George Jerums

Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement.

Optimal detection and subsequent risk stratification of people with chronic kidney disease (CKD) requires simultaneous consideration of both kidney function (glomerular filtration rate [GFR]) and kidney damage (as indicated by albuminuria or proteinuria). Measurement of urinary albuminuria and proteinuria is hindered by a lack of standardisation regarding requesting, sample collection, reporting and interpretation of tests. A multidisciplinary working group was convened with the goal of developing and promoting recommendations that achieve consensus on these issues. The working group recommended that the preferred method for assessment of albuminuria in both diabetic and non‐diabetic patients is urinary albumin‐to‐creatinine ratio (UACR) measurement in a first‐void spot urine specimen. Where a first‐void specimen is not possible or practical, a random spot urine specimen for UACR is acceptable. The working group recommended that adults with one or more risk factors for CKD should be assessed using UACR and estimated GFR every 1–2 years, depending on their risk‐factor profile. Recommended testing algorithms and sex‐specific cut‐points for microalbuminuria and macroalbuminuria are provided. The working group recommended that all pathology laboratories in Australia should implement the relevant recommendations as a vital component of an integrated national approach to detection of CKD.

Reduced Bone Mass in Daughters of Women with Osteoporosis

Abstract To determine whether premenopausal daughters of women with postmenopausal osteoporosis have lower bone mass than other women of the same age, we measured the bone mineral content of the lu...

Prevention of Diabetic Renal Disease with Special Reference to Microalbuminuria

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

Retardation by Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-Induced Diabetic Rat

This study evaluated the relationship between the development of fluorescence related to advanced glycosylation end products (AGEs) in the kidney and experimental diabetic nephropathy over a 32-wk period. Control, untreated diabetic, and aminoguanidine-treated diabetic rats were followed for 32 wk with eight weekly measurements of urinary albumin excretion. After 32 wk, collagen-related fluorescence in aorta and kidney (whole kidney, isolated glomeruli, and renal tubules) and glomerular ultrastructure were evaluated. Diabetes was associated with a significant increase in collagen-related fluorescence in the aorta and kidney. Aminoguanidine prevented the increases in collagen-related fluorescence in aorta, isolated glomeruli, and renal tubules but not in whole kidney. Diabetes was associated with increased albuminuria, fractional mesangial volume, and glomerular basement membrane (GBM) thickness. Aminoguanidine attenuated the rise in albuminuria and prevented mesangial expansion without influencing GBM thickness in diabetic rats. The concomitant changes in collagen-related fluorescence, albuminuria, and mesangial expansion with aminoguanidine therapy are consistent with the hypothesis that AGEs may play a role in the development of diabetic nephropathy.

Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)

Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Abs to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.

Low testosterone levels are common and associated with insulin resistance in men with diabetes.

CONTEXT Low testosterone levels are common in men with type 2 diabetes and may be associated with insulin resistance. OBJECTIVE We investigated prevalence of testosterone deficiency and the relationship between testosterone and insulin resistance in a large cohort of men with type 2 and type 1 diabetes. DESIGN The study was a cross-sectional survey of 580 men with type 2 diabetes and 69 men with type 1 diabetes. A subgroup of 262 men with type 2 diabetes was then reassessed after a median of 6 months. RESULTS Forty-three percent of men with type 2 diabetes had a reduced total testosterone, and 57% had a reduced calculated free testosterone. Only 7% of men with type 1 diabetes had low total testosterone. By contrast, 20.3% of men with type 1 diabetes had low calculated free testosterone, similar to that observed in type 2 diabetes (age-body mass index adjusted odds ratio = 1.4; 95% confidence interval = 0.7-2.9). Low testosterone levels were independently associated with insulin resistance in men with type 1 diabetes as well as type 2 diabetes. Serial measurements also revealed an inverse relationship between changes in testosterone levels and insulin resistance. CONCLUSIONS Testosterone deficiency is common in men with diabetes, regardless of the type. Testosterone levels are partly influenced by insulin resistance, which may represent an important avenue for intervention, whereas the utility of testosterone replacement remains to be established in prospective trials.

Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.

The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes

Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre‐formed AGEs within the kidney by a crosslink breaker, such as ALT‐711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross‐link breaker, ALT‐711, weeks 16–32 (DALT early); and c) ALT‐711, weeks 24–32 (DALT late). Treatment with ALT‐711 resulted in a significant reduction in diabetes‐induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross‐linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT‐711 treatment. ALT‐711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes‐induced increases in gene expression of transforming growth factor β1 (TGF‐β1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF‐β1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross‐link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.

Dietary salt intake and mortality in patients with type 2 diabetes.

OBJECTIVE Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hUNa). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS The mean baseline 24hUNa was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hUNa, after adjusting for other baseline risk factors (P < 0.001). For every 100 mmol rise in 24hUNa, all-cause mortality was 28% lower (95% CI 6–45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hUNa was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44–0.95]; P = 0.03). CONCLUSIONS In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting.

Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products.

The accelerated formation of advanced glycation end products (AGEs) and the overexpression of transforming growth factor beta (TGF-beta) have both been implicated in the pathogenesis of diabetic microvascular and macrovascular complications. Previous studies in our laboratory have demonstrated that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment. Animals were studied at 7 d, 3 wk, and 8 mo after induction of diabetes. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight and an increase in media wall/lumen area. By Northern analysis, TGF-beta1 gene expression was increased 100-150% (P < 0.01) and alpha1 (IV) collagen gene expression was similarly elevated to 30-110% compared to controls (P < 0.05). AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with aminoguanidine resulted in significant amelioration of the described pathological changes including overexpression of TGF-beta1 and alpha1 (IV) collagen. These data implicate the formation of AGEs in TGF-beta overexpression and tissue changes which accompany the diabetic state.