Progression of macrovascular diseases is reduced in type 1 diabetic patients after more than 5 years successful combined pancreas-kidney transplantation in comparison to kidney transplantation alone

Recent reports have demonstrated an improved cardiovascular outcome after simultaneous pancreas-kidney transplantation (SPKT) compared with kidney transplantation alone (KTA) in type 1 diabetic patients with end-stage renal disease. The purpose of this study was to determine the impact of SKPT and KTA on the progression of cerebrovascular disease (CVD), coronary heart disease (CHD) and peripheral vascular disease (PVD) 5 and 10 years after transplantation. Only patients with graft survival more than 5 years, were included in this study. In summary, 12 type 1 diabetic patients with SPKT and 10 diabetic subjects with KTA were evaluated. The immunosuppressive therapy was similar in both patient groups. The mean observation period was 124 (72-184) months in the SPKT group and 122 (64-216) months in the group with KTA. To investigate the vascular risk profile we examined mean HbA1c, blood pressure and lipid levels in both patient groups during the first 5 years (period I) and the second 5 years (period II) after transplantation (measurements at least at 3-month intervals). Additionally, we evaluated the prevalence of moderate (stage I-II) and severe (stage III-IV) macrovascular diseases prior as well as 5 and 10 years after transplantation. During period I the mean HbA1c-value was 5.7+/-0.4% in the group with SPKT versus 7.4+/-0.8% in the KTA group, and in period II 5.8+/-0.4% in the SPKT group versus 7.6+/-0.9% (P<0.001) in the patients with KTA. The cholesterol levels were approximately the same in both groups, the triglycerides were lower in the patients with SPKT than in the subjects with KTA with 1.3+/-0.4 vs. 2.2+/-0.9 mmol/l in period I, and 1.4+/-0.5 vs. 2.3+/-0.6 mmol/l in period II (P<0.05). The BP-values were similar in both groups. Five years after transplantation the prevalence of vascular diseases was not significantly different between both groups. During the following 5 years the prevalence of macrovascular diseases increased more in the KTA than in the SKPT group. After a mean observation period of 10 years the SKPT group showed a lower prevalence of vascular diseases (stage I-IV) with 41% CVD, 50% CHD and 50% PAV in comparison to the KTA group with a prevalence of 80% CVD, 90% CHD and 80% PAV), the difference was not statistically significant because of the small patient groups. The frequency of the vascular complications myocardial infarction (16% vs. 50%), stroke (16% vs. 40%) and amputations (16% vs. 30%) was in summary significant lower in the patients with SPKT than in the patients with KTA (P<0.05). In conclusion, while for the first 5 years after transplantation the progression of macroangiopathy in patients with SPKT and KTA was not significantly different, after a mean 10-year observation period the progression of macrovascular diseases was significantly lower in recipients with a functioning SPKT compared to patients with a KTA; this can be explained by a better vascular risk profile after SPKT. The 10-year patient survival was 83% in the SPKT group and 70% in patients with KTA.     

The effect of IGL-1 preservation solution on outcome after kidney transplantation: A retrospective single-center analysis

Institut Georges Lopez-1 (IGL-1) solution is increasingly used for kidney preservation, although little information on outcomes is available. Outcomes of all deceased donor kidneys preserved by IGL-1, University of Wisconsin solution (UW), or histidine-tryptophan-ketoglutarate (HTK) and transplanted in our center (2000-2018) were analyzed. Multivariable analysis for delayed graft function (DGF), functional DGF, estimated glomerular filtration rate (eGFR, CKD-EPI equation), proteinuria, acute rejection, death-censored graft loss, and patient survival were performed. A double robust approach, consisting of propensity score weighting and correction for confounders, minimized the risk of bias. In total, 1943 transplants were included: 234 with IGL-1, 1046 with UW, and 663 with HTK. As IGL-1 was only introduced in 2014, a prespecified sensitivity analysis of 917 kidneys (2010-2018) was performed using the same statistical approach. After weighting, IGL-1 retained a higher proportion of kidneys donated after circulatory death (DCD). IGL-1 was not independently associated with any of the outcomes when compared to UW or HTK. Sensitivity analysis between 2010 and 2018 showed similar results. In this retrospective analysis, using robust methodology to reduce the risk of bias, IGL-1 preservation results in equal outcomes compared to UW or HTK, despite more DCD transplants in the IGL-1 group.     

New onset diabetes after kidney transplantation in autosomal dominant polycystic kidney disease: a retrospective cohort study

Background: New onset diabetes after transplantation (NODAT) is a common adverse outcome of organ transplantation that increases the risk of cardiovascular disease, infection and graft rejection. In kidney transplantation, apart from traditional risk factors, autosomal dominant polycystic kidney disease (ADPKD) has also been reported by several authors as a predisposing factor to the development of NODAT, but any rationale for an association between ADPKD and NODAT is unclear. We examined the cumulative incidence of NODAT in or own transplant population comparing ADPKD patients with non‐ADPKD controls. Methods: A retrospective cohort study to determine the cumulative incidence of patients developing NODAT (defined by World Health Organization‐based criteria and/or use of hypoglycaemic medication) was conducted in 79 patients with ADPKD (79 transplants) and 423 non‐ADPKD controls (426 transplants) selected from 613 sequential transplant recipients over 8 years. Patients with pre‐existing diabetes as a primary disease or comorbidity and/or with minimal follow up or early graft loss/death were excluded. Results: Of the 502 patients (505 transplants) studied, 86 (17.0%) developed NODAT. There was no significant difference in the cumulative incidence of NODAT in the ADPKD (16.5%; CI 13.6–20.7%) compared with the non‐ADPKD (17.1%; CI 8.3–24.6%) control group. Of the 13 patients in the ADPKD group with NODAT, three required treatment with insulin with or without oral hypoglycaemic agents. Among the 73 NODAT patients in the non‐ADPKD group, eight received insulin with or without oral hypoglycaemics. Furthermore, of the patients that did develop NODAT, there was no difference in the time to its development in patients with and without ADPKD Conclusion: There was no evidence of an increased incidence of NODAT in ADPKD kidney transplant recipients.     

DCD供肾灌注液生物标志物预测肾移植术后移植物功能延迟恢复的临床应用研究

目的  探讨心脏死亡器官捐献（DCD）供肾静态冷保存（SCS）灌注液生物标志物预测肾移植受者术后发生移植物功能延迟恢复（DGF）的可行性。方法  回顾性分析DCD供肾肾移植的64例受者和47例供者的临床资料。根据受者术后是否发生DGF分为DGF组（7例）与即刻肾功能恢复（IGF）组（57例）,比较两组供肾SCS灌注液中4种生物标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、肝型脂肪酸结合蛋白（L-FABP）、白细胞介素-18（IL-18）、肾损伤分子-1（KIM-1）的水平并分析其与DGF的相关性,分析各生物标志物对肾移植受者术后发生DGF的预测价值。结果  DCD供肾肾移植受者术后DGF的发生率为11%（7/64）。DGF组供肾灌注液的NGAL水平高于IGF组（P=0.009）,供肾灌注液的NGAL水平与肾移植受者术后DGF的发生呈正相关（r=0.430, P < 0.001）。受试者工作特征（ROC）曲线分析结果显示,灌注液中的NGAL和KIM-1水平升高对肾移植受者术后发生DGF具有一定的预测价值（均为P < 0.05）,当联合检测NGAL和KIM-1时,预测肾移植受者术后发生DGF的曲线下面积（AUC）为0.932[95%可信区间（CI）0.850~1.000],灵敏度为1.000,特异度为0.754（P < 0.05）。结论  DCD供肾SCS灌注液中的NGAL水平与肾移植受者术后DGF的发生存在相关性,联合检测灌注液中的NGAL和KIM-1水平可以较为准确地预测肾移植受者术后DGF的发生。     

Recombinant PTH therapy for severe hypoparathyroidism after kidney transplantation in pre‐transplant parathyroidectomized patients: review of the literature and a case report

Although transient hypocalcemia following kidney transplantation can occur, severe refractory hypocalcemia is uncommon. We report a case of a 31‐yr‐old highly sensitized man with end‐stage renal disease caused by reflux nephropathy, who received an expanded criteria deceased donor kidney transplant. The post‐transplant course was significant for profound hypocalcemia despite treatment with large doses of calcium and vitamin D, in the setting of severe hypoparathyroidism following a subtotal parathyroidectomy three yr prior to the transplant. His course was also complicated by suboptimal allograft function with significant new vascular changes seen in the allograft biopsy by seven wk post‐transplant. Teriparatide (recombinant parathyroid hormone) injections were initiated (up to three times daily) with improvement in the vascular changes and a decrease in calcium phosphate calcification in biopsy, as well as reduction in hypercalciuria, restoration of calcium phosphate homeostasis and stabilization of allograft function. We describe six other cases of post‐transplant hypoparathyroidism, with five of six having decreased allograft function and three of those five demonstrating significant accelerated vascular changes on biopsy. We discuss the use of teriparatide injections for the treatment of renal transplant recipients with impaired renal function in the setting of hypoparathyroidism.     

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement‐driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement‐blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43‐48 hours prior to implantation into ABO‐compatible, nonsensitized, MHC‐mismatched recipients. Animals were divided into 3 donor‐treatment groups: G1 ‐ vehicle, G2 ‐ rhC1INH+heparin, and G3 ‐ heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b‐9, and reduced urinary neutrophil gelatinase–associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor‐management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD‐induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation.     

Should liver transplantation be performed before advanced renal insufficiency in primary hyperoxaluria type 1?

Primary hyperoxaluria type 1 (PH1) is a rare recessive autosomal inborn error of glyoxylate metabolism leading to oxalate retention, the first target of which is the kidney. The disease is caused by a defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase. Patients with pyridoxine-resistant forms of PH1 usually require organ replacement therapy, i.e. liver transplantation to supply the deficient enzyme and/or kidney transplantation to replace the affected organ. The current experience of the management of Ph1 has emphasized two main points: (1) end-stage renal failure must be avoided since it increases dramatically the risk of systemic involvement, (2) the correction of oxalate overproduction and organ overload requires the removal of the host liver. Practical attitudes towards these ideas are difficult to assess and an individualized strategy is therefore required. Isolated kidney transplantation should be limited to adult patients with late-onset and a mild course of the disease. The present experience of combined liver-kidney transplantation was gained mainly in adult patients with severe systemic involvement; the 3-year patient survival rate recently increased to 82%. This figure might be improved if the procedure were performed earlier while the glomerular filtration rate (GFR) is above 25 ml/min per 1.73 m². Isolated liver transplantation should be considered in carefully selected children with severe forms of pyridoxineresistance (PH1) before GFR has dropped to less than 30 ml/min per 1.73 m²; it seems to be indicated especially in the presence of a rapid decline of GFR in the preceding year. In two young children who underwent isolated liver transplantation in our units 4 years ago, renal function could be stabilized and severe extrarenal involvement prevented.     

肾移植术后Ⅰ型原发性高草酸尿症复发致移植肾功能不全的多学科综合诊疗

目的  探讨肾移植术后Ⅰ型原发性高草酸尿症（PH）复发的临床特点和多学科综合诊疗（MDT）的经验。方法  对1例接受同种异体肾移植手术后不明原因移植肾功能短期内迅速下降的病例进行MDT讨论,总结MDT在诊断罕见遗传性疾病以及提高肾移植受者长期存活中的作用。结果  经MDT讨论,患者确诊为Ⅰ型PH复发,排除排斥反应后恢复常规免疫抑制方案,嘱大量饮水,予优质蛋白和低磷饮食、维生素B6、钙剂等保守治疗措施并积极防治并发症。患者移植肾功能恶化延缓,但仍在肾移植术后5个月恢复规律血液透析至投稿日。结论肾移植术后Ⅰ型PH复发较为罕见,临床主要表现为复发性肾结石,移植肾功能下降,且并发症多,患者预后不良。通过MDT讨论患者病情,明确诊断,确定最佳治疗方案,延缓了病情进展,改善了患者预后。     

中国大陆原发性高草酸尿症1型临床特点及诊治情况总结

目的探讨原发性高草酸尿症1型(PH1)的临床表现、治疗及预后。方法检索维普网、中国知网、万方数据库、PubMed、Web of Science、Embase和Cochrane数据库中的相关文献,收集57例PH1患者的临床资料,对其临床表现、诊疗经过及预后情况进行分析。结果共纳入符合标准的文献35篇,共57例PH1患者,其中男39例,女18例,年龄0.2~57.0岁,发病年龄为出生后至42岁。57例PH1患者的临床症状表现特异性较低,肾结石41例,肾钙化和(或)肾钙质沉积21例,泌尿系统外草酸沉积12例,腰背腹痛12例,输尿管结石8例,此外尿量减少、代谢性酸中毒、水电解质紊乱、贫血、肉眼血尿等症状均有报道,有33例在诊断时已进入终末期肾病(ESRD)阶段。26例患者接受移植治疗,肾移植17例(2例因结石复发、恢复透析再次接受肝肾联合移植,1例恢复透析并再次接受肝移植),肝肾联合移植7例,肝移植2例,肝肾序贯移植3例。31例患者未接受移植治疗。接受移植治疗的患者与未接受移植治疗的患者存活率差异有统计学意义(85%比58%,P<0.05)。结论PH1的临床表现多样且缺乏特异性,发现时多已进入ESRD阶段,接受移植治疗较未接受移植治疗的患者预后更佳,应优先考虑预先肝移植或肝肾联合移植。     

Camrelizumab monotherapy leading to partial remission for relapsed upper tract urothelial carcinoma after radical nephroureterectomy: a case report

Upper tract urothelial carcinoma (UTUC) is a rare malignant disease, and while locally advanced non-metastatic UTUC can be cured by radical nephroureterectomy (RNU), this procedure leaves patients at high risk of relapse and death from cancer. Though the FDA has currently approved five agents for the systemic immunotherapy treatment of urothelial carcinoma (UC) patients, the effect of immunotherapy in patients with recurrent UTUC still lacks specific evidence. Camrelizumab is a programmed cell death protein 1 (PD-1) inhibitor which has been approved for the treatment of recurrent or refractory classical Hodgkin lymphoma in China and have achieved improvement in a verity of solid tumors with manageable safety profile. We herein report a case of an 80-year-old woman diagnosed with localized UTUC (pT4N0M0) for which she underwent RNU but relapsed after 2 months. As the toxic effects of chemotherapy were intolerable for the patient, she received the PD-1 inhibitor Camrelizumab as a salvage treatment to stop tumor growth. The tumor shrank and the patient achieved partial response (PR) after eight cycles but progressed after 14 cycles. Based on the current evidence, our case indicated that Camrelizumab is a promising agent in treating locally advanced and recurrent UTUC patients with poor performance status and imparted renal function.     

Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC^®) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1β (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.