PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (897894)

Clipboard (0)
None

Related Articles

1.  Uromodulin Upregulates TRPV5 by Impairing Caveolin-Mediated Endocytosis 
Kidney international  2013;84(1):130-137.
Uromodulin (UMOD) is synthesized in the thick ascending limb and secreted into urine as the most abundant protein. Association studies in humans suggest protective effects of UMOD against calcium-containing kidney stones. Mice carrying mutations of Umod found in human uromodulin-associated kidney disease (UAKD) and Umod deficient mice exhibit hypercalciuria. The mechanism for UMOD regulation of urinary Ca2+ excretion is incompletely understood. We examined if UMOD regulates TRPV5 and TRPV6, channels critical for renal transcellular Ca2+ reabsorption. Coexpression with UMOD increased whole-cell TRPV5 current density in HEK293 cells. In biotinylation studies UMOD increased TRPV5 cell-surface abundance. Extracellular application of purified UMOD upregulated TRPV5 current density within physiological relevant concentration ranges. UMOD exerted a similar effect on TRPV6. TRPV5 undergoes constitutive caveolin-mediated endocytosis. UMOD had no effect on TRPV5 in a caveolin-1 deficient cell line. Expression of recombinant caveolin-1 in these cells restored the ability of UMOD to upregulate TRPV5. Secretion of UAKD-mutant UMOD was markedly reduced and coexpression of mutant UMOD with TRPV5 failed to increase its current. Immunofluorescent studies demonstrated lower TRPV5 expression in Umod−/− mice compared to wild-type. UMOD upregulates TRPV5 by acting from extracellular and by decreasing endocytosis of TRPV5. The stimulation of Ca2+ reabsorption via TRPV5 by UMOD may contribute to protection against kidney stone formation.
doi:10.1038/ki.2013.63
PMCID: PMC3700562  PMID: 23466996
2.  Urinary Uromodulin Excretion Predicts Progression of Chronic Kidney Disease Resulting from IgA Nephropathy 
PLoS ONE  2013;8(8):e71023.
Background
Uromodulin, or Tamm-Horsfall protein, is the most abundant urinary protein in healthy individuals. Recent studies have suggested that uromodulin may play a role in chronic kidney diseases. We examined an IgA nephropathy cohort to determine whether uromodulin plays a role in the progression of IgA nephropathy.
Methods
A total of 344 IgA nephropathy patients were involved in this study. Morphological changes were evaluated with the Oxford classification of IgA nephropathy. Enzyme Linked Immunosorbent Assay (ELISA) measured the urinary uromodulin level on the renal biopsy day. Follow up was done regularly on 185 patients. Time-average blood pressure, time-average proteinuria, estimated glomerular filtration rate (eGFR) and eGFR decline rate were caculated. Association between the urinary uromodulin level and the eGFR decline rate was analyzed with SPSS 13.0.
Results
We found that lower baseline urinary uromodulin levels (P = 0.03) and higher time-average proteinuria (P = 0.04) were risk factors for rapid eGFR decline in a follow-up subgroup of the IgA nephropathy cohort. Urinary uromodulin level was correlated with tubulointerstitial lesions (P = 0.016). Patients that had more tubular atrophy/interstitial fibrosis on the surface had lower urinary uromodulin levels (P = 0.02).
Conclusions
Urinary uromodulin level is associated with interstitial fibrosis/tubular atrophy and contributes to eGFR decline in IgA nephropathy.
doi:10.1371/journal.pone.0071023
PMCID: PMC3750049  PMID: 23990922
3.  Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease 
BMC Nephrology  2011;12:2.
Background
A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk.
Methods
In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race.
Results
Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88).
Conclusions
This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations.
doi:10.1186/1471-2369-12-2
PMCID: PMC3031204  PMID: 21235779
4.  Standardized, Systemic Phenotypic Analysis of UmodC93F and UmodA227T Mutant Mice 
PLoS ONE  2013;8(10):e78337.
Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines UmodA227T and UmodC93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects.
doi:10.1371/journal.pone.0078337
PMCID: PMC3813435  PMID: 24205203
5.  Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression 
Human Molecular Genetics  2010;19(10):1985-1997.
Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the ‘nephronophthisis–MCKD complex’, a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease.
doi:10.1093/hmg/ddq077
PMCID: PMC2860893  PMID: 20172860
6.  CUBN as a Novel Locus for End-Stage Renal Disease: Insights from Renal Transplantation 
PLoS ONE  2012;7(5):e36512.
Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8–9.2] years (longitudinal study) documenting ESRD in transplanted kidneys – graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.
doi:10.1371/journal.pone.0036512
PMCID: PMC3344899  PMID: 22574174
7.  Association of Estimated Glomerular Filtration Rate and Urinary Uromodulin Concentrations with Rare Variants Identified by UMOD Gene Region Sequencing 
PLoS ONE  2012;7(5):e38311.
Background
Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.
Methodology/Principal Findings
Individuals (n = 485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF<0.05) variants. Five non-synonymous rare variants were identified in FHS; borderline enrichment of rare variants was found in the extremes of THP (SKAT p-value = 0.08). Only V458L was associated with THP in the FHS general-population validation sample (p = 9*10−3, n = 2,522), but did not show direction-consistent and significant association with eGFR in both the ARIC (n = 14,635) and FHS (n = 7,520) validation samples. Pooling all non-synonymous rare variants except V458L together showed non-significant associations with THP and eGFR in the FHS validation sample. Functional studies of V458L revealed no alternations in protein trafficking.
Conclusions/Significance
Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal.
doi:10.1371/journal.pone.0038311
PMCID: PMC3365030  PMID: 22693617
8.  Mutation analysis of the Uromodulin gene in 96 individuals with urinary tract anomalies (CAKUT) 
Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD). UMOD transcription is activated by the transcription factor HNF1B. Mutations in HNF1B cause a phenotype similar to FJHN/GCKD but also congenital anomalies of the kidney and the urinary tract (CAKUT). Moreover, we recently detected UMOD mutations in 2 patients with CAKUT. As HNF1B and UMOD act in the same pathway and cause similar phenotypes we here examined, whether UMOD mutations would be found in patients with CAKUT.
Mutation analysis of UMOD was performed in 96 individuals with CAKUT by direct sequencing of exons 4 and 5 and by heteroduplex analysis following CEL I digestion assay of the exons 3 and 6–12.
The mean age of patients was 11.4 years and in 36.4% of patients the family history was positive for CAKUT. In the CEL I assay 12 aberrant bands were detected in 103 of 960 PCR products and were sequenced. Two previously known and eight new SNPs were detected. As no UMOD mutations were identified in these 96 patients with CAKUT, UMOD mutations do not seem to be a significant cause of CAKUT in this cohort.
doi:10.1007/s00467-008-1016-6
PMCID: PMC3155267  PMID: 18846391
Uromodulin; Tamm-Horsfall protein; urinary tract malformation; CAKUT; mutation analysis
9.  Association of Family History of ESRD, Prevalent Albuminuria, and Reduced GFR With Incident ESRD 
Background
The contribution of albuminuria to the increased risk of incident end-stage renal disease (ESRD) in individuals with a family history of ESRD has not been well studied.
Study Design
Prospective cohort study.
Study Setting & Participants
We analyzed data for family history of ESRD collected from 19,409 participants of the Renal REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study.
Predictor
Family history of ESRD was ascertained by asking “Has anyone in your immediate family ever been told that he or she had kidney failure? This would be someone who is on or had been on dialysis or someone who had a kidney transplant.”
Study Outcomes
Incidence rate for ESRD.
Measurements
Morning urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the US Renal Data System.
Results
A family history of ESRD was reported by 11.1% of participants. Mean eGFRs for those with and without a family history of ESRD were 87.5 ± 22.2 (SD) and 86.5 ± 19.3 mL/min/1.73 m2, respectively (P = 0.05) and the respective geometric mean ACRs were 12.2 and 9.7 mg/g (P < 0.001). ESRD incidence rates for those with and without a family history of ESRD were 244.3 and 106.1/100,000 person-years, respectively. After adjusting for age, sex, and race, the ESRD HR for those with versus those without a family history of ESRD was 2.13 (95% CI, 1.18-3.83). Adjustment for comorbid conditions and socioeconomic status attenuated this association (HR, 1.82; 95% CI, 1.00-3.28), and further adjustment for baseline eGFR and ACR completely attenuated the association between family history of ESRD and incident ESRD (HR, 1.12; 95% CI, 0.69-1.80).
Limitations
The report of a family history of ESRD was not validated.
Conclusion
Family history of ESRD is common in older Americans and the increased risk of ESRD associated with a family history reflects lower GFR, higher albuminuria, and comorbid conditions.
doi:10.1053/j.ajkd.2011.09.018
PMCID: PMC3725825  PMID: 22078058
Race; albuminuria; end-stage renal disease; chronic kidney disease
10.  Epidemiology of Uromodulin-Associated Kidney Disease – Results from a Nation-Wide Survey 
Nephron Extra  2012;2(1):147-158.
Background/Aims
Uromodulin-associated kidney disease (UAKD) is caused by uromodulin mutations and leads to end-stage renal disease. Our objective was to examine the epidemiology of UAKD.
Methods
Data from all UAKD families in Austria were collected. Patients included in the Austrian Dialysis and Transplantation Registry (OEDTR) with unclear diagnoses or genetic diseases were asked whether they had (1) a family history of kidney disease or (2) had suffered from gout. Patients with gout and autosomal dominant renal disease underwent mutational analysis. Kaplan-Meier and Cox analysis was employed to estimate time to renal failure.
Results
Of the 6,210 patients in the OEDTR, 541 were approached with a questionnaire; 353 patients answered the questionnaire. Nineteen of them gave two affirmative answers. In 7 patients, an autosomal dominant renal disease was found; in 1 patient a UMOD mutation was identified. One family was diagnosed through increased awareness as a consequence of the study. At present, 14 UAKD patients from 5 families are living in Austria (1.67 cases per million), and 6 of them require renal replacement therapy (0.73 per 1,000 patients). Progression to renal failure was significantly associated with UMOD genotype.
Conclusion
UAKD patients can be identified by a simple questionnaire. UMOD genotype may affect disease progression.
doi:10.1159/000339102
PMCID: PMC3383240  PMID: 22740033
Clinical epidemiology; End-stage kidney disease; Genetic renal disease; Uromodulin
11.  Polycystic kidney disease in patients on the renal transplant waiting list: trends in hematocrit and survival 
BMC Nephrology  2002;3:7.
Background
The patient characteristics and mortality associated with autosomal dominant polycystic kidney disease (PKD) have not been characterized for a national sample of end stage renal disease (ESRD) patients on the renal transplant waiting list.
Methods
40,493 patients in the United States Renal Data System who were initiated on ESRD therapy between 1 April 1995 and 29 June 1999 and later enrolled on the renal transplant waiting list were analyzed in an historical cohort study of the relationship between hematocrit at the time of presentation to ESRD and survival (using Cox Regression) in patients with PKD as a cause of ESRD.
Results
Hematocrit levels at presentation to ESRD increased significantly over more recent years of the study. Hematocrit rose in parallel in patients with and without PKD, but patients with PKD had consistently higher hemoglobin. PKD was independently associated with higher hematocrit in multiple linear regression analysis (p < 0.0001). In logistic regression, higher hematocrit was independently associated with PKD. In Cox Regression analysis, PKD was associated with statistically significant improved survival both in comparison with diabetic (hazard ratio, 0.64, 95% CI 0.53–0.77, p < 0.001) and non-diabetic (HR 0.68, 95% CI 0.56–0.82, p = 0.001) ESRD patients, adjusted for all other factors.
Conclusions
Hematocrit at presentation to ESRD was significantly higher in patients with PKD compared with patients with other causes of ESRD. The survival advantage of PKD in ESRD persisted even adjusted for differences in hematocrit and in comparison with patients on the renal transplant waiting list.
doi:10.1186/1471-2369-3-7
PMCID: PMC122070  PMID: 12194700
Polycystic kidney disease; Caucasian; female; EPO; peritoneal dialysis; transplantation; complications; dialysis; USRDS; age; albumin; hemoglobin; weight; dysrythmias; mortality; frequency
12.  Uromodulin in Kidney Injury: An Instigator, Bystander, or Protector? 
Uromodulin, also known as Tamm-Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. Although the physiologic functions of this protein remain elusive, significant progress has been made over the last decade that highlights the importance of uromodulin in the pathophysiology of various diseases, such as medullary cystic kidney disease, urinary tract infections, and nephrolithiasis. Meanwhile, there is a renewed interest in the role of uromodulin in kidney injury, both acute and chronic. In this article, we review the existing evidence that supports a role for uromodulin in acute kidney injury (AKI), chronic kidney disease (CKD), and renal inflammation. Contrary to the conventional view of uromodulin as an instigator in kidney injury, new data from uromodulin knockout mice reveal a protective role for this protein in AKI, possibly through down-regulating interstitial inflammation. In CKD, uromodulin excretion, when adjusted for kidney function, is increased; the significance of this remains unclear. Although it has been suggested that uromodulin exacerbates progressive kidney injury, we propose that the elevation in uromodulin secretion is instead reactive to injury, and reflects an increase of uromodulin in the renal parenchyma where it slows the injury process.
doi:10.1053/j.ajkd.2011.10.054
PMCID: PMC3288726  PMID: 22277744
Inflammation; urinary casts; biomarker; tubular cross-talk; UMOD
13.  Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes 
Kidney international  2013;83(6):1136-1143.
Diabetic nephropathy is the leading cause of end stage renal disease. The urinary albumin to creatinine ratio is used as a predictor for the development of nephropathy but it is neither sensitive nor specific. Here we used liquid chromatography/mass spectrometry on urine of eight normoalbuminuric patients with type 2 diabetes from the VA Diabetes Trial to identify candidate markers for loss of renal function. Initial verification of 7 markers (agrin, haptoglobin, mannan-binding lectin serine protease 2, LAMP-2, angiotensinogen, NGAL and uromodulin) in the urine of an additional 30 patients showed that haptoglobin was the best predictor of early renal functional decline. We then measured this in the urine of 204 patients with type 2 diabetes who did not yet have significant kidney disease (eGFR stage 2 or better and an albumin to creatinine ratio less than 300 mg/g). In comparing the highest to lowest tertile, the odds ratio for having early renal function decline was 2.70 (CI 1.15, 6.32) using the haptoglobin to creatinine ratio compared to 2.50 (CI 1.14, 5.48) using the albumin to creatinine ratio after adjusting for treatment group and use of ACE inhibitors. Addition of the haptoglobin to creatinine ratio to a model using the albumin to creatinine ratio to predict early renal function decline resulted in improved predictive performance. Thus, the haptoglobin to creatinine ratio may be useful to predict patients with type 2 diabetes at risk of nephropathy prior to the development of macroalbuminuria or reduced GFR.
doi:10.1038/ki.2013.57
PMCID: PMC3672380  PMID: 23536133
Diabetes; diabetic nephropathy; type 2 diabetes; urine; biological markers; chronic kidney disease
14.  Marked Variation of the Association of ESRD Duration Before and After Wait Listing on Kidney Transplant Outcomes 
Numerous studies report a strong association between pretransplant end-stage renal disease (ESRD) duration and diminished transplant outcomes. However, cumulative waiting time may reflect distinct phases and processes related to patients’ physiological condition as well as pre-existing morbidity and access to care. The relative impact of pre- and postlisting ESRD durations on transplant outcomes is unknown. We examined the impact of these intervals from a national cohort of kidney transplant recipients from 1999 to 2008 (n = 112 249). Primary factors explaining prelisting ESRD duration were insurance and race, while primary factors explaining postlisting ESRD duration were blood type, PRA% and variation between centers. Extended time from ESRD to waitlisting had significant dose–response association with overall graft loss (AHR = 1.26 for deceased donors [DD], AHR = 1.32 for living donors [LD], p values < 0.001). Contrarily, time from waitlisting (after ESRD) to transplantation had negligible effects (p = 0.10[DD], p = 0.57[LD]). There were significant associations between pre- and postlisting ESRD time with posttransplant patient survival, however prelisting time had over sixfold greater effect. Prelisting ESRD time predominately explains the association of waiting time with transplant outcomes suggesting that factors associated with this interval should be prioritized for interventions and allocation policy. The degree to which the effect of prelisting ESRD time is a proxy for comorbid conditions, socioeconomic status or access to care requires further study.
doi:10.1111/j.1600-6143.2010.03213.x
PMCID: PMC3881969  PMID: 20645941
Access to care; African Americans; dialysis; ESRD; kidney transplantation; waiting list
15.  The clinical course of ANCA small-vessel vasculitis on chronic dialysis 
Kidney international  2009;76(6):644-651.
Antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis frequently affects the kidney. Here we describe the rates of infection, disease relapse, and death in patients with ANCA small-vessel vasculitis before and after end-stage renal disease (ESRD) in an inception cohort study and compare them to those of patients with preserved renal function. All patients had biopsy-proven ANCA small-vessel vasculitis. Fisher's exact tests and Wilcoxon rank sum tests were used to compare the characteristics by ESRD status. ESRD follow-up included time on dialysis with transplants censored. Over a median follow-up time of 40 months, 136 of 523 patients reached ESRD. ESRD was associated with new-onset ANCA small-vessel vasculitis in 51% of patients, progressive chronic kidney disease without active vasculitis in 43%, and renal relapse in 6% of patients. Relapse rates of ANCA small-vessel vasculitis, reported as episodes/person-year, were significantly lower on chronic dialysis (0.08 episodes) compared with the rate of the same patients before ESRD (0.20 episodes) or with patients with preserved renal function (0.16 episodes). Infections were almost twice as frequent among patients with ESRD on maintenance immunosuppressants and were an important cause of death. Given the lower risk of relapse and higher risk of infection and death, we suggest that immunosuppression be geared to patients with ESRD who present with active vasculitis.
doi:10.1038/ki.2009.218
PMCID: PMC2778281  PMID: 19536079
ANCA; chronic dialysis; glomerulonephritis
16.  Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD 
PLoS Genetics  2011;7(9):e1002292.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Author Summary
Chronic kidney disease (CKD) affects about 6%–11% of the general population, and progression to end stage renal disease (ESRD) has a significant public health impact. Family studies suggest that the risk for CKD and ESRD is heritable. Unraveling the genetic underpinning of risk for these diseases may lead to the identification of novel mechanisms and thus diagnostic and therapeutic tools. We have previously identified 16 genetic markers in association with kidney function and prevalent CKD in general population studies. However, little is known about the relevance of these SNPs to the initial development of CKD or to ESRD risk. Therefore, we have now analyzed the association of these markers with the initiation of CKD in more than 26,000 individuals from the general population using serial estimations of kidney function, and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). We show that many of the 16 markers are also associated or show a strong trend towards association with initiation of CKD, while only 2 markers are nominally associated with ESRD. Further work is required to characterize the association of genetic determinants of different stages of CKD progression.
doi:10.1371/journal.pgen.1002292
PMCID: PMC3183079  PMID: 21980298
17.  Common genetic variants of the human UMOD gene are functional on transcription and predict plasma uric acid in two distinct populations 
Kidney international  2013;83(4):733-740.
Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia, decreased renal excretion of UMOD and uric acid; such findings suggest a role for UMOD in the regulation of plasma uric acid. We screened common variants across the UMOD locus in two populations, one from a community-based Chinese population, the other from California twins and siblings. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK293 cells and mlMCD3 cells. By variance components in twin pairs, uric acid concentration and excretion were heritable traits. In the primary population from Beijing, we identified that carriers of haplotype GCC displayed higher plasma uric acid, and 3 UMOD promoter variants associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in an independent American population sample. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. These results suggest that UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, eventuating in elevation of plasma uric acid.
doi:10.1038/ki.2012.449
PMCID: PMC3687544  PMID: 23344472
Uromodulin; uric acid; Tamm-Horsfall protein; UMOD
18.  Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors 
Background
Despite improvements in survival with HIV infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals, and to compare ESRD risk by eGFR and proteinuria levels.
Study design
Retrospective cohort study.
Setting and Participants
22,156 HIV-infected veterans without preexisting ESRD receiving healthcare in the Veterans’ Affairs medical system between 1996 and 2004.
Predictors
Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin<3.5mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and estimated glomerular filtration rate (eGFR) were identified using the Veterans’ Affairs electronic record system.
Outcomes
ESRD was ascertained by the United States Renal Data System.
Results
366 cases of ESRD occurred, corresponding to 3 cases per 1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5–2.4), diabetes (HR, 1.7; 95% CI, 1.3–2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7–2.7) were independently associated with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/mm3 (HR, 1.5; 95% CI, 1.2–2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5–2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5–2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8–2.5). Compared to persons without chronic kidney disease (CKD), defined as eGFR>60mg/min/1.73m2 and no proteinuria, lower eGFR and higher proteinuria categories were jointly associated with exponentially higher ESRD rates, ranging from 6.6 per 1000 person-years for persons with proteinuria 30–100 mg/dL and eGFR>60ml/min/1.73m2, to 193 per 1000 person-years for persons with proteinuria ≥300mg/dL and eGFR<30ml/min/1.73m2.
Limitations
Results may not be generalizable to female and nonveteran populations.
Conclusions
In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for CKD staging is most effective for stratifying risk for ESRD.
doi:10.1053/j.ajkd.2011.10.050
PMCID: PMC3324595  PMID: 22206742
End-stage renal disease; HIV; chronic kidney disease; risk factors
19.  A Japanese Family Suffering from Familial Juvenile Hyperuricemic Nephropathy due to a Rare Mutation of the Uromodulin Gene 
We report the case of a Japanese family suffering from familial juvenile hyperuricemic nephropathy (FJHN) due to a rare missense mutation of the uromodulin (UMOD) gene. An 18-year-old male presented with gout, hyperuricemia, and stage 3 chronic kidney disease. Mostly, FJHN is caused by a mutation altering the cystine residue of UMOD/Tamm-Horsfall protein. However, in the present case, a T688C mutation was identified in exon 4, resulting in amino acid substitution with arginine replacing tryptophan at position 230 (Trp230Arg). This mutation was also found in his brother and father with the same phenotype, indicating autosomal dominant inheritance. The affected amino acid was conserved in 200 healthy Japanese controls. Therefore, mutation T688C most likely causes rare structural and/or functional abnormalities in UMOD/Tamm-Horsfall protein.
doi:10.1159/000337343
PMCID: PMC3482064  PMID: 23197950
Chronic kidney disease; Familial juvenile hyperuricemic nephropathy; Gene; mutation; Uromodulin
20.  Urine Biomarkers Predict Acute Kidney Injury in Newborns 
The Journal of pediatrics  2012;161(2):270-5.e1.
Objective
To identify urine biomarkers predictive of acute kidney injury (AKI) in infants admitted to level 2 and 3 neonatal intensive care units with birth weight >2000 g and 5-minute Apgar score ≤7.
Study design
A nested case-control study was performed comparing 8 candidate urine AKI biomarkers in infants with AKI (defined as a rise in serum creatinine of at least 0.3 mg/dL or a serum creatinine elevation ≥1.7 mg/dL persisting for 3 days) and 24 infants from the described cohort without AKI. Urine was analyzed for neutrophil gelatinase–associated lipocalin, osteopontin, cystatin C, albumin, β2 microglobulin, epithelial growth factor, uromodulin (UMOD), and kidney injury molecule 1.
Results
Compared with the infants without AKI, those with AKI had higher levels of urine cystatin C (1123 pg/mL [95% CI, 272-4635 pg/mL] vs 90 pg/mL [95% CI, 39-205 pg/mL]; P < .004; area under the receiver operating characteristic curve [AUC] = 0.82), lower levels of UMOD (11.0 pg/mL [95% CI, 5.7-21.4 pg/mL] vs 26.2 pg/mL [95% CI, 17.4-39.4 pg/mL]; P < .03; AUC = 0.77), and lower levels of epithelial growth factor (6.7 pg/mL [95% CI, 4.0-11.3 pg/mL] vs 17.4 pg/mL [95% CI, 12.7-23.8 pg/mL; P = .003; AUC = 0.82). Although the differences were not statistically significant, levels of urine neutrophil–associated gelatinase lipocalin, kidney injury molecule 1, and osteopontin trended higher in infants with AKI.
Conclusion
Urinary biomarkers can predict AKI in neonates admitted to level 2 and 3 neonatal intensive care units.
doi:10.1016/j.jpeds.2012.02.007
PMCID: PMC3598122  PMID: 22424940
21.  Impact of MELD-Based Allocation on End-Stage Renal Disease after Liver Transplantation 
The proportion of patients undergoing liver transplantation (LT) with concomitant renal dysfunction markedly increased after allocation by the Model for End-stage Liver Disease (MELD) score was introduced. We examined the incidence of subsequent post-LT end-stage renal disease (ESRD) before and after the policy was implemented. Data on all adult deceased-donor LT recipients between 4/27/95 and 12/31/08 (n=59,242) from the Scientific Registry of Transplant Recipients were linked with Centers for Medicare & Medicaid Services ESRD data. Cox regression was used to (i) compare pre-MELD and MELD eras with respect to post-LT ESRD incidence (ii) determine the risk factors for post-LT ESRD (iii) quantify the association between ESRD incidence and mortality. Crude rates of post-LT ESRD were 12.8 and 14.5 per 1,000 patient-years in the pre-MELD and MELD eras, respectively. Covariate-adjusted post-LT ESRD risk was higher in the MELD era (hazard ratio [HR] =1.15; p=0.0049). African-American race, hepatitis C, pre-LT diabetes, higher creatinine, lower albumin, lower bilirubin and sodium>141 mMol/L at LT were also significant predictors of post-LT ESRD. Post-LT ESRD was associated with higher post-LT mortality (HR=3.32; p<0.0001). The risk of post-LT ESRD, a strong predictor of post-LT mortality, is 15% higher in the MELD era. This study identified potentially modifiable risk factors of post-LT ESRD. Early intervention and modification of these risk factors may reduce the burden of post-LT ESRD.
doi:10.1111/j.1600-6143.2011.03703.x
PMCID: PMC3203341  PMID: 21883908
End-stage renal disease; Liver transplant; Model for end-stage renal disease; Mortality; Scientific Registry of Transplant Recipients
22.  Syndrome of rapid-onset end-stage renal disease in two consecutive renal transplant recipients 
Indian Journal of Nephrology  2013;23(3):222-225.
A syndrome of rapid-onset end-stage renal disease (SORO-ESRD) following acute kidney injury (AKI) in native kidneys was described recently. To what extent this syndrome of unanticipated and rapidly irreversible ESRD impacts renal allograft survival is unknown. Over 6 months, we managed two deceased donor renal transplant recipients (RTRs) with rapid acceleration of previously stable allograft chronic kidney disease to abruptly terminate in irreversible ESRD following AKI. These are the first reports of SORO-ESRD in RTRs. More research is needed to ascertain the contribution of SORO-ESRD to renal allograft loss.
doi:10.4103/0971-4065.111861
PMCID: PMC3692152  PMID: 23814425
Acute kidney injury; chronic kidney disease; end-stage renal disease; renal transplant recipient
23.  Treatments and Outcomes for End Stage Renal Disease Following Wilms Tumor 
Background
Little is known about treatment outcomes for children who have end stage renal disease (ESRD) after treatment for Wilms tumor (WT).
Methods
Time-to-transplant, graft failure and survival outcomes were examined for 173 children enrolled on the National Wilms Tumor Study who developed ESRD.
Results
Fifty-five patients whose ESRD resulted from progressive bilateral WT (PBWT) experienced high early mortality from WT that limited their opportunity for transplant (47% at 5 years) and survival (44% at 10 years) in comparison with population controls. The 118 patients whose ESRD was due to other causes (termed “chronic kidney disease”), many of whom had WT associated congenital anomalies, had transplant (77% at 5 years) and survival (73% at 10 years) outcomes no worse than those for population controls. Graft failure following transplant was comparable for the 2 groups. Minority children had twice the median time to transplant as non-Hispanic whites and twice the mortality rates, also reflecting population trends.
Conclusions
In view of the continuing high mortality in patients with ESRD, and the dramatic improvement in outlook following kidney transplantation, re-evaluation of current guidelines for a 2 year delay in transplant following WT treatment may be warranted.
doi:10.1007/s00467-012-2140-x
PMCID: PMC3383943  PMID: 22430485
Kidney Failure; Chronic; Transplantation; Graft Failure
24.  Near Normalization of Metabolic and Functional Features of the Central Nervous System in Type 1 Diabetic Patients With End-Stage Renal Disease After Kidney-Pancreas Transplantation 
Diabetes Care  2012;35(2):367-374.
OBJECTIVE
The pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD).
RESEARCH DESIGN AND METHODS
The aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects.
RESULTS
Magnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients.
CONCLUSIONS
Diabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia.
doi:10.2337/dc11-1697
PMCID: PMC3263904  PMID: 22190674
25.  Association of estimated glomerular filtration rate and albuminuria with mortality and end-stage renal disease: a collaborative meta-analysis of kidney disease cohorts 
Kidney international  2011;79(12):1331-1340.
Limited data are available on the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end stage renal disease (ESRD) among individuals with chronic kidney disease (CKD). We conducted a collaborative meta-analysis of 21,688 participants selected for CKD from 13 cohorts.
After adjustment for potential confounders and albuminuria, a 15 mL/min/1.73 m2 lower eGFR below 45 mL/min/1.73 m2 was significantly associated with mortality (pooled hazard ratio [HR] 1.47 [95% CI: 1.22–1.79]), and ESRD (pooled HR 6.24 [95% CI: 4.84–8.05]). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eight-fold higher albumin:creatinine ratio (ACR) or protein:creatinine ratio (PCR) was significantly associated with mortality (pooled HR 1.40 [95% CI: 1.27–1.55]), without evidence of significant heterogeneity. An eight-fold higher ACR or PCR was also strongly associated with ESRD (pooled HR 3.04 [95% CI: 2.27–4.08]), with significant heterogeneity between HR estimates.
Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD. The associations are stronger for ESRD than for mortality. The observed associations are consistent with CKD classification based on eGFR stages, and suggest that albuminuria provides additional prognostic information among individuals with CKD.
doi:10.1038/ki.2010.550
PMCID: PMC3917543  PMID: 21289598

Results 1-25 (897894)