Erosha Premaratne

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.

Thyrotoxicosis during sunitinib treatment for renal cell carcinoma

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.

Integrating albuminuria and GFR in the assessment of diabetic nephropathy.

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.

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.

The photon transport equation for turbid biological media with spatially varying isotropic refractive index

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.

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.

Lowering of Proteinuria in Response to Antihypertensive Therapy Predicts Improved Renal Function in Late but Not in Early Diabetic Nephropathy: A Pooled Analysis

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.

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

Diabet. Med. 27, 1401–1408 (2010)

Elevated baseline glomerular filtration rate (GFR) is independently associated with a more rapid decline in renal function of patients with type 1 diabetes

AIMS 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. METHODS 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. RESULTS 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 mGFR >125.5 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). CONCLUSIONS 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.