Outcomes after simultaneous kidney‐pancreas versus pancreas after kidney transplantation in the current era

Simultaneous pancreas and kidney (SPK) and pancreas after kidney (PAK) transplant are both potential options for diabetic ESRD patients. Historically, PAK pancreas graft outcomes were felt to be inferior to SPK pancreas graft outcomes. Little is known about outcomes in the modern era of transplantation. We analyzed our SPK and PAK recipients transplanted between 01/2000 and 12/2016. There were a total of 635 pancreas and kidney transplant recipients during the study period, 611 SPK and 24 PAK. Twelve of the PAK patients received a living donor kidney. There were no significant differences between the two groups in kidney or pancreas graft rejection at 1 year. Similarly, 1‐year graft survival for both organs was not different. At last follow‐up, uncensored and death‐censored graft survival was not statistically different for kidney or pancreas grafts. In addition, in Cox regression analysis SPK and PAK were associated with similar graft survival. Although the majority of pancreas transplants are in the form of SPK, PAK is an acceptable alternative. Simultaneous pancreas and kidney avoids donor risks associated with live donation, so may be preferable in regions with short wait times, but PAK with a living donor kidney may be the best alternative in regions with long SPK wait times.     

Kidney retransplantation following graft loss to polyoma virus-associated nephropathy: an effective treatment option in simultaneous pancreas and kidney transplant recipients.

Polyomavirus-associated nephropathy (PVAN) has emerged as an important cause of graft loss following kidney transplantation. Experience with kidney retransplantation (reKT) in PVAN is very limited, especially in the setting of uninterrupted immunosuppression protecting the still functioning pancreatic graft after simultaneous pancreas/kidney transplantation (SPK). We present a review of five cases of reKT in four SPK recipients with Type 1 diabetes mellitus from a single centre (a second reKT was performed in one patient following first reKT failure due PVAN recurrence). Pre-emptive nephrectomy of the failed graft was performed in three of the cases and all kidney grafts for reKT were harvested from cadaveric donors. All patients are dialysis- and insulin-independent at 30 (9-55), median (range), months following last reKT with maintenance immunosuppression consisting of tacrolimus/sirolimus in three and cyclosporine A/mycophenolate mofetil in one patient. In conclusion, reKT represents an effective treatment option in SPK patients with kidney failure on account of PVAN. Use of interventions designed to reduce active viral replication, including pre-emptive nephrectomy of the failed graft, should be considered before reKT.     

Potential pathological role of pro‐inflammatory cytokines (IL‐6, TNF‐α, and IL‐17) in xenotransplantation

The major limitation of organ transplantation is the shortage of available organs from deceased human donors which leads to the deaths of thousands of patients each year. Xenotransplantation is considered to be an effective way to resolve the problem. Immune rejection and coagulation dysfunction are two major hurdles for the successful survival of pig xenografts in primate recipients. Pro‐inflammatory cytokines, such as IL‐6, TNF‐α, and IL‐17, play important roles in many diseases and in allotransplantation. However, the pathological roles of these pro‐inflammatory cytokines in xenotransplantation remain unclear. Here, we briefly review the signaling transduction and expression regulation of IL‐6, TNF‐α, and IL‐17 and evaluate their potential pathological roles in in vitro and in vivo models of xenotransplantation. We found that IL‐6, TNF‐α, and IL‐17 were induced in most in vitro or in vivo xenotransplantation model. Blockade of these cytokines using gene modification, antibody, or inhibitor had different effects in xenotransplantation. Inhibition of IL‐6 signaling with tocilizumab decreased CRP but did not increase xenograft survival. The one possible reason is that tocilizumab can not suppress IL‐6 signaling in porcine cells or organs. Other drugs which inhibit IL‐6 signaling need to be investigated in xenotransplantation model. Inhibition of TNF‐α was beneficial for the survival of xenografts in pig‐to‐mouse, rat, or NHP models. Blockade of IL‐17 using a neutralizing antibody also increased xenograft survival in several animal models. However, the role of IL‐17 in the pig‐to‐NHP xenotransplantation model remains unclear and needs to be further investigated. Moreover, blockade of TNF‐α and IL‐6 together has got a better effect in pig‐to‐baboon kidney xenotransplantation. Blockade two or even more cytokines together might get better effect in suppressing xenograft rejection. Better understanding the role of these cytokines in xenotransplantation will be beneficial for choosing better immunosuppressive strategy or producing genetic modification pig.     

Performances of creatinine‐based glomerular filtration rate estimating equations in simultaneous pancreas‐kidney transplant recipients: a single center cohort study

Estimating glomerular filtration rate (GFR) is important for clinical management and research studies in simultaneous pancreas‐kidney transplantation (SPK) recipients. No study has specifically investigated the reliability of recent creatinine–based GFR estimating equations in this singular population. We assessed the performances of CKD‐EPI, MDRD, Schwartz‐2009, Schwartz‐Lyon, Lund‐Malmo and Full Age Spectrum equations for estimating GFR after SPK. 126 patients were included. GFR was measured by a reference method (mGFR) one year after SPK and estimated with the different equations from a standardized measure of serum creatinine. Relative bias, precisions, 10% and 30% accuracies (P30) were used to determine equations reliability. Ages ranged from 29 to 58. Mean mGFR was 56.3 ± 13.3 [23.6–92.5] ml/min/1.73 m². In the whole population, P30 of the CKD‐EPI and MDRD equations were 42% (38.0; 46.0) and 65% (61.5; 69) respectively. As compared to the other equations, the Schwartz‐Lyon equation was significantly more accurate (P30 = 86.0% [83.5–88.0], P < 0.01) and less biased (1.13 [1.06–1.19], P < 0.01). Conclusions were similar whatever the age class (<40 or ≥40) and mGFR level (<60 or ≥60 ml/min/1.73 m²). This study suggests that the CKD‐EPI and MDRD equations have poor performances in SPK recipients and that the Schwartz‐Lyon equation is a reliable alternative.     

Combined effects of TNF‐α, IL‐1β, and HIF‐1α on MMP‐2 production in ACL fibroblasts under mechanical stretch: An in vitro study

The dynamics between inflammatory factors, mechanical stress, and healing factors, in an intra‐articular joint, are very complex after injury. Injury to intra‐articular tissue [anterior cruciate ligament (ACL), synovium] results in hypoxia, accumulation of various pro‐inflammatory factors, cytokines, and metalloproteases. Although the presence of increased amounts of matrix‐metalloproteinases (MMP) in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP‐2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury, inflammation and hypoxia induced factor‐1α (HIF‐1α) on induction of MMP‐2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF‐α and IL‐1β elevate the activity of MMP‐2 in a dose‐ and time‐dependent manner. In addition, mechanical stretch further enhances the MMP‐2 protein levels with TNF‐α, IL‐1β, and their mixture. CoCl₂‐induced HIF‐1α (100 and 500 µM) also increases the levels and activity of MMP‐2. Mechanical stretch has a strong additional effect on MMP‐2 production with HIF‐1α. Our results conclude that mechanical injury, HIF‐1α and inflammatory factors collectively induce increased MMP‐2 production in ACL fibroblasts, which was inhibited by NF‐κB pathway inhibitor (Bay‐11‐7082). © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1008–1014, 2011     

Interleukin‐1β stimulates stromal‐derived factor‐1α expression in human subacromial bursa

Chemokines produced by synoviocytes of the subacromial bursa are up‐regulated in subacromial bursitis and rotator cuff disease. We hypothesized that SDF‐1α production in bursal synoviocytes may be induced by local cytokines such as interleukin IL‐1β and IL‐6. Subacromial bursa specimens were obtained from patients undergoing shoulder surgery. Bursal specimens were stained with anti‐human antibodies to IL‐1, IL‐6, and SDF‐1α by immunohistochemistry and compared to normal and rheumatoid controls. Bursal cells were also isolated from specimens and cultured. Early passaged cells were then treated with cytokines (IL‐1β and IL‐6) and SDF‐1α expression was measured by ELISA and RT‐PCR. SDF‐1α, IL‐1β, and IL‐6 were expressed at high levels in bursitis specimens from human subacromial bursa compared to normal controls. In cultured bursal synoviocytes, there was a dose‐dependent increase in SDF‐1α production in the supernatants of cells treated with IL‐1β. SDF‐1α mRNA expression was also increased in bursal cells treated with IL‐1β. IL‐6 caused a minimal but not statistically significant increase in SDF‐1α expression. SDF‐1α, IL‐1β, and IL‐6 are expressed in the inflamed human subacromial bursal tissues in patients with subacromial bursitis. In cultured bursal synoviocytes, SDF‐1α gene expression and protein production are stimulated by IL‐1β. IL‐1β produced by bursal syvoviocytes and inflammatory cells in the human subacromial bursa is an important signal in the inflammatory response that occurs in subacromial bursitis and rotator cuff disease. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1695–1699, 2011     

Late pancreatic panniculitis in a simultaneous pancreas kidney transplant patient with failed allografts

We present a rare case of pancreatic panniculitis in a 59‐year‐old male simultaneous pancreas–kidney (SPK) recipient with failed allografts. The patient presented with fever and painful erythematous nodules on his leg 1 month after stopping all immunosuppression. A thorough infectious and rheumatological workup was negative. He had pancreas rejection 4 years after SKP transplant and was restarted on dialysis after 14 years when his renal allograft failed due to chronic allograft nephropathy. His chronic immunosuppression (tacrolimus, azathioprine) was stopped and prednisone was weaned over 3 months at that time. A skin biopsy revealed saponification of the subcutaneous fat with inflammation pathognomonic of pancreatic panniculitis. Concurrent allograft pancreatitis confirmed with elevated lipase and a computed tomography scan finding of peripancreatic graft stranding and atrophic native pancreas. He was started on pulse steroid therapy for 3 days followed by oral taper. This resulted in dramatic resolution of all skin lesions and normalization of lipase levels within 1 week, followed by resumption of low‐dose tacrolimus and azathioprine. This is an extremely rare occurrence of panniculitis in pancreas allograft after 10 years of pancreatic failure associated with stopping immunosuppression.     

Clinical validation of a novel enzyme‐linked immunosorbent spot assay‐based in vitro diagnostic assay to monitor cytomegalovirus‐specific cell‐mediated immunity in kidney transplant recipients: a multicenter,longitudinal, prospective,observational study

Impaired cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) is a major cause of CMV reactivation and associated complications in solid‐organ transplantation. Reliably assessing CMV‐CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T‐Track^® CMV, a novel IFN‐γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE‐I CMV proteins, to monitor CMV‐CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate‐risk renal transplant recipients. CMV‐CMI, CMV viral load, and clinical complications were monitored over 6 months post‐transplantation. Ninety‐five percent and 88–92% ELISpot assays were positive pre‐ and post‐transplantation, respectively. CMV‐specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65‐specific response was ninefold higher in patients with self‐clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T‐Track^® CMV is a highly sensitive IFN‐γ ELISpot assay, suitable for the immunomonitoring of CMV‐seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV‐related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).     

Exogenous Interferon‐γ Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients

The incidence of invasive fungal infections (IFIs) in nonneutropenic solid organ transplant patients is increasing. We report our clinical experience with the use of interferon‐γ (IFN‐γ) immunotherapy in seven renal transplant patients who developed life threatening, disseminated IFIs refractory to conventional antifungal drug therapy. The infections were all microbiologically and histologically proven. The rapid cure of these disseminated infections with exogenous IFN‐γ injections was not associated with impaired kidney allograft function despite the use of liposomal amphotericin B in all cases. No clinical toxicity from the IFN‐γ immunotherapy was seen and no IFI relapsed during long‐term follow‐up. Our experience is both uncontrolled and in patients with unpredictable fungal infection‐related outcomes. However, compared to standard approaches, the accelerated cure of life threatening, disseminated IFIs with 6 weeks of combination antifungal drug therapy and IFN‐γ immunotherapy saved lives, retained allograft function and led to substantial cost savings in this small patient group.     

Increased gene expression of TGF‐β in peripheral blood mononuclear cells from renal transplant patients with polyomavirus BK viremia

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty‐eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real‐time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)‐2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)‐β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF‐β, but not IL‐2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF‐β and IL‐6 mRNA. After adjusting for age and sex in the regression model, both age and TGF‐β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF‐β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF‐β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients.     

Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance

The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.     

The liver recipient with acute renal dysfunction: A single institution evaluation of the simultaneous liver‐kidney transplant candidate

The Organ Procurement Transplant Network (OPTN) listing criteria for simultaneous liver‐kidney transplant (SLK) are not well defined. Concerns remain about rising numbers of SLKs, which divert quality kidneys from candidates awaiting kidney transplants (KT). We performed a retrospective review of liver transplants (LTs) at our center from 2004 to 2014; 127 recipients (liver transplant alone; 102 LTA, 25 SLK) were identified with short‐term preoperative kidney dysfunction (creatinine >4 mg/dL or preoperative hemodialysis [HD] for <6 weeks). Both cohorts had comparable baseline demographic characteristics with the exception of higher model for end‐stage liver disease (MELD) score in the LTA group (41.4 vs 32.9, P < .0001) and higher incidence of pre‐LT diabetes in the SLK cohort (52% vs 26.5%, P = .0176). Duration of pre‐LT HD was higher in SLK recipients, but the difference was not statistically significant (P = .39). Renal nonrecovery (RNR) rate in LTA cohort was low (<5%). No significant difference was noted in 1‐year mortality, liver graft rejection/failure, or length of stay (LOS) between the cohorts. Thus, it appears that liver recipients with short‐term (<6 weeks) HD or AKI without HD have comparable outcomes between LTA and SLK. With provisions for a KT safety net, as proposed by OPTN, LTA may be the most adequate option for these patients.