Patrick Luke

REVERSAL OF STEROID- AND ANTI-LYMPHOCYTE ANTIBODY- RESISTANT REJECTION USING INTRAVENOUS IMMUNOGLOBULIN (IVIG) IN RENAL TRANSPLANT RECIPIENTS

Background. Despite the recent advances in immunosuppression, steroid-resistant rejection remains a difficult problem in renal transplant recipients. Methods. We reviewed our experience with i.v. immunoglobulin (IVIG) in the treatment of steroid- and antilymphocyte antibody-resistant rejection in renal transplant patients. Between September 1996 and March 1999, 17 patients were treated with IVIG to reverse steroid- or antilymphocyte antibody-resistant rejection. A total of 2 g/kg of IVIG was administered to patients during each treatment course. Results. With a mean follow-up of 21.5±9.5 months from the time of IVIG administration, patient and graft survival rates were 94% (16/17) and 71% (12/17), respectively. The baseline mean serum creatinine level prior to rejection was 2.2±0.7 mg/dl and peaked at 3.3±1.1 mg/dl at the time of the diagnosis of refractory rejection. IVIG therapy was associated with a fall in the mean creatinine to 2.8±1.1 mg/dl. The most recent serum creatinine in patients with functioning grafts was 2.8±1.6 mg/dl. In 82% of allograft biopsies after IVIG, reversal or reduction in the severity of rejection was demonstrated. In addition, IVIG therapy rescued three of four patients with antilymphocyte antibody-resistant rejection. Conclusions. IVIG rescue therapy for steroid- or antilymphocyte antibody-resistant rejection is associated with resolution or improvement of rejection severity, stable renal function, and reasonable graft survival.

Carbon monoxide-releasing molecules protect against ischemia–reperfusion injury during kidney transplantation

Carbon monoxide (CO) can provide beneficial antiapoptotic and anti-inflammatory effects in the context of ischemia-reperfusion injury (IRI). Here we tested the ability of pretreating the kidney donor with carbon monoxide-releasing molecules (CORM) to prevent IRI in a transplant model. Isogeneic Brown Norway donor rats were pretreated with CORM-2 18 h before kidney retrieval. The kidneys were then cold-preserved for 26 h and transplanted into Lewis rat recipients that had undergone bilateral nephrectomy. Allografts from Brown Norway to Lewis rats were also performed after 6 h of cold ischemic time with low-dose tacrolimus treatment. All recipients receiving CORM-2-treated isografts survived the transplant process and had near-normal serum creatinine levels, whereas all control animals died of uremia by the third post-operative day. This beneficial effect was also seen in isografted Lewis recipients receiving kidneys perfused with CORM-3, indicating that CORMs have direct effects on the kidney. Pretreatment of human umbilical vein endothelial cells in culture with CORM-2 for 1 h significantly reduced cytokine-induced nicotinamide adenine dinucleotide phosphate-dependent production of superoxide, activation of the inflammation-relevant transcription factor nuclear factor-κB, upregulated expression of E-selectin and intercellular adhesion molecule-1 adhesion proteins, and leukocyte adhesion to the endothelial cells. Thus, CORM-2-derived CO protects renal transplants from IRI by modulating inflammation.

Epstein-Barr virus seronegativity is a risk factor for late-onset posttransplant lymphoproliferative disorder in adult renal allograft recipients

Background. Posttransplant lymphoproliferative disorder (PTLD) remains a difficult management issue; therefore, many studies focus on the identification of risk factors to allow for preventive strategies. We investigated risk factors for PTLD in the adult renal transplant setting. Methods. A single-center, matched case-control study design was used. Cases were identified from patients who underwent a first renal transplant between January 1, 1985, and December 1, 2001. Two controls were chosen per case, matched (±1 year) by date of transplant and graft survival. Clinical and demographic data were ascertained from medical records. Pretransplant serology for Epstein-Barr virus (EBV) and cytomegalovirus was confirmed on frozen, stored sera. Statistical analysis included univariate and multivariable examination of putative risk factors using conditional logistic regression. Results. Twenty cases of PTLD were identified, an incidence of 2.4%. Median time from transplant to diagnosis was 55 months (range, 3–168 months), with 16 cases of late-onset PTLD (>1 year posttransplant). The only significant risk in univariate analysis was EBV-negative status at transplant (risk ratio 6.0, P =0.03). In multivariable analysis, EBV-negative status remained significant (adjusted risk ratio 8.9, P =0.01). The risk related to EBV status held true when late cases were analyzed separately (adjusted risk ratio 7.1, P =0.03). Conclusions. Pretransplant EBV-seronegative status is a strong risk for development of PTLD in adult renal allograft recipients, even in late disease. These results indicate that primary infection with EBV may have a pathogenic role in some cases of late PTLD.

Long-term results of pediatric renal transplantation into a dysfunctional lower urinary tract

Background. The authors reviewed their long-term experience with pediatric renal transplantation into a dysfunctional lower urinary tract to evaluate the results of contemporary lower urinary tract evaluation and management on graft survival and function. Methods. Between 1990 and 1996, 21 renal transplants were performed in 20 children with dysfunctional lower urinary tracts and 61 transplants were performed in 61 patients with normal lower urinary tracts. The minimum follow-up was 36 months (mean, 62.0±19.6 months). The cause of lower urinary tract dysfunction included posterior urethral valves (n=13), prune belly syndrome (n=4), meningomyelocele (n=2), and urogenital sinus abnormality (n=1). Urodynamics were performed on all children with dysfunctional lower urinary tracts. Using these perioperative assessments, lower tract management strategies were devised, including timed voiding alone (n=6), clean intermittent catheterization (n=8), bladder augmentation (n=4), and supravesical urinary diversion (n=2). Results. Overall 5-year actuarial patient and graft survival rates were 100% versus 95% (P =not significant [NS]) and 83% versus 69% in the dysfunctional and normal urinary tract groups (P =NS), respectively. Mean serum creatinine levels in dysfunctional and normal urinary tract patients with functioning grafts at 3 years were 1.3±0.5 and 1.3±0.7 mg/dL, respectively (P =NS). However, 35% of patients with a dysfunctional lower urinary tract experienced urologic complications. Conclusions. Pediatric renal transplantation into a dysfunctional lower urinary tract yields outcomes comparable to transplantation into the normal lower urinary tract. Because of the high urologic complication rates, careful surveillance of lower urinary tract function by urodynamic evaluation is essential to optimize these outcomes.

Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression

PURPOSE The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed. METHODS From July 4, 1994 until April 30, 1998, 147 pancreas transplantations were performed in 141 patients, including 126 simultaneous pancreas-kidney transplantations, 13 pancreas after kidney transplantation, and 8 pancreas transplantations alone. Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Twenty-three patients were excluded from analysis because of early graft loss in 17 cases, retransplantation in 5 cases, and simultaneous pancreas-kidney transplantation after heart transplantation in 1 patient. RESULTS With a mean follow-up of 2.8+/-1.1 years (range 1.0 to 4.8 years), complete steroid withdrawal was achieved in 58 (47%) patients with a mean time to steroid withdrawal of 15.2+/-8 months (range 4 to 40 months after transplantation). Of the entire cohort of 141 patients, overall 1-, 2-, and 4-year patient survival rates were 98%, 95.5%, and 86%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 83%, 80%, and 71% (pancreas) and 95%, 91%, and 84% (kidney), respectively. Of the 124 patients analyzed for steroid withdrawal, 1-, 2-, and 4-year patient survival rates were 98%, 97%, and 92%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 98%, 91.5%, 83% (pancreas) and 97%, 95%, and 91% (kidney). Patient, pancreas, and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids) versus 97%, 91%, and 96% (on steroids, all NS) and at 4 years were 100%, 94%, and 95% (off steroids) versus 78%, 68%, and 85% (on steroids, P = 0.01, 0.002, and NS, respectively). The cumulative risk of rejection at the time of follow-up was 76% for patients on steroids versus 74% for patients off steroids (P = NS). Seven patients originally tapered off steroids were treated for subsequent rejection episodes, which were all steroid sensitive, and two of these seven patients are currently off steroids. Thirteen patients received antilymphocyte therapy for steroid-resistant rejection, five of whom are now off steroids. Tacrolimus trough levels were 9.3+/-2.4 ng/ml (off steroids) and 9.7+/-4.3 (on steroids, P = NS). Mean fasting glucose levels were 98+/-34 mg/dl (off steroids) and 110+/-41 mg/dl (on steroids, P = NS). Mean glycosylated hemoglobin levels were 5.2+/-0.9% (off steroids) and 6.2+/-2.1% (on steroids, P = 0.02), and mean serum creatinine levels were 1.4+/-0.8 mg/dl (off steroids) and 1.7+/-1.0 mg/dl (on steroids, P = 0.02). CONCLUSION These data show for the first time that steroid withdrawal can be safely accomplished in pancreas transplant recipients maintained on tacrolimus-based immunosuppression. Steroid withdrawal is associated with excellent patient and graft survival with no increase in the cumulative risk of rejection.

Renal Perfusion Pump vs. Cold Storage for Donation After Cardiac Death Kidneys: A Systematic Review.

PURPOSE Static cold storage is generally used to preserve kidney allografts from deceased donors. Hypothermic machine perfusion may improve the outcome after transplantation but few studies with limited power have addressed this issue. We reviewed evidence of the effectiveness of storing kidneys from deceased donors after cardiac death before transplantation using cold static storage solution or pulsatile hypothermic machine perfusion. MATERIALS AND METHODS We searched electronic databases in September 2011 for systematic reviews and/or meta-analyses, randomized, controlled trials and studies of other designs that compared delayed graft function and graft survival. Sources included The Cochrane Library, PubMed® and EMBASE®. Studies excluded from review included those that did not discriminate between donation after cardiac death and donation from a neurologically deceased donor. Primary outcomes were delayed graft function and 1-year graft survival. Statistical analysis was done using RevMan (http://ims.cochrane.org/revman). RESULTS Nine studies qualified for review. Pulsatile perfusion pumped kidneys from donation after cardiac death donors had decreased delayed graft function compared to kidneys placed in cold storage (OR 0.64, 95% CI 0.43-0.95, p = 0.03). There was a trend toward improved 1-year graft survival in the pulsatile perfusion group but statistical significance was not attained (OR 0.74, 95% CI 0.48-1.13, p = 0.17). CONCLUSIONS Pulsatile machine perfusion of donation after cardiac death kidneys appears to decrease the delayed graft function rate. We noted no benefit in 1-year graft survival. Due to the great heterogeneity among the trials as well as several confounding factors, the overall impact on allograft function and survival requires more study.

Acute Page Kidney Following Renal Allograft Biopsy: A Complication Requiring Early Recognition and Treatment

The acute Page kidney phenomenon occurs as a consequence of external compression of the renal parenchyma leading to renal ischemia and hypertension. Between January 2000 and September 2007, 550 kidney transplants and 518 ultrasound‐guided kidney biopsies were performed. During that time, four recipients developed acute oligo‐anuria following ultrasound‐guided allograft biopsy. Emergent doppler‐ultrasounds were performed demonstrating absence of diastolic flow as well as a sub‐capsular hematoma of the kidney. Prompt surgical exploration with allograft capsulotomy was performed in all cases. Immediately after capsulotomy, intraoperative Doppler study demonstrated robust return of diastolic flow. Three patients maintained good graft function, and one kidney was lost due to acute antibody‐mediated rejection. We conclude that postbiopsy anuria associated with a subcapsular hematoma and acute absence of diastolic flow on doppler ultrasound should be considered pathognomonic of APK. All renal transplant specialists should be able to recognize this complication, because immediate surgical decompression can salvage the allograft.

Small interfering RNA targeting RelB protects against renal ischemia-reperfusion injury.

Background. Nuclear factor &kgr;B (NF-&kgr;B) has been found to be critical to the pathogenesis of renal ischemia-reperfusion injury (IRI). Using small interfering RNA (siRNA) to silence the expression of RelB, a component of the transcription factors Rel/nuclear factor &kgr;B, may protect renal IRI. Here, we report an siRNA-based treatment of preventing IRI. Methods. Renal IRI was induced in mice by clamping the left renal pedicle for 25 or 35 min. The therapeutic effects of siRNA were evaluated in renal function, histologic examination, and overall survival after lethal IRI. Results. A single injection of RelB siRNA resulted in knockdown of renal RelB expression. In comparison with control mice, levels of blood urea nitrogen and serum creatinine were significantly decreased in mice treated with siRNA. Pathologic examination demonstrated that tissue injury caused by IRI was markedly reduced as a result of RelB siRNA treatment. Additionally, with RelB siRNA treatment, immunohistochemistry showed a significant attenuation of tumor necrosis factor-&agr; expression. Furthermore, survival experiments revealed that more than 90% of control mice died from lethal IRI, whereas 80% of siRNA-pretreated mice survived until the end of the 8-day observation period. Conclusion. Silencing RelB, using siRNA, can significantly attenuate IRI-induced renal dysfunction and protect mice against lethal kidney ischemia, highlighting the potential for siRNA-based clinical therapy.

Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function.

Abstract:  Recurrence of focal segmental glomerular sclerosis (FSGS) in the allograft following renal transplantation can be graft threatening. To assess risk factors associated with FSGS recurrence, we analyzed 22 patients with FSGS who underwent transplantation between 1996 and 2004. Five patients (Group I, 23%) developed FSGS post‐transplantation. Of these patients, 60% had undergone bilateral nephrectomy (BN) for progressive disease compared with none of the patients that were free of recurrence (Group II) (p = 0.0006). Other factors linked with recurrent FSGS were time to first dialysis (Group I: 3.1 ± 1.1 yr vs. Group II: 11.9 ± 1.9 yr; p = 0.03), pre‐transplant proteinuria (Group I: 7.0 ± 1.8 g/d vs. Group II: 2.5 ± 0.7 g/d; p = 0.02), young age at transplantation (p = 0.09) and female sex (Group I: 80% vs. Group II: 24%; p = 0.021). Eighty percent of Group I patients received a living related transplant vs. 24% in Group II (p = 0.021). All grafts continue to function at last follow‐up with comparable serum creatinines. Overall, post‐transplant FSGS recurrence may be associated with BN, severity of pre‐transplant FSGS, female gender, and living donation. These patients should be monitored closely for early recurrence and may benefit from early plasmapheresis to restore and facilitate long‐term graft function.

Factors that impact the outcome of minimally invasive pyeloplasty: Results of the multi-institutional laparoscopic and robotic pyeloplasty collaborative group

PURPOSE We compared laparoscopic and robotic pyeloplasty to identify factors associated with procedural efficacy. MATERIALS AND METHODS We conducted a retrospective multicenter trial incorporating 865 cases from 15 centers. We collected perioperative data including anatomical and procedural factors. Failure was defined subjectively as pain that was unchanged or worse per medical records after surgery. Radiographic failure was defined as unchanged or worsening drainage on renal scans or worsening hydronephrosis on computerized tomography. Bivariate analyses were performed on all outcomes and multivariate analysis was used to assess factors associated with decreased freedom from secondary procedures. RESULTS Of the cases 759 (274 laparoscopic pyeloplasties with a mean followup of 15 months and 465 robotic pyeloplasties with a mean followup of 11 months, p <0.001) had sufficient data. Laparoscopic pyeloplasty, previous endopyelotomy and intraoperative crossing vessels were associated with decreased freedom from secondary procedures on bivariate analysis, with a 2-year freedom from secondary procedures of 87% for laparoscopic pyeloplasty vs 95% for robotic pyeloplasty, 81% vs 93% for patients with vs without previous endopyelotomy and 88% vs 95% for patients with vs without intraoperative crossing vessels, respectively. However, on multivariate analysis only previous endopyelotomy (HR 4.35) and intraoperative crossing vessels (HR 2.73) significantly impacted freedom from secondary procedures. CONCLUSIONS Laparoscopic and robotic pyeloplasty are highly effective in treating ureteropelvic junction obstruction. There was no difference in their abilities to render the patient free from secondary procedures on multivariate analysis. Previous endopyelotomy and intraoperative crossing vessels reduced freedom from secondary procedures.