Reversing CXCL10 Deficiency Ameliorates Kidney Disease in Diabetic Mice.

The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR- CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis. Although the plasma concentrations of CXCL9 and CXCL11 were similar, those of CXCL10 were markedly lower in diabetic db/db mice compared with control db/m mice. In cell culture, CXCL10 inhibited kidney fibroblast collagen production in response to high glucose and the prosclerotic growth factor, transforming growth factor-ß. In vivo, recombinant murine CXCL10 reduced mesangial and peritubular matrix expansion, albuminuria, and glomerular hypertrophy in db/db mice. In bone marrow, a major source of circulating chemokines, the concentration of CXCL10 was lower in cells derived from diabetic mice than from their nondiabetic counterparts. Silencing of CXCR3, the cognate receptor for CXCL10, abrogated the antifibrotic effects of bone marrow-derived secretions. In conclusion, experimental diabetes is a state of CXCL10 deficiency and that restoration of CXCL10 abundance prevented fibrosis and the development of diabetic kidney disease in mice.

The Effect of Preoperative Administration of Intravenous Tranexamic Acid During Revision Hip Arthroplasty: A Retrospective Study.

BACKGROUND: Revision hip arthroplasty poses several challenges, including the management of perioperative blood loss. Recent studies have validated the use of tranexamic acid in primary total hip arthroplasty, showing reduced blood loss and decreased number of allogenic blood transfusions. The effectiveness of tranexamic acid has not been well studied in the revision hip arthroplasty setting. METHODS: We performed a retrospective review of 1,072 patients who underwent revision hip arthroplasty at our institution from 2008 to 2016. A total of 634 patients met the inclusion criteria, and comparisons were made between 232 consecutive patients without the use of tranexamic acid and 402 consecutive patients with the use of tranexamic acid. Patients were subdivided into 4 groups based on the complexity of revision surgical procedures: (1) major revision, (2) isolated femoral component revision, (3) isolated acetabular component revision, and (4) isolated femoral head and acetabular liner exchange. Within these groups, we compared the demographic data, estimated intraoperative blood loss, perioperative blood units transfused, postoperative hemoglobin drop, and thromboembolic complications between patients receiving either tranexamic acid or no antifibrinolytic therapy. RESULTS: The primary outcomes of our study (estimated intraoperative blood loss, postoperative hemoglobin drop, and perioperative blood transfusion) were all reduced in patients who received tranexamic acid compared with patients who received no antifibrinolytic therapy. When analyzed on the basis of the complexity of surgical revision, there was a decrease in estimated intraoperative blood loss following tranexamic acid administration in the major revision group (845 compared with 1,095 mL; p < 0.001). The postoperative drop in hemoglobin was lower in the major revision group with tranexamic acid administration (by 8.9 g/L; p < 0.01) and the isolated acetabular component revision group with tranexamic acid administration (by 11.9 g/L; p < 0.001). The need for perioperative blood transfusion was reduced across all revisions treated with tranexamic acid (major revision group, 1.79 compared with 3.33 units, p < 0.001; femoral revision only, 0.97 compared with 2.25 units, p < 0.01; acetabular revision only, 0.73 compared with 1.72 units, p < 0.001; and head and liner exchange, 0.15 compared with 0.89 unit, p < 0.05). CONCLUSIONS: Based on this study, preoperative administration of intravenous tranexamic acid in revision hip arthroplasty reduces allogenic blood transfusions and perioperative blood loss. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Does Chronic Kidney Disease-Induced Cognitive Impairment Affect Driving Safety?

PURPOSE OF REVIEW: One of the principal mechanisms by which illness can affect driving safety is by impairing cognition. Nevertheless, despite the substantial evidence demonstrating cognitive impairment in chronic kidney disease (CKD), little is known about the effects of CKD on driving safety. OBJECTIVE: Investigate the current national medical guidelines and research literature with respect to CKD and driving safety. SOURCES OF INFORMATION: Medline, CINAHL, PEDro, Scopus as of August 2017. The most up to date national driving guidelines and available information provided by the provincial and territorial ministries of transportation across Canada. FINDINGS: Fives studies of driving fitness in patients with CKD have been published with minimal data available for patients at early stages of the disease. Amongst these studies, only two come from an era when modern end stage renal disease therapies were routinely provided. The first study demonstrated that 40% of 186 surveyed patients on hemodialysis felt uncomfortable driving and that 1/3 of patients were involved in motor vehicle collisions (MVC) since starting dialysis. Of the patients who felt comfortable driving, more than 75% were found to be at increased driving risk. The second study reported that 15% of patients on hemodialysis were involved in MVCs over a three year span and that the "Am I A Safe Driver" assessment tool by the American Medical Association may not capture all patients at high driving risk. Despite these alarming numbers, national guidelines place few driving restrictions on this patient population and only 3 of 11 available provincial or territorial driving forms include kidney disease as a category that physicians should consider when assessing medical fitness to drive. LIMITATIONS: Our review is limited by the lack of randomized control studies evaluating the effects of CKD on driving safety. IMPLICATIONS: Our review demonstrates that driving safety in this patient population remains poorly understood. The limited evidence that does exist, however, suggests that these patients are at substantial risk for unsafe driving. Future research is necessary to determine the impact of CKD-associated cognitive impairment on driving risk, and to parse out the contributions of CKD and its various treatments to driving impairment.

MOTIF DE LA REVUE: La réduction de la vigilance engendrée par la maladie est un des principaux mécanismes par lesquels celle-ci peut affecter la sécurité au volant. Cependant, malgré des données probantes faisant état de troubles cognitifs associés à l'insuffisance rénale chronique (IRC), on en sait peu sur l'incidence de l'IRC sur la conduite. OBJECTIF DE LA REVUE: Examiner les travaux de recherche et les recommandations médicales nationales en matière de sécurité routière en contexte d'IRC. SOURCES: Ont été consultés 1- les articles traitant du sujet publiés en date d'août 2017 sur Medline, CINAHL, PEDro et Scopus; 2- les plus récentes recommandations routières nationales et l'information fournie par les ministères des transports provinciaux et territoriaux du Canada. CONSTATATIONS: Cinq études faisant état des aptitudes de conduite de patients atteints d'IRC ont été publiées. Ces études contenaient toutefois peu de données concernant les patients atteints des premiers stades de la maladie. Seules deux études étaient datées d'une époque où on appliquait systématiquement les traitements modernes de l'insuffisance rénale terminale. La première mentionnait que 40 % des 186 patients hémodialysés sondés se disaient mal à l'aise de conduire, et que le tiers avait été impliqué dans un accident de la route depuis le début de leurs traitements de dialyse. Parmi les patients qui se disaient à l'aise de conduire, plus de 75 % se sont avérés des conducteurs à risque. La deuxième étude rapportait que 15 % des patients hémodialysés avaient été impliqués dans une collision automobile sur une période de trois ans. Cette étude ajoutait que l'outil d'évaluation Am I A Safe Driver? (Association médicale américaine) pouvait ne pas dépister tous les patients à risque élevé. Malgré ces chiffres alarmants, les recommandations nationales n'imposent que très peu de restrictions aux patients hémodialysés. De plus, seulement trois des onze formulaires de conduite provinciaux ou territoriaux répertorient la néphropathie comme maladie à considérer lors de l'évaluation médicale des aptitudes de conduite. LIMITES DE L'ÉTUDE: Notre revue est limitée par le manque d'études contrôlées à répartition aléatoire évaluant l'effet de l'IRC sur la conduite. CONCLUSION: Notre revue démontre que la sécurité au volant demeure mal comprise au sein de la population de patients hémodialysés. Les données examinées, quoique parcimonieuses, suggèrent que ces patients posent un risque substantiel à la sécurité routière. Des études additionnelles sont nécessaires pour évaluer l'incidence des troubles cognitifs associés à l'IRC sur les risques d'accidents de la route, et pour établir un lien entre l'IRC (et ses divers modes de traitement) sur la réduction des aptitudes de conduite.

Revision Total Hip Arthroplasty for Fractured Ceramic Bearings: A Review of Best Practices for Revision Cases.

BACKGROUND: Total hip arthroplasty revision for a fractured ceramic bearing is rare but offers unique challenges. The purpose of this review was to provide a summary of existing literature on fractured ceramic bearings. METHODS: Two authors performed a literature search of the MEDLINE OVID and PubMed databases with the following search terms: ceramic, fracture, total hip arthroplasty, and revision. RESULTS: The search identified 228 articles of which 199 were selected for review. CONCLUSIONS: It is mandatory to perform a complete synovectomy and thorough debridement of the fractured ceramic fragments. A well-fixed acetabular component should be removed if either the locking mechanism is damaged or the component is malpositioned. If the femoral stem taper is damaged, the femoral stem should be removed. However, if minimal damage is present, the femoral stem may be retained and revised using a fourth generation ceramic head with a titanium sleeve. Metal bearings should be avoided and revision with ceramic bearings should be performed whenever possible.

Sirtuin 1 Activation Reduces Transforming Growth Factor-ß1-Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease.

Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor ß (TGF-ß), is thought to play a pivotal role. With the recent understanding that TGF-ß's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD+-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-ß1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity. In the remnant kidney model (subtotally or 5/6 nephrectomized rats) that develops progressive kidney disease in association with TGF-ß overexpression, administration of SRT3025 attenuated glomerular filtration rate decline and proteinuria without affecting blood pressure. Glomerulosclerosis and tubulointerstitial fibrosis were similarly reduced with Sirt1 activation as were cardiac structure and function in this rodent model of primary kidney and secondary cardiac disease. Relating these findings to the human setting, we noted a reduction in SIRT1 mRNA in kidney biopsies obtained from individuals with focal glomerulosclerosis. Together these studies highlight the potential of SIRT1 activation as a therapeutic strategy in progressive, fibrotic kidney disease.

Progenitor cell secretory products exert additive renoprotective effects when combined with ace inhibitors in experimental CKD.

HYPOTHESIS/INTRODUCTION: Renal fibrovascular injury often persists in chronic kidney disease patients treated with renin-angiotensin system blockers. Intriguingly, early outgrowth cell-derived factor infusion also inhibits chronic renal injury. We sought to determine whether early outgrowth cell-derived factor administration provides further renoprotection when added to renin-angiotensin system blockade. MATERIALS AND METHODS: Conditioned medium was generated by incubating rat early outgrowth cells with serum-free endothelial basal medium-2 to collect their secreted factors. Subtotal nephrectomy rats received enalapril 0.5 mg/L in drinking water or placebo, beginning 8 weeks post-surgery. Four weeks later, enalapril-treated rats received intravenous injections of either conditioned medium or control endothelial basal medium-2 for 2 weeks. Glomerular filtration rate, urinary protein excretion and renal structure were assessed 4 weeks later at 16 weeks post-surgery. RESULTS: Enalapril-treated subtotal nephrectomy rats receiving control endothelial basal medium-2 injections experienced only partial renoprotection when compared to vehicle-treated subtotal nephrectomy rats. In contrast, conditioned medium infusion, when administered in addition to enalapril, attenuated the progression of renal dysfunction in subtotal nephrectomy rats, improving glomerular filtration rate and reducing proteinuria without affecting blood pressure. CONCLUSIONS: Early outgrowth cell-derived factors exert additive renoprotective effects on top of angiotensin-converting enzyme inhibitor therapy in experimental chronic kidney disease, providing the rationale for clinical trials of early outgrowth cell-based therapies for chronic kidney disease.

Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease.

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.

Repeated treatment with bone marrow cell secretory products maintains long-term renoprotection in experimental chronic kidney disease: a placebo-controlled trial.

BACKGROUND: Bone marrow-derived early outgrowth cells (EOCs) secrete soluble factors that exert potent renoprotective effects, such that infusion of their conditioned medium recapitulates the affects of the cells themselves. OBJECTIVES: The objective of this study is to test whether the protective effect of conditioned medium infusion wanes with time and whether tachyphylaxis occurs with repeated administration. DESIGN: This is a placebo-controlled animal study. SETTING: The study was conducted at St. Michael's Hospital, Toronto, Ontario, Canada. SUBJECTS: Fischer 344 (F344) rats were used in this study. MEASUREMENTS: The following were measured: (1) urinary protein:creatinine ratio, (2) glomerular filtration rate, (3) systolic blood pressure, (4) body weight, (5) glomerular endothelial cell density, and (6) glomerular and tubulointerstitial type IV collagen deposition. METHODS: Subtotally nephrectomized F344 rats, a model of progressive chronic kidney disease, were randomized 4 weeks post-surgery to receive thrice-weekly intravenous injections of concentrated EOC-conditioned medium (EOC CM) or unconditioned medium (UCM) over 2 weeks. Three animal groups were studied, according to whether they were administered conditioned medium: once (Initial Therapy Only group), twice (Repeat Therapy group), or not at all (No Therapy group). RESULTS: Following initial therapy, EOC CM-treated animals excreted less urinary protein, a marker of renal injury, than their UCM-treated counterparts. At 10 weeks post-subtotal nephrectomy, however, mean urinary protein excretion in conditioned medium-treated animals was fourfold greater than at the completion of the initial treatment course. At this time point, conditioned medium-treated animals were randomized to receive a second course of either conditioned medium (Repeat Therapy group) or unconditioned medium (Initial Therapy Only group). At study end (14 weeks post-subtotal nephrectomy), Repeat Therapy animals demonstrated higher glomerular filtration rate, less proteinuria, preserved renal microvasculature, and diminished fibrosis when compared with the No Therapy group. Initial Therapy Only animals exhibited an intermediate effect. LIMITATIONS: Testing the effect of EOC-conditioned medium in a single model of chronic kidney disease (CKD) has limitations. CONCLUSIONS: These findings suggest that early outgrowth cell-derived factors, while renoprotective, have a limited duration of action. Repeated administration of these factors, however, is able to extend the duration of efficacy and attenuate the progression of experimental chronic kidney disease.

CONTEXTE: Les cellules à croissance précoce (CCP) provenant de la moelle osseuse sécrètent des facteurs solubles qui procurent des effets néphroprotecteurs très efficaces. Une simple infusion de milieu de culture conditionné par des CCP permet d'instaurer des effets protecteurs dans les cellules rénales. BUT DE L'ÉTUDE: Vérifier si l'effet néphroprotecteur d'une infusion de milieu conditionné décline dans le temps et déterminer si l'administration répétée engendre une tachyphylaxie. TYPE D'ÉTUDE: Essai contrôlé par placebo sur modèles animaux. ÉTABLISSEMENT: Hôpital St. Micheal's de Toronto, ON, Canada. SUJETS: Rats Fisher (F344). MESURES: (1) le ratio urinaire « protéines/créatinine ¼ (2) le débit de filtration glomérulaire (3) la pression systolique (4) le poids corporel (5) la densité des cellules endothéliales glomérulaires et (6) le dépôt tubulo-interstitiel et glomérulaire de collagène de type IV. MÉTHODE: Quatre semaines suivant la chirurgie, deux groupes expérimentaux ont été formés par randomisation de rats F344 partiellement néphrectomisés (un modèle utilisé pour l'étude de l'insuffisance rénale chronique et dégénérative). Durant 2 semaines, les animaux recevaient 3 injections intraveineuses par semaine d'un concentré de milieu conditionné par cellules à croissance précoce (MC-CCP) ou d'un concentré de milieu non conditionné (MNC). Les animaux du groupe MC-CCP ont, plus tard au cours de l'étude, été divisés en 2 sous-groupes. L'un d'eux a reçu une deuxième série d'injections de MC-CCP et l'autre, de MNC. Ainsi, 3 groupes ont été étudiés, selon qu'ils ont été traités au MC-CCP une seule fois (groupe « Traitement Initial Seulement ¼), deux fois (groupe « Traitement Répété ¼) ou en aucun temps (groupe « Non Traité ¼). RÉSULTATS: Dès le traitement initial, une diminution de l'excrétion urinaire de protéines (un indicateur de lésions aux reins) a été observée chez les sujets du groupe MC-CCP par rapport aux niveaux de leurs homologues du groupe MNC. Par contre, la moyenne d'excrétion urinaire de protéines chez les sujets du groupe MC-CCP avait tout de même quadruplé, 10 semaines suivant la chirurgie, par rapport aux taux mesurés après la première ronde de traitements. À ce stade de l'étude, les sujets du groupe MC-CCP ont été divisés et randomisés en deux sous-groupes à qui une deuxième ronde de traitements, soit par MC-CCP (groupe « Traitement Répété ¼), soit par MNC (groupe « Traitement Initial Seulement ¼) a été administrée. Au terme de l'étude (14 semaines suivant la chirurgie), les animaux du groupe « Traitement Répété ¼ ont démontré un débit de filtration glomérulaire supérieur, une diminution de la protéinurie, une préservation de la microvasculature rénale et une réduction de la fibrose, lorsque comparés au groupe non traité. Les animaux du groupe « Traitement Initial Seulement ¼ ont montré des résultats intermédiaires. LIMITATIONS: L'effet d'un traitement avec MC-CCP n'a été testé que dans un seul modèle expérimental d'insuffisance rénale chronique. CONCLUSIONS: Ces constatations suggèrent que, tout néphroprotecteurs qu'ils soient, les facteurs solubles dérivant de la culture de cellules à croissance précoce provenant de moelle osseuse ont une action de courte durée. En revanche, il apparait qu'une administration répétée de ces facteurs permet d'en prolonger l'action tout en freinant la progression de l'insuffisance rénale chronique dans les modèles expérimentaux.

Application of Modular Therapy for Renoprotection in Experimental Chronic Kidney Disease.

Cell-based regenerative therapies offer a new alternative approach to the treatment of chronic disease. Specifically, studies by our laboratory and others have shown that a subpopulation of cells derived from the bone marrow, known as early outgrowth cells (EOCs), are able to attenuate the progression of chronic kidney disease (CKD). In this study we examined the efficacy of a tissue engineering system, in which EOCs were embedded into submillimeter-sized collagen cylinders. These small individual units are referred to as modules and together form a functional microtissue. Due to their resemblance to endothelial cells, late outgrowth cells (LOCs) were used to coat the module surface, hypothesizing that as such they would promote vascularization and enhance engraftment of the encapsulated EOCs. These coated modules were transplanted subcutaneously into the subtotally nephrectomized rat model of CKD. While coated module therapy significantly improved both renal structure and function, noncoated modules with embedded EOCs were unable to reproduce these salutary effects on the kidney. Nevertheless, in both treatments, the embedded EOCs quickly degraded the modular environment and were seen to migrate to the liver, spleen, and bone marrow as early as 6 days after transplantation. With the efflux of EOCs, and unexpectedly no evidence of vascularization, we hypothesized that the LOCs did not enhance EOC engraftment, but rather augmented the renoprotection provided by EOCs by secretion of their own soluble and potent antifibrotic factors. To the best of our knowledge, this is the first study to document an effective subcutaneous approach for renoprotection.

SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: Nutrient overabundance and diminished physical activity underlie the epidemic of obesity and its consequences of insulin resistance and type 2 diabetes. These same phenomena, obesity and insulin resistance, are also observed in mammals as they ready themselves for the nutrient deprivation of winter, yet their plasma glucose does not rise. Given the role of silent information regulator 2 (Sir2) and its mammalian orthologue, Sirt1, in survival and life extension during energy deprivation, we hypothesised that enhancing its activity may reduce the insensible energy loss engendered by hyperglycaemia and glycosuria. METHODS: At 8 weeks of age, db/db and db/m mice were randomised to receive the SIRT1 activator SRT3025 milled in chow (3.18 g/kg) or regular chow and followed for a further 12 weeks. RESULTS: When compared with vehicle, SIRT1 activation greatly improved glycaemic control, augmented plasma insulin concentrations, increased pancreatic islet beta cell mass and elevated hepatic expression of the beta cell growth factor, betatrophin in db/db mice. Despite the dramatic reduction in hyperglycaemia, db/db mice displayed worsening insulin resistance, diminished physical activity and further weight gain. These findings along with reduced food intake and reduction in body temperature resembled torpor and hibernation. By contrast, SIRT1 activation conferred only minimal changes in non-diabetic db/m mice. CONCLUSIONS/INTERPRETATION: While reducing hyperglycaemia and promoting beta cell expansion, enhancing the activity of SIRT1 facilitates a phenotypic change in a db/db mouse model of diabetes to one that more closely resembles the physiological state of torpor or hibernation.

Early outgrowth cells release soluble endocrine antifibrotic factors that reduce progressive organ fibrosis.

Adult bone marrow-derived cells can improve organ function in chronic disease models, ostensibly by the release of paracrine factors. It has, however, been difficult to reconcile this prevailing paradigm with the lack of cell retention within injured organs and their rapid migration to the reticuloendothelial system. Here, we provide evidence that the salutary antifibrotic effects of bone marrow-derived early outgrowth cells (EOCs) are more consistent with an endocrine mode of action, demonstrating not only the presence of antifibrotic factors in the plasma of EOC-treated rats but also that EOC conditioned medium (EOC-CM) potently attenuates both TGF-ß- and angiotensin II-induced fibroblast collagen production in vitro. To examine the therapeutic relevance of these findings in vivo, 5/6 subtotally nephrectomized rats, a model of chronic kidney and heart failure characterized by progressive fibrosis of both organs, were randomized to receive i.v. injections of EOC-CM, unconditioned medium, or 10(6) EOCs. Rats that received unconditioned medium developed severe kidney injury with cardiac diastolic dysfunction. In comparison, EOC-CM-treated rats demonstrated substantially improved renal and cardiac function and structure, mimicking the changes found in EOC-treated animals. Mass spectrometric analysis of EOC-CM identified proteins that regulate cellular functions implicated in fibrosis. These results indicate that EOCs secrete soluble factor(s) with highly potent antifibrotic activity, that when injected intravenously replicate the salutary effects of the cells themselves. Together, these findings suggest that an endocrine mode of action may underlie the effectiveness of cell therapy in certain settings and portend the possibility for systemic delivery of cell-free therapy.

Early-outgrowth bone marrow cells attenuate renal injury and dysfunction via an antioxidant effect in a mouse model of type 2 diabetes.

Cell therapy has been extensively investigated in heart disease but less so in the kidney. We considered whether cell therapy also might be useful in diabetic kidney disease. Cognizant of the likely need for autologous cell therapy in humans, we sought to assess the efficacy of donor cells derived from both healthy and diabetic animals. Eight-week-old db/db mice were randomized to receive a single intravenous injection of PBS or 0.5 × 10(6) early-outgrowth cells (EOCs) from db/m or db/db mice. Effects were assessed 4 weeks after cell infusion. Untreated db/db mice developed mesangial matrix expansion and tubular epithelial cell apoptosis in association with increased reactive oxygen species (ROS) and overexpression of thioredoxin interacting protein (TxnIP). Without affecting blood glucose or blood pressure, EOCs not only attenuated mesangial and peritubular matrix expansion, as well as tubular apoptosis, but also diminished ROS and TxnIP overexpression in the kidney of db/db mice. EOCs derived from both diabetic db/db and nondiabetic db/m mice were equally effective in ameliorating kidney injury and oxidative stress. The similarly beneficial effects of cells from healthy and diabetic donors highlight the potential of autologous cell therapy in the related clinical setting.