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The Cochrane Database of Systematic... Jan 2023Diabetic kidney disease (DKD) continues to be the leading cause of kidney failure across the world. For decades dietary protein restriction has been proposed for... (Review)
Review
BACKGROUND
Diabetic kidney disease (DKD) continues to be the leading cause of kidney failure across the world. For decades dietary protein restriction has been proposed for patients with DKD with the aim to retard the progression of chronic kidney disease (CKD) towards kidney failure. However, the relative benefits and harms of dietary protein restriction for slowing the progression of DKD have not been addressed.
OBJECTIVES
To determine the efficacy and safety of low protein diets (LPD) (0.6 to 0.8 g/kg/day) in preventing the progression of CKD towards kidney failure and in reducing the incidence of kidney failure and death (any cause) in adult patients with DKD. Moreover, the effect of LPD on adverse events (e.g. malnutrition, hyperglycaemic events, or health-related quality of life (HRQoL)) and compliance were also evaluated.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) or quasi-RCTs in which adults with DKD not on dialysis were randomised to receive either a LPD (0.6 to 0.8 g/kg/day) or a usual or unrestricted protein diet (UPD) (≥ 1.0 g/kg/day) for at least 12 months.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. Summary estimates of effect were obtained using a random-effects model. Results were summarised as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised MD (SMD) with 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
We identified eight studies involving 486 participants with DKD. The prescribed protein intake in the intervention groups ranged from 0.6 to 0.8 g/kg/day. The prescribed protein intake in the control groups was ≥ 1.0 g/kg/day, or a calculated protein intake ≥ 1.0 g/kg/day if data on prescribed protein intake were not provided. The mean duration of the interventions was two years (ranging from one to five years). Risks of bias in most of the included studies were high or unclear, most notably for allocation concealment, performance and detection bias. All studies were considered to be at high risk for performance bias due to the nature of the interventions. Most studies were not designed to examine death or kidney failure. In low certainty evidence, a LPD may have little or no effect on death (5 studies, 358 participants: RR 0.38, 95% CI 0.10 to 1.44; I² = 0%), and the number of participants who reached kidney failure (4 studies, 287 participants: RR 1.16, 95% CI 0.38 to 3.59; I² = 0%). Compared to a usual or unrestricted protein intake, it remains uncertain whether a LPD slows the decline of glomerular filtration rate over time (7 studies, 367 participants: MD -0.73 mL/min/1.73 m²/year, 95% CI -2.3 to 0.83; I² = 53%; very low certainty evidence). It is also uncertain whether the restriction of dietary protein intake impacts on the annual decline in creatinine clearance (3 studies, 203 participants: MD -2.39 mL/min/year, 95% CI -5.87 to 1.08; I² = 53%). There was only one study reporting 24-hour urinary protein excretion. In very low certainty evidence, a LPD had uncertain effects on the annual change in proteinuria (1 study, 80 participants: MD 0.90 g/24 hours, 95% CI 0.49 to 1.31). There was no evidence of malnutrition in seven studies, while one study noted this condition in the LPD group. Participant compliance with a LPD was unsatisfactory in nearly half of the studies. One study reported LPD had no effect on HRQoL. No studies reported hyperglycaemic events.
AUTHORS' CONCLUSIONS
Dietary protein restriction has uncertain effects on changes in kidney function over time. However, it may make little difference to the risk of death and kidney failure. Questions remain about protein intake levels and compliance with protein-restricted diets. There are limited data on HRQoL and adverse effects such as nutritional measures and hyperglycaemic events. Large-scale pragmatic RCTs with sufficient follow-up are required for different stages of CKD.
Topics: Adult; Humans; Kidney Failure, Chronic; Diet, Protein-Restricted; Diabetic Nephropathies; Renal Insufficiency, Chronic; Malnutrition; Hyperglycemia; Diabetes Mellitus; Randomized Controlled Trials as Topic
PubMed: 36594428
DOI: 10.1002/14651858.CD014906.pub2 -
Endocrinology, Diabetes & Metabolism Jan 2021With increasing numbers of patients with type 2 diabetes mellitus (T2DM) worldwide, the number of associated diabetic foot complications might also increase. This...
AIMS
With increasing numbers of patients with type 2 diabetes mellitus (T2DM) worldwide, the number of associated diabetic foot complications might also increase. This systematic review was performed to summarize published data about risk factors for the diabetic foot (DF) syndrome in order to improve the identification of high-risk patients.
MATERIALS AND METHODS
Six electronic databases were searched for publications up to August 2019 using predefined stringent inclusion and exclusion criteria.
RESULTS
Of 9,476 identified articles, 31 articles from 28 different study populations fulfilled the criteria for our evaluation. The overall quality of the studies was good, and the risk of bias was low. There was large heterogeneity among the studies concerning study protocols and patient populations analysed. A total of 79 risk factors were analysed within this review. The majority of studies described a consistently positive association with different outcomes of interest related to DF for gender, peripheral neuropathy, retinopathy, nephropathy, poor glycaemic control, insulin use, duration of diabetes, smoking and height. For age, hypertension, dyslipidaemia and body mass index, the results remain inconsistent.
CONCLUSION
A most up-to-date literature review resulted in glycaemic control and smoking as the only amenable risk factors with a consistently positive association for DF. Due to the high personal and financial burden associated with DF and the large heterogeneity among included studies, additional longitudinal studies in large patient populations are necessary to identify more modifiable risk factors that can be used in the prediction and prevention of DF complications.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Glycemic Control; Humans; Male; Middle Aged; Risk Factors; Sex Factors; Smoking; Young Adult
PubMed: 33532615
DOI: 10.1002/edm2.175 -
BMJ (Clinical Research Ed.) Sep 2021To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
OBJECTIVES
To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
DESIGN
Systematic review and external validation.
DATA SOURCES
PubMed and Embase.
ELIGIBILITY CRITERIA
Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes.
METHODS
Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell's C statistic).
RESULTS
41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons.
CONCLUSIONS
This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020192831.
Topics: Aged; Albuminuria; Calibration; Clinical Decision Rules; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Prognosis; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Assessment; Risk Factors
PubMed: 34583929
DOI: 10.1136/bmj.n2134 -
The Cochrane Database of Systematic... Aug 2022Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to cardiovascular (CV) disease and infection. Established treatments include erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions. Oral hypoxia-inducible factors (HIF) stabilisers are now available to manage anaemia in people with CKD.
OBJECTIVES
We aimed to assess the benefits and potential harms of HIF stabilisers for the management of anaemia in people with CKD.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 22 November 2021 through contact with the Information Specialist using search terms relevant to our review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised and quasi-randomised studies evaluating hypoxia-inducible factors stabilisers compared to placebo, standard care, ESAs or iron supplementation in people with CKD were included.
DATA COLLECTION AND ANALYSIS
Five authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects pair-wise meta-analysis and expressed as a relative risk (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Evidence certainty was assessed using GRADE.
MAIN RESULTS
We included 51 studies randomising 30,994 adults. These studies compared HIF stabilisers to either placebo or an ESA. Compared to placebo, HIF stabiliser therapy had uncertain effects on CV death (10 studies, 1114 participants): RR 3.68, 95% CI 0.19 to 70.21; very low certainty evidence), and nonfatal myocardial infarction (MI) (3 studies, 822 participants): RR 1.29, 95% CI 0.31 to 5.36; I² = 0%; very low certainty evidence), probably decreases the proportion of patients requiring blood transfusion (8 studies, 4329 participants): RR 0.51, 95% CI 0.44 to 0.60; I² = 0%; moderate certainty evidence), and increases the proportion of patients reaching the target haemoglobin (Hb) (10 studies, 5102 participants): RR 8.36, 95% CI 6.42 to 10.89; I² = 37%; moderate certainty evidence). Compared to ESAs, HIF stabiliser therapy may make little or no difference to CV death (17 studies, 10,340 participants): RR 1.05, 95% CI 0.88 to 1.26; I² = 0%; low certainty evidence), nonfatal MI (7 studies, 7765 participants): RR 0.91, 95% CI 0.76 to 1.10; I² = 0%; low certainty evidence), and nonfatal stroke (5 studies, 7285 participants): RR 1.06, 95% CI 0.71 to 1.56; I² = 8%; low certainty evidence), and had uncertain effects on fatigue (2 studies, 3471 participants): RR 0.80, 95% CI 0.56 to 1.16; I² = 0%; very low certainty evidence). HIF stabiliser therapy probably decreased the proportion of patients requiring blood transfusion (11 studies, 10,786 participants): RR 0.87, 95% CI 0.76 to 1.00; I² = 25%; moderate certainty evidence), but may make little or no difference on the proportion of patients reaching the target Hb (14 studies, 4601 participants): RR 1.00, 95% CI 0.93 to 1.07; I² = 70%; low certainty evidence), compared to ESA. The effect of HIF stabilisers on hospitalisation for heart failure, peripheral arterial events, loss of unassisted dialysis vascular access patency, access intervention, cancer, infection, pulmonary hypertension and diabetic nephropathy was uncertain. None of the included studies reported life participation. Adverse events were rarely and inconsistently reported.
AUTHORS' CONCLUSIONS
HIF stabiliser management of anaemia had uncertain effects on CV death, fatigue, death (any cause), CV outcomes, and kidney failure compared to placebo or ESAs. Compared to placebo or ESAs, HIF stabiliser management of anaemia probably decreased the proportion of patients requiring blood transfusions, and probably increased the proportion of patients reaching the target Hb when compared to placebo.
Topics: Adult; Anemia; Cardiovascular Diseases; Cause of Death; Fatigue; Humans; Hypoxia; Iron; Renal Insufficiency, Chronic
PubMed: 36005278
DOI: 10.1002/14651858.CD013751.pub2 -
Renal Failure Dec 2022The role of probiotics in the management of diabetic kidney disease (DKD) has been shown. Several current trials are investigating the effect of probiotics, which are... (Meta-Analysis)
Meta-Analysis
AIMS
The role of probiotics in the management of diabetic kidney disease (DKD) has been shown. Several current trials are investigating the effect of probiotics, which are widely used to modulate biomarkers of renal function, glucose, lipids, inflammation and oxidative stress in patients with DKD. However, their findings are controversial. This study aimed to systematically evaluate the impact of probiotics on patients with DKD meta-analysis.
METHODS
PubMed, The Cochrane Library, Web of Science, Scopus, Embase, China National Knowledge Infrastructure, Chinese Wanfang Database and Chinese VIP Database were searched for relevant studies from the establishment of these databases to September 2021. The pooled results evaluated the impact of probiotics on renal function, glucose, lipids, inflammation and oxidative stress indicators in patients with DKD. Additionally, subgroup analysis was performed based on intervention duration, probiotic dose and probiotic consumption patterns, respectively.
RESULTS
Ten trials that included 552 participants were identified for analysis. Compared with the controls, probiotics significantly decreased serum creatinine (Scr) [WMD = -0.17 mg/dL; 95%CI = -0.29, -0.05; = 0.004], blood urea nitrogen (BUN) [WMD = -1.36 mg/dL; 95%CI = -2.20, -0.52; = 0.001], cystatin C (Cys C) [WMD = -29.50 ng/mL; 95%CI = -32.82, -26.18; < 0.00001], urinary albumin/creatinine ratio (UACR) [WMD = -16.05 mg/g; 95%CI = -27.12, -4.99; = 0.004] and natrium (Na) [WMD = -0.94 mmol/L; 95%CI = -1.82, -0.05; = 0.04] in patients with DKD. Enhanced glycemic control was observed in patients with DKD receiving probiotics compared with controls, as demonstrated by reduced levels of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model of assessment-estimated insulin resistance (HOMA-IR), and increased quantitative insulin sensitivity check index (QUICKI). Probiotics affected lipid metabolism parameters with decreasing triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels in patients with DKD. Probiotics could also could improve inflammation and oxidative stress by decreasing high-sensitivity C-reactive protein (hs-CRP), plasma malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione (GSH) and nitric oxide (NO). Additionally, subgroup analysis showed that those who received multiple species probiotics had a statistically significant difference in BUN, FPG, HOMA-IR, high-density lipoprotein cholesterol (HDL-c), MDA, TAC, and NO. Meanwhile, Scr, LDL-c, HDL-c, MDA, and TAC were ameliorated when the intervention duration was more than eight weeks and BUN, FPG, HOMA-IR, and MDA were improved when the probiotic dose was greater than four billion CFU/day.
CONCLUSIONS
Our analysis revealed that probiotics could delay the progression of renal function injury, improve glucose and lipid metabolism, and reduce inflammation and oxidative stress in patients with DKD. Subgroup analysis showed that intervention duration, probiotic dose and probiotic consumption patterns had an effect of probiotics on outcomes.
Topics: Blood Glucose; C-Reactive Protein; Cholesterol, LDL; Diabetes Mellitus; Diabetic Nephropathies; Glucose; Humans; Inflammation; Insulin Resistance; Kidney; Oxidative Stress; Probiotics
PubMed: 35611435
DOI: 10.1080/0886022X.2022.2079522 -
Cardiovascular Diabetology Mar 2022We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD).
METHODS
We searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia).
RESULTS
A total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7-41.8% women, 53.2-93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75-0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58-0.75), HHF (HR 0.62, 95% CI 0.55-0.71), cardiovascular death (HR 0.84, 95% CI 0.74-0.96), MI (HR 0.78, 95% CI 0.67-0.92), stroke (HR 0.76, 95% CI 0.59-0.97), and all-cause death (HR 0.86, 95% CI 0.77-0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m). The relative risks (95% CI) for adverse events were 3.89 (1.42-10.62) and 2.50 (1.32-4.72) for mycotic infections in men and women respectively, 3.54 (0.82-15.39) for DKA, and 1.29 (1.13-1.48) for volume depletion.
CONCLUSIONS
Among adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.
Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Diabetic Nephropathies; Female; Heart Failure; Humans; Kidney; Male; Myocardial Infarction; Sodium-Glucose Transporter 2 Inhibitors; Stroke
PubMed: 35321742
DOI: 10.1186/s12933-022-01476-x -
PloS One 2023Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis.
METHODS
We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation).
RESULTS
Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others.
CONCLUSIONS
As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.
Topics: Adult; Humans; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Angiotensin Receptor Antagonists; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Kidney Failure, Chronic; Angiotensins; Diabetes Mellitus
PubMed: 37917640
DOI: 10.1371/journal.pone.0293183 -
Frontiers in Immunology 2023Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2... (Review)
Review
Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, emerging as novel hypoglycemic agents, have demonstrated significant cardiorenal protective effects in patients with DKD. Initially, it was believed that the efficacy of SGLT-2 inhibitors declined as the estimated glomerular filtration rate (eGFR) decreased, which led to their preferential use in DKD patients at G1-G3 stages. However, recent findings from the DAPA-CKD and EMPA-KIDNEY studies have revealed equally beneficial cardiorenal effects of SGLT-2 inhibitors in individuals at stage G4 DKD, although the underlying mechanism behind this phenomenon remains unclear. In this comprehensive analysis, we provide a systematic review of the mechanisms and functioning of SGLT-2 inhibitors, potential renal protection mechanisms, and the therapeutic efficacy and safety of SGLT-2 inhibitors in kidney diseases, with a particular focus on stage G4 DKD. Gaining a deeper understanding of the renal protective effect of SGLT-2 inhibitors and their underlying mechanisms is highly significance for the successful utilization of these inhibitors in the treatment of diverse kidney disorders.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Kidney
PubMed: 37809091
DOI: 10.3389/fimmu.2023.1213473 -
Pharmacology & Therapeutics Sep 2023We have performed a systematic review of studies reporting on the renal effects of SGLT2 inhibitors in rodent models of diabetes. In 105 studies, SGLT2 inhibitors... (Review)
Review
We have performed a systematic review of studies reporting on the renal effects of SGLT2 inhibitors in rodent models of diabetes. In 105 studies, SGLT2 inhibitors improved not only the glycemic control but also various aspects of renal function in most cases. These nephroprotective effects were similarly reported whether treatment with the SGLT2 inhibitor started concomitant with the onset of diabetes (within 1 week), early after onset (1-4 weeks) or after nephropathy had developed (>4 weeks after onset) with the latter probably having the greatest translational value. They were observed across various animal models of type 1 and type 2 diabetes/obesity (4 and 23 models, respectively), although studies in the type 2 diabetes model of db/db mice more often had negative data than in other models. Among possibly underlying pathophysiological mechanisms of nephroprotection, treatment with SGLT2 inhibitors had beneficial effects on lipid metabolism, blood pressure, glomerulosclerosis as well as renal tubular fibrosis, apoptosis, oxidative stress, and inflammation. These pathomechanisms highly influence atherosclerosis and renal health, which are two major factors that lead to an enhanced mortality in patients with diabetes and/or chronic kidney disease. Interestingly, renal SGLT2 inhibitor effects did not always correlate with those on glucose homeostasis, particularly in a limited number of direct comparative studies with other anti-diabetic treatments, indicating that nephroprotection may at least partly occur by mechanisms other than improving glycemic control. Our analyses did not provide evidence for different nephroprotective efficacy between SGLT2 inhibitors. Importantly, only four of 105 studies reported on female animals, and none provided direct comparative data between sexes. We conclude that more data on female animals and more direct comparative studies with other anti-diabetic compounds and combinations of treatments are needed.
Topics: Animals; Female; Mice; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37495021
DOI: 10.1016/j.pharmthera.2023.108503 -
Stem Cells Translational Medicine Sep 2021Regenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this... (Meta-Analysis)
Meta-Analysis Review
Regenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta-analysis summarized the effect of cell-based interventions in DKD animal models and treatment-related factors modifying outcomes. Electronic databases were searched for original investigations applying cell-based therapy in diabetic animals with kidney endpoints (January 1998-May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random-effects models. Subgroup analyses tested treatment-related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non-MSC (15%), and cell-derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell-based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial-mesenchymal-transition, oxidative stress). Preconditioning, xenotransplantation, and disease-source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell-based interventions in diabetic animals improved kidney function and reduced injury with treatment-related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.
Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Fibrosis; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Umbilical Cord
PubMed: 34106528
DOI: 10.1002/sctm.19-0419