Can Existing Drugs Approved for Other Indications Retard Renal Function Decline in Patients With Type 1 Diabetes and Nephropathy?

Doria, Alessandro; Niewczas, Monika A.; Fiorina, Paolo

doi:10.1016/j.semnephrol.2012.07.006

Cited by 28 publications

(19 citation statements)

References 72 publications

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“…1,2,22 Despite the extensive use of angiotensin-converting enzyme inhibitors and renin-angiotensin system blockers and the overall improvement in glycemic and BP control therapies, the burden of DN has not declined and DN remains a primary cause of ESRD onset. 23,24 Several of the recently tested approaches have failed to provide clear benefits, [25][26][27][28][29] whereas others have offered such a narrow therapeutic window 30 that the pursuit for novel therapeutic approaches is necessary.…”

Section: Discussionmentioning

confidence: 99%

Role of Podocyte B7-1 in Diabetic Nephropathy

Fiorina

Vergani

Bassi

et al. 2014

Journal of the American Society of Nephrology

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119

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Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase-dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Role of Podocyte B7-1 in Diabetic Nephropathy

Fiorina

Vergani

Bassi

et al. 2014

Journal of the American Society of Nephrology

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119

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“…Yet, studies of the clinical utility of sTNFR measurements and how to best intervene in individuals with elevated sTNFRs are scarce. Interestingly, CKD progression and kidney function decline have been shown to be inhibited with recombinant antibodies against TNF-α [32,33,34], and micro-albuminuria has been shown to be reduced in rats treated with TNF-α inhibitors [35]. The TNF-α inhibitors have been suggested to be safe in patients with acute kidney failure treated for rheumatoid arthritis [36]; yet, we warrant clinical studies in humans to elucidate if anti-TNF therapy can also halt CKD progression and micro-albuminuria, and if levels of sTNFR1 can be used to monitor these effects.…”

Section: Discussionmentioning

confidence: 99%

Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals

Carlsson

Nordquist²,

Larsson

et al. 2015

Cardiorenal Med

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Objective: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes. Research Design and Methods: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as ≥60, 30-60, and <30 ml/min/1.73 m². Results: In longitudinal multivariable logistic regression models adjusted for inflammatory markers and established cardiovascular risk factors, higher serum sTNFR1 was significantly associated with an increased risk to progress to a lower GFR category in both ULSAM and PIVUS [odds ratio (OR) per standard deviation (SD) increase 1.28 (95% CI 1.03-1.60) and OR 1.56 (95% CI 1.30-1.87), respectively]. Also, in subgroup analyses in individuals with a GFR ≥60 ml/min/1.73 m² at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes. Conclusions: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings.

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“…25 Recombinant antibodies against TNF-a and sTNFR have been suggested as potential drugs that may halt decline in kidney function. 26 In fact, studies have demonstrated that progression of CKD can be inhibited by anti-TNF therapy. 27,28 Additional clinical studies are warranted to elucidate whether anti-TNF therapy can halt GFR decline and microalbuminuria in patients with rapid nephropathy and high circulating levels of sTNFRs.…”

Section: Discussionmentioning

confidence: 99%

Soluble TNF Receptors and Kidney Dysfunction in the Elderly

Carlsson

Larsson

Helmersson‐Karlqvist

et al. 2014

Journal of the American Society of Nephrology

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The importance of TNF-a and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent communitybased cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=20.52 for estimated GFR, R=0.22 for urinary albuminto-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P,0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P,0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.

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Can Existing Drugs Approved for Other Indications Retard Renal Function Decline in Patients With Type 1 Diabetes and Nephropathy?

Cited by 28 publications

References 72 publications

Role of Podocyte B7-1 in Diabetic Nephropathy

Role of Podocyte B7-1 in Diabetic Nephropathy

Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals

Soluble TNF Receptors and Kidney Dysfunction in the Elderly

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