Richard J. MacIsaac

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.

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.

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.

Urinary Proteomics for Early Diagnosis in Diabetic Nephropathy

Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis–coupled mass spectrometry was used to profile the low–molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve [AUC] 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3–5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments.

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.

Nonalbuminuric Renal Impairment in Type 2 Diabetic Patients and in the General Population (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [NEFRON] 11)

OBJECTIVE Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m2) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m2 (95% CI 21.8–24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1–1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5–0.7, P < 0.001). CONCLUSIONS Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.

Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease

Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers.

Diabetic kidney disease with and without albuminuria

Purpose of reviewHistorically, for people at risk of developing diabetic chronic kidney disease (CKD), an initial increase in albumin excretion rate (AER) has been linked to a subsequent decline in glomerular filtration rate (GFR). We review recent findings that suggest that in some people with diabetic CKD there is an uncoupling of progressive increases in AER and declining GFR. Recent findingsApproximately 20% of people with type 2 diabetes develop at least stage 3 CKD, defined as an estimated GFR (eGFR) less than 60 ml/min/1.73 m2, after accounting for the use of renin–angiotensin system blockers, while remaining normoalbuminuric. A recent analysis from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study has shown that 24% of people with type 1 diabetes reached an eGFR threshold of less than 60 ml/min/1.73 m2 that was not associated with a rise in albuminuria to the microalbuminuria or macroalbuminuria range. This discordance between changes in GFR and AER has resulted in a search for new markers that identify people with diabetes who are at risk of declining GFR independent of progressive increases in AER. SummaryThe conventional paradigm of kidney disease in people with diabetes has been challenged. Changes in AER and GFR are being increasingly recognized as complementary rather than obligatory manifestations of diabetic CKD.

Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies

Background: Diabetic emergencies associated with ketoacidosis (DKA) and a hyperosmolar, hyperglycaemic state (HHS) are both acute life‐threatening metabolic disturbances. Traditionally, DKA and HHS have been classified as distinct entities but there is evidence to suggest that patients can present with elements of both conditions.

Parathyroid hormone-related protein: a possible endocrine function in lactation

OBJECTIVE Parathyroid hormone‐related protein (PTHrP), initially discovered as the factor responsible for the syndrome of humoral hypercalcaemia of malignancy, has also been found to be expressed in placenta, in pregnant uterus, in the fetus at many locations, and in the lactating mammary gland. This study sought to establish whether PTHrP reaches the maternal circulation when it is expressed in mammary tissue during lactation or in the maternal reproductive tract during gestation.