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Cited by 63Chronic Kidney Disease and DiabetesAcute Kidney Injury ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes

Open access
Frazier, Rebecca, Mehta, Rupal, Cai, Xuan, Lee, Jungwha, Napoli, Sara, Craven, Timothy, Tuazon, Jennifer, Safdi, Adam +3 more·2019·Kidney International Reports
DOI 10.1016/j.ekir.2018.09.006PMC PMC6308372
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Abstract

Introduction Abnormalities in lipid metabolism may contribute to the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR), but it may have protective effects on microvascular complications of diabetes. We hypothesized that randomization to fenofibrate versus placebo would be associated with beneficial long-term effects on kidney outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. Methods We conducted a post hoc analysis in the ACCORD Lipid Trial to examine the association of randomization to fenofibrate versus placebo with change in eGFR and with time-to-development of microalbuminuria, macroalbuminuria, CKD, and kidney failure. Results We analyzed 2636 participants in the fenofibrate arm and 2632 in the placebo arm. During a median follow-up of 4 years, treatment with fenofibrate was associated with lower rate of eGFR decline (−0.28 ml/min per 1.73 m 2 per year in the fenofibrate group vs. −1.25 ml/min per 1.73 m 2 per year in the placebo group, P < 0.01) and with lower incidence of microalbuminuria (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.43–0.72, P < 0.001) and macroalbuminuria (HR 0.72, 95% CI 0.57–0.91, P < 0.001). There was no difference in incidence of CKD (HR 0.92, 95% CI 0.74–1.15, P = 0.46) and/or kidney failure (HR 0.95, 95% CI 0.68–1.33, P = 0.76). Conclusion Compared with placebo, randomization to fenofibrate was associated with lower rates of incident albuminuria and a slower eGFR decline, but no difference in incidence of CKD or kidney failure in ACCORD participants.

AI snapshot

Written from the paper’s full text.

TL;DR

In a post hoc analysis of the ACCORD Lipid Trial, randomization to fenofibrate versus placebo was associated with slower eGFR decline and lower incidence of microalbuminuria and macroalbuminuria, but no difference in incident CKD or kidney failure. These hypothesis-generating findings suggest possible renoprotection despite fenofibrate’s early reversible eGFR reduction.

Key findings

  • Among 5268 participants (2636 fenofibrate, 2632 placebo), median follow-up 4 years, adjusted eGFR slope was −0.28 ml/min per 1.73 m² per year with fenofibrate versus −1.25 ml/min per 1.73 m² per year with placebo (P < 0.001).
  • Fenofibrate was associated with lower adjusted risk of incident microalbuminuria (HR 0.56, 95% CI 0.43–0.72, P < 0.001) and macroalbuminuria (HR 0.72, 95% CI 0.57–0.91; Table 3 P = 0.006; abstract reports P < 0.001).
  • There was no significant difference in incident CKD (HR 0.92, 95% CI 0.74–1.15, P = 0.46) or kidney failure (HR 0.95, 95% CI 0.68–1.33, P = 0.76).
  • In 2736 ACCORDION follow-on participants, mean eGFR at the first posttrial time point was modestly higher in the fenofibrate arm (77.4 ± 21.4 vs. 75.6 ± 21.8 ml/min per 1.73 m², P = 0.04), and similar at the second posttrial endpoint (75.4 ± 22.6 vs. 74.3 ± 22.0 ml/min per 1.73 m², P = 0.28).

Methods

  • Post hoc analysis of the ACCORD Lipid Trial; included 5268 participants with a month 4 eGFR (fenofibrate n = 2636, placebo n = 2632), analyzed by intention-to-treat.
  • Outcomes were longitudinal eGFR change from month 4 to end of follow-up and time to microalbuminuria (UACR ≥30 mg/g), macroalbuminuria (UACR ≥300 mg/g), incident CKD (new eGFR <60 ml/min per 1.73 m², ≥25% decrease from month 4 eGFR, or eGFR slope >1 ml/min per 1.73 m² per year), and kidney failure (dialysis, transplantation, or serum creatinine >3.3 mg/dl without reversible cause).
  • Linear mixed models estimated eGFR slope; Cox models estimated time-to-event outcomes with sequential adjustment models; exploratory analyses adjusted for time-varying lipids and examined ACCORDION follow-on data.

Limitations

  • Stated by authors: post hoc, hypothesis-generating analysis; short study duration and exclusion of patients with creatinine >1.5 mg/dl yielded few incident ESRD events, so fenofibrate’s effect on ESRD is unclear; most participants were middle-aged white males with mostly normal kidney function, limiting generalizability to minorities, younger populations, or those with advanced kidney dysfunction.
  • Evident from the text: no adjustment for multiple testing, and reported P values are nominal; incident outcome analyses had varying sample sizes because participants with the relevant baseline condition were excluded.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ekir.2018.09.006

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 36 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR).

    “Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR)”
    • Also stated in: § Conclusion · boosted
      “Data from the ACCORD trial previously demonstrated that fenofibrate induced early and reversible reduction in kidney function without significant differences in onset of ESRD.13, 14”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Mychaleckyj, 2012, Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants, Diabetes Care source
    • cites [14] Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med source

      The Results > Safety section (page not provided) reports that serum creatinine rose in the fenofibrate group within the first year and that more patients in that group stopped treatment because of decreased estimated GFR. This supports an early reduction in estimated GFR, but our copy does not report that the reduction was reversible. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Fenofibrate may have protective effects on microvascular complications of diabetes.

    “Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR), but it may have protective effects on microvascular complications of diabetes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Davis, 2011, Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, Diabetologia source
  • Premisecitation

    Dyslipidemia and abnormalities in renal lipid metabolism may predispose diabetic individuals to lipid accumulation in glomeruli and tubules.

    “Dyslipidemia and abnormalities in renal lipid metabolism may predispose diabetic individuals to lipid accumulation in glomeruli and tubules, which may lead to fibrosis and accelerated CKD progression.9, 10”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Chahil, 2006, Diabetic dyslipidemia, Endocrinol Metab Clin North Am source
    • cites [10] Stadler, 2015, The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease, Curr Diab Rep source
  • Premisecitation

    Fenofibrate is not associated with significant differences in onset of ESRD.

    “Data from the ACCORD trial previously demonstrated that fenofibrate induced early and reversible reduction in kidney function without significant differences in onset of ESRD.13, 14”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Mychaleckyj, 2012, Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants, Diabetes Care source

      The Results and Conclusions report changes in creatinine and estimated GFR, including their reversibility after fenofibrate was stopped, but do not report the onset of ESRD. Searches for ESRD, end-stage renal disease, kidney failure, and dialysis found no comparison of ESRD onset between treatment groups in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [14] Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med source
  • Premisecitation

    Lipid accumulation in glomeruli and tubules may lead to fibrosis and accelerated CKD progression.

    “Dyslipidemia and abnormalities in renal lipid metabolism may predispose diabetic individuals to lipid accumulation in glomeruli and tubules, which may lead to fibrosis and accelerated CKD progression.9, 10”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Chahil, 2006, Diabetic dyslipidemia, Endocrinol Metab Clin North Am source
    • cites [10] Stadler, 2015, The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease, Curr Diab Rep source

      The Introduction (page not provided) links lipid deposition in glomeruli and tubules with kidney injury, and the Abstract links defective fatty-acid utilization to fibrosis and CKD progression. But the ‘Lipid Accumulation—Lipotoxicity Versus Lipid Overload’ section reports that lipid accumulation alone did not cause fibrosis in a mouse model. The claim omits that distinction between lipid accumulation and harmful defects in lipid metabolism. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 23
  • May combine two claims. 17

  • Classified as probably not a substantial claim.

    Premisecitation

    Fenofibrate has beneficial effects on albuminuria and eGFR in the diabetic population.

    “and the finding of beneficial effects of fenofibrate on albuminuria and eGFR in the diabetic population.12”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Davis, 2011, Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, Diabetologia source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Use of statins is associated with modest preservation of eGFR.

    “In support of this hypothesis are data suggesting that use of statins is associated with modest preservation of eGFR,11”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Wheeler, 2004, Does lipid-lowering therapy slow progression of chronic kidney disease?, Am J Kidney Dis source

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies have suggested that high lipid levels and altered lipid metabolism in diabetic kidney disease may contribute to kidney function decline.

    “Previous studies have suggested that high lipid levels and altered lipid metabolism in diabetic kidney disease may contribute to kidney function decline.9, 10”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Chahil, 2006, Diabetic dyslipidemia, Endocrinol Metab Clin North Am source
    • cites [10] Stadler, 2015, The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease, Curr Diab Rep source

  • May combine two claims.

    Premisecitation

    Individuals with diabetes and CKD have high levels of circulating lipids that are filtered by the kidney and accumulate in tubular epithelial cells, which may lead to fibrosis and accelerated CKD progression.

    “Individuals with diabetes and CKD have high levels of circulating lipids that are filtered by the kidney and accumulate in tubular epithelial cells, which may lead to fibrosis and accelerated CKD progression.23, 24”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [23] Susztak, 2005, Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy, PLoS Med source

      The Results report that free fatty acid levels may be elevated in people with type 2 diabetes and that palmitic acid induced apoptosis in human proximal tubular cells. The Introduction and Discussion link tubular degeneration and interstitial fibrosis with progression of diabetic nephropathy. But the paper does not establish that circulating lipids are filtered by the kidney and accumulate in tubular cells, or that such accumulation causes fibrosis and accelerated progression. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] Ruggiero, 2014, Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis, Am J Physiol Renal Physiol source

      The Abstract (page unavailable) says that albumin can carry fatty acids to proximal tubules, that albumin becomes saturated with fatty acids in proteinuric diseases such as diabetes, and that these fatty acids may aggravate tubulointerstitial injury. It also links proteinuria with renal-disease progression and fibrosis. It does not establish that people with both diabetes and CKD generally have high circulating lipid levels, or that filtered lipids accumulate inside tubular epithelial cells and thereby accelerate CKD progression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other studies suggest that fenofibrate has anti-inflammatory effects with reduction of inflammatory cytokines, which may also have beneficial effects on the kidney.

    “Other studies suggest that fenofibrate has anti-inflammatory effects with reduction of inflammatory cytokines, which may also have beneficial effects on the kidney.27”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Han, 2005, Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators, Hypertension source

      The Effects on Inflammation section reports that fenofibrate lowered TNF-α levels and reduced IL-1β expression or release, supporting the claim about anti-inflammatory effects and cytokines. The Effects on Vasomotor Function section mentions renal tubules in connection with blood-pressure lowering, but the paper does not link cytokine reduction to a potential kidney benefit. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Fenofibrate may have renoprotective effects by affecting circulating lipid levels.

    “Fenofibrate may have renoprotective effects by affecting circulating lipid levels.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] Chahil, 2006, Diabetic dyslipidemia, Endocrinol Metab Clin North Am source
    • cites [10] Stadler, 2015, The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease, Curr Diab Rep source

      The Clinical Implications section reports reduced albuminuria with fenofibrate and a small benefit for GFR decline, supporting possible renoprotection. It does not establish that this benefit comes from changing circulating lipids: the reported GFR effect was independent of serum triglyceride levels and may reflect an intrarenal mechanism. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] Susztak, 2005, Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy, PLoS Med source

      The Results section (page unavailable) reports that a saturated free fatty acid induced apoptosis in human proximal tubular cells, providing a possible link between lipids and kidney injury. It does not examine fenofibrate, changes in circulating lipid levels, or renoprotection from treatment; the patient summary says the findings have no immediate clinical implications. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The FIELD study took place in Finland, New Zealand, and Australia, whereas the ACCORD study recruited participants from 77 North American centers.

    “Finally, the FIELD study took place in Finland, New Zealand, and Australia, whereas the ACCORD study recruited participants from 77 North American centers.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Davis, 2011, Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, Diabetologia source

      The Methods section (page not available in our copy) says FIELD recruited participants at 63 sites in Australia, New Zealand and Finland. The paper mentions ACCORD, but the passages found do not give its recruitment locations or a count of 77 centers; that part of the sentence is unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Experimental studies demonstrate that fenofibrate increases fatty acid oxidation and protects against renal fibrosis in animals.

    “Experimental studies support this hypothesis by demonstrating that fenofibrate increases fatty acid oxidation and protects against renal fibrosis in animals.10”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Stadler, 2015, The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease, Curr Diab Rep source

  • May combine two claims.

    Premisecitation

    The FIELD study showed that compared with placebo, use of fenofibrate led to a rise in serum creatinine in the short-term, but in the long-term it reduced eGFR decline and lowered albuminuria without impacting the rate of ESRD onset.

    “Similar to our analysis, the FIELD study showed that compared with placebo, use of fenofibrate led to a rise in serum creatinine in the short-term, but in the long-term it reduced eGFR decline and lowered albuminuria without impacting the rate of ESRD onset.”
    • Also stated in: § Discussion · plain
      “The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study previously showed beneficial effects of fenofibrate on kidney function.12”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Davis, 2011, Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, Diabetologia source

  • Classified as probably not a substantial claim. May combine two claims.

    Findingnone given

    Most patients in the ACCORD study were middle-aged white males with mostly normal kidney function.

    “In addition, most patients in the ACCORD study were middle-aged white males with mostly normal kidney function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among follow-on participants, there was an early steep decline in eGFR in the fenofibrate group, followed by more gradual decline in eGFR in both groups.

    “Consistent with the findings in the ACCORD Lipid Trial, among the follow-on participants, we observed an early steep decline in eGFR in the fenofibrate group, which was followed by more gradual decline in eGFR in both groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Discontinuation of fenofibrate resulted in reversal of eGFR decline, with mean eGFR at the first posttrial time point modestly higher in the fenofibrate arm than placebo (77.4 vs 75.6 ml/min per 1.73 m2, P=0.04).

    “Discontinuation of fenofibrate resulted in reversal of eGFR decline, such that mean eGFR at the first posttrial time point was modestly higher in the fenofibrate arm compared with the placebo arm (77.4 ± 21.4 ml/min per 1.73 m2 vs. 75.6 ± 21.8 ml/min per 1.73 m2, P = 0.04).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the ACCORD study, fenofibrate use was associated with improved albuminuria and reduced eGFR decline.

    “Our findings of improved albuminuria and reduced eGFR decline associated with fenofibrate use in the ACCORD study confirm the findings of the FIELD study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The macroalbuminuria analyses were adjusted for month 4 eGFR and microalbuminuria.

    “In the macroalbuminuria analyses, we adjusted for month 4 eGFR and microalbuminuria.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The linear mixed model for eGFR change (model 1) was adjusted for glycemia trial and network.

    “In model 1, we adjusted for glycemia trial and network.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The primary exposure, allocation to the fenofibrate arm, was analyzed in an intention-to-treat manner.

    “The primary exposure was allocation to the fenofibrate arm, which we analyzed in an intention-to-treat manner.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The kidney failure analyses were adjusted for month 4 eGFR, microalbuminuria, and macroalbuminuria.

    “In the kidney failure analyses, we adjusted for month 4 eGFR, microalbuminuria, and macroalbuminuria.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In additional exploratory analyses, the final models were further adjusted for time-varying total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein to test whether effects of fenofibrate were mediated by changes in lipid levels.

    “In additional exploratory analyses, to test whether the effects of fenofibrate were mediated by changes in lipid levels during follow-up, we further adjusted our final models for time-varying levels of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The linear mixed model for eGFR change (model 3) was adjusted for model 2 factors plus month 4 eGFR and baseline microalbuminuria and macroalbuminuria.

    “In model 3, we adjusted for factors in model 2 and for kidney-specific factors, including month 4 eGFR, and presence of microalbuminuria and macroalbuminuria at baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The proportional hazards assumption was met for kidney failure and development of macroalbuminuria.

    “The proportional hazards assumption was met for kidney failure, and development of macroalbuminuria, but it was violated for development of microalbuminuria.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A time-by-fenofibrate interaction term was included in the microalbuminuria models to accommodate non-proportional hazards.

    “To accommodate non–proportional hazards of development of microalbuminuria, we included time by fenofibrate interaction term in the microalbuminuria models.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    No adjustment for multiple testing was made because the objective was hypothesis-generating; reported P values are nominal.

    “Because the objective of our post hoc analysis study was to produce hypothesis-generating results, we did not adjust for multiple testing. Reported P values are of nominal significance and serve as guides for possible associations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The linear mixed model for eGFR change (model 4) was adjusted for model 3 factors plus baseline comorbidities and concomitant medications.

    “In model 4, we adjusted for factors in model 3 and baseline comorbidities and concomitant medications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The linear mixed model for eGFR change (model 2) was adjusted for model 1 factors plus age, gender, and race.

    “In model 2, we adjusted for factors in model 1 and for age, gender, and race.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The microalbuminuria and CKD analyses were adjusted for month 4 eGFR.

    “In the microalbuminuria and CKD analyses, the data were adjusted for month 4 eGFR.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The proportional hazards assumption was tested using the Schoenfeld residual for the effect of fenofibrate use.

    “We tested proportional hazards assumption using the Schoenfeld residual for the effect of fenofibrate use.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Cox models were adjusted for the same covariates as the linear mixed models, with exceptions for model 3.

    “We adjusted the Cox models for the same covariates we included in the linear mixed models with exceptions for model 3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The abnormal fatty acid levels create toxic byproducts that cause cell apoptosis, contributing to kidney failure.

    “The abnormal fatty acid levels create toxic byproducts that cause cell apoptosis, contributing to kidney failure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Son, 2010, PPARgamma-induced cardiolipotoxicity in mice is ameliorated by PPARalpha deficiency despite increases in fatty acid oxidation, J Clin Invest source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study assessed incident CKD, which was defined based on rigid criteria.

    “In addition, we were able to assess incident CKD, which we defined based on rigid criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings may not apply to minorities, younger populations, or those with advanced kidney dysfunction.

    “These findings may not apply to minorities, younger populations, or those with advanced kidney dysfunction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The investigators of the experimental study concluded that fenofibrate may attenuate diabetes-induced hyperfiltration by preventing the upregulation of renal cyclooxygenase-2 expression that accompanies diabetes.

    “The investigators concluded that fenofibrate may attenuate diabetes-induced hyperfiltration by preventing the upregulation of renal cyclooxygenase-2 expression that accompanies diabetes.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Chen, 2008, Fenofibrate treatment of diabetic rats reduces nitrosative stress, renal cyclooxygenase-2 expression, and enhanced renal prostaglandin release, J Pharmacol Exp Ther source

  • May combine two claims.

    Interpretationown data

    These findings suggest that fenofibrate may have renoprotective effects, despite causing early decline in eGFR.

    “These findings suggest that fenofibrate may have renoprotective effects, despite causing early decline in eGFR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The ACCORD study examined changes in eGFR after stopping fenofibrate over a 4-year follow-up period, which was longer than the 1-year follow-up after fenofibrate washout in the FIELD study.

    “In addition, we were able to examine changes in eGFR after stopping fenofibrate over a 4-year follow-up period, which was longer than the 1-year follow-up after fenofibrate washout in the FIELD study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with diabetic kidney disease have altered activity of lipid-metabolizing enzymes, which may lead to a reduction in fatty acid metabolism.

    “Patients with diabetic kidney disease have altered activity of lipid-metabolizing enzymes, which may lead to a reduction in fatty acid metabolism.25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Son, 2010, PPARgamma-induced cardiolipotoxicity in mice is ameliorated by PPARalpha deficiency despite increases in fatty acid oxidation, J Clin Invest source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Fenofibrate may be a tool to help reduce diabetic complications in a vulnerable population.

    “Fenofibrate may be a tool to help reduce diabetic complications in a vulnerable population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study is a post hoc analysis of the ACCORD Lipid Trial, and thus the results are hypothesis-generating.

    “It is a post hoc analysis of the ACCORD Lipid Trial, and thus our results are hypothesis-generating.”
    Quote in the paperSubstantial claim
36 of 36

  • The paper relies on this without support.

    The long-term effects of fenofibrate on development and progression of CKD in ACCORD participants have not been examined in detail in dedicated studies.

    “The long-term effects of fenofibrate on development and progression of CKD in ACCORD participants have not been examined in detail in dedicated studies.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Macroalbuminuria P value differs between the abstract and Table 3

    Minor

    The abstract reports P < 0.001 for the adjusted macroalbuminuria result, whereas Table 3 reports P = 0.006 for the same hazard ratio and confidence interval.

1 of 1

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Authors
Frazier, R., Mehta, R., Cai, X., Lee, J., Napoli, S., Craven, T., Tuazon, J., Safdi, A., Scialla, J., Susztak, K., & Isakova, T.
Affiliations
  • Northwestern University (US)
  • Wake Forest University Health Sciences (US)
  • Duke University (US)
Corresponding author
Isakova, Tamara
ORCID
Venue
Kidney International Reports
Publisher
Elsevier BV
Published
2019-01
Volume
4
Issue
1
Pages
94-102
ISSN
2468-0249 (ISSN-L)
DOI
10.1016/j.ekir.2018.09.006
PMC
PMC6308372
OpenAlex
W2889812284
Semantic Scholar
21af558f51b43ddf53bed87c4cebb23352bb2ab5
Cited by
63
References
31
Citations by year
2026: 4 · 2025: 14 · 2024: 9 · 2023: 10 · 2022: 10 · 2021: 8 · 2020: 6 · 2018: 1
FWCI
2.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Kidney International Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
fenofibrate, chronic kidney disease, type 2 diabetes, estimated glomerular filtration rate decline, albuminuria, microalbuminuria, macroalbuminuria, renal failure, lipid-lowering therapy, cardiovascular risk reduction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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