International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.

Diabetes mellitus is a non-communicable metabolic derangement afflicting several millions of individuals globally. It is associated with several micro and macrovascular complications and is also a leading cause of mortality. The unresolved issue is that of definition of the diagnostic threshold for diabetes. The World Health Organization and the American Diabetes Association (ADA) have laid down several diagnostic criteria for diagnosing diabetes and prediabetes based on the accumulating body of evidence.This review has attempted to analyse the scientific evidence supporting the justification of these differing criteria. The evidence for diagnosing diabetes is strong, and there is a concordance between the two professional bodies. The controversy arises when describing the normal lower limit of fasting plasma glucose (FPG) with little evidence favouring the reduction of the FPG by the ADA. Several studies have also shown the development of complications specific for diabetes in patients with prediabetes as defined by the current criteria though there is a significant overlap of such prevalence in individuals with normoglycemia. Large multinational longitudinal prospective studies involving subjects without diabetes and retinopathy at baseline will ideally help identify the threshold of glycemic measurements for future development of diabetes and its complications.

The aim of the present study was to investigate whether an oral glucose load can induce an increase in urinary albumin excretion (UAE).

One hundred and thirty subjects without macroalbuminuria or increased fasting serum glucose (≥7.0 mmol/L) were included in the study. At 0600 hours, subjects were asked to empty their bladder and drink 300 mL water. At 0800 hours, venous blood and 2-h urine were collected for fasting examination. Subjects were then asked to drink 300 mL solution containing 75 g glucose and, at 1000 hours, samples were collected again for post-challenge examination. Concentrations of serum glucose, urinary glucose, albumin, N-acetyl-β-D-glucosaminidase and retinol-binding protein were measured.

Based on the results of the oral glucose tolerance test, subjects were divided into three groups: (i) normal glucose tolerance (NGT; n = 55); (ii) impaired glucose tolerance (IGT; n = 39); and (iii) newly diagnosed diabetes mellitus (NDM; n = 36). In the NDM group, post-challenge urinary excretion of glucose and albumin was 14- and 1.6-fold greater than fasting values, respectively. In the IGT and NGT groups, although post-challenge urinary glucose excretion was 2.6- and 1.6-fold greater than fasting values, UAE did not increase. There was a positive correlation between post-challenge serum glucose and the UAE rate (UAER; r = 0.24, P < 0.01) and the UAER increment (ΔUAER; r = 0.19, P < 0.05), as well as between the serum glucose increment and post-challenge UAER (r = 0.23, P < 0.01) and ΔUAER (r = 0.18, P < 0.05). Post-challenge serum glucose levels were independently correlated with logarithmically converted post-challenge UAER (β = 0.322, P = 0.008).

Oral glucose load can induce a significant increase in UAE in NDM subjects. The main mechanism may be glomerular hyperfiltration.

To examine whether elevated glycosylated hemoglobin A1c (HbA1c) is associated with hyperfiltration in a middle-aged and elderly Chinese population.

Anthropometric and biochemical examinations were performed in 2491 individuals from the general population, aged 40-79 years, who participated in the Huaian Diabetes Prevention Program. The estimated glomerular filtration rate (eGFR) was calculated from creatinine levels using the CKD-EPI formula. Hyperfiltration was defined as eGFR >90(th) percentile.

After adjustment [for age, gender, waistline, body mass index, blood pressure, smoking, alcohol consumption, cholesterol, log(triglycerides), high-density lipoprotein, low-density lipoprotein, serum uric acid, sodium intake, hypertension, and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers], HbA1c and fasting plasma glucose (FPG) were found to be independently positively associated with eGFR. Additionally, after multivariate adjustment, the odds ratios (95 % CI) for hyperfiltration calculated for a 1-unit increase in HbA1c and FPG were 1.396 (1.089-1.790) and 1.306 (1.117-1.526), respectively. Compared with participants with HbA1c levels <5.7%, the odds ratios (95 % CI) for hyperfiltration were 2.344 (1.025-5.364) in participants with HbA1c levels of 6.21-6.49%, and 2.965 (1.537-5.720) in those with HbA1c levels ≥ 6.5%.

Elevated HbA1c (≥ 6.21%) is associated with an increased odds of hyperfiltration in middle-aged and elderly Chinese. Longitudinal studies are needed to explore whether hyperfiltration increases the odds of diabetic nephropathy in individuals with prediabetes.

Estimation of glomerular filtration rate (eGFR) is one of the current clinical methods for identifying risk for diabetic nephropathy in subjects with type 1 diabetes (T1D). Hyperglycemia is known to influence GFR in T1D and variability in blood glucose at the time of eGFR measurement could introduce bias in eGFR. We hypothesized that simultaneously measured blood glucose would influence eGFR in adults with T1D.

Longitudinal multivariable mixed-models were employed to investigate the relationships between blood glucose and eGFR by CKD-EPI eGFRCYSTATIN C over 6-years in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study. All subjects with T1D and complete data including blood glucose and cystatin C for at least one of the three visits (n = 616, 554, and 521, respectively) were included in the longitudinal analyses.

In mixed-models adjusting for sex, HbA1c, ACEi/ARB, protein and sodium intake positive associations were observed between simultaneous blood glucose and eGFRCYSTATIN C (β±SE:0.14±0.04 per 10 mg/dL of blood glucose, p<0.0001), and hyperfiltration as a dichotomous outcome (OR: 1.04, 95% CI: 1.01-1.07 per 10 mg/dL of blood glucose, p = 0.02).

In our longitudinal data in subjects with T1D, simultaneous blood glucose has an independent positive effect on eGFRCYSTATIN C. The associations between blood glucose and eGFRCYSTATIN C may bias the accurate detection of early diabetic nephropathy, especially in people with longitudinal variability in blood glucose.

Increased glomerular filtration rate (GFR), also called hyperfiltration, is a proposed mechanism for renal injury in diabetes. The causes of hyperfiltration in individuals without diabetes are largely unknown, including the possible role of borderline hyperglycemia. We assessed whether impaired fasting glucose (IFG; 5.6-6.9 mmol/L), elevated HbA1c, or hyperinsulinemia are associated with hyperfiltration in the general middle-aged population.

A total of 1,560 individuals, aged 50-62 years without diabetes, were included in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). GFR was measured as single-sample plasma iohexol clearance. Hyperfiltration was defined as GFR>90th percentile, adjusted for sex, age, weight, height, and use of renin-angiotensin system inhibitors.

Participants with IFG had a multivariable-adjusted odds ratio of 1.56 (95% CI 1.07-2.25) for hyperfiltration compared with individuals with normal fasting glucose. Odds ratios (95% CI) of hyperfiltration calculated for a 1-unit increase in fasting plasma glucose (FPG) and HbA1c, after multivariable-adjustment, were 1.97 (1.36-2.85) and 2.23 (1.30-3.86). There was no association between fasting insulin levels and hyperfiltration. A nonlinear association between FPG and GFR was observed (df=3, P<0.0001). GFR increased with higher glucose levels, with a steeper slope beginning at FPG≥5.4 mmol/L.

Borderline hyperglycemia was associated with hyperfiltration, whereas hyperinsulinemia was not. Longitudinal studies are needed to investigate whether the hyperfiltration associated with IFG is a risk factor for renal injury in the general population.

Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine. The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking. It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.

Renal haemodynamics estimated using inulin- and para-aminohippuric acid-(PAH) clearances and segmental tubular handling of sodium as estimated using lithium clearance where studied in fourteen healthy men. Volume expansion was induced by a 2 h (25 ml kg-1) infusion of 0.9% sodium chloride (NaCl) load. Eight of the 14 subjects were rechallenged with a 2 h infusion of 5% glucose (25 ml kg-1). In addition, ten healthy subjects were investigated with inulin and PAH-clearances during water diuresis. When NaCl was infused glomerular filtration rate (GFR) decreased from 115 to 103 ml min-1 (p < 0.002) and fractional sodium excretion increased by 85%. The fall in GFR could be due to tubuloglomerular feedback as a result of inhibition of proximal tubular sodium reabsorption. The fall in GFR raises doubt about the usefulness of NaCl as an inert control infusion in metabolic studies. During glucose infusion blood glucose rose from 4.3 to 10.9 mmol l-1 with no significant change in GFR, but fractional sodium excretion was reduced by almost 40%. The etiology of the acute antinatriuretic effect of volume expansion with glucose infusion in healthy humans is not known but a blunted decrease in plasma renin activity and erythrocyte volume fraction in conjunction with a failure to mobilize renal dopamine and an increase in plasma levels of antinatriuretic factors such as insulin and norepinephrine are all factors that may contribute to the antinatriuretic effect of a glucose infusion.

Glomerular hyperfiltration has been claimed to be a risk factor for the development of diabetic nephropathy. Protein intake and hyperglycemia can both increase GFR in diabetic and normal subjects. Our study was designed to explore the relative importance of short-term changes in protein intake and glycemia on the modulation of renal hemodynamics in insulin-dependent diabetic (IDDM) patients with and without glomerular hyperfiltration. The renal hemodynamic response to a protein challenge was studied in eight hyperfiltering (HF) and eight normofiltering (NF) patients after a three week period of low or normal protein diet (LPD, NPD), each study being conducted twice, in random order, under conditions of prevailing hyperglycemia (H) and euglycemia (E). In HF patients GFR failed to increase significantly in response to protein challenge during NPD under conditions of either H or E (Baseline vs. 2 hr H: 151 +/- 4 vs. 155 +/- 6, NS; E 147 +/- 4 vs. 157 +/- 7 ml/min/1.73 m2, NS). A more normal response was restored following LPD with GFR increasing in all but one patient after challenge during H and in all patients during E (Baseline vs. 2 hr H: 130 +/- 7 vs. 145 +/- 8, P less than 0.07; E: 127 +/- 7 vs. 143 +/- 7 ml/min/1.73 m2, P less than 0.01). Changes in RPF paralleled the changes in GFR and filtration fraction remained stable under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was the evaluation, in healthy subjects, of the renal functional reserve (RFR), that is, the GFR increase induced by a combined infusion of amino acids (AA) and dopamine (D), in conditions of extracellular volume depletion caused by diuretic administration. In particular, this study was undertaken: a) to evaluate whether and to which extent, AA + D can reverse the functional GFR impairment induced by salt depletion, without volume restoration; b) to study whether any relationship may be found between the GFR in normal condition (the so-called "resting" GFR), and/or the renal functional reserve and the GFR impairment induced by salt depletion, in order to understand the role of both "resting" GFR and RFR in the degree of renal dysfunction induced by salt depletion. In control conditions the i.v. infusion of AA + D significantly increased RPF (+ 41% vs. baseline period) with a mean absolute increase of 211 ml/min. A similar pattern was observed in GFR behavior (+31.5% with 34 ml/min of mean absolute increase). A significant inverse exponential relationship was observed between GFR before AA + D i.v. infusion ("resting" GFR) and renal functional reserve (P less than 0.05), suggesting that, in normal conditions, these inversely related parameters may widely vary according to the tone of the glomerular arterioles. Following salt depletion, we observed a variable degree of GFR impairment. Both GFR and RPF were significantly decreased (-25.9%, P less than 0.05 and -29%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the association between renal hemodynamic abnormalities and the development of diabetic kidney disease, glomerular filtration rate (GFR) and renal plasma flow (RPF) have been determined in dogs with alloxan-induced diabetes or experimental galactosemia of 1 to 5 years duration. GFR and RPF were significantly greater than normal in insulin-deficient diabetic dogs. GFR was also significantly greater than normal in the galactosemic animals, and RPF tended to be elevated even though GFR and RPF were measured at time of day when plasma galactose is no longer elevated. GFR and effective RPF (eRPF) were found to increase in normal animals upon acute elevation of blood galactose or glucose concentration. Thus, GFR is supranormal in experimental galactosemia, as well as in diabetes, although galactosemia has been shown not to cause nephromegaly, mesangial expansion, or glomerular obliteration, which are typical of diabetes. Administration of an aldose reductase inhibitor (Sorbinil) at dosages sufficient to significantly reduce erythrocyte polyol concentration did not significantly influence GFR or RPF in diabetic or galactosemic dogs.

Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.

The prevailing blood-glucose level has been found to influence renal haemodynamics in type 1 (insulin-dependent) diabetes mellitus. In a group of 48 type 1 diabetic patients with normal serum creatinine (less than 120 mumol l-1) and without persistent proteinuria, no relationship was present between blood glucose, corrected to near normoglycaemia (6.8 [6.2 to 7.3] mmol l-1 (median [95% confidence interval]), and glomerular filtration rate (GFR), effective renal plasma flow (ERPF) determined with 125I-iothalamate and 131I-hippuran respectively. GFR tended to increase (2 [-1 to +4] ml min-1 1.73 m-2, 0.05 less than P less than 0.10) and ERPF did not change after a blood glucose rise of 7.9 (7.0 to 8.9) mmol l-1, achieved by an intravenous glucose load in 31 patients. The individual changes in GFR and ERPF were correlated (r = 0.60, P less than 0.005). The changes in GFR were inversely related to baseline blood glucose (r = -0.45, P less than 0.02), but not to baseline GFR. GFR increased (3.5 [0 to +12] ml min-1 1.73 m-2, P less than 0.01) if baseline blood glucose was less than or equal to 6.8 mmol l-1 (n = 16) but ERPF did not. Achievement of near normoglycaemia before measurement of kidney function in type 1 diabetes appears to reduce the influence of variation in glycaemia on renal haemodynamics and thus would improve comparison between and within individuals. Moderate hyperglycaemia can cause a small rise in the glomerular filtration rate.

Using a prospective randomised double-blind crossover design, the effect of the angiotensin converting enzyme inhibitor enalapril compared to a placebo was studied in 18 normotensive, normoalbuminuric Type 1 (insulin-dependent) diabetic children. Each patient had a high normal or clearly elevated glomerular filtration rate (145 ml.min-1.1.73 m2 or higher) in the 6 months prior to the study. Enalapril, 0.5 mg.kg-1.day-1, was given for 4 weeks followed by placebo for 4 weeks, or vice versa. At the end of each period, glomerular filtration rate, renal plasma flow, blood pressure, plasma renin activity, and converting enzyme activity were determined. Enalapril caused significant reduction (p = less than 0.001) in blood pressure and converting enzyme activity and a rise in plasma renin activity. A slight but not significant rise in glomerular filtration rate and renal plasma flow without change in filtration fraction was observed. These data suggest that the renin angiotensin system is not involved in the glomerular hyperfiltration of Type 1 diabetes, and can be interpreted as showing no evidence for the presence of intraglomerular hypertension in these patients.