Inverse relationship between glomerular hyperfiltration and C-peptide level in Type 1 diabetes

Background: Increased glomerular filtration rate (GFR) commonly develops in early diabetes and is closely correlated with the development of diabetic nephropathy. Objective: The aim was to study the relationship between GFR, C-peptide level and other parameters at diagnosis of Type 1 diabetes. Methods: We determined GFR, Cpeptide level, glycated hemoglobin (HbA1c), body mass index (BMI) SDS and loss of weight at diagnosis of Type 1 diabetes in 495 children (231 females). Linear and multiple regression analysis was used to test for the associations between GFR and other parameters. Results: In the 495 patients, GFR median (interquartile range) was increased vs normal values (p = 0.0001). GFR was significantly negatively correlated with age (p < 0.001) and C-peptide level (p = 0.001), and positively correlated with weight loss (p = 0.02). The multiple regression analysis showed that age (p = 0.001) and C-peptide level (p = 0.05) were independently and negatively related to GFR. Conclusions: This study shows that, at onset of Type 1 diabetes, higher the GFR, younger the age and lower the C-peptide level are. The role of this hyperfiltration in the development of later nephropathy and the putative preventive effect of C-peptide administration need to be evaluated.

Evaluation of Glomerular Hyperfiltration and Albuminuria in Sickle Cell Disease Adolescents: Cross-Sectional Retrospective Study

Background: Sickle Cell Disease (SCD) renal abnormalities commence early in childhood. The glomerular abnormalities, glomerular hyperfiltration and albuminuria are the most prevalent. However, these SCD glomerulopathies have not been considered exclusively in the adolescent age group. Objective: To determine the prevalence of glomerular hyperfiltration and albuminuria as well as identify the determinants for glomerular hyperfiltration in adolescents with SCD. Patients and Methods: The electronic patient records of 153 adolescents with SCD aged 10 - <19 years, attending the Paediatrics Haematology Clinic at Evelina London Children’s Hospital, United Kingdom, were reviewed from the 10th to 23rd June 2019. Clinical information and laboratory parameters were obtained. The glomerular filtration rate was derived using the Bedside Schwartz’s method. Grouping of the adolescents was based on the presence and absence of glomerular hyperfiltration, which was defined as glomerular filtration rate > 140 ml/min/m2. The presence of albuminuria was defined as urine albumin-to-creatinine ratio > 3 mg/mmol or protein-to-creatinine ratio of >15 mg/mmol. The clinical and laboratory determinants of glomerular hyperfiltration in the total study population were investigated. Result: Prevalence of glomerular hyperfiltration was 33.3% in the adolescents studied, and that of albuminuria was 15.7% amongst the SCD adolescents studied, of which 13.7% of those with glomerular hyperfiltration also had albuminuria. On univariable analysis, the SCD adolescents with glomerular hyperfiltration had significantly lower weight (48.0 ± 18.0 versus 54.8 ± 17.0 kg;p = 0.02), height (155.1 ± 13.1 versus 160.6 ± 13.1 cm;p = 0.01), body mass index (19.4 ± 5.0 versus 21.0 ± 4.3;p = 0.04), haemoglobin level (88.7 ± 13.3 versus 98.1 ± 21.7 g/L;p = 0.001), and serum creatinine level (0.4 ± 0.1 versus 0.6 ± 0.2 mg/dl;p = 0.0001) as compared to those with no glomerular hyperfiltration. The SCD adolescents with glomerular hyperfiltration also had significantly higher lactate dehydrogenase levels (525.9 ± 180.3 versus 449.6 ± 170.3 IU/L;p = 0.01) than those with no glomerular hyperfiltration. But, multivariable analysis revealed no associations. Conclusion: This study revealed that the prevalence of glomerular hyperfiltration in SCD children in the adolescent age group is high, and the high glomerular filtration rates begin to decline toward normal values in middle adolescence.

Experimental Evidence for Hyperfiltration of Saline Water through Compacted Clay Aquitard in the Hebei Plain

It becomes an increasing concern that groundwater quality in exploited deep confined aquifer may deteriorate due to brackish water leakage from its overlying saline aquifer in Hebei Plain. However, the monitoring data show that the TDS does not significantly change in the exploited aquifer. Some physics or chemistry processes must have taken place in aquitards during brackish leakage. The semi-permeable membrane function of clay aquitard during the process of hyperfiltration（reverse osmosis） should be one of the most important processes. To confirm and test this hyperfiltration mechanism, a series of experiments were performed in which Na Cl solutions were hydraulically forced through different clay sampled from aquitard. The solution 7 g/L in NaC l was forced through at 20 °C by a fluid pressure of 0.5 kN. The results show that hyperfiltration indeed happens in caly aquitard. Semi-permeability is quantified by the reflection coefficient σ. The mean rejection coefficients（σ） for clay samples #1, #2 and #3 were estimated to be 0.063, 0.164 and 0.040, respectively. This behavior of clay was well explained with the theory of the diffuse double layer. The hyperfiltration effect is to the great extent responsible for the chemical process in the aquitard.

How the kidney hyperfiltrates in diabetes:From molecules to hemodynamics

In this review,we focused on two molecules,connexin and sodium-glucose cotransporter,which can link to diabetic hyperfiltration.In diabetic kidney,the activation of renin-angiotensin system occurs simultaneously with glomerular hyperfiltration.The latter largely dependson pathophysiological afferent arteriolar dilation in the presence of high angiotensin Ⅱ.As a mechanistic basis for the above,tubular hypothesis has been proposed for type 1 diabetic patients as well as experimental models.Although tubular hypothesis has not been well evaluated in type 2 diabetes,clinical observations support that tubular hypothesis is true also in type 2 diabetes.Recent results on tubular hypothesis along with connexin abnormality in type 2 diabetes were revisited.In addition,the importance of sodium-glucose cotransporter in diabetic hyperfiltration is discussed.The link between salt paradox and the activation of reninangiotensin system will be also reviewed.

Establishing the presence or absence of chronic kidney disease:Uses and limitations of formulas estimating the glomerular filtration rate

The development of formulas estimating glomerular filtration rate(eG FR) from serum creatinine and cystatin C and accounting for certain variables affecting the production rate of these biomarkers, including ethnicity, gender and age, has led to the current scheme of diagnosing and staging chronic kidney disease(CKD),which is based on e GFR values and albuminuria.This scheme has been applied extensively in various populations and has led to the current estimates of prevalence of CKD. In addition, this scheme is applied in clinical studies evaluating the risks of CKD and the efficacy of various interventions directed towards improving its course. Disagreements between creatinine-based and cystatin-based e GFR values and between e GFR values and measured GFR have been reported in various cohorts. These disagreements are the consequence of variations in the rate of production and in factors, other than GFR, affecting the rate of removal of creatinine and cystatin C. The disagreements create limitations for all e GFR formulas developed so far. The main limitations are low sensitivity in detecting early CKD in several subjects, e.g., those with hyperfiltration, and poor prediction of the course of CKD. Research efforts in CKD are currently directed towards identification of biomarkers that are better indices of GFR than the current biomarkers and,particularly, biomarkers of early renal tissue injury.

Salvianolic acid A ameliorates AGEs-induced glomerular endothelial dysfunction and protects against diabetic nephropathy

OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities.Salvianolic acid A(SalA)has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy.The present study was designed to investigate the effects of SalA on glomerular endothelial dysfunctionand diabetic nephropathy.METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products(AGEs).AGEs-induced changes of Rho A/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunofluorescence.The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin(35 mg·kg^(-1),ip).Renal function and architectonic changes were evaluated by biochemical assay and PAS staining.RESULTS SalA 3μMameliorated AGEs-induced glomerular endothelial permeability(P<0.05)and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-Rho A/ROCK pathway.SalA1 mg·kg^(-1)markedly reduced endothelium loss(P<0.01)and glomerular hyperfiltration(P<0.05)in diabetic kidney.Subsequently,SalA 1 mg·kg^(-1) suppressed glomerular hypertrophy and mesangial matrix expansion,eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen(BUN),serum creatinine(Scr)and serum n-acetyl-β-d-glucosaminidase(NAG).AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg^(-1).CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability,and effectively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway.Thus,SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.

Insulin sensitivity and complications in type 1 diabetes: New insights

Despite improvements in glucose, lipids and bloodpressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.