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1.  UMOD as a susceptibility gene for end-stage renal disease 
BMC Medical Genetics  2012;13:78.
Background
In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant.
Methods
To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation.
Results
The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Böger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts.
Conclusions
Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD.
doi:10.1186/1471-2350-13-78
PMCID: PMC3495046  PMID: 22947327
UMOD; Uromodulin; Polymorphisms; SNP; End-stage renal disease; Kidney transplantation
2.  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
3.  Vesicoureteral Reflux, Reflux Nephropathy, and End-Stage Renal Disease 
Advances in Urology  2008;2008:508949.
Objective. To review the contribution of vesicoureteral reflux and reflux nephropathy to end-stage renal disease. Data Source. Published research articles and publicly available registries. Results. Vesicoureteral reflux (VUR) is commonly identified in pediatric patients and can be associated with reflux nephropathy (RN), chronic kidney disease (CKD), and rarely end-stage renal disease (ESRD). Patients with reduced GFR, bilateral disease, grade V VUR, proteinuria, and hypertension are more likely to progress to CKD and ESRD. Because progression to ESRD is rare in VUR and often requires many decades to develop, there are limited prospective, randomized, controlled trials available to direct therapy to prevent progression to ESRD. Conclusions. Identification of patients with increased risk of progression to CKD and ESRD should be the goal of clinical, biochemical, and radiological evaluation of patients with VUR. Treatment of patients with VUR should be directed at preventing new renal injury and preserving renal function.
doi:10.1155/2008/508949
PMCID: PMC2478704  PMID: 18670633
4.  The FTO gene polymorphism is associated with end-stage renal disease: two large independent case–control studies in a general population 
Nephrology Dialysis Transplantation  2011;27(3):1030-1035.
Background.
Genome-wide association studies identified the FTO (fat mass and obesity gene) gene as an important determinant of body weight. More recently, the FTO gene was reported to be associated with other outcomes, including major risk factors for chronic kidney disease (CKD). We investigated the role of this gene in the risk of end-stage renal disease (ESRD) caused by CKD.
Methods.
We conducted two large population-based case–control studies of ESRD. Study 1 compared 984 haemodialysed patients with ESRD with 2501 participants in the Czech post-MONICA study; Study 2 compared 1188 patients included in a kidney transplantation programme for ESRD with 6681 participants in the Czech HAPIEE study. The frequencies of the FTO rs17817449 single nucleotide polymorphism genotype were compared between cases and controls.
Results.
The FTO rs17817449 genotype was significantly associated with CKD in both studies (P-values 0.00004 and 0.006, respectively). In the pooled data, the odds ratios of CKD for GG and GT, versus TT genotype, were 1.37 (95% confidence interval 1.20–1.56) and 1.17 (1.05–1.31), respectively (P for trend <0.0001). Among haemodialysed and kidney transplant patients, the onset of ESRD in GG homozygotes was 3.3 (P = 0.012) and 2.5 (P = 0.032) years, respectively, earlier than in TT homozygotes.
Conclusions.
These two large independent case–control studies in the general population found robust associations between the FTO rs17817449 polymorphism and the ESRD. The results suggest that the morbidities associated with the FTO gene include CKD.
doi:10.1093/ndt/gfr418
PMCID: PMC3289895  PMID: 21788373
chronic kidney disease; end-stage renal disease; FTO; genetic epidemiology
5.  Syndrome of rapid onset end stage renal disease in incident Mayo Clinic chronic hemodialysis patient 
Indian Journal of Nephrology  2014;24(2):75-81.
Despite decades of research, a full understanding of chronic kidney disease (CKD)-end stage renal disease (ESRD) progression remains elusive. The common consensus is a predictable, linear, progressive and time-dependent decline of CKD to ESRD. Acute kidney injury (AKI) on CKD is usually assumed to be transient, with recovery as the expected outcome. AKI-ESRD association in current nephrology literature is blamed on the so-called “residual confounding.” We had previously described a relationship between AKI events and rapid onset yet irreversible ESRD happening in a continuum in a high-risk CKD cohort. However, the contribution of the syndrome of rapid onset-ESRD (SORO-ESRD) to incident United States ESRD population remained conjectural. In this retrospective analysis, we analyzed serum creatinine trajectories of the last 100 consecutive ESRD patients in 4 Mayo Clinic chronic hemodialysis units to determine the incidence of SORO-ESRD. Excluding 9 patients, 31 (34%) patients, including two renal transplant recipients, had SORO-ESRD: 18 males and 13 females age 72 (range 50-92) years. Precipitating AKI followed pneumonia (8), acutely decompensated heart failure (7), pyelonephritis (4), post-operative (5), sepsis (3), contrast-induced nephropathy (2), and others (2). Time to dialysis was shortest following surgical procedures. Concurrent renin angiotensin aldosterone system blockade was higher with SORO-ESRD - 23% versus 5%, P = 0.0113. In conclusion, SORO-ESRD is not uncommon among the incident general US ESRD population. The implications for ESRD care planning, AV-fistula-first programs, general CKD care and any associations with renal ageing/senescence warrant further study.
doi:10.4103/0971-4065.127886
PMCID: PMC3968613
Acute kidney injury; chronic kidney disease; end stage renal disease; renal replacement therapy
6.  Concise Review: Kidney Stem/Progenitor Cells: Differentiate, Sort Out, or Reprogram? 
Stem Cells (Dayton, Ohio)  2010;28(9):1649-1660.
End-stage renal disease (ESRD) is defined as the inability of the kidneys to remove waste products and excess fluid from the blood. ESRD progresses from earlier stages of chronic kidney disease (CKD) and occurs when the glomerular filtration rate (GFR) is below 15 ml/minute/1.73 m2. CKD and ESRD are dramatically rising due to increasing aging population, population demographics, and the growing rate of diabetes and hypertension. Identification of multipotential stem/progenitor populations in mammalian tissues is important for therapeutic applications and for understanding developmental processes and tissue homeostasis. Progenitor populations are ideal targets for gene therapy, cell transplantation, and tissue engineering. The demand for kidney progenitors is increasing due to severe shortage of donor organs. Because dialysis and transplantation are currently the only successful therapies for ESRD, cell therapy offers an alternative approach for kidney diseases. However, this approach may be relevant only in earlier stages of CKD, when kidney function and histology are still preserved, allowing for the integration of cells and/or for their paracrine effects, but not when small and fibrotic end-stage kidneys develop. Although blood- and bone marrow-derived stem cells hold a therapeutic promise, they are devoid of nephrogenic potential, emphasizing the need to seek kidney stem cells beyond known extrarenal sources. Moreover, controversies regarding the existence of a true adult kidney stem cell highlight the importance of studying cell-based therapies using pluripotent cells, progenitor cells from fetal kidney, or dedifferentiated/reprogrammed adult kidney cells. Stem Cells 2010; 28:1649–1660.
doi:10.1002/stem.486
PMCID: PMC2996087  PMID: 20652959
Adult stem cells; Kidney; Cell surface markers; Cellular therapy; Developmental biology; Embryonic stem cells; Fetal stem cells
7.  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
8.  Evolving Pandemic Diabetic Nephropathy 
The expanding impact of chronic kidney disease (CKD) due to pandemic diabetes mellitus is recounted emphasizing its epidemiology that has induced global socioeconomic stress on health care systems in industrialized nations now attempting to proffer optimal therapy for end stage renal disease (ESRD). Strategies to delay and perhaps prevent progression of diabetic nephropathy from minimal proteinuria through nephrotic range proteinuria and azotemia to ESRD appear to have decreased the rate of persons with diabetes who develop ESRD. For those with ESRD attributed to diabetes, kidney transplantation affords better survival and rehabilitation than either hemodialysis or peritoneal dialysis. It is likely that advances in genetics and molecular biology will suggest early interventions that will preempt diabetic complications including renal failure.
doi:10.5041/RMMJ.10005
PMCID: PMC3721652  PMID: 23908777
diabetic nephropathy; chronic kidney disease; glycation; renal failure; renoprotection
9.  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
10.  Advances in the Use of Multi-Marker Panels for Renal Risk Stratification 
Purpose of Review
The purpose of this review is to discuss novel studies in the last year that have examined the use of combinations of multiple markers to improve risk prediction in the setting of chronic kidney disease (CKD). We will focus on multi-marker panels to improve prediction of CKD onset; improve classification of CKD and risk-stratification of persons with CKD; and develop individual-level risk scores for progression to ESRD.
Recent Findings
One study reported that several novel circulation biomarkers may aid in predicting incident CKD and microalbuminuria. Second, our group has shown that the combination of creatinine, cystatin C and albuminuria improves detection and risk stratification for death, heart failure, cardiovascular events, and end stage renal disease compared with creatinine alone. Finally, a highly accurate individual risk score was developed to predict progression to ESRD using readily available clinical markers.
Summary
The combination of multiple markers improves detection and risk stratification in CKD. Future research is needed in understanding the use of a “renal panel” for detection, classification and risk stratification in kidney disease in diverse populations. The studies presented here represent the beginning of a paradigm shift to multi-marker panels in nephrology.
doi:10.1097/MNH.0b013e328352132d
PMCID: PMC3353750  PMID: 22449944
Chronic kidney disease; albuminuria; creatinine; cystatin C; multi-marker
11.  Selecting the optimal cell for kidney regeneration 
Organogenesis  2011;7(2):123-134.
Chronic kidney disease (CKD) is a progressive loss in renal function over a period of months or years. End-stage renal disease (ESRD) or stage 5 CKD ensues when renal function deteriorates to under 15% of the normal range. ESRD requires either dialysis or, preferentially, a kidney organ allograft, which is severely limited due to organ shortage for transplantation. To combat this situation, one needs to either increase supply of organs or decrease their demand. Two strategies therefore exist: for those that have completely lost their kidney function (ESRD), we will need to supply new kidneys. Taking into account the kidneys' extremely complex structure, this may prove to be impossible in the near future. In contrast, for those patients that are in the slow progression route from CKD to ESRD but still have functional kidneys, we might be able to halt progression by introducing stem cell therapy to diseased kidneys to rejuvenate or regenerate individual cell types. Multiple cell compartments that fall into three categories are likely to be worthy targets for cell repair: vessels, stroma (interstitium) and nephron epithelia. Different stem/progenitor cells can be linked to regeneration of specific cell types; hematopoietic progenitors and hemangioblastic cell types have specific effects on the vascular niche (vasculogenesis and angiogenesis). Multipotent stromal cells (MSC), whether derived from the bone marrow or isolated from the kidney's non-tubular compartment, may, in turn, heal nephron epithelia via paracrine mechanisms. Nevertheless, as we now know that all of the above lack nephrogenic potential, we should continue our quest to derive genuine nephron (epithelial) progenitors from differentiated pluripotent stem cells, from fetal and adult kidneys and from directly reprogrammed somatic cells.
doi:10.4161/org.7.2.15783
PMCID: PMC3142449  PMID: 21519195
kidney regeneration; kidney stem cells; surface markers; reprogramming; tissue specific stem cells; renal progenitors
12.  Estimating the long term impact of kidney donation on life expectancy and end stage renal disease 
Background
Long term studies of live kidney donation do not show evidence of appreciable risks to the donor. However nephrectomy reduces total glomerular filtration rates (GFR) and is associated with increased rates of proteinuria and possibly hypertension. It is not clear to what extent these changes are associated with reduced life expectancy (LE) or increased risk of end stage renal disease (ESRD) since follow up is incomplete in most reports.
Methods
In a computer simulation model based on a US population chronic kidney disease model, increased hazard rates for higher blood pressure, proteinuria and low GFR were applied to healthy individuals undergoing donor nephrectomy. Subsequent LE and cumulative risk of ESRD were calculated.
Results
Kidney donation is projected to reduce LE by 0.83 years and increase the absolute cumulative risk of ESRD by 0.89% for a 40-year-old white male. White females were predicted to have slightly greater loss of life and less added ESRD risk. Conversely, Blacks have greater risks of ESRD after donation. Older donors with hypertension were predicted to lose less life years and lower cumulative ESRD risks than young donors. Despite these increased risks most donors will have better life expectancy and lower ESRD rates than the general population since they are a highly selected cohort.
Conclusions
This study attempts to quantify increases in death and ESRD from donor nephrectomy assuming the risk factors of hypertension, low GFR and proteinuria have the same significance in this population as in the general population. Further study is required to better estimate the risks of donation and test whether these assumptions are valid.
doi:10.1186/2047-1440-2-2
PMCID: PMC3577426  PMID: 23414596
Quality of life; Nephrectomy; Live donation; End stage renal disease; Life expectancy
13.  Vitamin D insufficiency and deficiency with stages of chronic kidney disease in an Asian population 
BMC Nephrology  2013;14:206.
Background
Vitamin D insufficiency is associated with proteinuria and could be a risk factor for end-stage renal disease (ESRD). However, few studies have examined the significance of vitamin D insufficiency as a contributing factor for the development of ESRD in the Asian chronic kidney disease (CKD) population.
Methods
Authors examined the relationship between vitamin D status and the staging of CKD using data from an outpatient clinic-based screening in 2,895 Thai CKD patients. Serum levels of 25-hydroxyvitamin D were analyzed according to CKD stages. Vitamin D deficiency and insufficiency were defined as a serum 25-hydroxyvitamin D concentration < 10 ng/mL and 10–30 ng/mL, respectively.
Results
The mean (SD) 25-hydroxyvitamin D levels were significantly lower according to severity of renal impairment (CKD stage 3a: 27.84±14.03 ng/mL, CKD stage 3b: 25.86±11.14 ng/mL, CKD stage 4: 24.09±11.65 and CKD stage 5: 20.82±9.86 ng/mL, p<0.001). The prevalence of vitamin D deficiency/insufficiency was from CKD stage 3a, 3b, 4 to 5, 66.6%, 70.9%, 74.6%, and 84.7% (p<0.001). The odds ratio (95% CI) of vitamin D insufficiency/deficiency (serum 25-hydroxyvitamin D ≤ 30 ng/mL) and vitamin D deficiency (serum 25-hydroxyvitamin D < 10 ng/mL) for developing ESRD, after adjustment for age, gender, hemoglobin, serum albumin, calcium, phosphate and alkaline phosphatase were 2.19 (95% CI 1.07 to 4.48) and 16.76 (95% CI 4.89 to 57.49), respectively.
Conclusion
This study demonstrates that 25-hydroxyvitamin D insufficiency and deficiency are more common and associated with the level of kidney function in the Thai CKD population especially advanced stage of CKD.
doi:10.1186/1471-2369-14-206
PMCID: PMC3850679  PMID: 24083392
Vitamin D deficiency; Chronic kidney disease; 25-hydroxyvitamin D
14.  HLA Polymorphism and Susceptibility to End-Stage Renal Disease in Cantonese Patients Awaiting Kidney Transplantation 
PLoS ONE  2014;9(3):e90869.
Background
End-Stage Renal Disease (ESRD) is a worldwide public health problem. Currently, many genome-wide association studies have suggested a potential association between human leukocyte antigen (HLA) and ESRD by uncovering a causal relationship between HLA and glomerulonephritis. However, previous studies, which investigated the HLA polymorphism and its association with ESRD, were performed with the modest data sets and thus might be limited. On the other hand, few researches were conducted to tackle the Chinese population with ESRD. Therefore, this study aims to detect the susceptibilities of HLA polymorphism to ESRD within the Cantonese community, a representative southern population of China.
Methods
From the same region, 4541 ESRD patients who were waiting for kidney transplantation and 3744 healthy volunteer bone marrow donors (controls) were randomly chosen for this study. Polymerase chain reaction-sequence specific primer method was used to analyze the HLA polymorphisms (including HLA-A, HLA-B and HLA-DRB1 loci) in both ESRD patients and controls. The frequencies of alleles at these loci and haplotypes were compared between ESRD patients and controls.
Results
A total of 88 distinct HLA alleles and 1361 HLA A-B-DRB1 haplotypes were detected. The frequencies of five alleles, HLA-A*24, HLA-B*55, HLA-B*54, HLA-B*40(60), HLA-DRB1*04, and one haplotype (HLA-A*11-B*27-DRB1*04) in ESRD patients are significantly higher than those in the controls, respectively.
Conclusions
Five HLA alleles and one haplotype at the HLA-A, HLA-B and HLA-DRB1 loci appear to be associated with ESRD within the Cantonese population.
doi:10.1371/journal.pone.0090869
PMCID: PMC3946267  PMID: 24603486
15.  Prevalence of chronic kidney disease in Thai adults: a national health survey 
BMC Nephrology  2009;10:35.
Background
The prevalence of patients with end stage renal disease (ESRD) who need dialysis and/or transplantation has more than doubled in Thailand during the past two decades. It has been suggested that therapeutic strategies to reduce the risk of ESRD and other complications in CKD are now available, thus the early recognition and the institution of proven therapeutic strategies are important and beneficial. We, therefore, aimed to determine the prevalence of CKD in Thai adults from the National Health Examination Survey of 2004.
Methods
Data from a nationally representative sample of 3,117 individuals aged 15 years and older was collected using questionnaires, physical examination and blood samples. Serum creatinine was measured by Jaffé method. GFR was estimated using the Chinese modified Modification of Diet in Renal Disease Study equation. Chronic kidney Disease (CKD) stages were classified based on Kidney Disease Outcome Quality Initiative (K/DOQI).
Results
The prevalence of CKD in Thai adults weighted to the 2004 Thai population by stage was 8.1% for stage 3, 0.2% and 0.15% for stage 4 and 5 respectively. Compared to non-CKD, individuals with CKD were older, had a higher level of cholesterol, and higher blood pressure. Those with cardiovascular risk factors were more likely to have CKD (stage 3-5) than those without, including hypertension (OR 1.6, 95%CI 1.1, 3.4), diabetes (OR 1.87, 95%CI 1.0, 3.4). CKD was more common in northeast (OR 2.1, 95%CI 1.3, 3.3) compared to central region. Urinalysis was not performed, therefore, we could not have data on CKD stage 1 and 2. We have no specific GFR formula for Thai population.
Conclusion
The identification of CKD patients should be evaluated and monitored for appropriate intervention for progression to kidney disease from this screening.
doi:10.1186/1471-2369-10-35
PMCID: PMC2781792  PMID: 19878577
16.  Incident Atrial Fibrillation and Risk of End-Stage Renal Disease in Adults with Chronic Kidney Disease 
Circulation  2012;127(5):569-574.
Background
Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD). However, the long-term impact of development of AF on the risk of adverse renal outcomes in patients with CKD is unknown. In this study, we determined the association between incident AF and risk of end-stage renal disease (ESRD) among adults with CKD.
Methods and Results
We studied adults with CKD (defined as persistent glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 by the CKD-EPI equation) enrolled in Kaiser Permanente Northern California who were identified between 2002–2010 and who did not have prior ESRD or previously documented AF. Incident AF was identified using primary hospital discharge diagnoses and/or two or more outpatient visits for AF. Incident ESRD was ascertained from a comprehensive health plan registry for dialysis and renal transplant. Among 206,229 adults with CKD, 16,463 developed incident AF. During a mean follow-up of 5.1± 2.5 years, there were 345 cases of ESRD that occurred after development of incident AF (74 per 1000 person-years) compared with 6505 cases of ESRD during periods without AF (64 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 67% increase in rate of ESRD (hazard ratio 1.67, 95% confidence interval: 1.46–1.91).
Conclusions
Incident AF is independently associated with increased risk of developing ESRD in adults with CKD. Further study is needed to identify potentially modifiable pathways through which AF leads to a higher risk of progression to ESRD.
doi:10.1161/CIRCULATIONAHA.112.123992
PMCID: PMC3676734  PMID: 23275377
arrhythmia; fibrillation; kidney
17.  Successful disease-specific induced pluripotent stem cell generation from patients with kidney transplantation 
Introduction
End-stage renal disease (ESRD) is a major public health problem. Although kidney transplantation is a viable therapeutic option, this therapy is associated with significant limitations, including a shortage of donor organs. Induced pluripotent stem (iPS) cell technology, which allows derivation of patient-specific pluripotent stem cells, could provide a possible alternative modality for kidney replacement therapy for patients with ESRD.
Methods
The feasibility of iPS cell generation from patients with a history of ESRD was investigated using lentiviral vectors expressing pluripotency-associated factors.
Results
In the present article we report, for the first time, generation of iPS cells from kidney transplant recipients with a history of autosomal-dominant polycystic kidney disease (ADPKD), systemic lupus erythematosus, or Wilms tumor and ESRD. Lentiviral transduction of OCT4, SOX2, KLF4 and c-MYC, under feeder-free conditions, resulted in reprogramming of skin-derived keratinocytes. Keratinocyte-derived iPS cells exhibited properties of human embryonic stem cells, including morphology, growth properties, expression of pluripotency genes and surface markers, spontaneous differentiation and teratoma formation. All iPS cell clones from the ADPKD patient retained the conserved W3842X mutation in exon 41 of the PKD1 gene.
Conclusions
Our results demonstrate successful iPS cell generation from patients with a history of ESRD, PKD1 gene mutation, or chronic immunosuppression. iPS cells from autosomal kidney diseases, such as ADPKD, would provide unique opportunities to study patient-specific disease pathogenesis in vitro.
doi:10.1186/scrt89
PMCID: PMC3340557  PMID: 22142803
18.  Chronic Kidney Disease after Acute Kidney Injury: A Systematic Review and Meta-analysis 
Kidney international  2011;81(5):442-448.
Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk of CKD, ESRD and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8/100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks of developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0) and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) than patients without AKI. The relationship between AKI and CKD or ESRD was graded depending on the severity of AKI and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, and death and other important non-renal outcomes.
doi:10.1038/ki.2011.379
PMCID: PMC3788581  PMID: 22113526
19.  Long-term renal function, complications and life expectancy in living kidney donors 
Living kidney transplantation is now a widely accepted treatment for end stage renal disease (ESRD) because it provides excellent outcomes for recipients. However, long-term outcomes of living kidney donors have not been well understood. Because securing the safety of the donor is essential to the continued success of this procedure, we reviewed articles discussing long-term outcomes of living kidney donors. Most studies found no decrease in long-term survival or progressive renal dysfunction in previous kidney donors. Moreover, the prevalence of hypertension was comparable to that expected in the general population, although some did report otherwise. Urinary protein showed small increases in this population and was associated with hypertension and a lower glomerular filtration rate. Quality of life following living kidney donation seems to be better than the national norm. We also encountered several reports of ESRD in previous living kidney donors. Regular follow-up of kidney donors is recommended and future controlled, prospective studies will better delineate risk factors which cause health problems following living kidney donation.
doi:10.5500/wjt.v2.i1.5
PMCID: PMC3812927  PMID: 24175190
Living kidney donor; Long-term survival; Hypertension; Proteinuria; Renal function; Quality of life
20.  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
21.  Chronic Kidney Disease and the Risk of End-Stage Renal Disease versus Death 
ABSTRACT
BACKGROUND
Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.
OBJECTIVE
To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.
Design
The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.
PARTICIPANTS
1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.
MAIN MEASURES
The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.
KEY RESULTS
During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.
CONCLUSIONS
Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.
doi:10.1007/s11606-010-1511-x
PMCID: PMC3055978  PMID: 20853156
renal disease; cardiovascular disease; clinical epidemiology
22.  The Relationship between Health-Promoting Behaviors and Resilience in Patients with Chronic Kidney Disease 
The Scientific World Journal  2013;2013:124973.
This cross-sectional research study explored differences in health-promoting behavior and resilience among three groups of chronic kidney disease patients (high-risk, early chronic kidney disease; early CKD and pre-end stage renal disease; pre-ESRD) treated at the Nephrology outpatient clinic in northern Taiwan. A total of 150 CKD outpatients were interviewed using structured questionnaires including a CKD Health to Promote Lifestyle Scale, and resilience scale. We found that the pre-ESRD group had lower resilience than either high-risk or early CKD groups. Factors affecting pre-ESRD resilience were gender, occupational status, diabetes and health-promoting behaviors. Factors affecting resilience of the high-risk group included level of education and health-promoting behaviors while factors affecting resilience in the early CKD group involved whether they are employed and health promoting behaviors. A significant positive correlation was found between health promoting behavior and resilience in all study subjects. Multiple regression analysis found that factors which could effectively predict resilience in patients at high-risk for CKD were gender, whether the patient had a job, nutrition, self-actualization, and stress level, accounting for 69.7% of the variance. Therefore, nursing education should focus on health promotion advocacy throughout the life of not only patients but also their families.
doi:10.1155/2013/124973
PMCID: PMC3621294  PMID: 23589703
23.  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
24.  Prediction of ESRD and Death Among People With CKD: The Chronic Renal Impairment in Birmingham (CRIB) Prospective Cohort Study 
American Journal of Kidney Diseases  2010;56(6-2):1082-1094.
Background
Validated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD).
Study Design
Prospective cohort study with validation in a separate cohort.
Setting & Participants
Cox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort).
Factors
44 baseline characteristics (including 30 blood and urine assays).
Outcomes
ESRD and all-cause mortality.
Results
In the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death.
Limitations
Other important factors may have been missed because of limited study power.
Conclusions
Simple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.
doi:10.1053/j.ajkd.2010.07.016
PMCID: PMC2991589  PMID: 21035932
Chronic kidney disease; risk prediction; outcomes; death; end-stage renal disease
25.  Association Between Lack of Health Insurance and Risk of Death and ESRD: Results From the Kidney Early Evaluation Program (KEEP) 
Background
Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000–2011 data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) to examine this association.
Methods
The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables.
Results
Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 or urine albumin-creatinine ratio ≥30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56–2.12; P < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33–2.22; P < 0.001). The association between insurance and outcomes varied by CKD stage.
Conclusions
Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.
doi:10.1053/j.ajkd.2012.12.015
PMCID: PMC3739048  PMID: 23507267
Chronic kidney disease; end-stage renal disease; health insurance; mortality; public health

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