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BackgroundAfrican Americans have persistently poor access to living donor kidney transplants (LDKT). We conducted a small randomized trial to provide preliminary evidence of the effect of informational decision support and donor financial assistance interventions on African American hemodialysis patients' pursuit of LDKT.MethodsStudy participants were randomly assigned to receive (1) Usual Care; (2) the Providing Resources to Enhance African American Patients' Readiness to Make Decisions about Kidney Disease (PREPARED); or (3) PREPARED plus a living kidney donor financial assistance program. Our primary outcome was patients' actions to pursue LDKT (discussions with family, friends, or doctor; initiation or completion of the recipient LDKT medical evaluation; or identification of a donor). We also measured participants' attitudes, concerns, and perceptions of interventions' usefulness.ResultsOf 329 screened, 92 patients were eligible and randomized to Usual Care (n = 31), PREPARED (n = 30), or PREPARED plus financial assistance (n = 31). Most participants reported interventions helped their decision making about renal replacement treatments (62%). However there were no statistically significant improvements in LDKT actions among groups over 6 months. Further, no participants utilized the living donor financial assistance benefit.ConclusionsFindings suggest these interventions may need to be paired with personal support or navigation services to overcome key communication, logistical, and financial barriers to LDKT.Trial registrationClinicalTrials.gov [ NCT01439516 ] [August 31, 2011].

T cells mediate organ injury and repair. A proportion of unconventional kidney T cells called double-negative (DN) T cells (TCR+ CD4− CD8−), with anti-inflammatory properties, were previously demonstrated to protect from early injury in moderate experimental acute kidney injury (AKI). However, their role in repair after AKI has not been studied. We hypothesized that DN T cells mediate repair after severe AKI. C57B6 mice underwent severe (40 min) unilateral ischemia-reperfusion injury (IRI). Kidney DN T cells were studied by flow cytometry and compared with gold-standard anti-inflammatory CD4+ regulatory T cells (Tregs). In vitro effects of DN T cells and Tregs on renal tubular epithelial cell (RTEC) repair after injury were quantified with live-cell analysis. DN T cells, Tregs, CD4, or vehicle were adoptively transferred after severe AKI. Glomerular filtration rate (GFR) was measured using fluorescein isothiocyanate (FITC)-sinistrin. Fibrosis was assessed with Masson's trichrome staining. Profibrotic genes were measured with qRT-PCR. Percentages and the numbers of DN T cells substantially decreased during repair phase after severe AKI, as well as their activation and proliferation. Both DN T cells and Tregs accelerated RTEC cell repair in vitro. Post-AKI transfer of DN T cells reduced kidney fibrosis and improved GFR, as did Treg transfer. DN T cell transfer lowered transforming growth factor (TGF)β1 and α-smooth muscle actin (αSMA) expression. DN T cells reduced effector-memory CD4+ T cells and IL-17 expression. DN T cells undergo quantitative and phenotypical changes after severe AKI, accelerate RTEC repair in vitro as well as improve GFR and renal fibrosis in vivo. DN T cells have potential as immunotherapy to accelerate repair after AKI. NEW & NOTEWORTHY: Double-negative (DN) T cells (CD4− CD8−) are unconventional kidney T cells with regulatory abilities. Their role in repair from acute kidney injury (AKI) is unknown. Kidney DN T cell population decreased during repair after ischemic AKI, in contrast to regulatory T cells (Tregs) which increased. DN T cell administration accelerated tubular repair in vitro, while after severe in vivo ischemic injury reduced kidney fibrosis and increased glomerular filtration rate (GFR). DN T cell infusion is a potential therapeutic agent to improve outcome from severe AKI. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors.

Although the United States possesses one of the most comprehensive transplant registries in the world, nationally representative data on how transplant care is structured and delivered is lacking. Therefore, we surveyed all 208 adult kidney transplant centers in the United States, excluding 37 pediatric and 58 inactive adult centers. Respondents were asked about the characteristics of their kidney transplant programs (25 items), the structure and process of care (18 items), coordination of care (10 items), and the characteristics of transplant physicians and surgeons (9 items). The survey was completed by directors of 156 transplant centers (75% response). The results demonstrated significant variation between centers in several domains. Sixty-five percent of transplant centers do not have a dedicated transplant pharmacist in outpatient care. Two thirds of transplant centers do not see the kidney transplant recipients at least monthly during the first year. Less than 30% of centers perform joint sit-down or walking rounds between nephrology and transplant surgery. There was significant variation in the structure and process of care in kidney transplantation. This implies variation in the use of resources at the transplant centers. This variation should be studied to determine best practices associated with optimal kidney allograft and patient survival.

There are currently over 750,000 patients with end-stage renal disease (ESRD) in the United States. Globally, 2.6 million patients receive renal replacement therapy with either dialysis or a kidney transplant, [...]

Acute organ injuries such as acute cerebrovascular accidents, myocardial infarction, acute kidney injury, acute lung injury, and others are among the leading causes of death worldwide. Dysregulated or insufficient organ repair mechanisms limit restoration of homeostasis and contribute to chronic organ failure. Studies reveal that both humans and mice harness potent non-stem cells that are capable of directly or indirectly promoting tissue repair. Specific populations of T lymphocytes have emerged as important reparative cells with context- specific actions. These T cells can resolve inflammation and secrete reparative cytokines and growth factors as well as interact with other immune and stromal cells to promote the complex and active process of tissue repair. This Review focuses on the major populations of T lymphocytes known to mediate tissue repair, their reparative mechanisms, and the diseases in which they have been implicated. Elucidating and harnessing the mechanisms that promote the reparative functions of these T cells could greatly improve organ dysfunction after acute injury., Introduction Acute, repeated, and chronic injuries lead to organ dysfunction. In the aftermath of injury, tissue repair and regeneration are essential to restoring organ homeostasis, and defective or insufficient repair [...]

BackgroundA comprehensive assessment of the association of patients' renal replacement therapy (RRT) modality with their participation in life activities (physical function, travel, recreation, freedom, and work) is needed.Study designSystematic review of peer-reviewed published studies.Setting & populationAdults undergoing RRT (hemodialysis, peritoneal dialysis, or transplantation).Selection criteria for studiesWe searched PubMed, Cochrane Library, and EMBASE from January 1980 through April 2012 for English-language articles that compared participation in life activities among patients receiving: (1) hemodialysis compared with peritoneal dialysis, (2) hemodialysis compared with kidney transplantation, or (3) peritoneal dialysis compared with kidney transplantation.PredictorRRT modality.OutcomesReported rates of physical function, travel, recreation, freedom, and work-related activities by RRT modality.Results46 studies (6 prospective cohort, 38 cross-sectional, and 2 pre-post transplantation) provided relevant comparisons of life participation activities among patients treated with hemodialysis, peritoneal dialysis, and kidney transplantation. Studies were conducted in 1985-2011 among diverse patient populations in 16 distinct locations. A majority of studies reported greater life participation rates for patients with kidney transplants compared with patients receiving either hemodialysis or peritoneal dialysis. In contrast, a majority of studies reported no differences in outcomes between patients receiving hemodialysis and patients receiving peritoneal dialysis. These results were consistent throughout the study period, across diverse populations, and among the subset of studies that performed appropriate adjustments for potential confounding factors.LimitationsMany studies included in the review had significant design weaknesses.ConclusionsEvidence suggests that patients with kidney transplants may experience better rates of life participation compared with patients receiving dialysis, whereas patients receiving hemodialysis and patients receiving peritoneal dialysis may experience similar rates of life participation. Rigorously performed studies are needed to better inform patients about the association of RRT with these important patient-reported outcomes.

Abstract Background Little is known regarding the types of information African American and non-African American patients with chronic kidney disease (CKD) and their families need to inform renal replacement therapy (RRT) decisions. Methods In 20 structured group interviews, we elicited views of African American and non-African American patients with CKD and their families about factors that should be addressed in educational materials informing patients’ RRT selection decisions. We asked participants to select factors from a list and obtained their open-ended feedback. Results Ten groups of patients (5 African American, 5 non-African American; total 68 individuals) and ten groups of family members (5 African American, 5 non-African American; total 62 individuals) participated. Patients and families had a range (none to extensive) of experiences with various RRTs. Patients identified morbidity or mortality, autonomy, treatment delivery, and symptoms as important factors to address. Family members identified similar factors but also cited the effects of RRT decisions on patients’ psychological well-being and finances. Views of African American and non-African American participants were largely similar. Conclusions Educational resources addressing the influence of RRT selection on patients’ morbidity and mortality, autonomy, treatment delivery, and symptoms could help patients and their families select RRT options closely aligned with their values. Including information about the influence of RRT selection on patients’ personal relationships and finances could enhance resources’ cultural relevance for African Americans.

Abstract Background Few educational resources have been developed to inform patients’ renal replacement therapy (RRT) selection decisions. Patients progressing toward end stage renal disease (ESRD) must decide among multiple treatment options with varying characteristics. Complex information about treatments must be adequately conveyed to patients with different educational backgrounds and informational needs. Decisions about treatment options also require family input, as families often participate in patients’ treatment and support patients’ decisions. We describe the development, design, and preliminary evaluation of an informational, evidence-based, and patient-and family-centered decision aid for patients with ESRD and varying levels of health literacy, health numeracy, and cognitive function. Methods We designed a decision aid comprising a complementary video and informational handbook. We based our development process on data previously obtained from qualitative focus groups and systematic literature reviews. We simultaneously developed the video and handbook in “stages.” For the video, stages included (1) directed interviews with culturally appropriate patients and families and preliminary script development, (2) video production, and (3) screening the video with patients and their families. For the handbook, stages comprised (1) preliminary content design, (2) a mixed-methods pilot study among diverse patients to assess comprehension of handbook material, and (3) screening the handbook with patients and their families. Results The video and handbook both addressed potential benefits and trade-offs of treatment selections. The 50-minute video consisted of demographically diverse patients and their families describing their positive and negative experiences with selecting a treatment option. The video also incorporated health professionals’ testimonials regarding various considerations that might influence patients’ and families’ treatment selections. The handbook was comprised of written words, pictures of patients and health care providers, and diagrams describing the findings and quality of scientific studies comparing treatments. The handbook text was written at a 4th to 6th grade reading level. Pilot study results demonstrated that a majority of patients could understand information presented in the handbook. Patient and families screening the nearly completed video and handbook reviewed the materials favorably. Conclusions This rigorously designed decision aid may help patients and families make informed decisions about their treatment options for RRT that are well aligned with their values.

Abstract Background Living related kidney transplantation (LRT) is underutilized, particularly among African Americans. The effectiveness of informational and financial interventions to enhance informed decision-making among African Americans with end stage renal disease (ESRD) and improve rates of LRT is unknown. Methods/design We report the protocol of the Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease (PREPARED) Study, a two-phase study utilizing qualitative and quantitative research methods to design and test the effectiveness of informational (focused on shared decision-making) and financial interventions to overcome barriers to pursuit of LRT among African American patients and their families. Study Phase I involved the evidence-based development of informational materials as well as a financial intervention to enhance African American patients’ and families’ proficiency in shared decision-making regarding LRT. In Study Phase 2, we are currently conducting a randomized controlled trial in which patients with new-onset ESRD receive 1) usual dialysis care by their nephrologists, 2) the informational intervention (educational video and handbook), or 3) the informational intervention in addition to the option of participating in a live kidney donor financial assistance program. The primary outcome of the randomized controlled trial will include patients’ self-reported rates of consideration of LRT (including family discussions of LRT, patient-physician discussions of LRT, and identification of a LRT donor). Discussion Results from the PREPARED study will provide needed evidence on ways to enhance the decision to pursue LRT among African American patients with ESRD. Trial registration ClinicalTrials.gov NCT01439516

We conducted focus group meetings of African American and non-African American patients with end-stage renal disease (six groups) and their family members (six groups), stratified by race/ethnicity and treatment. We elicited differences in participants' experiences with shared decision making about initiating renal replacement therapy (RRT; that is, hemodialysis, peritoneal dialysis, or a kidney transplant). Patients were often very sick when initiating RRT, and had little, if any, time to make a decision about what type of RRT to initiate. They also lacked sufficient information about alternative treatment options prior to initiation. Family members played supportive roles and shared in decision making when possible. Reports were similar for African American and non-African American participants. Our findings suggest that a greater emphasis on the improved engagement of patients and their families in shared decision making about RRT initiation is needed for both ethnic/racial minorities and nonminorities.

The late Colombian Nobel Prize-winning author Gabriel Garcia Marquez wrote 'Love in the Time of Cholera,' a complex depiction of the struggle to love during an infectious epidemic (1). In [...]

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing [beta] cells in islets of Langerhans. Many genetic and immunological insights into autoimmune disease pathogenesis were initially uncovered in the context of T1D and facilitated by preclinical studies using the nonobese diabetic (NOD) mouse model. Recently, the study of T1D has led to the discovery of fatty acid esters of hydroxyl fatty acids (FAHFAs), which are naturally occurring hybrid peptides that modulate inflammation and diabetes pathogenesis, and a hybrid lymphocyte that expresses both B and T cell receptors. Palmitic acid esters of hydroxy stearic acids (PAHSAs) are the most extensively studied FAHFA. In this issue of the JCI, Syed et al. have shown that PAHSAs both attenuate autoimmune responses and promote [beta] cell survival in NOD mice. Given the lack of effective T1D therapies and the paucity of known side effects of PAHSAs, this lipid may have therapeutic potential for individuals at risk for or newly diagnosed with T1D., Introduction Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing [beta] cells by autoreactive T cells (1). This loss of [beta] cells results in insulin [...]

Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 (Havcrl) and lipocalin 2 (Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-l, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-I and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI. ischemia-reperfusion injury; gene expression profiling; chronic kidney disease doi: 10.1152/ajprenal.00619.2009.

Early exposure to germs modifies kidney damage and inflammation after experimental ischemia-reperfusion injury. Am J Physiol Renal Physiol 297: F1457-F1465, 2009. First published August 12, 2009; doi:10.1152/ajprenal.90769.2008.--Kidney ischemia-reperfusion injury (IRI) is, in part, mediated by immune and inflammatory factors. Since microbial stimuli are known to alter immune and inflammatory responses, we hypothesized that differences in perinatal microbial status would modify renal injury following IRI. We performed bilateral renal IRI on 6-wk-old germ-free and control mice and studied the effects on kidney lymphocyte trafficking, cytokines, function, and structure. Compared with control mice, normal kidneys of germ-free mice exhibited more NKT cells and lower IL-4 levels. Postischemia, more CD8 T cells trafficked into postischemic kidneys of germ-free mice compared with control mice. Renal structural injury and functional decline following IRI were more severe in germ-free mice compared with control mice. When germ-free mice were conventionalized with the addition of bacteria to their diet, the extent of renal injury after IRI became equivalent to age-matched control mice, with similar numbers and phenotypes of T cells and NKT cells, as well as cytokine expression in both normal kidneys and postischemic kidneys of conventionalized germ-free mice and age-matched control mice. Thus microbial stimuli influence the phenotype of renal lymphocytes and the expression of cytokines of normal kidneys and also modulate the outcome of IRI. germ-free status; immune modulation doi: 10.1152/ajprenal.90769.2008.

Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes are associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALl), we hypothesized that AKI leads to pulmonary proapoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and 2) active caspase-3 (aC3) activity, immunoblotting, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and colocalization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with the caspase inhibitor Z-VAD-FMK (0.25 mg ip) or vehicle 1 h before and 8 h after sham or kidney IRI, and bronchoalveolar lavage fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild-type control mice during AKI was absent in [TNFR.sup.-/-] mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI. lung injury; AKI; inflammation; TNF receptor

We hypothesized that the influence of acute kidney injury (AKI) on the sensitivity of the lung to an injurious process varies with the severity of the injurious process. Thus, we thought that AKI would exacerbate lung injury from low degrees of lung trauma but attenuate lung injury from higher degrees of lung trauma. C57BL/6 mice underwent AKI (30-min kidney ischemia) or sham surgery, followed at 24 h by 4 h of spontaneous breathing (SB), mechanical ventilation with low tidal volume (7 ml/kg, LTV), or mechanical ventilation with high tidal volume (30 ml/kg, HTV). Compared with LTV, median bronchoalveolar lavage (BAL) protein leak was significantly lower with SB and greater with HTV in both sham and AKI mice. Compared with LTV, median Evans blue dye-labeled albumin extravasation in lungs (L-EBD) was also significantly lower with SB and greater with HTV. L-EBD showed a significant interaction between ventilatory mode and kidney health, such that AKI attenuated the L-EBD rise seen in HTV vs. LTV sham mice. An interaction between ventilatory mode and kidney health could also be seen in BAL neutrophil number (PMN). Thus, AKI attenuated the BAL PMN rise seen in HTV vs. LTV sham mice. These data support the presence of a complex interaction between mechanical ventilation and AKI in which the sensitivity of the lung to trauma varies with the magnitude of the trauma and may involve a modification of pulmonary neutrophil activity by AKI. acute kidney injury; Evans blue dye