The impact of hyperfiltration on the diabetic kidney.

More than two decades ago, hyperfiltration (HF) in diabetes was postulated to be a maladaptive response observed early in the course of diabetic kidney disease (DKD), which may eventually predispose to irreversible damage to nephrons and development of progressive renal disease. Despite this, the potential mechanisms leading to renal HF in diabetes are not fully understood, although several hypotheses have been proposed, including alterations in glomerular haemodynamic function and tubulo-glomerular feedback. Furthermore, the role of HF as a causative factor in renal disease progression is still unclear and warrants further prospective longer-term studies. Although HF has been entrenched as the first stage in the classic albuminuric pathway to end-stage renal disease in DKD, and HF has been shown to predict the progression of albuminuria in many, but not all studies, the concept that HF predisposes to the development of chronic kidney disease (CKD) stage 3, that is, glomerular filtration rate (GFR) decline to<60mL/min/1.73m(2), remains to be proved. Further long-term studies of GFR gradients therefore are required to establish whether HF ultimately leads to decreased kidney function, after adjustment for glycaemic control and other confounders. Whether reversal of HF with therapeutic agents is protective against reducing the risk of development of albuminuria and renal impairment is also worth investigating in prospective randomized trials.

High sodium and low potassium intake in patients with Type 2 diabetes.

AIMS: To document dietary sodium and potassium intake and adherence to the Australian National Heart Foundation (NHF) guidelines in patients with Type 2 diabetes mellitus attending an Australian tertiary referral and university teaching hospital. METHODS: In a longitudinal study, 24h urinary sodium (uNa), potassium (uK), creatinine (uCr), urea (uUrea) and glucose (uGlu) excretions, urine volume (uVol) and body mass index were recorded in 122 regular attenders over an 8 year period (2001-2008; mean of 1.9 samples/patient/year). In a cross-sectional study, the same measurements were recorded in patients providing urine samples in the month of June from 2001 to 2009 (782 patients, averaging 87/year). RESULTS: In the longitudinal study, uNa (mmol/24 h) was 170 ± 53 (mean ± SD) in males and 142 ± 51 in females, whereas uK (mmol/24 h) was 75 ± 22 in males and 62 ± 18 in females. Once adjusted for insensible losses, only 3% of males and 14% of females met the NHF dietary sodium intake guidelines, and 14% of males and 3% of female patients met the NHF dietary potassium guidelines. Body mass index, uUrea, uVol and uGlu were independent predictors of uNa (adjusted r(2) =0.57, P<0.0001). The mean intra-individual coefficient of variation of the corrected uNa was 21 ± 1%. The cross-sectional study confirmed these findings, and no temporal trends were observed. There was no correlation with glycated haemoglobin to suggest natriuresis with hyperglycaemia. CONCLUSIONS: Most patients with Type 2 diabetes mellitus do not meet NHF sodium or potassium intake guidelines. A diet high in sodium and low in potassium may contribute to the development of hypertension and to resistance to blood-pressure-lowering therapies.

The clinical significance of hyperfiltration in diabetes.

Glomerular filtration rate is commonly elevated in early diabetes and patients with this symptom are arbitrarily considered to have hyperfiltration. The prevalence of hyperfiltration in type 1 diabetes varies from less than 25% to more than 75%. The corresponding figures in type 2 diabetes are significantly lower, ranging between 0% and more than 40%. Several factors, methodological and biological, may contribute to the wide variation in estimates of hyperfiltration prevalence. Methodological differences in measurement and evaluation of GFR apply in particular to the handling of plasma disappearance curves of filtration markers. Biological factors that may influence GFR in the hyperfiltration range include glycaemic control, diabetes duration, BMI, sex, pubertal status in type 1 diabetes and age in type 2 diabetes. Hyperglycaemia may influence GFR and albuminuria, and may therefore confound the evaluation of hyperfiltration as an independent risk factor for diabetic nephropathy. Adequate assessment of the relationship between glycaemic control, GFR and AER therefore requires serial measurements of all three variables followed by multivariate analysis. A recent meta-analysis of ten type 1 diabetes studies concluded that the presence of hyperfiltration at baseline more than doubled the risk of developing micro- or macroalbuminuria at follow-up. However, not all studies allowed for confounding factors or regression dilution bias. Future studies will therefore need to address the independent role of hyperfiltration, not only in the evolution of albuminuria, but also in the subsequent decline of GFR.

Salt supplementation blunts the blood pressure response to telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes.

AIMS/HYPOTHESIS: We assessed the effects of sodium chloride (NaCl) supplementation on the blood pressure response to treatment with telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes and habitually high (HDS, sodium excretion >200 mmol/24 h on two out of three consecutive occasions) or low (LDS, sodium excretion <100 mmol/24 h on two out of three consecutive occasions) salt intake. METHODS: Patients received 4 weeks of telmisartan followed by 4 weeks of telmisartan plus hydrochlorothiazide. In a double-blind randomised fashion, patients received sodium chloride (NaCl, 100 mmol/24 h) or placebo capsules in addition to their habitual salt intake during the last 2 weeks of telmisartan and telmisartan plus hydrochlorothiazide therapy. The protocol was repeated with NaCl and placebo capsules administered in reverse order to allow each participant to act as his or her own control. At 0, 4, 8, 14, 18 and 22 weeks, 24 h ambulatory blood pressure (ABP) and 24 h urine collections were performed. RESULTS: No statistically significant differences were seen in the ABP response in the LDS vs HDS groups to any of the interventions (p = 0.58). NaCl supplementation reduced the effect of telmisartan with or without hydrochlorothiazide on systolic BP by approximately 50% (-5.8 mmHg during NaCl supplementation vs -11.3 mmHg during placebo, mean difference 5.6 mmHg [95% CI 1.7-9.4 mmHg], p = 0.005), irrespective of habitual salt intake. By contrast, addition of hydrochlorothiazide increased the antihypertensive effect of telmisartan on systolic BP by approximately 35% (p = 0.048) in both groups of patients. CONCLUSIONS/INTERPRETATION: NaCl supplementation blunts the effectiveness of telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes, independently of habitual low or high salt intake.

New and old markers of progression of diabetic nephropathy.

The onset of diabetic nephropathy is characterised by a rise in albumin excretion rate (AER) and/or a transient rise in glomerular filtration rate (GFR) (hyperfiltration). Without intervention AER increases exponentially and there is a linear decrease in GFR after onset of overt nephropathy. In overt nephropathy, AER is a predictor of decline in GFR and the early AER response to antihypertensive therapy correlates with long-term decline in GFR. AER can be measured by immunoassay or by other techniques including HPLC. However, HPLC assays result in higher levels of AER in normal subjects compared with immunoassayable AER. Recent data suggest that there are distinct albuminuric and non-albuminuric pathways to renal impairment in type 1 and type 2 diabetes. In type 2 diabetes, the non-albuminuric pathway may explain a decline in GFR to <60 ml/min/1.73 m(2) in approximately one in four subjects after accounting for the use of renin angiotensin system inhibitors. In established nephropathy (chronic kidney disease (CKD) stages 3 and 4), plasma cystatin C based estimates of GFR are marginally superior to creatinine based estimates. However, cystatin C clearly outperforms creatinine based estimates of GFR decline at GFR levels >60 ml/min/1.73 m(2) (CKD stages 1 and 2). Other potential markers of progression of diabetic nephropathy include transforming growth factor beta (TGFbeta) and connective tissue growth factor (CTGF). However, long-term studies are needed to define their roles as markers of progression. Diabetic nephropathy is likely to be more susceptible to intervention at an early stage and accurate estimation of GFR is already possible with cystatin C. However, improved formulas for estimating GFR based on using creatinine or other markers are still required, because this may still provide the most cost effective approach applicable to existing clinical practice.

The accuracy of cystatin C and commonly used creatinine-based methods for detecting moderate and mild chronic kidney disease in diabetes.

BACKGROUND: The accuracy of measuring serum cystatin C levels for detecting various stages of chronic kidney disease (CKD) in diabetes is still unclear. METHODS: In a cross-sectional study of 251 subjects, a reference glomerular filtration rate (GFR) was measured using (99c)Tc-DTPA plasma clearance (iGFR). Multivariate analysis was used to identify independent clinical and biochemical associations with serum cystatin C and iGFR levels. The diagnostic accuracy of cystatin C and commonly used creatinine-based methods of measuring renal function (serum creatinine, the MDRD four-variable and Cockcroft-Gault formulae) for detecting mild and moderate CKD was also compared. RESULTS: In the entire study population the same five variables, age, urinary albumin excretion rates, haemoglobin, history of macrovascular disease and triglyceride levels were independently associated with both cystatin C and iGFR levels. A serum cystatin C level cut-off > 82.1 nmol/l (1.10 mg/l) had the best test characteristics as a screening tool for detecting moderate CKD (< 60 ml/min per 1.73 m(2)) when compared with creatinine-based methods. At the upper threshold for mild CKD (< 90 ml/min per 1.73 m(2)), cystatin C also had greater diagnostic accuracy than creatinine, but had similar diagnostic accuracy when compared with creatinine-based formulae for predicting renal function. CONCLUSIONS: This study suggests that the clinical and biochemical parameters associated with serum cystatin C levels are closely linked to those associated with GFR and highlights the potential usefulness of screening for moderate or mild CKD in subjects with diabetes by simply measuring serum cystatin C levels.

Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C- and creatinine-based methods.

AIMS/HYPOTHESIS: We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes. SUBJECTS, MATERIALS AND METHODS: In a cross-sectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of (99m)Tc-diethylene-triamine-penta-acetic acid) GFR (iGFR) was 88+/-2 ml min(-1) 1.73 m(-2). A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft-Gault (C-G) formulas were then compared in a validation population (n=126). RESULTS: There was no difference in renal function (ml min(-1) 1.73 m(-2)) as measured by iGFR (89.2+/-3.0), eGFR-cystatin C (86.8+/-2.5), MDRD-4 (87.0+/-2.8) or C-G (92.3+/-3.5). All three estimates of renal function had similar precision and accuracy. CONCLUSIONS/INTERPRETATION: Estimates of GFR based solely on serum cystatin C levels had the same predictive potential when compared with the MDRD-4 and C-G formulas.

Renal hyperfiltration in type 2 diabetes: effect of age-related decline in glomerular filtration rate.

AIMS/HYPOTHESIS: We sought to characterise the effect of the age-related decline of GFR on hyperfiltration in type 2 diabetes and to identify clinical characteristics associated with hyperfiltration. MATERIALS AND METHODS: GFR was measured in 662 type 2 diabetic patients by plasma disappearance of 99 m-technetium-diethylene-triamine-penta-acetic acid. The prevalence of hyperfiltration was calculated using both an age-unadjusted GFR threshold of >130 ml min(-1) 1.73 m(-2) and an age-adjusted threshold incorporating a decline of 1 ml min(-1) year(-1) after the age of 40. The hyperfiltering patients were compared with type 2 diabetic subjects who had a GFR between 90 and 130 ml min(-1) 1.73 m(-2) and were matched for age, sex and disease duration to allow for identification of modifiable factors associated with hyperfiltration. RESULTS: The prevalence of hyperfiltration was 7.4% when age-unadjusted and 16.6% when age-adjusted definitions were used. The age-unadjusted vs -adjusted prevalence rates for hyperfiltration were 50 vs 50%, 12.9 vs 23.4% and 0.3 vs 9.0% for patients aged <40 years, 40 to 65 years and >65 years, respectively. Both the age-unadjusted and -adjusted hyperfiltration groups had lower mean diastolic blood pressure and lower serum creatinine levels than the control groups. Although the age-unadjusted hyperfiltration group had larger kidneys compared to the control group, this difference was no longer significant when the age-adjusted definition was used. There were no differences in HbA(1)c, mean arterial pressure, antihypertensive use, insulin therapy, dyslipidaemia, frequency of macro- or microvascular complications, BMI, urinary sodium, urea and albumin excretion between the groups. CONCLUSIONS/INTERPRETATION: Hyperfiltration was still more common among younger patients with type 2 diabetes even after adjusting for the expected age-related decline in GFR. Hyperfiltration was associated with a lower mean diastolic blood pressure independent of age.

Detection of the "small for gestational age" fetus: comparison of a teaching hospital with field clinics.

INTRODUCTION: Low birthweight babies make a disproportionate contribution to perinatal morbidity and mortality. Antenatally they manifest as "small for gestational age" fetuses. Their detection is an important aspect of antenatal care. OBJECTIVES: To compare the effectiveness of antenatal detection of "small for gestational age", fetuses by a clinic in a teaching hospital and field clinics. DESIGN: Comparative descriptive study. SETTING: Professorial Obstetric Unit of De Soysa Maternity Hospital, Colombo. METHODS: Antenatal records of 67 consecutive women who delivered low birthweight babies at term were reviewed. Entries in the teaching hospital clinic records and the pregnancy record of the field clinics were studied. A deviation corresponding to more than two weeks' growth was considered significant. The period of gestation at which the deviation was first detected and any follow up action taken were noted. RESULTS: Of the total sample of 67 women 56 had also attended a field clinic. A significantly greater percentage of small for dates fetuses were detected by the primary care staff (71.4 vs 53.7%; p < 0.05). They also detected them earlier in pregnancy (26.4 vs 30.7 weeks; p < 0.05). However, referral for specialised care was arranged only in 32% by the field clinics. CONCLUSION: The detection rate of small for gestational age fetuses by staff of field clinics was close to the higher rates quoted in the literature. Only a minority of these fetuses were assessed further in both settings indicating a deficiency in antenatal care.