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Renal hyperfiltration is observed prior to the development of diabetic kidney disease (DKD) in patients with type 1 diabetes (T1DM); however its significance remains uncertain. Longitudinal data were used to investigate the association between measured baseline glomerular filtration rate (GFR) and renal function decline in patients with T1DM.This study included 142 adult patients with T1DM and ≥2 measurements of glomerular filtration rate (mGFR; determined by diethylene-triamine-penta-acetic acid plasma clearance). Median follow up was 19 years. Patients were stratified by baseline mGFR quartile. The relationship between baseline mGFR and rate of renal function decline was assessed using random-effect generalized least squares regression, adjusted for age, duration of diabetes, HbA1c, blood pressure, renin-angiotensin-aldosterone system inhibitor therapy, LDL and BMI.The average rates of decline in renal function for the 2nd (baseline mGFR: 96.4-112.6 ml min-(1) 1.73 m-(2)), 3(rd) (baseline mGFR: 112.6-125.5 ml min- (1) 1.73 m-(2)) and 4th quartiles (baseline mGFR125.5 ml min-(1) 1.73 m-(2)) were significantly faster than the first quartile (baseline mGFR: 60.9-96.4 ml min-(1) 1.73 m-(2)). In further detail, the average rates of decline in the 2nd (rate of decline 1.25 ml min- (1) 1.73 m-(2) per year, 95% CI: 0.97; 1.52, p=0.008), 3rd (rate of decline 1.35 ml min-(1) 1.73 m-(2) per year, 95% CI: 1.08; 1.62, p= 0.001) and 4th quartiles (rate of decline 1.6 ml min-(1) 1.73 m-(2) per year, 95% CI: 1.34, 1.88,0.0001) were significantly faster when compared to the first quartile (rate of decline 0.67 ml min-(1) 1.73 m-(2) per year, 95% CI: 0.37; 0.96). Sub-analysis of quartile 4 revealed higher HbA1c measurements throughout follow-up in those with rapid mGFR decline (3.0 ml min(-1)1.73 m(-2)/year).In patients with T1DM, higher baseline mGFR is associate ed with more rapid mGFR decline. Patients with high baseline mGFR who developed rapid mGFR decline had higher HbA1c measurements throughout the study. These findings are consistent with the concept that poor glycaemic control over time may be a determining factor for the rapid renal function decline observed in some hyperfiltering patients.

Diabet. Med. 27, 1401–1408 (2010) Abstract 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 r2 = 0.57, P

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.

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 excretion200 mmol/24 h on two out of three consecutive occasions) or low (LDS, sodium excretion100 mmol/24 h on two out of three consecutive occasions) salt intake.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.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.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.

The evaluation of diabetic nephropathy from research and clinical viewpoints depends on the assessment of two continuous variables, albumin excretion rate (AER) and glomerular filtration rate (GFR). These two parameters form the basis of both the European classification of five stages of diabetic nephropathy, assessed according to changes in AER and GFR (hyperfiltration, normoalbuminuria, microalbuminuria, macroalbuminuria and end-stage renal disease), and the National Kidney Foundation classification of five stages of chronic kidney disease based on categories of estimated GFR. Although increases in AER generally precede a decline in GFR, some patients follow a non-albuminuric pathway to renal impairment. In addition, studies indicate that GFR decreases in a linear fashion from normal or above-normal levels. Whether hyperfiltration is part of the pathogenetic process leading to diabetic nephropathy remains unclear. Ideally, both AER and GFR should be assessed at an early stage in patients being evaluated for diabetic nephropathy. New methods such as the use of cystatin-C-based equations for estimating GFR should be considered because current creatinine-based estimates are inaccurate at normal or high GFRs. Serial assessments of both AER and GFR might allow diabetic nephropathy to be diagnosed at early stages of the disease process that are selectively responsive to new interventions. The successful integration of AER categories with the recently defined stages of GFR represents a new challenge in the management 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 to60 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 levels60 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.

Summary Context Sunitinib malate is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumours. Hypothyroidism has been observed in patients treated with sunitinib, but the mechanism whereby sunitinib induces hypothyroidism is unknown. Objective To describe a series of six patients who developed thyrotoxicosis while on sunitinib for metastatic RCC. Setting The study was conducted at Austin Health, a tertiary teaching hospital in Melbourne, Australia. Results Two patients developed severe thyrotoxicosis within 10 weeks after commencing sunitinib. In contrast, in the four patients who presented with later onset (16–30 weeks) thyrotoxicosis, the thyrotoxicosis was relatively mild, self-limiting and rapidly progressed to hypothyroidism. These patients experienced recurrent episodes of thyrotoxicosis in temporal relation to their cyclical sunitinib treatment. One patient had cytological evidence of lymphocytic thyroiditis. Conclusions These findings suggest that sunitinib-induced hypothyroidism may be a consequence of preceding thyroiditis with associated transient thyrotoxicosis. As predictive factors are currently unknown, we suggest regular monitoring of thyroid function in all patients commenced on sunitinib. Clinicians treating patients with sunitinib or other similar kinase inhibitors should to be alerted to thyroid dysfunction as a potential toxicity of these agents.

In late diabetic nephropathy (DN) the initial lowering of albumin excretion rate (AER) with antihypertensive therapy is proportional to the degree of subsequent preservation of glomerular filtration rate (GFR). Whether a similar relationship exists between AER and GFR in early diabetes is not known. The present analysis has compared AER and GFR responses to antihypertensive therapy in 33 published studies (77 treatment groups) of early and late DN in type 1 (T1) and type 2 (T2) diabetes, analyzed on an intention-to-treat basis. Prospective trials were included if the initial change in AER during the first year of therapy and the change in GFR during at least 2 years of follow-up could be estimated from group mean data. The initial % decreases in AER were 5.9 +/- 4.3 (T1), 10.5 +/- 5.4 (T2, normotensive) and 18.4 +/- 6.2 (T2, hypertensive) in early DN and 7.6 +/- 11.1 (T1) and 20.8 +/- 5.5 (T2) in late DN. The corresponding annual % rates of decline of GFR were 2.0 +/- 0.5 (T1), 1.6 +/- 0.5 (T2, normotensive) and 2.1 +/- 0.3 (T2, hypertensive) in early DN and 9.8 +/- 1.5 (T1) and 9.2 +/- 1.1 (T2) in late DN. AER and GFR responses in each treatment group were closely correlated in late nephropathy (T1, r = -0.67, p = 0.03; T2, r = 0.57, p = 0.02) but not in early nephropathy. In contrast to late DN, the initial decrease in AER with antihypertensive therapy was not shown to predict the subsequent rate of decline of GFR in early DN. It follows that assessment of renoprotection during antihypertensive therapy in early nephropathy should be based not only on albuminuria but also on the GFR response.

Background Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. Methods In a cross-sectional study, bias (eGFR – mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m2 per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. Results In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p 90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.

We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes.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).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.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.

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.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 of130 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.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 aged40 years, 40 to 65 years and65 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.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.

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

OBJECTIVE—Cystatin C–and creatinine-based methods were compared with 99m-technetium-diethylene-triamine-penta-acetic acid (99mTc-DTPA) plasma clearance (isotopic glomerular filtration rate [iGFR]) for detecting declining renal function. RESEARCH DESIGN AND METHODS—Glomerular filtration rate (GFR) was monitored over a mean of 10.1 years in 85 subjects with type 1 diabetes (with an average of 5.6 measurements per individual). Baseline mean ± SD iGFR of the cohort was 106.1 ± 2.6 ml/min per 1.73 m2. The rates of decline in GFR (ΔGFR) were derived using linear regression. RESULTS—In 19 of 85 subjects with declining renal function (i.e., ΔiGFR >3.3 ml/min per 1.73 m2 per year), ΔGFR (ml/min per 1.73 m2 per year) was 6.5 by iGFR, 4.2 by 104/creatinine, 3.6 by Cockcroft-Gault formula, 3.4 by the Modification of Diet in Renal Disease (MDRD)-6 equation, and 3.5 by the MDRD-4 variable equation (P < 0.01 vs. iGFR). In comparison, ΔGFR was 6.1 using the formula Cys-GFR = (86.7/cystatin C concentration) − 4.2 (not significant). CONCLUSIONS—Cystatin C was more accurate in detecting decline in renal function than creatinine-based methods in this population of subjects with type 1 diabetes and a normal mean baseline GFR.

Aims The prevalence of diabetes is rising, and people with diabetes have higher rates of musculoskeletal-related comorbidities. HbA1c testing is a superior option for diabetes diagnosis in the inpatient setting. This study aimed to (i) demonstrate the feasibility of routine HbA1c testing to detect the presence of diabetes mellitus, (ii) to determine the prevalence of diabetes in orthopedic inpatients and (iii) to assess the association between diabetes and hospital outcomes and post-operative complications in orthopedic inpatients. Methods All patients aged ≥54 years admitted to Austin Health between July 2013 and January 2014 had routine automated HbA1c measurements using automated clinical information systems (CERNER). Patients with HbA1c ≥6.5% were diagnosed with diabetes. Baseline demographic and clinical data were obtained from hospital records. Results Of the 416 orthopedic inpatients included in this study, 22% (n = 93) were known to have diabetes, 4% (n = 15) had previously unrecognized diabetes and 74% (n = 308) did not have diabetes. Patients with diabetes had significantly higher Charlson comorbidity scores compared to patients without diabetes (median, IQR; 1 [0,2] vs 0 [0,0], p

Using the principle of energy conservation and laws of geometrical optics, we derive the photon transport equation for turbid biological media with spatially varying isotropic refractive index. We show that when the refractive index is constant, our result reduces to the standard radiative transfer equation and when the medium is lossless and free of scattering to the well known geometrical optics equations in refractive media.

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 99cTc-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 (