Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF).

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

Idiopathic Scrotal Calcinosis: A Case Report.

Idiopathic scrotal calcinosis is formation of calcium deposits in the dermal layers of the scrotum. It results in the formation of single or multiple nodular calcifications that vary in size and number. First reported in 1883, this condition is common in the third decade of life. The presenting complaints range from disfigurement to itching, leading to decreased quality of life. The diagnosis is usually made on a clinical basis and can be confirmed by the histopathology of the excised nodules. Surgical removal of the nodules is the generally recommended treatment. The surgery aims to eradicate the nodules leaving the scrotal skin enough for scrotoplasty. We present a case of idiopathic scrotal calcinosis in a 37 years old male who came for radiological examination.

Trans-ventricular catheter device-based closure of postmyocardial infarction ventricular septal defect following coronary artery bypass grafting: A staged hybrid approach.

A 66-year-old woman with a history of hypertension, ischemic stroke, and rheumatoid arthritis presented to the hospital with severe angina pectoris and dyspnea and was diagnosed with myocardial infarction (MI). Coronary angiography revealed multisystem coronary artery occlusive disease. Due to refractory myocardial ischemia/evolving MI, emergency coronary artery bypass grafting (CABG) was undertaken. Intraoperative transesophageal echocardiography additionally revealed an apical muscular ventricular septal defect (VSD). Concomitant VSD repair was deferred due to the absence of surface evidence of transmural MI for left ventriculotomy, in the setting of pre-existing severe left ventricular dysfunction. An initial totally percutaneous attempt to close the VSD postoperatively failed. A hybrid surgical/catheter-based VSD closure was performed on postoperative day 4, with a successful outcome. The patient did well postoperatively and currently is alive in good condition. To the best of our knowledge, this is the first report of a staged (post-CABG) and hybrid surgical/catheter-based technique without the utilization of cardiopulmonary bypass.

Clinically Important Misclassification of Aortic Valve Stenosis Severity Using Non-Invasive Techniques: Simultaneous Echocardiography and Cardiac Catheterization During Transcatheter Aortic Valve Implantation in Awake Patients.

BACKGROUND: Suitability for transcatheter aortic valve (AV) implantation (TAVI) is determined by using transthoracic echocardiography (TTE), although left-sided cardiac catheterization (LCC) provides directly measured pressure data. TAVI in awake patients permits simultaneous comparison of TTE and LCC under physiologically relevant left ventricular loading conditions. We hypothesized that clinically important discrepancies between TTE and LCC would be identified. METHODS AND RESULTS: TAVI was performed in 108 awake patients undergoing intra-procedural TTE and LCC between January 1, 2016 and December 31, 2016, based upon pre-procedure TTE data. Intra-procedural assessments simultaneously were performed before and after prosthesis implantation. Based upon mean trans-AV systolic ejection pressure gradient (MSEPG), AS was graded as: mild (<20 mm Hg; grade 1), moderate (20 - <40 mm Hg; grade 2), or severe (≥40 mm Hg; grade 3). In 79 of the 108 (73.1%) patients, intra-procedural TTE and LCC assessments were concordant. In 2 of the 108 (1.9%) patients, TTE overestimated AS severity by ≥1 grade. In 27 of the 108 (25.0%) patients, TTE underestimated AS severity by ≥1 grade. In total, AS severity reclassification occurred in 29 (26.9%) patients. Overall, TTE underestimated MSEPG by 8.9 ± 1.2 mm Hg (TTE MSEPG versus LCC MSEPG; P < .001). CONCLUSION: Current TTE criteria appear to frequently and importantly underestimate AS severity. Because decision-making regarding TAVI often exclusively is based upon TTE data, these findings suggest either a continued role for LCC in the diagnostic assessment of AS in patients who do not meet standard TTE criteria or lowering TTE cutoffs for TAVI.

Fingolimod (FTY720) Preserves High Energy Phosphates and Improves Cardiac Function in Heterotopic Heart Transplantation Model.

During heart transplantation, donor heart leads to reduced oxygen supply resulting in low level of high energy phosphate (HEP) reserves in cardiomyocyte. Lower HEP is one of the underlying reasons of cell death due to ischemia. In this study we investigated the role of Fingolimod (FTY720) in heart transplantation ischemia. Eight groups of Sprague-Dawley rats (n = 5 for each subgroup) were made, A1 and C1 were given FTY720 1 mg/kg while B1 and D1 were given normal saline. The hearts were implanted into another set of similar rats after preservation period of 1 h at 4-8 °C. Significantly higher Left ventricular systolic pressure (LVSP), dP/dT maximum (p < 0.05), dP/dT minimum (p < 0.05) were recorded in the FTY720 treated group after 24 h of reperfusion while after 1 h of reperfusion, there were no significant differences in LVSP, maximum and negative dP/dT, and Left ventricular end diastolic pressure (LVEDP) between the control and the FTY720-treated transplant groups. Coronary blood flow (CBF) was enhanced (p < 0.05) in the FTY720 treated group after 1 and 24 h. ATP p < 0.001, p < 0.05 at 1 and 24 h, ADP p < 0.001, p > 0.05 at 1 and 24 h, and phosphocreatine p < 0.05, p > 0.05 at 1 and 24 h were better preserved by FTY720 treatment as compared to control group. The study concluded that pretreatment of grafted hearts with FTY720 improved hemodynamics, CBF, high energy phosphate reserves, reduces the peroxynitrite level and poly (ADP ribose) polymerase (PARP) inhibition that prevents ischemia-reperfusion injury.

Acute Kidney Injury With Ventricular Assist Device Placement: National Estimates of Trends and Outcomes.

RATIONALE & OBJECTIVE: Ventricular assist devices (VADs) are used for end-stage heart failure not amenable to medical therapy. Acute kidney injury (AKI) in this setting is common due to heart failure decompensation, surgical stress, and other factors. Little is known about national trends in AKI diagnosis and AKI requiring dialysis (AKI-D) and associated outcomes with VAD implantation. We investigated national estimates and trends for diagnosed AKI, AKI-D, and associated patient and resource utilization outcomes in hospitalizations in which implantable VADs were placed. STUDY DESIGN: Cohort study of 20% stratified sample of US hospitalizations. SETTING & PARTICIPANTS: Patients who underwent implantable VAD placement in 2006 to 2015. EXPOSURE: No AKI diagnosis, AKI without dialysis, AKI-D. OUTCOMES: In-hospital mortality, length of stay, estimated hospitalization costs. ANALYTICAL APPROACH: Multivariate logistic and linear regression using survey design methods to account for stratification, clustering, and weighting. RESULTS: An estimated 24,140 implantable VADs were placed, increasing from 853 in 2006 to 3,945 in 2015. AKI was diagnosed in 56.1% of hospitalizations and AKI-D occurred in 6.5%. AKI diagnosis increased from 44.0% in 2006 to 2007 to 61.7% in 2014 to 2015; AKI-D declined from 9.3% in 2006 to 2007 to 5.2% in 2014 to 2015. Mortality declined in all AKI categories but this varied by category: those with AKI-D had the smallest decline. Adjusted hospitalization costs were 19.1% higher in those with diagnosed AKI and 39.6% higher in those with AKI-D, compared to no AKI. LIMITATIONS: Administrative data; timing of AKI with respect to VAD implantation cannot be determined; limited pre-existing chronic kidney disease ascertainment; discharge weights not derived for subpopulation of interest. CONCLUSIONS: A decreasing proportion of patients undergoing VAD implantation experience AKI-D, but mortality among these patients remains high. AKI diagnosis with VAD implantation is increasing, possibly reflecting changes in AKI surveillance, awareness, and coding.

Sonographically guided metalic clip placement for tumour localization in early breast cancer patients undergoing neoadjuvant chemotherapy.

OBJECTIVE: To determine the outcome of sonographically-guided indigenous low-cost metallic clip placement for tumour localisation in patients of early breast cancer undergoing neoadjuvant chemotherapy. . METHODS: The prospective analytical study was conducted at the Institute of Nuclear Medicine and Oncology, Lahore, Pakistan, from May 2016 to December 2017, and comprised biopsy-proven breast cancer cases. Under sonographic guidance, metallic clips were placed as markers within the lesions before their scheduled preoperative neoadjuvant chemotherapy. The procedure was performed using an 18 gauge lumbar puncture needle and 25 gauge needle by a locally devised simple and cost-effective technique. Post-procedure mammography was performed to confirm the location of clips within the lesions and to evaluate its role in imaging assessment of treatment response after neo adjuvant chemotherapy. SPSS 20 was used for data analysis. RESULTS: There were 30 women with a mean age of 40.43+11.35 years (range: 21-60 years). These women had 32 lesions with a mean size of 26.72+9.85mm (range: 8-58mm). Breast conserving surgery was performed on 28(87.5%) lesions and negative margins were achieved in all these cases. Modified radical mastectomy was performed on 4(12/5%) non-responding lesions. No complication was noted in association with metallic clip placement, and the clips were easily visualised on mammograms without causing any interference with treatment response. CONCLUSIONS: Sonographically-guided metallic clip placement by a simple indigenously devised technique before neoadjuvant chemotherapy was found to be a well-tolerated, safe and cost-effective method for accurate preoperative localisation of tumour bed and to assess response to therapy.

Contemporary management and outcomes of acute type A aortic dissection: An analysis of the STS adult cardiac surgery database.

PURPOSE: Management of acute type A aortic dissection (AAAD) is challenging and operative strategies are varied. We used the STS Adult Cardiac Surgery Database (STS ACSD) to describe contemporary surgical strategies and outcomes for AAAD. METHODS: Between July 2011 and September 2012, 2982 patients with AAAD underwent operations at 640 centers in North America. RESULTS: In this cohort, median age was 60 years old, 66% were male, and 80% had hypertension. The most common arterial cannulation strategies included femoral (36%), axillary (27%), and direct aortic (19%). The median perfusion and cross-clamp times were 181 and 102 min, respectively. The lowest temperature on bypass showed significant variation. Hypothermic circulatory arrest (HCA) was used in 78% of cases. Among those undergoing HCA, brain protection strategies included antegrade cerebral perfusion (31%), retrograde cerebral perfusion (25%), both (4%), and none (40%). Median HCA plus cerebral perfusion time was 40 min. Major complications included prolonged ventilation (53%), reoperation (19%), renal failure (18%), permanent stroke (11%), and paralysis (3%). Operative mortality was 17%. The median intensive care unit and hospital length of stays were 4.7 and 9.0 days, respectively. Among 640 centers, the median number of cases performed during the study period was three. Resuscitation, unresponsive state, cardiogenic shock, inotrope use, age >70, diabetes, and female sex were found to be independent predictors of mortality. CONCLUSIONS: These data describe contemporary patient characteristics, operative strategies, and outcomes for AAAD in North America. Mortality and morbidity for AAAD remain high.

Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support.

BACKGROUND: Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). METHODS AND RESULTS: Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs. CONCLUSIONS: The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.

BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.

Management for breast implants in patients undergoing mitral valve surgery through a right minithoracotomy.

We present the surgical technique and rationale for the management of breast implants in two patients who underwent mitral valve repair through a right minithoracotomy.

Lost Connection: A Case Report of Interrupted Pituitary Stalk Syndrome.

Pituitary stalk interruption syndrome is a triad of thin (<1 mm) or complete absence of the pituitary stalk with either an aplastic or ectopic posterior lobe of the pituitary gland and a hypoplastic or absent anterior lobe of the pituitary. Patients present with growth retardation, short height, seizures, intellectual disability, and absence of sexual maturation at the expected time. Here, we presented a case of a 12-year-old male with stunted growth. Upon examination, there was reduced height, more than 3 standard deviations below the average for his chronological age. Laboratory results showed reduced levels of growth hormone and thyrotropin. Dual-energy X-ray absorptiometry revealed osteoporosis, while an X-ray of the wrist for bone age corresponded to seven years. MRI imaging confirmed the classical triad of findings for pituitary stalk interruption syndrome. Consequently, the patient was referred back to the endocrinology clinic for further management.

Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure.

BACKGROUND: Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. METHODS AND RESULTS: We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m(2); age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. CONCLUSIONS: Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.

Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis.

Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the ß-intercalated cell secretes HCO(3) by an apical Cl:HCO(3) named pendrin and a basolateral vacuolar (V)-ATPase. Acid secretion is mediated by the α-intercalated cell, which has an apical V-ATPase and a basolateral Cl:HCO(3) exchanger (kAE1). We previously suggested that the ß-cell converts to the α-cell in response to acid feeding, a process that depended on the secretion and deposition of an extracellular matrix protein termed hensin (DMBT1). Here, we show that deletion of hensin from intercalated cells results in the absence of typical α-intercalated cells and the consequent development of complete distal renal tubular acidosis (dRTA). Essentially all of the intercalated cells in the cortex of the mutant mice are canonical ß-type cells, with apical pendrin and basolateral or diffuse/bipolar V-ATPase. In the medulla, however, a previously undescribed cell type has been uncovered, which resembles the cortical ß-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of ß1 integrin, and deletion of this gene from the intercalated cell caused a phenotype that was identical to the deletion of hensin itself, supporting its critical role in hensin function. Because previous studies suggested that the conversion of ß- to α-intercalated cells is a manifestation of terminal differentiation, the present results demonstrate that this differentiation proceeds from HCO(3) secreting to acid secreting phenotypes, a process that requires deposition of hensin in the ECM.

Alterations in Coronary Blood Flow and the Risk of Left Ventricular Distension in Venoarterial Extracorporeal Membrane Oxygenation.

Previous theoretical studies have suggested that veno-arterial extracorporeal membrane oxygenation (VA-ECMO) ought to consistently result in markedly increased left ventricular (LV) intracavitary pressures and volumes because of increased LV afterload. However, this phenomenon of LV distension does not universally occur and occurs only in a minority of cases. We sought to explain this discrepancy by considering the potential implications of VA-ECMO support on coronary blood flow and consequently improved LV contractility (the "Gregg" effect), in addition to the effects of VA-ECMO support upon LV loading conditions, in a lumped parameter-based theoretical circulatory model. We found that LV systolic dysfunction resulted in reduced coronary blood flow; VA-ECMO support augmented coronary blood flow proportionally to the circuit flow rate. On VA-ECMO support, a weak or absent Gregg effect resulted in increased LV end-diastolic pressures and volumes and increased end-systolic volume with decreased LV ejection fraction (LVEF), consistent with LV distension. In contrast, a more robust Gregg effect resulted in unaffected and/or even reduced LV end-diastolic pressure and volume, end-systolic volume, and unaffected or even increased LVEF. Left ventricular contractility augmentation proportional to coronary blood flow increased by VA-ECMO support may be an important contributory mechanism underlying why LV distension is observed only in a minority of cases.

Atrial Fibrillation Ablation-induced Pulmonary Venous Occlusion Requiring Pneumonectomy.

A 71-year-old woman with a history of atrial fibrillation underwent a catheter-based ablation procedure. Months later, she presented with dyspnea and a left-sided pleural effusion. Diagnostic evaluation revealed left-sided pulmonary venous occlusion, with essentially absent left lung perfusion. The patient underwent left pneumonectomy, with left atrial appendage occlusion. Although lobectomy for pulmonary venous occlusion of a single vein after pulmonary vein isolation has been described, this appears to be a novel report of occluded pulmonary venous drainage of an entire lung necessitating pneumonectomy.

Peri-Renal Lymphangiomatosis: A Case Report Presenting a Rare Disease at a Rarer Location.

Renal lymphangiomatosis is a rare pathology wherein dilatation of perirenal, parapelvic, and intrarenal lymphatics is observed and can occur in both children and adults. It has no gender predilection and can present in unilateral and bilateral forms. Clinical symptomatology ranges from incidental findings to flank pain, hematuria, and abdominal swelling. Radiological appearances may mimic renal cysts, peripelvic cysts, perinephric abscesses, or collections. This emphasizes the importance of developing familiarity with the imaging characteristics of this rare entity. We present the case of an 11-year-old boy whose chief complaint was abdominal distension and bilateral flank pain. The radiological assessment revealed bilateral perinephric collections, which, along with clinical correlation, led to the diagnosis of bilateral peri-renal lymphangiomatosis.

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma.

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) have disease that relapses. Allogeneic (allo-) hematopoietic cell transplantation (HCT) is a potentially curative option for a subgroup of patients with high-risk MM. This study assessed the long-term outcome of MM patients who underwent allo-HCT while in first remission as consolidation treatment. Thirty-three patients with newly diagnosed MM who underwent allo-HCT as part of consolidation therapy between 1994 and 2016 were reviewed retrospectively. Of these patients, 70% underwent autologous HCT before allo-HCT. All patients were chemosensitive and achieved at least partial response before proceeding to allo-HCT. Most received nonmyeloablative/reduced-intensity conditioning (88%) and a matched sibling donor graft (85%). Acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. The median duration of follow-up was 64.1 months (range, 1.4 to 199.2 months) for all patients and 164.4 months (range, 56.0 to 199.2 months) for survivors. The median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 to 73.0 months). The median time from treatment to progression was 73.0 months (95% CI, 30.6 months to not reached). The median overall survival (OS) was 131.9 months (95% CI, 38.4 months to not reached). Of all patients, 39% were alive for more than 10 years, with 46% (n = 6) without progression or relapse. The cumulative incidence of relapse was 18% at 1 year, 39% at 5 years, and 46% at 10 years post-allo-HCT. The cumulative incidence of nonrelapse mortality was 3% at 100 days, 18% at 1 year, 21% at 3 years, and 24% at 5 year post-allo-HCT. On multivariable analysis, high-risk cytogenetics were associated with a shorter PFS (hazard ratio [HR], 2.7; 95% CI, 1.01 to 7.21; P = .047) and OS (HR, 4.91; 95% CI, 1.48 to 16.27; P = .009). Achieving complete remission after allo-HCT also was associated with longer PFS (HR, 0.24; 95% CI, 0.09 to 0.64; P = .004) and OS (HR, .23; 95% CI, .07 to .72; P = .012). Allo-HCT may confer a survival advantage in a selected population of MM patients when performed early in the disease course; additional data on identifying the patients who will benefit the most are needed.

SDF-1 activates papillary label-retaining cells during kidney repair from injury.

The adult kidney contains a population of low-cycling cells that resides in the papilla. These cells retain for long periods S-phase markers given as a short pulse early in life; i.e., they are label-retaining cells (LRC). In previous studies in adult rat and mice, we found that shortly after acute kidney injury many of the quiescent papillary LRC started proliferating (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315-2327, 2009; Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q. J Clin Invest 114: 795-804, 2004) and, with cell-tracking experiments, we found upward migration of some papillary cells including LRC (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315-2327, 2009). To identify molecular cues involved in the activation (i.e., proliferation and/or migration) of the papillary LRC that follows injury, we isolated these cells from the H2B-GFP mice and found that they migrated and proliferated in response to the cytokine stromal cell-derived factor-1 (SDF-1). Moreover, in a papillary organ culture assay, the cell growth out of the upper papilla was dependent on the interaction of SDF-1 with its receptor Cxcr4. Interestingly, location of these two proteins in the kidney revealed a complementary location, with SDF-1 being preferentially expressed in the medulla and Cxcr4 more abundant in the papilla. Blockade of Cxcr4 in vivo prevented mobilization of papillary LRC after transient kidney ischemic injury and worsened its functional consequences. The data indicate that the SDF-1/Cxcr4 axis is a critical regulator of papillary LRC activation following transient kidney injury and during organ repair.