Management of type 2 diabetes using non-insulin glucose-lowering therapies: a critical appraisal of clinical practice guidelines with the AGREE II instrument.

AIM: Type 2 diabetes is a major global epidemic affecting over 400 million people worldwide. The objective of this systematic review was to provide an overview of recommendations from clinical practice guidelines (guidelines) addressing non-insulin based pharmacological management of among non-pregnant adults in an outpatient setting, and critically appraise their methodological development. METHODS: We systematically searched MEDLINE and Embase databases, for relevant guidelines using the Ovid interface. We scanned the bibliographies of all eligible guidelines for additional relevant citations. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility and appraised the reporting quality of guidelines using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE II) instrument. RESULTS: Our search yielded 11264 unique citations, of which 124 were retrieved for full-text review; 17 guidelines proved eligible. The highest scoring AGREE domain was 'clarity of presentation' (66%; range 7-92%), followed by 'scope and purpose' (58%; range 25-92%), 'editorial independence' (55%; range 0-91%), 'stakeholder involvement' (45%; range 11-90%) and 'rigour of development' (43%; range 4-92%). The poorest domain was 'applicability' (37%; range 6-84%). The guidelines authored by the World Health Organization group achieved the highest AGREE overall score. CONCLUSIONS: Most of the guidelines provided recommendations with a local jurisdictional focus and showed significant variation in the quality. Nevertheless, only a small number of those scored well overall.

Plasma uric acid effects on glomerular haemodynamic profile of patients with uncomplicated Type 1 diabetes mellitus.

AIMS: Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. METHODS: PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. RESULTS: In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. CONCLUSIONS: The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.

Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects.

AIMS: To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m2 ) or renal normofiltration (GFR 90-134 ml/min/1.73 m2 ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. METHODS: Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. RESULTS: At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm5 ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than both healthy control subjects and patients with Type 1 diabetes and normofiltration (66 ± 6 vs. 60 ± 3 vs. 55 ± 3 mmHg; P < 0.05). Similar findings for afferent arteriolar resistance, efferent arteriolar resistance, glomerular hydrostatic pressure and filtration pressure were observed during clamped hyperglycaemia. CONCLUSION: Hyperfiltration in Type 1 diabetes is primarily driven by alterations in afferent arteriolar resistance rather than efferent arteriolar resistance. Renal protective therapies should focus on afferent renal arteriolar mechanisms through the use of pharmacological agents that target tubuloglomerular feedback, including sodium-glucose cotransporter 2 inhibitors and incretins.

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus.

AIMS/HYPOTHESIS: High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. METHODS: Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFRINULIN] ≥ 135 ml min⁻¹ 1.73 m⁻², n = 28) or normofiltration (n = 21) and healthy control individuals (n = 18). RESULTS: Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165 ± 9 vs 113 ± 2 and 116 ± 4 ml min⁻¹ 1.73 m⁻², respectively, p < 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p < 0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p ≤ 0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p < 0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p < 0.01). CONCLUSIONS/INTERPRETATION: Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.

Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria.

AIMS: Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation. METHODS: Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups. RESULTS: At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01). CONCLUSIONS: Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Ability of cystatin C to detect acute changes in glomerular filtration rate provoked by hyperglycaemia in uncomplicated Type 1 diabetes.

AIMS: Systematic study of hyperfiltration in diabetic nephropathy has been hindered by the lack of a simple glomerular filtration rate (GFR) measure that is accurate in this range of renal function. Serum cystatin C (GFR(CYSTATIN C) ) reflects long-term trends in GFR in normal or elevated ranges. To test whether it can reflect acute changes, we examined the impact of clamped hyperglycaemia on GFR(CYSTATIN C) and GFR(INULIN) in subjects with Type 1 diabetes. METHODS: GFR(INULIN) and GFR(CYSTATIN C) were measured in 32 normotensive, normoalbuminuric subjects during clamped euglycaemia and hyperglycaemia. For comparison, GFR(MDRD) was estimated according to the four-variable equation. RESULTS: During clamped euglycaemia, agreement between GFR(CYSTATIN C) and GFR(INULIN) was excellent, with mean bias +1.9 (90% distribution -29 to +31) ml min(-1) 1.73 m(-2), while GFR(MDRD) had mean bias +11.4 (-45 to +51) ml min(-1) 1.73 m(-2). With exposure to clamped hyperglycaemia, the mean increase in GFR(CYSTATIN C) (+17.5 ± 13.5 ml min(-1) 1.73 m(-2) ) reflected that observed with GFR(INULIN) (+15.3 ± 28.1 ml min(-1) 1.73 m(-2), P = 0.74), while GFR(MDRD) demonstrated a mean decline of -4.4 ± 33.6 ml min(-1) 1.73 m(-2) (P = 0.01). In all 24 subjects in whom GFR(INULIN) increased in response to hyperglycaemia, GFR(CYSTATIN C) reflected a concordant change (sensitivity, 100%) while GFR(MDRD) increased in 10/24 (sensitivity, 42%). In the eight remaining subjects, specificity was 25 and 75% for GFR(CYSTATIN C) and GFR(MDRD), respectively. CONCLUSION: GFR(CYSTATIN C) reflects normal and elevated renal function better than GFR(MDRD) even under the acute influences of hyperglycaemia, suggesting a role for cystatin C in clinical practice and research for the study of early renal function changes in Type 1 diabetes.

The effect of oral contraceptives on the nitric oxide system and renal function.

We have demonstrated that oral contraceptive (OC) users exhibit elevated angiotensin II levels and angiotensin II type 1 receptor expression, indicative of renin-angiotensin system (RAS) activation, yet the renal and systemic consequences are minimal, suggesting that there is increased vasodilatory activity, counteracting the effect of RAS activation. We hypothesized that the nitric oxide (NO) system would be upregulated in OC users and that this would be reflected by a blunted hemodynamic response to l-arginine infusion. All subjects were studied after a 7-day controlled sodium and protein diet. Inulin and para-aminohippurate clearance techniques were used to assess renal function. l-Arginine was infused at 100, 250, and 500 mg/kg, each over 30 min. Skin endothelial NO synthase mRNA expression was assessed by real-time PCR. While OC nonusers exhibited significant increases in effective renal plasma flow (670.8 +/- 35.6 to 816.2 +/- 59.7 ml.min(-1).1.73 m(-2)) and glomerular filtration rate (133.4 +/- 4.3 to 151.0 +/- 5.7 ml.min(-1).1.73 m(-2), P = 0.04) and declines in renal vascular resistance (81.1 +/- 6.1 to 63.5 +/- 6.2 mmHg.ml(-1).min, P = 0.001) at the lower l-arginine infusion rates, the responses in OC users were blunted. While l-arginine reduced mean arterial pressure at the 250 and 500 mg/kg doses in OC nonusers, OC users only exhibited a decrease in mean arterial pressure at the highest infusion rate. In contrast, tissue endothelial NO synthase mRNA levels were higher in the OC users (P = 0.04). In summary, these findings suggest that the NO system is upregulated by OC use in young, healthy women. Increased activity of the NO pathway may modulate the hemodynamic effects of RAS activation in OC users.

Acute hyponatraemia and 'ecstasy': insights from a quantitative and integrative analysis.

A 20-year-old woman attended a 'rave party' where she took the drug 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). She had used this drug previously without serious adverse effects. On this occasion, while both she and her friends drank a large quantity of water, only she became seriously ill. The initial manifestation was an altered sensorium; several hours later she had a grand mal seizure. In the Emergency Department, the most striking features were the severe degree of hyponatraemia (112 mmol/l) and cerebral oedema. To explain the basis for this life-threatening clinical presentation, an imaginary consultation was sought with Professor McCance. Using both a deductive and a quantitative analysis that involved several medical subspecialties, he illustrated that a simple story of water ingestion and vasopressin release was not sufficient to explain her hyponatraemia. It was only after events in her gastrointestinal tract were analysed that a plausible hypothesis could be constructed.