Thomas Baudoux

Delayed Graft Function in Kidney Transplants: Time Evolution, Role of Acute Rejection, Risk Factors, and Impact on Patient and Graft Outcome

Background. Although numerous risk factors for delayed graft function (DGF) have been identified, the role of ischemia-reperfusion injury and acute rejection episodes (ARE) occurring during the DGF period is ill-defined and DGF impact on patient and graft outcome remains controversial. Methods. From 1983 to 2014, 1784 kidney-only transplantations from deceased donors were studied. Classical risk factors for DGF along with two novel ones, recipients perioperative saline loading and residual diuresis, were analyzed by logistic regression and receiver operating characteristic (ROC) curves. Results. Along with other risk factors, absence of perioperative saline loading increases acute rejection incidence (OR = 1.9 [1.2–2.9]). Moreover, we observed two novel risk factors for DGF: patients residual diuresis ≤500 mL/d (OR = 2.3 [1.6–3.5]) and absence of perioperative saline loading (OR = 3.3 [2.0–5.4]). Area under the curve of the ROC curve (0.77 [0.74–0.81]) shows an excellent discriminant power of our model, irrespective of rejection. DGF does not influence patient survival (P = 0.54). However, graft survival is decreased only when rejection was associated with DGF (P < 0.001).  Conclusions. Perioperative saline loading efficiently prevents ischemia-reperfusion injury, which is the predominant factor inducing DGF. DGF per se has no influence on patient and graft outcome. Its incidence is currently close to 5% in our centre.

Patient and graft outcome in current era of immunosuppression: a single centre pilot study

Abstract Objectives: The present single centre study aims at analyzing the impact on renal allograft outcome of the important changes which occurred in the transplant population and immunosuppressive therapy during the last two decades. Methods: From 2000 to 2013, 779 single kidney transplantations were performed on 635 patients who all received on an intent-to-treat basis steroids, a calcineurin inhibitor, mycophenolate mofetil and an induction therapy with either antithymocyte globulin or an antagonist directed to the interleukin (IL)-2 receptor. Uni- and multivariate analyses of patient and immunologic graft survival were conducted. Results: The sole factor predicting patient survival is recipient’s age: 10-year survival rates are 94·7, 81·6 and 57·9% for the <45, 45–60 and >60 years age groups, respectively (P<0·001). Peak (>50% panel reactive antibodies) anti-human leucocyte antigens (HLA) sensitization, cold ischaemia time and HLA-B and -DR mismatches (MM) influence graft outcome: at 10 years, the difference in 10-year survival rates is 5·9% between grafts from sensitized and not sensitized patients (90·9 vs 96·8%, P = 0·002), 3·8% between grafts with <18 and ≧18 hours cold ischaemia (96·6 vs 92·8%, P = 0·003), 7·3% between grafts with no MM and either B or DR MM versus those with B and DR MM (96·8 vs 89·5%, P = 0·002). Conclusion: In our single centre experience, graft survival was most strongly determined by HLA matching, offering excellent long term graft outcome to most patients.

Nephrotoxicity of herbal products

The kidney is one of the major routes of excretion of drugs and metabolites, and given its high blood flow and metabolic activity, it is highly susceptible to injury by toxic drugs and herbs. In addition, high concentrations of toxic metabolites are in close contact with tubular cells due to urine concentration, especially during a state of fluid deprivation. The incidence of nephrotoxicity related to alternative medicines is not known. However, regarding the large number of individuals consuming herbs as alternative remedies and regarding the lack of control of over-the-counter products, clinicians should consider alternative medicine consumption in the differential diagnosis of unexplained kidney injury.

Early detection of acute cisplatin nephrotoxicity: Interest of urinary monitoring of proximal tubular biomarkers

Abstract Background Renal toxicity induced by cisplatin (CisPt) is a clinical issue in patients with or without chronic kidney disease (CKD). Proximal tubular injury can result in acute kidney injury (AKI), which may compromise the course of chemotherapy and the prognosis. The purpose of this study was to investigate the time course of urinary markers of acute tubulotoxicity and to assess the usefulness of such monitoring in a routine clinical setting. Methods This work is an open prospective pilot study carried out among 23 patients receiving a platinum-based chemotherapy. Individual comorbidities, plasma parameters of kidney function (urea, creatinine) and estimated glomerular filtration rate were registered. Urinary excretion of leucine aminopeptidase, neutrophil gelatinase-associated lipocalin, cystatin C, liver fatty acid-binding protein and interleukin-18 were monitored during successive chemotherapy cycles. Episodes of AKI were identified according to KDIGO (Kidney Disease Improving Global Outcomes) 2012 guidelines. Results A total of 28 patients were recruited; among them 23 agreed to be part of the study, of whom 18 received CisPt and 5 carbo- or oxaliplatin. Of the 18 CisPt patients, 12 had a preexisting CKD. Sixteen AKI episodes were observed in 13 patients receiving CisPt with a pejorative evolution in seven cases (partial recovery of the renal function); a transient but dramatic increase in urinary biomarkers was observed 3 h after chemotherapy initiation, whereas plasma creatinine rise appeared 72 h after the end of CisPt treatment. Identified precipitating factors included: dehydration due to lack of fluid intake or diuretic use, exposure to high CisPt doses, regular use of nonsteroidal anti-inflammatory drugs and/or iodinated contrast agents and sepsis. Conclusion Even if numerous precipitating factors could be avoided, the monitoring of urinary markers seemed helpful for the early detection of subclinical AKI induced during CisPt chemotherapy.

CD4 + and CD8 + T Cells Exert Regulatory Properties During Experimental Acute Aristolochic Acid Nephropathy

Experimental aristolochic acid nephropathy is characterized by transient acute proximal tubule necrosis and inflammatory cell infiltrates followed by interstitial fibrosis and tubular atrophy. The respective role of T-cell subpopulations has never been studied in the acute phase of the mouse model, and was heretofore exclusively investigated by the use of several depletion protocols. As compared to mice injected with aristolochic acids alone, more severe acute kidney injury was observed after CD4+ or CD8+ T-cells depletion. TNF-alpha and MCP-1 mRNA renal expressions were also increased. In contrast, regulatory T-cells depletion did not modify the severity of the aristolochic acids induced acute kidney injury, suggesting an independent mechanism. Aristolochic acids nephropathy was also associated with an increased proportion of myeloid CD11bhighF4/80mid and a decreased proportion of their counterpart CD11blowF4/80high population. After CD4+ T-cell depletion the increase in the CD11bhighF4/80mid population was even higher whereas the decrease in the CD11blowF4/80high population was more marked after CD8+ T cells depletion. Our results suggest that CD4+ and CD8+ T-cells provide protection against AA-induced acute tubular necrosis. Interestingly, T-cell depletion was associated with an imbalance of the CD11bhighF4/80mid and CD11blowF4/80high populations.

Donor Cancer Transmission in Kidney Transplantation

INTRODUCTION D espite careful donor selection, cancer transmission remains a rare but dramatic complication of renal transplantation. In the light of a case report, we first review recent evidence regarding the risk of cancer transmission in kidney recipients. Second, we discuss the difficult task of assessing the benefit–risk balance in the decision process of accepting organs from cancer patients.

CD44-positive cells and hyaluronan are a hallmark of a rat model of aristolochic acid nephropathy

Background: Aristolochic acid (AA) Nephropathy (AAN) is characterized by tubulointerstitial injury leading to fibrosis and tubular atrophy. Defective regeneration of tubular cells was hypothesized as a mechanism leading to Proximal Tubular Epithelial Cell (PTEC) atrophy. Here, we examined the distribution of CD44, an adhesion molecule involved in differentiation, and its main ligand, Hyaluronan (HA), in an experimental AAN model. Methods: Wistar rats were injected daily with AA or vehicle during 35 days. Tubular enzymuria and tissue expression of CD44 and HA were evaluated at days 3, 7, 10, 21 and 35. Co-expressions of CD44 and PCNA (proliferation), vimentin (mesenchymal phenotype), a-SMA (myofibroblasts), and CD133 (progenitor cells) were investigated. Results: AA induced acute tubular damage followed by PTEC atrophy. In controls, CD44 was limited to the basolateral membrane of collecting ducts while HA expression was confined to the medullary interstitium. CD44 was overexpressed as soon as 3 days after AA exposure, spreading to the apical and basolateral membranes of dedifferentiated PTECs and appearing on numerous interstitial cells along with marked HA accumulation around necrotic tubules. Both CD44 and HA expressions increased steadily throughout the 1-month follow-up. A large amount of tubular and interstitial CD44+ cells were proliferative (PCNA+) and mesenchymal-like (vimentin+). Few CD44+ cells expressed a-SMA or CD133. Conclusions: Our results suggest CD44 is a strong marker of dedifferentiation, and thus of regeneration, in a rat model of AAN. Concomitant HA accumulation around necrotic tubules may create a sustained crosstalk between CD44+ cells and their interstitial ligand. PTEC atrophy is accompanied by overexpression, not deficiency, of the CD44-HA axis.

Risk of urinary tract carcinoma in aristolochic acid nephropathy

Sir, The article by Yang et al. [1] is of great interest. Indeed, the acknowledgement of the grim reality of aristolochic acid nephropathy (AAN) by Chinese scientists is of paramount importance for public health in Asia. The authors focused on variation in clinical presentation, essentially acute or chronic renal failure as well as tubular disorders. Unfortunately, they do not discuss the cases of haematuria related to a urinary tract carcinoma, which represent apparently the first clinical presentation in 3% of studied patients (Table 1 of the paper). Besides the renal injury, urinary tract carcinoma is actually a major complication of AAN (prevalence superior to 40%) [2, 3]. Accordingly to our experience, urothelial cancer may occur during AAN progression from the very early stage to the end-stage disease. After kidney transplantation, urothelial dysplasias or carcinomas are present in the native upper urinary tract of AAN patients. Therefore, prophylactic bilateral ureteronephrectomy is strongly recommended in all patients with end-stage AAN [2–4]. Moreover, AAN transplant patients remain at risk for the development of bladder cancer [4]. Therefore, a regular screening by cystoscopy is strongly recommended [4, 5]. In our experience, such cystoscopic examination performed every 6 months demonstrated its efficiency in detecting bladder tumours at an early stage, namely non-muscle invasive carcinoma of high grade (pT1G3) and/or carcinoma in situ [5]. In conclusion, the diagnosis of urinary tract cancer must be considered by the clinician in all patients suspected to have been exposed to aristolochic acid, and regular screening procedures are required during the long-term follow-up of these patients.