its anti-inflammatory effect, but its mechanism has yet to be elucidated. The present study was designed to evaluate the inhibitory effects of colchicine on osteopontin (OPN) expression and the macrophage accumulation in chronic cyclosporine (CsA) nephrotoxicity in rats. Methods: Male adult Sprague-Dawley rats on a low salt diet (LSD, 0.05% sodium) were treated daily with Col (30 µg/kg), CsA (15 mg/kg), and both CsA and colchicine or vehicle (olive oil 1 ml/kg) for 4 weeks. The effects of colchicine on chronic CsA nephrotoxicity were evaluated by examining renal function, histopathology, and ED-1 positive cells. The expressions of OPN mRNA and protein were estimated respectively by Northern blot and immunohistochemistry. Results: Compared with vehicle-treated rats, CsA-treated rats showed an increase in serum creatinine, a decline in creatinine clearance rate, and tubulointerstitial fibrosis (all p < 0.01). Concomitant administration of colchicine reversed all of the above parameters (all p < 0.01). Of note, the upregulated expression of osteopontin mRNA and protein seen in CsA-treated rats was significantly decreased after colchicine treatment. Furthermore, the expression of osteopontin mRNA was strongly correlated with the number of ED-1 positive cells (r = 0.712, p < 0.001) and the tubulointerstitial fibrosis score (r = 0.586, p = 0.007). Conclusion: Colchicine is capable of abrogating the upregulation of chemotactic OPN expression and macrophage influx, and this is associated with improved renal tubulointerstitial fibrosis in chronic CsA nephrotoxicity.

Comparisons of clinicopathological correlations between immediate and slow graft function in renal transplant recipients

Abstract: The functional recovery state of renal transplants can be divided into three types: immediate graft function (IGF), slow graft function (SGF) and delayed graft function (DGF). In contrast to the well‐known clinical outcomes for IGF and DGF, the pathological findings and clinical outcomes of SGF are undetermined. This study evaluated possible clinicopathological correlations in 237 patients with SGF compared with patients with IGF. IGF and SGF were defined by serum creatinine levels (IGFu2003<u20031.2u2003mg/day l; SGF: ≥1.2u2003mg/dL) at day 14 after renal transplantation. Graft biopsy was performed on this day, and pathological classification was performed using the Banff schema. The SGF group of patients (nu2003=u2003121) showed higher rates of cadaver donors and male recipients than the IGF group (nu2003=u2003116), but there were no significant differences in recipient or donor age, numbers of HLA mismatches, types of immunosuppressant or follow‐up periods between two groups. The SGF group showed higher serum creatinine levels at discharge, and a higher incidence of acute rejection than the IGF group (24.8% vs. 8.6%, Pu2003<u20030.05) and lower graft survival rates (1u2003year, 93.3% vs. 100%; 5u2003years, 85.4% vs. 98.6%, respectively; Pu2003<u20030.05). The presence of acute rejection in the SGF patients indicated a significantly decreased 5‐year survival rate compared with the IGF group. The SGF group of patients with borderline pathology had a higher incidence of acute rejection than the IGF group, and significant increases in the expression of mRNA for pro‐apoptotic genes (Fas‐ligand, granzyme B and perforin) compared with the IGF group. In conclusion, SGF represents the activated immune state and is associated with poor graft outcome. Anti‐rejection treatment or modified immunosuppressive regimen may thus be indicated for patients with SGF.

Impact of mesangial IgA deposits in 14th-post operative-day routine renal allograft biopsies

SUMMARY: Three hundred fourteen 14th‐postoperative‐day routine renal allograft biopsies were evaluated together with clinical data. Out of 314 biopsies, mesangial IgA deposits were positive in 122 biopsies (39%). According to Banff classification, the rate of acute rejection was significantly lower in mesangial IgA deposit‐positive (IgA(+)) patients (7.4%) than in mesangial IgA deposit‐negative (IgA(‐)) patients (19.7%) on the 14th postoperative day. Thereafter, rate of biopsy‐proven and clinical acute rejection was continuously lower for up to 12u2003months in IgA(+) patients than in IgA(‐) patients. The detection rate of mesangial IgA deposits was significantly higher in human leucocyte antigen (HLA)‐well‐matched (HLA mismatch number was <3) patients than in HLA‐poorly matched (HLA mismatch number was ≥3) patients. In HLA‐well‐matched patients, the serum creatinine levels were significantly lower in IgA(+) patients than in IgA(‐) patients after 3u2003post‐transplant months and up to 1u2003post‐transplant year. Follow‐up (mean interval: 13u2003months) allograft biopsies were performed in 34 patients out of 122 IgA(+) patients. In the follow‐up biopsies, initially detected mesangial IgA deposits had disappeared in 22 patients (65%) out of 34 patients. Twelve patients (35%) still had mesangial IgA deposits, and all of them had clinical and pathological findings consistent with IgA nephropathy. Patients with continuous mesangial IgA deposits in the follow‐up biopsies had a better renal function at 1u2003year and a higher 5‐year graft survival rate compared with patients who lost the initially deposited IgA. The present study demonstrates that long‐lasting mesangial IgA deposits in renal transplants prevent allografts from acute rejection, which leads to better graft outcome.