W. Rowinski

Ischemia/Reperfusion Injury in Kidney Transplantation: Mechanisms and Prevention

Ischemia has been an inevitable event accompanying kidney transplantation. Ischemic changes start with brain death, which is associated with severe hemodynamic disturbances: increasing intracranial pressure results in bradycardia and decreased cardiac output; the Cushing reflex causes tachycardia and increased blood pressure; and after a short period of stabilization, systemic vascular resistance declines with hypotension leading to cardiac arrest. Free radical-mediated injury releases proinflammatory cytokines and activates innate immunity. It has been suggested that all of these changes-the early innate response and the ischemic tissue damage-play roles in the development of adaptive responses, which in turn may lead to an acute font of kidney rejection. Hypothermic kidney storage of various durations before transplantation add to ischemic tissue damage. The final stage of ischemic injury occurs during reperfusion. Reperfusion injury, the effector phase of ischemic injury, develops hours or days after the initial insult. Repair and regeneration processes occur together with cellular apoptosis, autophagy, and necrosis; the fate of the organ depends on whether cell death or regeneration prevails. The whole process has been described as the ischemia-reperfusion (I-R) injury. It has a profound influence on not only the early but also the late function of a transplanted kidney. Prevention of I-R injury should be started before organ recovery by donor pretreatment. The organ shortage has become one of the most important factors limiting extension of deceased donor kidney transplantation worldwide. It has caused increasing use of suboptimal deceased donors (high risk, extended criteria [ECD], marginal donors) and uncontrolled non-heart-beating (NHBD) donors. Kidneys from such donors are exposed to much greater ischemic damage before recovery and show reduced chances for proper early as well as long-term function. Storage of kidneys, especially those recovered from ECD (or NHBD) donors, should use machine perfusion.

Machine Perfusion Preservation Improves Renal Allograft Survival

Machine perfusion (MP) has been used as the kidney preservation method in our center for over 10 years. The first, small (n = 74) prospective, single‐blinded randomized study comparing MP and Cold Storage (CS) showed that the incidence of delayed graft function was higher after CS. There have been no reports in the literature on the effect of storage modality on long‐term function of renal allografts. This paper presents an analysis of long‐term results of renal transplantation in 415 patients operated on between 1994 and 1999. Of those, 227 kidneys were MP‐stored prior to KTx. The control group consisted of 188 CS kidney transplants. Kidneys were not randomized to MP or to CS. Donor demographics, medical and biochemical data, cold ischemia time, HLA match and recipient data were collected. Standard triple‐drug immunosuppression was administered to both groups. Mortality, graft survival and incidence of return to hemodialysis treatment were analyzed. Despite longer cold ischemia time and poorer donor hemodynamics in MP group, 5‐year Kaplan‐Meier graft survival was better in MP‐stored than in CS‐stored kidneys (68.2% vs. 54.2%, p = 0.02). Conclusion: In this nonrandomized analysis, kidney storage by MP improved graft survival and reduced the number of patients who returned to dialysis.

Long‐term results of treatment of chronic hepatitis B, C and D with interferon‐α in renal allograft recipients

Abstract The aim of this study was to evaluate the efficacy and safety of interferon‐a (IFN‐α) therapy of chronic hepatitis B, C and D (HBV, HCV and HDV, respectively) in renal transplant recipients. A group of 42 patients (30 males, 12 females, mean age 38 years) with documented viraemia and chronic active hepatitis (CAH) were studied, of whom 1 had HBV infection alone, 11 had HCV infection alone, 3 had HBV and HDV infection concomitantly, 12 had HBV and HCV infection concomitantly, and 2 had HBV, HCV and HDV infection concomitantly. Patients received 3 MU IFN‐α three times weekly for 6 months. After IFN‐α therapy, 18 patients (43 %) achieved normal alanine aminotransferase (ALT) activity and a partial response was observed in 12 (29%) patients. Two patients relapsed (one with HCV and one with HBV + HCV infection) immediately after the cessation of IFN‐α therapy. Repeated liver biopsy was performed in 16 patients after 6–24 months of therapy and revealed progression to cirrhosis in five patients, remission in two and stable disease in nine. None of the patients cleared HCV RNA, four patients cleared HBeAg (two also HDV), and one both HBV and HCV. Five patients died during IFN‐α therapy (one as a consequence of liver failure), and four died during the 6 months after therapy (two as a consequence of liver failure). During IFN‐α therapy renal allograft function remained stable in 31 patients and acute rejection episodes occurred in 7, of whom 5 lost their graft and all had experienced rejection episodes before. In 16 patients normalization of ALT continued during long‐term follow‐up (median 22 months, range 0–84 months). IFN‐α seemed to be moderately effective in the treatment of chronic HBV or HCV infections, but cannot be recommended for recipients infected with both HBV and HCV.

Blood cytokine levels rise even after minor surgical trauma.

The exact changes in cytokine production and clinical implications of the increased cytokine levels following operative trauma remain unclear. In this study, systemic production of a spectrum of cytokines, including IL1α, IL1β, IL6, IL8, IL10, and IFNγ, was examined in patients undergoing minor elective operative trauma. The levels of IL1 receptor antagonist (ra) and IL6 soluble receptor (sR) were also determined. Although there were no changes in IL1α and IL1β plasma levels during the entire observation period, there was a significant rise in IL1 ra level in all patients between postoperative day 1 and postoperative day 14. A significant increase in the IL6 plasma level was seen on days 1, 3, and 7 after surgery and an increase in the IL6 sR level was observed on postoperative days 10 and 14. Interestingly, the IL8 plasma values had risen significantly on days 1 and 3 following the operation. In some patients, an elevation in IL10 plasma level was noted on days 1 and 3 postsurgery. Results demonstrated that even a minor surgical procedure such as cholecystectomy with uneventful wound healing was followed by an appearance in the blood circulation of significant levels of cytokines between day 1 and day 14 after surgery. These observations point to the necessity of searching for methods of down-regulating the systemic cytokine effects after surgical trauma for the routine postoperative management.

Urinary tract infections in the early posttransplant period after kidney transplantation: etiologic agents and their susceptibility.

OBJECTIVE Urinary tract infection (UTI) is among the most common infections in solid organ transplantation, especially in kidney transplantation. PATIENTS AND METHODS This study included 295 adult patients undergoing KTx between September 2001 and December 2007. All patients were followed prospectively for UTI during the first 4 weeks after surgery. Samples of urine were investigated by bacteriological cultures to identify microorganisms in accord with standard procedures. Susceptibility testing was performed using Clinical and Laboratory Standards Institute procedures. RESULTS Urine specimens (n=582) were obtained from 84.5% of 245 recipients during the first month after transplantation. Among the isolated bacterial strains (n=291), the most common were Gram-negative bacteria (56.4%) predominantly Serratia marcescens (32.3%) and Enterobacter cloacae (14.6%). Extended- spectrum beta-lactamase (ESBL+) strains were isolated in 52.5% of cases. Gram-positive bacteria comprised 35.7%; most commonly, high-level aminoglycoside resistant (HLAR; 87.8%) and vancomycin-resistant (VRE; 11%) Enterococci. There were fungal strains in 23 cases (7.9%). CONCLUSION Our study showed predominantly Gram-negative rods from the Enterobacteriaceae family comprising (84.8%) of Gram-negative isolates: 52.5% ESBL and resistant enterococci (87.5%) in Gram-positive isolates. The increased proportion of isolates of multi-drug-resistant bacterial agents which can cause severe UTIs may be due to our frequent use of ceftriaxone for perioperative bacterial prophylaxis.

Efficacy of rapamycin in patient with juvenile rheumatoid arthritis

Juvenile rheumatoid arthritis (JRA) is an immune‐mediated disease characterized by articular inflammation and subsequent tissue damage that may result in severe disability. Several combinations of drugs, including immunosuppressive agents have been used to control disease progression. Although there is no information available on rapamycin efficacy in JRA, it has demonstrated a potential to inhibit inflammatory processes observed in adult rheumatoid arthritis (RA). We present a 21 years old renal transplant recipient with JRA, primarily treated with tacrolimus and steroids, who achieved a long‐term disease remission after introduction of rapamycin. As long as pathogenesis of JRA and RA is similar, we conclude that rapamycin could be promising immunosuppressant for patients after renal transplantation suffering from both JRA and RA.

Transplantation of kidneys harvested from non‐heart‐beating donors: early and long‐term results

Abstract  The purpose of this retrospective study was to evaluate results of non‐heart‐beating donor (NHBD) kidney transplantation. Between Jan 1986 and Dec 1994,80 out of 582 cadaveric kidneys were harvested from NHBD (31.9 min ± 24 after cardiac arrest). The results in the NHBD group (76 recipients) were compared with those obtained after transplantation of kidneys harvested from heart‐beating donors (HBD) with respect to early graft function, and the graft and recipients survival. Both groups were matched for sex, age, PRA level, number of HLA mismatches, and cold ischemia time. Triple immunosuppression therapy was used in both groups. Acute tubular necrosis (ATN) was observed significantly more frequently in the NHBD group (50 of 76 recipients vs 33 of 100 in the HBD group). The striking finding of this study was that the occurrence of primary non‐function was the same in both groups and that the main cause of it was acute rejection. The 1‐year patient and graft survival rates were 98.7 % and 81.6 % for the NHBD group and 99 % and 90 % for the HBD group, respectively. There was also no statistical difference in the serum creat‐inine concentration in both groups. We concluded that despite an increased incidence of ATN in the NHBD kidney recipients, the long‐term results are good and comparable with those in the HBD group.

Surgical complications observed in simultaneous pancreas-kidney transplantation : Thirteen years of experience of one center

SIMULTANEOUS pancreas and kidney transplantation (SPKTx) is the procedure of choice for a majority of transplant candidates with end-stage renal disease and diabetes mellitus. Recent evidence supports its benefits on the maintenance of normoglycemia and the arrest or even possibily of reversal of diabetic complications, such as vasculopathy, nephropathy, and neuropathy. However, pancreas transplant has been associated with the highest surgical complication rate of all the routinely performed organ transplant procedures. A significant number of pancreas grafts are lost early post-transplant secondary to surgical complications. Over the last decade, the operative procedure has been refined and immunosuppressive regiments have improved such that 1-year graft survival routinely exceeds 75%. The purpose of this study was to assess our improved results and to determine other risk factors that may help us decrease the complication rate further.

The Assessment of Residual Kidney Function After Living Donor Nephrectomy

BACKGROUND The number of patients on the waiting list for kidney transplantation is increasing as a result of the cadaveric donor shortage. One way to expand the pool is living donor transplantation. However, only 2% of kidney transplants in Poland come from living-related donors. AIM We sought to assess residual renal function, incidence of hypertension, and proteinuria among living kidney donors. PATIENTS AND METHODS Between 2004 and 2007, we performed 46 living donor open nephrectomies. The mean age of the kidney donor was 39 years (range, 25-57). The donors were predominantly females (61%). Mean hospitalization time was 8 days (range, 4-22). Nine donors did not report for follow-up visits. The observation periods ranged from 1 to 24 months. Physical examination, blood and urine tests, as well as ultrasound scans were performed before nephrectomy and at every follow-up visit (1, 3, 12, and 24 months post operatively). RESULTS Mean creatinine concentration was higher at 3 months after nephrectomy than preoperatively (P < .05). Mean creatinine clearance according to Cockroft-Gault formula and mean creatinine clearance according to abbreviated modification of diet in renal disease equation (aMDRD) decreased after donation by 30% (P < .05). No cases of proteinuria were observed. Hypertension occurred in 1 donor (2.7%). CONCLUSION Living kidney donation resulted in a reduced creatinine clearance in the donor. Follow-up of living kidney donors is essential to determine risk factors for deterioration of residual kidney function.

Surgical site infections in the early posttransplant period after simultaneous pancreas-kidney transplantation.

OBJECTIVE Urinary tract infection (UTI) is among the common infection in simultaneous pancreas-kidney transplantation (SPKT). PATIENTS AND METHODS The study included 26 adult patients undergoing SPKT between September 2001 and December 2006. All the patients were followed prospectively for UTI during the first 4 weeks after surgery. Urine samples were investigated for bacteriologic cultures. The micro-organisms were identified in accordance with standard bacteriologic procedures. Susceptibility testing was carried out using Clinical and Laboratory Standards Institute (CLSI) procedures. RESULTS Among 77 urine specimens obtained from all recipients during the first month, there were 30 isolated bacterial strains. The most common were Gram-positive bacteria (53.3%) with predominance of enterococci (75%) associated with high levels of aminoglycoside resistant strains (HLAR; 58.3%) and vancomycin-resistant strains (VRE; 25%). Gram-negative bacteria were detected in 46.7% of positive cultures. CONCLUSIONS In our study, enterococci predominated as 75% of Gram-positive isolates. The increased proportion of multi-drug-resistant bacteria, which can caused severe UTI in patients after SPKT, may be due to the frequent use of prophylaxis of bacterial infections in patients.