Repression of Interstitial Identity in Nephron Progenitor Cells by Pax2 Establishes the Nephron-Interstitium Boundary during Kidney Development.

The kidney contains the functional units, the nephrons, surrounded by the renal interstitium. Previously we discovered that, once Six2-expressing nephron progenitor cells and Foxd1-expressing renal interstitial progenitor cells form at the onset of kidney development, descendant cells from these populations contribute exclusively to the main body of nephrons and renal interstitial tissues, respectively, indicating a lineage boundary between the nephron and renal interstitial compartments. Currently it is unclear how lineages are regulated during kidney organogenesis. We demonstrate that nephron progenitor cells lacking Pax2 fail to differentiate into nephron cells but can switch fates into renal interstitium-like cell types. These data suggest that Pax2 function maintains nephron progenitor cells by repressing a renal interstitial cell program. Thus, the lineage boundary between the nephron and renal interstitial compartments is maintained by the Pax2 activity in nephron progenitor cells during kidney organogenesis.

Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis.

MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this, we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle's loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal, whereas peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation, and morphogenic functions including α-smooth muscle actin, integrin-α8, -ß1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p, and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration, and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis.

Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis.

The mammalian kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during mammalian kidney organogenesis.

A population-based assessment of the familial component of acute kidney allograft rejection.

BACKGROUND: The genetic determinants of acute kidney transplant rejection (AR) are not well studied, and familial aggregation has never been demonstrated. The goal of this retrospective case-control study was to exploit the unique nature of the Utah Population Database (UPDB) to evaluate if AR or rejection-free survival aggregates in families. METHODS: We identified 891 recipients with genealogy data in the UPDB with at least one year of follow-up, of which 145 (16.1%) had AR and 77 recipients had biopsy-proven rejection graded >or=1A. We compared the genealogical index of familiality (GIF) in cases and controls (i.e. recipients with random assignment of rejection status). RESULTS: We did not find evidence for familial clustering of AR in the entire patient population or in the subgroup with early rejection (n = 52). When the subgroup of recipients with rejection grade >or=1A (n = 77) was analysed separately, we observed increased familial clustering (GIF = 3.02) compared to controls (GIF = 1.96), although the p-value did not reach the level of statistical significance (p = 0.17). Furthermore, we observed an increase in familial clustering in recipients who had a rejection-free course (GIF = 2.45) as compared to controls (GIF = 2.08, p = 0.04). When all recipients were compared to non-transplant controls, they demonstrated a much greater degree of familiality (GIF = 2.03 versus GIF 0.63, p < 0.001). CONCLUSIONS: There is a familial component to rejection-free transplant course and trend to familial aggregation in recipients with AR grade 1A or higher. If a genetic association study is performed, there are families in Utah identified in the current study that can be targeted to increase the power of the test.

Familiality of cardiovascular mortality in end-stage renal disease patients.

A very high rate of cardiovascular (CV) death is well recognized in individuals with end-stage renal disease (ESRD). Besides many other factors, this excess risk may also be related to familiality. We tested this hypothesis by estimating the risk of CV death among both ESRD patients and their relatives. In this case-control study, we used the Utah Population Database (UPDB), which includes genealogy records, state-wide death certificates as well as other data sets. These have been linked to the University of Utah Health Sciences Enterprise Data Warehouse which provides multiple diagnosis data sources. Patients with ESRD either on dialysis or who received a kidney transplant were identified in the clinical databases at the University of Utah Dialysis Program and Kidney Transplant Program or from Utah death certificates. CV deaths were identified by the reporting on the death certificates. The relative risks for CV death, adjusted for several potential confounders in the ESRD patients (n = 516) and in their first-degree (n = 2,418) and second-degree (n = 7,720) relatives were estimated in relation to the general population. Using information from death certificates, ESRD patients were found to have disproportionately increased risk for CV mortality (relative risk or RR = 2.4; 95% CI 2.11-2.72), compared to the general population. First-degree relatives of ESRD patients were also found to have an increased CV mortality risk (RR = 1.10; 95% CI 1.01-1.20). When the specific categories of CVD were analyzed, the first-degree relatives also had higher risks for death from acute myocardial infarction (RR = 1.20; 95% CI 1.03-1.40) or heart failure (RR = 1.32; 95% CI 1.12-1.56). An increased risk for CV mortality was, however, not observed in second-degree relatives of ESRD patients, except for the subcategory of hypertensive heart disease (RR = 1.24, 95% CI 1.01-1.49). In conclusion, this study suggests that, in addition to many putative risk factors, the increased risk of CV death in ESRD patients may have a familial contribution.

Genetic prediction of renal transplant outcome.

PURPOSE OF REVIEW: In the present study, we reviewed recent publications regarding potential genetic predictors of transplant outcome, including acute rejection, metabolism of immunosuppressive medications, long-term transplant outcome, and posttransplant complications. RECENT FINDINGS: Recent studies are based on the candidate gene analysis; specifically, cytokine genes and innate immune response molecules present popular targets for studies of acute rejection and long-term outcome. Pharmacogenomic studies are mostly focused on the genes of drug targets or the corresponding enzymes metabolizing the drug. Posttransplant complications (i.e. infections, diabetes, and malignancies) are associated with a variety of genes of different pathways. Most of the studies are based on just recipient, but not donor, genotype analysis. Positive results are balanced by reports of no association when evaluating the same genetic polymorphisms. Some of the reports might be affected by insufficient study design, including small sample size, lack of adjustment for potential confounders, and multiple comparisons. SUMMARY: The field remains controversial because of differences in populations, study design, and statistical methods. Studies are based on candidate gene analysis; however, genome-wide association studies are lacking. Future research should be directed at better designed studies, larger sample size, evaluating both recipients and donors, and implementation of genome-wide association studies.

Role of pre-transplant marital status in renal transplant outcome.

BACKGROUND: End-stage renal disease is associated with illness-induced disruptions that challenge patients and their families to accommodate and adapt. However, the impact of patients' marital status on kidney transplant outcome has never been studied. This project, based on data from United States Renal Data System (USRDS), helps to answer how marriage affects renal transplant outcome. METHODS: Data have been collected from USRDS on all kidney/kidney-pancreas allograft recipients between January 1, 1995 and June 30, 2002, who were 18 yr old or older and had information about their marital status prior to the kidney transplantation (n = 2061). Survival analysis was performed using Kaplan-Meier methods and Cox proportional hazards modeling to control for confounding variables. RESULTS: Overall findings of this study suggest that being married has a significant protective effect on death-censored graft survival [Hazard Ratio (HR) 0.80, p < 0.05] but a non-significant effect on recipient survival (HR 0.85, p = 0.122). When stratified by gender, the effect was still present in males for death-censored graft survival (HR 0.75, p < 0.05), but not for recipient survival (HR 0.86, p = 0.24). The effect was not observed in females, where neither graft (HR 0.90, p = 0.55) nor recipient (HR 0.8, p = 0.198) survival had an association with marital status. In subgroup analysis similar association was found in the recipients of a single transplant. CONCLUSION: Based on our analysis, being married in the pre-transplant period is associated with positive outcome for the graft, but not for the recipient survival. When analyzed separately, the effect is present in male, but not in female recipients.

A population-based assessment of the familial component of chronic kidney disease mortality.

BACKGROUND/AIM: While the familial nature of chronic kidney disease (CKD) has been recognized, it has primarily been defined from studies of first-degree relatives of selected sets of cases. The goal of this study is an evaluation of the familial clustering of end-stage renal disease (ESRD) and CKD mortality using a population-based genealogy of Utah. This is the first population-based analysis of the familial component of ESRD and non-ESRD CKD. METHODS: We have defined two distinct patient groups for this analysis, using individuals with death certificates in the Utah Population Database indicating ESRD (n = 192) and non-ESRD CKD (n = 335) as the cause of death. Two measures of familiality were used: (1) relative risk (RR) of CKD or ESRD death in relatives of cases and (2) an average relatedness statistic, i.e., the Genealogical Index of Familiality. RESULTS: The RR for dying with ESRD among the first-degree relatives of individuals dying with ESRD is estimated to be 10.1 (p = 0.0007, 95% confidence interval CI 2.76-25.95), but is not significantly elevated among second-degree relatives. The RR for dying with non-ESRD CKD among first- and second-degree relatives of individuals dying with non-ESRD CKD was 3.89 (p = 0.0051, 95% CI 1.43-8.46) and 3.11 (p = 0.04, 95% CI 0.85-7.95), respectively. The Genealogical Index of Familiality statistic demonstrated that the individuals dying with ESRD are significantly more related than expected in this population (p = 0.013); significant excess relatedness was also observed for individuals dying with non-ESRD CKD (p = 0.006), suggesting a familial component for both, with evidence for common environmental and genetic effects. CONCLUSION: The results of this analysis of individuals dying with ESRD and non-ESRD CKD supports a significant and independent familial component to both conditions, suggesting a heritable factor playing a role.