Background/Objectives: Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth... more Background/Objectives: Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth factor 23 (FGF23) is elevated in CKD and associated with frailty among non-CKD older adults and individuals with human immunodeficiency virus. Whether FGF23 is associated with frailty and falls in CKD is unknown.
Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of t... more Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. Methods: We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. Results: A total of 3,361 CRIC participants had plasma available for analysis at year 1. The me...
This study assessed the potential role of differential diuretic drugs in preventing incident acut... more This study assessed the potential role of differential diuretic drugs in preventing incident acute decompensated heart failure (ADHF) in the SPRINT (Systolic Blood Pressure Intervention Trial) study. BACKGROUND SPRINT showed that intensive blood pressure reduction in older patients (50 to 97 years of age) resulted in 36% fewer incident cases of ADHF. However, some investigators have questioned whether this was due merely to intergroup differences in diuretic medications. METHODS Detailed use of medication data prospectively collected throughout the trial were examined. RESULTS ADHF events occurred in 173 of 9,361 participants. Diuretic medication increased in both arms from screening to baseline visit (from 45% to 50% in the standard arm; and from 43% to 63% in the intensive arm) and then remained steady. The lowest use of diuretic agents was among participants in the standard arm who never had an ADHF event. Withdrawal of diuretic agents at the baseline visit occurred in 6.1% (n ¼ 284) of participants in the standard arm and 2.3% (n ¼ 107) of participants in the intensive arm. Of these, only 11 developed ADHF during the trial (10 in the standard arm, 1 in the intensive arm), and only 1 occurred #1 month after diuretic withdrawal. The benefit of ADHF reduction remained significant even after excluding those 11 participants (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.5 to 0.94; p ¼ 0.02). Most ADHF events occurred in participants who were taking prescribed diuretic therapy at the last visit, prior to the ADHF event. There was limited use of loop (<6%) and potassium-sparing diuretic agents (2%).
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aims: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and m... more Aims: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and may contribute to kidney function decline, but evidence is inconsistent. We hypothesized that greater baseline arterial stiffness (assessed as pulse pressure (PP) and carotid-femoral pulsewave velocity CFPWV)) was independently associated with kidney disease progression over the follow-up period (3.8 years) in the Systolic Blood Pressure Intervention Trial (SPRINT). Materials and methods: 8,815 SPRINT participants were included in the analysis of PP. 592 adults who participated in a SPRINT ancillary study that measured CFPWV were included in subgroup analyses. Cox proportional hazards analysis was used to examine the association between PP and time to kidney disease progression endpoints: (A) incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2 in non-CKD participants at baseline; (B) 50% decline in eGFR, initiation of dialysis, or transplant in those with baseline CKD. Mixed model analyses examined the association of baseline PP/CFPWV with follow-up eGFR. Results and conclusion: Mean ± SD age was 68 ± 10 years, baseline PP was 62 ± 14 mmHg, and CFPWV was 10.8 ± 2.7 m/s. In the fully adjusted model, PP ≥ median was associated with an increased hazard of kidney disease progression endpoints (HR: 1.93 (1.43-2.61)). The association remained significant in individuals without (2.05 (1.47-2.87)) but not with baseline CKD (1.28 (0.55-2.65)). In fully adjusted models, higher baseline PP associated with eGFR decline (p < 0.0001 (all, CKD, non-CKD)), but baseline CFPWV did not. Among older adults at high risk for cardiovascular events, baseline PP was associated with kidney disease progression.
It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an... more It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an older population with greater cardiovascular risk, including those with chronic kidney disease. The authors investigated the association between MetS and AF in participants in SPRINT (Systolic Blood Pressure Intervention Trial). MetS was defined based on the Modified Third National Cholesterol Education Program. The baseline prevalence rate for MetS was 55%, while 8.2% of the participants had AF. In multivariate regression analyses, AF was not associated with presence of MetS in either chronic kidney disease or non-chronic kidney disease subgroups. Age, race, history of cardiovascular diseases, decreased triglycerides, decreased pulse pressure, and albuminuria remained significantly associated with AF risk. In contrast to the general population, MetS was not associated with AF in the older population with increased cardiovascular risk studied in SPRINT. | 1153 CHO et al.
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2015
Plant protein intake is associated with lower production of uremic toxins and lower serum phospho... more Plant protein intake is associated with lower production of uremic toxins and lower serum phosphorus levels. Therefore, at a given total protein intake, a higher proportion of dietary protein from plant sources might be associated with lower mortality in chronic kidney disease. Observational study. 14,866 NHANES III participants 20 years or older without missing data for plant and animal protein intake and mortality. Plant protein to total protein ratio and total plant protein intake. Patients were stratified by estimated glomerular filtration rate (eGFR)<60 or ≥60mL/min/1.73m(2). All-cause mortality. Plant and total protein intakes were estimated from 24-hour dietary recalls. Mortality was ascertained by probabilistic linkage with National Death Index records through December 31, 2000. Mean values for plant protein intake and plant protein to total protein ratio were 24.6±13.2 (SD) g/d and 33.0% ± 14.0%, respectively. The prevalence of eGFRs<60mL/min/1.73m(2) was 4.9%. There ...
Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is cau... more Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, alpha-galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and su...
The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of Afr... more The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR ¼ 5.0, 95% CI ¼ 3.5-7.1; P ¼ 4 Â 10 À23 , n ¼ 852). This association extended to hypertensive ESKD (OR ¼ 2.2, 95% CI ¼ 1.5-3.4; n ¼ 433), but not type 2 diabetic ESKD (n ¼ 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.
Journal of the American Society of Nephrology, 2011
Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, bu... more Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
Journal of the American Society of Nephrology, 2007
Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial a... more Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3Ј untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR ϭ 4.9, P ϭ 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR ϭ 0.5, P ϭ 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
Importance of the field-Many chronic diseases of various etiologies universally lead to fibrosis ... more Importance of the field-Many chronic diseases of various etiologies universally lead to fibrosis and organ dysfunction. Despite many advances in medicine in recent years, options to slow the progression of fibrotic diseases have remained limited. The recent availability of pirfenidone, an anti-fibrotic and anti-inflammatory investigational agent, thus offers a new hope for treating progressive fibrotic diseases. Areas covered in this review-This review provides concise review of the available data regarding mechanism and pharmacokinetics of pirfenidone and preclinical and clinical data regarding efficacy and safety in fibrotic diseases of the kidney. It also reviews results of clinical trials involving pirfenidone in other fibrotic diseases. What the reader will gain-The review will provide in-depth review of pirfenidone with a renal focus. Take home message-Because many of the available clinical trials have been small and/or uncontrolled, conclusive evidence regarding efficacy and safety of pirfenidone is lacking, particularly in patients with renal or hepatic dysfunction. Larger studies are needed both to better understand long-term efficacy and safety of this medication in various patient populations.
Clinical Journal of the American Society of Nephrology, 2007
Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown b... more Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis. Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m 2 , was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment. Results: The monthly change in GFR improved from a median of ؊0.61 ml/min per 1.73 m 2 (interquartile range ؊1.31 to ؊0.41) during the baseline period to ؊0.45 ml/min per 1.73 m 2 (interquartile range ؊0.78 to ؊0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis. Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.
Rationale and Objectives-To develop and validate an automated method to segment renal cortex on c... more Rationale and Objectives-To develop and validate an automated method to segment renal cortex on contrast-enhanced abdominal CT images from kidney donors, and to track the cortex volume change after donation. Materials and Methods-A 3D fully automated renal cortex segmentation method was developed and validated on 37 arterial phase CT data sets (27 patients, 10 of them had two CT scans before and after nephrectomy) using leave-one-out strategy. Two expert interpreters manually segmented the cortex slice-by-slice, the linear regression analysis and Bland-Altman plots were used to compare the automated and manual segmentations. The true positive and false positive volume fractions were also calculated to evaluate the accuracy of the proposed method. Volume changes of cortex for 10 subjects were also calculated. Results-The linear regression analysis results showed Auto and manual methods had strong correlations with Pearson correlation value of 0.9529, 0.9309, 0.9283 and 0.9124 between intraobserver variations, inter-observer variations, Auto and User1, and Auto and User2, respectively (p<0.001 for all the analysis). The Bland-Altman plots for cortex segmentation also showed Auto and manual methods had agreeable segmentation. The mean volume increase of the cortex for the 10 subjects was 35.1%±13.2% (p<0.01 by paired t-test). The overall true positive and false positive volume fractions for cortex segmentation were 90.15 ± 3.11% and 0.85 ± 0.05%. With the proposed automatic method, the time for cortex segmentation was reduced from 20 minutes of manual segmentation time to 2 minutes. Conclusions-The proposed method was accurate and efficient and can replace the current subjective and time-consuming manual procedure. The computer measurement confirms the volume of renal cortex increases after kidney donation.
Background/Objectives: Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth... more Background/Objectives: Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth factor 23 (FGF23) is elevated in CKD and associated with frailty among non-CKD older adults and individuals with human immunodeficiency virus. Whether FGF23 is associated with frailty and falls in CKD is unknown.
Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of t... more Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. Methods: We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. Results: A total of 3,361 CRIC participants had plasma available for analysis at year 1. The me...
This study assessed the potential role of differential diuretic drugs in preventing incident acut... more This study assessed the potential role of differential diuretic drugs in preventing incident acute decompensated heart failure (ADHF) in the SPRINT (Systolic Blood Pressure Intervention Trial) study. BACKGROUND SPRINT showed that intensive blood pressure reduction in older patients (50 to 97 years of age) resulted in 36% fewer incident cases of ADHF. However, some investigators have questioned whether this was due merely to intergroup differences in diuretic medications. METHODS Detailed use of medication data prospectively collected throughout the trial were examined. RESULTS ADHF events occurred in 173 of 9,361 participants. Diuretic medication increased in both arms from screening to baseline visit (from 45% to 50% in the standard arm; and from 43% to 63% in the intensive arm) and then remained steady. The lowest use of diuretic agents was among participants in the standard arm who never had an ADHF event. Withdrawal of diuretic agents at the baseline visit occurred in 6.1% (n ¼ 284) of participants in the standard arm and 2.3% (n ¼ 107) of participants in the intensive arm. Of these, only 11 developed ADHF during the trial (10 in the standard arm, 1 in the intensive arm), and only 1 occurred #1 month after diuretic withdrawal. The benefit of ADHF reduction remained significant even after excluding those 11 participants (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.5 to 0.94; p ¼ 0.02). Most ADHF events occurred in participants who were taking prescribed diuretic therapy at the last visit, prior to the ADHF event. There was limited use of loop (<6%) and potassium-sparing diuretic agents (2%).
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aims: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and m... more Aims: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and may contribute to kidney function decline, but evidence is inconsistent. We hypothesized that greater baseline arterial stiffness (assessed as pulse pressure (PP) and carotid-femoral pulsewave velocity CFPWV)) was independently associated with kidney disease progression over the follow-up period (3.8 years) in the Systolic Blood Pressure Intervention Trial (SPRINT). Materials and methods: 8,815 SPRINT participants were included in the analysis of PP. 592 adults who participated in a SPRINT ancillary study that measured CFPWV were included in subgroup analyses. Cox proportional hazards analysis was used to examine the association between PP and time to kidney disease progression endpoints: (A) incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2 in non-CKD participants at baseline; (B) 50% decline in eGFR, initiation of dialysis, or transplant in those with baseline CKD. Mixed model analyses examined the association of baseline PP/CFPWV with follow-up eGFR. Results and conclusion: Mean ± SD age was 68 ± 10 years, baseline PP was 62 ± 14 mmHg, and CFPWV was 10.8 ± 2.7 m/s. In the fully adjusted model, PP ≥ median was associated with an increased hazard of kidney disease progression endpoints (HR: 1.93 (1.43-2.61)). The association remained significant in individuals without (2.05 (1.47-2.87)) but not with baseline CKD (1.28 (0.55-2.65)). In fully adjusted models, higher baseline PP associated with eGFR decline (p < 0.0001 (all, CKD, non-CKD)), but baseline CFPWV did not. Among older adults at high risk for cardiovascular events, baseline PP was associated with kidney disease progression.
It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an... more It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an older population with greater cardiovascular risk, including those with chronic kidney disease. The authors investigated the association between MetS and AF in participants in SPRINT (Systolic Blood Pressure Intervention Trial). MetS was defined based on the Modified Third National Cholesterol Education Program. The baseline prevalence rate for MetS was 55%, while 8.2% of the participants had AF. In multivariate regression analyses, AF was not associated with presence of MetS in either chronic kidney disease or non-chronic kidney disease subgroups. Age, race, history of cardiovascular diseases, decreased triglycerides, decreased pulse pressure, and albuminuria remained significantly associated with AF risk. In contrast to the general population, MetS was not associated with AF in the older population with increased cardiovascular risk studied in SPRINT. | 1153 CHO et al.
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2015
Plant protein intake is associated with lower production of uremic toxins and lower serum phospho... more Plant protein intake is associated with lower production of uremic toxins and lower serum phosphorus levels. Therefore, at a given total protein intake, a higher proportion of dietary protein from plant sources might be associated with lower mortality in chronic kidney disease. Observational study. 14,866 NHANES III participants 20 years or older without missing data for plant and animal protein intake and mortality. Plant protein to total protein ratio and total plant protein intake. Patients were stratified by estimated glomerular filtration rate (eGFR)<60 or ≥60mL/min/1.73m(2). All-cause mortality. Plant and total protein intakes were estimated from 24-hour dietary recalls. Mortality was ascertained by probabilistic linkage with National Death Index records through December 31, 2000. Mean values for plant protein intake and plant protein to total protein ratio were 24.6±13.2 (SD) g/d and 33.0% ± 14.0%, respectively. The prevalence of eGFRs<60mL/min/1.73m(2) was 4.9%. There ...
Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is cau... more Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, alpha-galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and su...
The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of Afr... more The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR ¼ 5.0, 95% CI ¼ 3.5-7.1; P ¼ 4 Â 10 À23 , n ¼ 852). This association extended to hypertensive ESKD (OR ¼ 2.2, 95% CI ¼ 1.5-3.4; n ¼ 433), but not type 2 diabetic ESKD (n ¼ 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.
Journal of the American Society of Nephrology, 2011
Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, bu... more Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
Journal of the American Society of Nephrology, 2007
Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial a... more Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3Ј untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR ϭ 4.9, P ϭ 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR ϭ 0.5, P ϭ 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
Importance of the field-Many chronic diseases of various etiologies universally lead to fibrosis ... more Importance of the field-Many chronic diseases of various etiologies universally lead to fibrosis and organ dysfunction. Despite many advances in medicine in recent years, options to slow the progression of fibrotic diseases have remained limited. The recent availability of pirfenidone, an anti-fibrotic and anti-inflammatory investigational agent, thus offers a new hope for treating progressive fibrotic diseases. Areas covered in this review-This review provides concise review of the available data regarding mechanism and pharmacokinetics of pirfenidone and preclinical and clinical data regarding efficacy and safety in fibrotic diseases of the kidney. It also reviews results of clinical trials involving pirfenidone in other fibrotic diseases. What the reader will gain-The review will provide in-depth review of pirfenidone with a renal focus. Take home message-Because many of the available clinical trials have been small and/or uncontrolled, conclusive evidence regarding efficacy and safety of pirfenidone is lacking, particularly in patients with renal or hepatic dysfunction. Larger studies are needed both to better understand long-term efficacy and safety of this medication in various patient populations.
Clinical Journal of the American Society of Nephrology, 2007
Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown b... more Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis. Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m 2 , was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment. Results: The monthly change in GFR improved from a median of ؊0.61 ml/min per 1.73 m 2 (interquartile range ؊1.31 to ؊0.41) during the baseline period to ؊0.45 ml/min per 1.73 m 2 (interquartile range ؊0.78 to ؊0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis. Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.
Rationale and Objectives-To develop and validate an automated method to segment renal cortex on c... more Rationale and Objectives-To develop and validate an automated method to segment renal cortex on contrast-enhanced abdominal CT images from kidney donors, and to track the cortex volume change after donation. Materials and Methods-A 3D fully automated renal cortex segmentation method was developed and validated on 37 arterial phase CT data sets (27 patients, 10 of them had two CT scans before and after nephrectomy) using leave-one-out strategy. Two expert interpreters manually segmented the cortex slice-by-slice, the linear regression analysis and Bland-Altman plots were used to compare the automated and manual segmentations. The true positive and false positive volume fractions were also calculated to evaluate the accuracy of the proposed method. Volume changes of cortex for 10 subjects were also calculated. Results-The linear regression analysis results showed Auto and manual methods had strong correlations with Pearson correlation value of 0.9529, 0.9309, 0.9283 and 0.9124 between intraobserver variations, inter-observer variations, Auto and User1, and Auto and User2, respectively (p<0.001 for all the analysis). The Bland-Altman plots for cortex segmentation also showed Auto and manual methods had agreeable segmentation. The mean volume increase of the cortex for the 10 subjects was 35.1%±13.2% (p<0.01 by paired t-test). The overall true positive and false positive volume fractions for cortex segmentation were 90.15 ± 3.11% and 0.85 ± 0.05%. With the proposed automatic method, the time for cortex segmentation was reduced from 20 minutes of manual segmentation time to 2 minutes. Conclusions-The proposed method was accurate and efficient and can replace the current subjective and time-consuming manual procedure. The computer measurement confirms the volume of renal cortex increases after kidney donation.
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