Circulating CASK is associated with recurrent focal segmental glomerulosclerosis after transplantation.

INTRODUCTION: Focal and Segmental GlomeruloSclerosis (FSGS) can cause nephrotic syndrome with a risk of progression to end-stage renal disease. The idiopathic form has a high rate of recurrence after transplantation, suggesting the presence of a systemic circulating factor that causes glomerular permeability and can be removed by plasmapheresis or protein-A immunoadsorption. RESULTS: To identify this circulating factor, the eluate proteins bound on therapeutic immunoadsorption with protein-A columns were analyzed by comparative electrophoresis and mass spectrometry. A soluble form of calcium/calmodulin-dependent serine protein kinase (CASK) was identified. CASK was immunoprecipitated only in the sera of patients with recurrent FSGS after transplantation and not in control patients. Recombinant-CASK (rCASK) induced the reorganization of the actin cytoskeleton in immortalized podocytes, a redistribution of synaptopodin, ZO-1,vinculin and ENA. rCASK also induced alterations in the permeability of a monolayer of podocytes and increased the motility of pdodocytes in vitro. The extracellular domain of CD98, a transmembrane receptor expressed on renal epithelial cells, has been found to co-immunoprecipitated with rCASK. The invalidation of CD98 with siRNA avoided the structural changes of rCask treated cells suggesting its involvement in physiopathology of the disease. In mice, recombinant CASK induced proteinuria and foot process effacement in podocytes. CONCLUSION: Our results suggest that CASK can induce the recurrence of FSGS after renal transplantation.

Efficacy and Safety of Intra-gastric Balloon Placement in Dialyzed Patients Awaiting Kidney Transplantation.

BACKGROUND: The number of obese patients who are candidates for renal transplantation has considerably increased, but obesity can be a barrier to kidney transplantation. Weight loss is often difficult through diet alone. We studied the efficacy and tolerance of the intra-gastric balloon (IGB) procedure in obese patients who were undergoing dialysis and were candidates for a renal transplantation. PATIENTS AND METHODS: Obese patients (BMI > 30 kg/m2) who were candidates for renal transplantation were prospectively included in the study between 2010 and 2012. The balloon was inserted and removed during a gastric endoscopy under general anesthesia. The treatment lasted 6 months. The end point was a decrease in BMI after 6 months. Body impedance spectrometry (BIS) and nutritional statute were evaluated initially and then after IGB removal. RESULTS: Seventeen patients (nine females and eight males) with a mean age of 53.4 years [19.4-69.4] were included. The decrease in body mass index (BMI) during the 6-month placement was 3 kg/m2 (from 37.7 to 34.4 kg/m2). The mean weight loss was 7 kg. The mean percentage of excess weight loss after 6 months was 20.2 (± 11.4). The tolerance was good without any complications. Eleven patients underwent kidney transplantation. CONCLUSION: IGB in obese dialyzed patients who are candidates for renal transplantation is safe and effective. However, the amount of weight loss can vary.

Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients.

BACKGROUND: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics. METHODS: 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0-24h and the AUC-to-trough concentration ratios. RESULTS: The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0-24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10-5). In contrast, both the post-transplantation period (p=1.53×10-4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0. CONCLUSIONS: This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0-24h for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure.

Impact of arteriovenous fistula cannulation on the quality of dialysis.

INTRODUCTION: Adequate hemodialysis directly improves health. Puncturing an arteriovenous fistula (AVF) and the amount of blood recirculation greatly affect the quality of dialysis. Few studies have assessed the method to cannulate a fistula and its influence on efficiency of hemodialysis. METHODS: This prospective pilot study included 14 patients with end-stage renal failure receiving regular intermittent hemodialysis. Patients received three consecutive treatments with both needles directed upstream then three consecutive treatments with the venous needle directed upstream and the arterial needle directed downstream. With both techniques, the distance between the needles was kept constant at 2.5 cm. Recirculation rate and Kt/V ratio were measured during each treatment using thermodilution and a diascan Fresenius generator. FINDINGS: The 14 patients received 84 hemodialysis sessions: i.e., 8 (57.1%) males and 6 (42.8%) females, mean age 62.3 ± 15.57 years. Results showed that mean recirculation rates and Kt/V did not significantly differ between the two techniques. DISCUSSION: Because no significant difference was found between the two techniques, the direction of insertion of needles should be decided upon on a case-by-case basis depending on the anatomy of the AVF and the feasibility of the puncture.

Optimal management of primary focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated. Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. This study reviews the treatment of primary FSGS and the recurrence of FSGS after kidney transplantation in adults.

Comparison of the AN69ST Membrane versus Citrate-Enriched Dialysate on Clotting Events during Hemodialysis without Systemic Anticoagulation.

BACKGROUND: The optimal management of anticoagulation in hemodialyzed patients with a high risk of bleeding is controversial. METHODS: We compared premature termination of dialysis caused by clotting events between AN69ST membranes (G1) and 0.8 mmol/L citrate-enriched dialysate (G2). The number of sessions that had increased venous pressure (VP) and variations in urea-reduction ratio (URR) were analyzed. RESULTS: Six hundred and two sessions were analyzed in 259 patients: 22.4% had sessions that ended prematurely (25% in G1 and 19.1% in G2, p = ns, OR 0.60 [0.34-1.08], p = 0.08). The increase in VP was lower in G2 (23 vs. 70, p < 0.001). URR was higher in G2 (0.56 vs. 0.60, p < 0.001). CONCLUSION: Clotting events that led to the termination of dialysis were comparable in the 2 groups. However, UUR was better in G2, and the number of patients with increased VP in the sessions was lower in G2. SHORT SUMMARY: Our study compared the effects of the AN69ST membrane and citrate-enriched dialysate on clotting events during the dialysis of 259 patients with a high risk of bleeding. URR was significantly better and fewer cases of increased VP occurred in the citrate group compared to the AN69 ST group. No significant difference was observed regarding the need to prematurely terminate a dialysis session.

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus.

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged-release tacrolimus-based immunosuppressive regimens. On Days 0-27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolonged-release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m2 ; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged-release tacrolimus plus MMF (Arm 1) versus lower dose prolonged-release tacrolimus plus sirolimus (Arm 2).

[Role of cannabinoid receptors in renal diseases]. / Rôle des récepteurs cannabinoïdes au cours des maladies rénales.

Chronic kidney disease remains a major challenge for public health systems and corresponds to the replacement of renal functional tissue by extracellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for chronic kidney disease except nephroprotective strategies. The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in chronic kidney disease. Experimental data obtained in models of diabetes and obesity suggested that CB1 blockade and CB2 stimulation may slow the development of diabetic nephropathy. In human kidneys, CB1 expression is increased in various chronic nephropathies and correlates with renal function. Moreover, endogenous CB1 and CB2 ligands are greatly increased during renal fibrogenesis. A microarray analysis performed in an experimental model of renal fibrosis found that the gene encoding for the CB1 receptor was among the most upregulated genes. We also demonstrated that renal fibrogenesis could be reduced by CB1 inhibition and CB2 stimulation in an experimental model through a direct mechanism involving CB1 on myofibroblasts, which are the major effector cells during renal fibrosis. Therefore, CB1 blockers may represent a novel therapeutic target in chronic kidney disease and diabetes.

Cannabinoid receptor 1 is a major mediator of renal fibrosis.

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-ß1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Protein A immunoadsorption cannot significantly remove the soluble receptor of urokinase from sera of patients with recurrent focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a serious disease, the pathogenesis of which is unknown. Its recurrence after transplantation (Tx) and its partial remission after treatment with immunoadsorption (IA) on a protein A column indicate the existence of a circulating factor responsible for the disease that is able to bind to a protein A column. Recently, the soluble receptor of urokinase (suPAR) was described as the factor responsible for FSGS. We tested the capacity of suPAR to bind to protein A and to be eliminated by IA. METHODS: We measured suPAR in eluates of protein A columns from seven patients with recurrent FSGS after Tx (rFSGS) treated with IA, and in the serum of 13 patients with rFSGS and 11 healthy donors (HDs). Additionally, the plasma of these patients was immunoadsorbed in vitro on a protein A Sepharose column, and we quantified suPAR in the eluates and in pre- and post-column samples. RESULTS: The concentration of suPAR was higher in the plasma of patients with rFSGS than that of HD patients. However, the concentration of suPAR was similar before and after IA on protein A for the rFSGS and HD samples. The suPAR concentration was very low in the eluates from protein A columns incubated with plasma from HD or rFSGS patients. However, 85% of rFSGS patients showed a decrease in immunoglobulin G and proteinuria. CONCLUSIONS: Thus, suPAR does not significantly bind to protein A in vitro or in vivo.

Belatacept utilization recommendations: an expert position.

INTRODUCTION: There is a continuing need for an immunosuppressive therapy that offers a high benefit-risk profile for renal transplant recipients, supporting long-term patient and graft survival while minimizing cumulative nephrotoxicity and other side effects. Belatacept , the first biological agent developed for primary maintenance immunosuppression, was recently approved for use in Europe. Belatacept combined with corticosteroids and a mycophenolic acid is indicated for prophylaxis of graft rejection in adults receiving renal transplant. Its use is contraindicated in Epstein-Barr virus seronegative or serostatus unknown patients due to increased risk of developing posttransplant lymphoproliferative disorder. AREAS COVERED: This review provides practical recommendations for the use of belatacept, based on safety and efficacy data from Phase II and Phase III clinical trials in de novo kidney transplant recipients. EXPERT OPINION: Treatment with belatacept is associated with improved long-term graft function, making belatacept an important option for prevention of kidney allograft rejection. Furthermore, efficacy and safety data over several years of therapy suggest that belatacept is particularly suitable for long-term immunosuppression, and the selective targeting offered by belatacept may help avoid some of the non-specific chronic safety risks associated with calcineurin inhibitors and steroids. Future studies will clarify the optimal regimen for belatacept usage.

[Necessary but sometimes complicated coordination of healthcare procedures. The example of chronic renal failure]. / Une coordination des soins nécessaire mais parfois compliquée. Exemple de l'insuffisance rénale chronique.

Chronic renalfailure (CRF), one of several disorders involving progressive loss of function of a vital organ, is a paradigm for medical/paramedical coordination networks, especially in view of the explosion of the geriatric CRF/dialysis population. An efficient network is crucial in this setting, given the very high incidence of CRF, its cost, its impact on employment, quality of life and quality of care; and the progression from medical treatment to replacement therapy (peritoneal or hemodialysis) and, eventually, organ transplantation from a living or deceased donor. There is a constant flow of patients entering and exiting care pathways between community practices (public or private), hospitals (general or teaching), medical laboratories, pharmacies (commuity and hospital) and a large number of allied health professions (nurses, social workers, dieticians, physiotherapists, secretaries, etc.). In the predialytic stage of CRF the goal of the network is to establish the diagnosis, slow disease progression, prevent or treat the many potentially complications, inform patients and their families, and postpone the need for dialysis and transplantation. When renal replacement therapy becomes necessary, the choice between peritoneal dialysis and hemodialysis follows strict rules and requires a more technical approach, with predominant involvement of the nephrologist. Finally, transplantation is highly hospital-centered, but patient monitoring in the community requires an approach very similar to that of the predialytic stage, with the involvement of specialists in internal medicine/general practitioners, as the potential complications cover a very broad field of disciplines (infectious, cardiovascular, metabolic, cancer). CRF is a major public health problem that requires a network-based approach involving multiple specialties and skills, the most difficult problem being its coordination. A similar approach can probably be extrapolated to other patients with chronically failing major organs (liver, lungs, heart).

Belatacept: a novel immunosuppressive agent for kidney transplant recipients.

Long-term graft and patient survival remain the most significant challenges in kidney transplantation, and new therapies are needed to improve long-term outcomes. Belatacept, a first-in-class selective costimulation blocker, has been approved for prophylaxis of organ rejection in kidney transplant recipients who are positive for EBV. In Phase III trials, belatacept demonstrated superior preservation of renal function and comparable patient/graft survival compared with cyclosporine, while avoiding the renal toxicities and other adverse events associated with the use of a calcineurin inhibitor. Patients treated with belatacept had higher rates of acute rejection than cyclosporine-treated patients. However, acute rejection episodes that occurred early and did not recur were generally not associated with donor-specific antibodies, and few belatacept patients had graft loss due to rejection. The improved renal benefit with belatacept may translate into improvements in long-term graft and patient outcomes. Targeting T-cell costimulation is an important new option for maintenance immunosuppression in kidney transplant recipients.

Liver-kidney recipients with chronic viral hepatitis C treated with interferon-alpha.

Antiviral therapy with interferon-alpha (IFN-alpha) and pegylated IFN-alpha (PEG-IFN-alpha) for chronic hepatitis C (HCV)-infected kidney recipients remains controversial. IFN-alpha is not recommended in most cases because it induces severe acute graft rejection. However, IFN-alpha, as PEG-IFN-alpha, is associated with a more pronounced immune response, and is well tolerated in HCV-infected liver recipients without causing graft rejection. In combined liver-kidney transplant (LKT) recipients, IFN-alpha has been occasionally used and appears to be well tolerated. All LKT recipients with a functioning kidney and liver having a HCV replication and who needed IFN-alpha therapy have been included in the study. The occurrence of liver and/or renal acute rejection as well as the HCV replication has been collected. A total of 12 LKT patients treated with PEG-IFN-alpha plus ribavirin have been studied. No acute rejection was observed. Renal function remained stable during and after discontinuing treatment, without any graft dysfunction. Two patients had a partial viral response and four had a sustained viral response. All patients, whatever their viral response, had decreased liver-enzyme levels. Response to PEG-IFN-alpha therapy was correlated with steroid dose and transaminase level when PEG-IFN-alpha was started. These data suggest that the combination therapy of PEG-IFN-alpha plus ribavirin did not have a higher risk of acute kidney-graft rejection after liver-kidney transplantation.

Surgical prevention and management of vascular complications of kidney transplantation.

The main surgical changes in kidney procurement, preparation, and transplantation procedures occurred 20 years ago and were undertaken despite the inability to design randomized studies. The objective was to assess the evolution of vascular complications after kidney transplantation in a setting of surgical preventive measures in a historical series. A monocentric series of 3129 consecutive kidney transplantations performed over 3 decades was reviewed. The occurrence of arterial or venous thromboses, stenoses, and aneurysms was analyzed in relation with kidney procurement, preparation, and transplantation techniques. Vascular complications occurred in 13.5% of the recipients with a mean 3-year decrease in kidney graft function. The transplantation of a right kidney without renal vein extension, multiple renal arteries, ex vivo vascular repairs, and end-to-end arterial anastomoses were the unfavorable surgical vascular factors. It was possible to manage Transplant Renal Artery Stenosis (TRAS) nonsurgically in 80% of the cases. The prevention of vascular complications begins from the time of organ procurement by skilled surgeons. The aims of organ preparation are to evaluate the vascular risk, select the organs, and to simplify the anatomical constraints of vascular implantations. The three surgical steps of kidney transplantation are determinant in postoperative vascular complications and the duration of graft function.

Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience.

The diabetes and renal phenotype of patients with maturity-onset diabetes of the young (MODY) on a transplantation waiting list is not known; neither is their outcome after pancreas (PT) and/or kidney transplantation (KT). Between 2002 and 2009, we screened 50 of 150 patients referred for kidney and pancreas transplantation to the Kremlin-Bicêtre center for HNF1B and HNF1A mutations if one or more of the following criteria was present (i) an atypical history of diabetes (ii) diabetes with at least one affected parent or two affected relatives, (iii) an absence of auto-antibodies at diagnosis (iv) a persistent secretion of fasting C peptide (v) a personal or a family history of renal cysts or dysplasia. Their phenotype and their outcome were analyzed. Four HNF1A (MODY3) and eight HNF1B mutations [renal cysts and diabetes (RCAD)] were identified. All MODY3 patients had diabetic nephropathy, but only 50% of RCAD patients. Four patients underwent a kidney and pancreas transplantation and two a kidney transplant alone. After 4.1 ± 1.1 years of follow-up, 83% of patients still have a functioning kidney and 75% a functioning pancreas. PT can be proposed with good results for MODY3 and RCAD patients.

Interleukin-15 plays a central role in human kidney physiology and cancer through the γc signaling pathway.

The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Rαßγc complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the γc-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of γc-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the γc/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Rαß heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/γc-dependent signaling (STAT5), by co-transfecting γc and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and γc-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation).

Differentiation therapy: targeting human renal cancer stem cells with interleukin 15.

BACKGROUND: Many renal cancer patients experience disease recurrence after immunotherapy or combined treatments due to persistence of cancer stem cells (CSCs). The identification of reliable inducers of CSC differentiation may facilitate the development of efficient strategies for eliminating CSCs. We investigated whether interleukin 15 (IL-15), a regulator of kidney homeostasis, induces the differentiation of CD105-positive (CD105(+)) CSCs from human renal cancers. METHODS: CD105(+) CSCs were cultured to preserve their stem cell properties and treated with recombinant human IL-15 (rhIL-15) to evaluate their ability to differentiate, to acquire sensitivity to chemotherapeutic drugs, and to form spheroids in vitro and tumors in vivo. Expression of stem cell and epithelial markers were studied by flow cytometry, immunocytochemistry, and immunoblotting. Identification of a CSC side population fraction and its sensitivity to chemotherapy drugs and expression of ATP-binding cassette (ABC) transporters and aldehyde dehydrogenase (ALDH) activities were determined by flow cytometry. Spheroid formation was determined in limiting dilution assay. Xenograft tumors were generated in severe combined immunodeficient mice (n = 12-18 mice per group). All statistical tests were two-sided. RESULTS: CD105(+) CSCs treated with rhIL-15 at 10 pg/mL differentiated into cells expressing epithelial markers. rhIL-15 induced epithelial differentiation of all CD105(+) CSCs subsets and blocked CSC self-renewal (sphere-forming ability) and their tumorigenic properties in severe combined immunodeficient mice. Vinblastine and paclitaxel induced statistically significant higher levels of apoptosis in rhIL-15-differentiated epithelial cells compared with CD105(+) CSCs (mean percentage of apoptotic cells, vinblastine: 33% vs 16.5%, difference = 16.5%, 95% confidence interval = 12.25% to 20.74%, P = .0025; paclitaxel: 35% vs 11.6%, difference = 23.4%, 95% confidence interval = 22.5% to 24.24%, P = .0015). The higher sensitivity of rhIL-15-differentiated epithelial cells to chemotherapeutic drugs was associated with loss of detoxifying mechanisms such as ALDH and ABC transporter activities. CONCLUSION: IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.