Relationship Between Urinary Phosphate and All-Cause and Cardiovascular Mortality in a National Population-Based Longitudinal Cohort Study.

OBJECTIVES: High dietary phosphate intake may lead to adverse outcomes including cardiovascular disease (CVD). Urinary phosphate excretion, a marker of intestinal phosphate absorption, may be a more reliable marker of phosphate homeostasis in steady state than serum phosphate. Studies report good agreement between urine phosphate-to-creatinine ratio (uPiCr) and 24-hour urinary phosphate; however, whether uPiCr is associated with increased risk of CVD or mortality remains uncertain. This study aimed to assess the relationship between uPiCr and all-cause and CVD mortality. DESIGN AND METHODS: This is an observational longitudinal cohort study using data from the population-based national Australian Diabetes, Obesity and Lifestyle study (n = 10,014 participants). Non-linear association between uPiCr and all-cause and CVD mortality was assessed using fractional polynomial transformations. Cox proportional hazards regression models were used to estimate adjusted hazard ratios for all-cause and CVD mortality. RESULTS: Median age [interquartile range] was 50 [41-62] years, and 46% were male. Median uPiCr was 1.38 [1.02-1.79] mmol/mmol. Median follow-up time was 16.9 years with 1,735 deaths. uPiCr was associated with all-cause and CVD mortality in univariate models and when adjusted for age and gender. However, associations were not significant in multivariate models. Sensitivity analyses excluding participants with chronic kidney disease (CKD) revealed a significant J-shaped association between uPiCr and all-cause mortality. Urine phosphate alone showed an association with increased all-cause mortality in a similar J-shape relationship. CONCLUSION: Although no association between uPiCr and all-cause and CVD mortality was observed in multivariate analyses in the whole cohort, a significant relationship between uPiCr and mortality in those without CKD suggests that uPiCr may have predictive validity for future adverse outcomes in people with no CKD.

Serum 25-hydroxyvitamin D deficiency and the 5-year incidence of CKD.

BACKGROUND: Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with chronic kidney disease in cross-sectional studies. However, this association has not been studied prospectively in a large general population-based cohort. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 6,180 adults 25 years or older participating in the baseline and 5-year follow-up phases of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. PREDICTOR: Serum 25(OH)D levels <15 ng/mL were considered deficient. OUTCOMES & MEASUREMENTS: Incident chronic kidney disease was defined as being negative at baseline but positive after 5 years for (1) reduced estimated glomerular filtration rate (eGFR; <60 mL/min/1.72 m²) or (2) albuminuria (spot urine albumin-creatinine ratio ≥2.5 mg/mmol [≥22.1 mg/g] for men and ≥3.5 mg/mmol [≥30.9 mg/g] for women). RESULTS: 623 (10.9%) participants were vitamin D deficient, 161 developed incident reduced eGFR, and 222 developed incident albuminuria. In participants with and without vitamin D deficiency, annual age-standardized incidences were 0.92% (95% CI, 0.56%-1.30%) and 0.59% (95% CI, 0.51%-0.68%), respectively, for eGFR <60 mL/min/1.72 m² and 1.50% (95% CI, 1.06%-1.95%) and 0.66% (95% CI, 0.56%-0.76%), respectively, for albuminuria. In multivariate regression models, vitamin D deficiency was associated significantly with the 5-year incidence of albuminuria (OR, 1.71; 95% CI, 1.12-2.61; P = 0.01), but not reduced eGFR (OR, 0.93; 95% CI, 0.53-1.66; P = 0.8). LIMITATIONS: The observational nature of the study does not account for unmeasured confounders. Only baseline 25(OH)D level was measured and therefore may not accurately reflect lifetime levels. Differences in baseline characteristics of participants who were included compared with those excluded due to missing data or follow-up may limit the applicability of results to the original AusDiab cohort. CONCLUSIONS: Our prospective cohort study shows that vitamin D deficiency is associated with a higher annual incidence of albuminuria and reduced eGFR and independently predicts the 5-year incidence of albuminuria. These associations warrant further exploration in long-term prospective clinical trials.

Residual proteinuria and eGFR predict progression of renal impairment within 2 years in type 2 diabetic patients with nephropathy who are receiving optimal treatment with angiotensin receptor blockers.

AIM: Proteinuria and estimated glomerular filtration rate (eGFR) predict progression of renal impairment in type 2 diabetic nephropathy (DN) but are they still predictive when these patients are treated with angiotensin receptor blockers (ARB)? We investigated whether residual (after ≥3 months of ARB treatment) urinary protein/creatinine ratio (rPCR) or urinary albumin/creatinine ratio (rACR) and residual eGFR (reGFR), predict subsequent progression. METHODS: One thousand, two hundred and forty-five patients with type 2 DN from two international multi-center studies were analysed. Cross classification of rPCR, rACR with reGFR (rPCR: <1000, 1000-<2000 and ≥2000 mg/g; rACR: <666.7, 666.7-<1333.3 and ≥1333.3 mg/g; reGFR: 15-29, 30-44 and 45-59 mL/min per 1.73 m2). Progression of renal disease exhibited as: end stage renal failure, doubling of serum creatinine, or serum creatinine ≥6 mg/dL. RESULTS: Increasing rPCR or rACR, and decreasing reGFR were strongly associated with increasing risk of renal disease progression, with no evidence of interaction between rPCR and reGFR, or rACR and reGFR. The estimated 24-month risk was low (<8%) for patients with rPCR <1000 mg/g regardless of reGFR, for patients with reGFR ≥45 mL/min per 1.73 m2 regardless of rPCR, or with rPCR between 1000-<2000 mg/g and reGFR ≥30 mL/min per 1.73 m2 . However, the risk rose steeply (to 39.4%) for reGFR <30 mL/min per 1.73 m2 and rPCR ≥2000 mg/g. CONCLUSION: Despite DN patients being treated with ARB, renal disease progression risk over 2 years increases with increasing proteinuria, albuminuria and decreasing eGFR. Recognition of these risk factors' impact is important in patient management and future clinical trial design.

Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy.

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Pyridorin in type 2 diabetic nephropathy.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

25-Hydroxyvitamin D levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study.

BACKGROUND: Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study). METHODS: 10,732 adults ≥ 25 years of age participating in the baseline survey of the AusDiab study (1999-2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m(2). Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥ 2.5 mg/mmol for men and ≥ 3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models. RESULTS: 30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07). CONCLUSIONS: Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.

Diagnostic accuracy of urine dipsticks for detection of albuminuria in the general community.

BACKGROUND: Urine dipsticks, an inexpensive accessible test for proteinuria, are widely advocated for mass screening; however, their diagnostic accuracy in the general community is largely unknown. STUDY DESIGN: Evaluation of diagnostic test accuracy in a cross-sectional cohort. SETTING & PARTICIPANTS: AusDiab, a representative survey of Australian adults 25 years and older (conducted in 1999/2000). Stratified cluster random sampling from 11,247 individuals participating in the biomedical examination; complete urinalysis data available for 10,944. INDEX TEST: Urine dipsticks (Bayer Multistix), with a positive result defined as ≥1+ or trace or higher protein. REFERENCE TEST: Albumin-creatinine ratio (ACR), measured on a random spot urine sample. Reference test positivity was defined as ACR ≥30 mg/g or ACR ≥300 mg/g. RESULTS: Numbers of participants with ACR <30, 30-300, and ≥300 mg/g were 10,219 (93.4%), 634 (5.8%), and 91 (0.8%), respectively. The area under the receiver operating characteristic curve (AUC) for dipstick detection of ACR ≥30 mg/g was 0.8451 ± 0.0129 (SE) in men and 0.7775 ± 0.0131 in women (P < 0.001). The AUROC for dipstick detection of ACR ≥300 mg/g was 0.9904 ± 0.0030 in men and 0.9950 ± 0.0016 in women (P = 0.02). Dipstick result ≥1+ identified ACR ≥30 mg/g with 57.8% sensitivity (95% CI, 54.1%-61.4%) and 95.4% specificity (95% CI, 95.0%-95.8%) and identified ACR ≥300 mg/g with 98.9% sensitivity (99% CI, 92.1%-100%) and 92.6% specificity (99% CI, 92.0%-93.3%). A dipstick result of trace or higher identified ACR ≥30 mg/g with 69.4% sensitivity (95% CI, 65.9%-72.7%) and 86.8% specificity (95% CI, 86.1%-87.4%) and identified ACR ≥300 mg/g with 100% sensitivity (99% CI, 94.3%-100%) and 83.7% specificity (99% CI, 82.8%-84.6%). A negative dipstick result (less than trace) had a negative predictive value of 97.6% (95% CI, 97.2%-97.9%) for ACR ≥30 mg/g and a negative predictive value of 100% (99% CI, 99.9%-100%) for ACR ≥300 mg/g. The probability of an ACR ≥30 mg/g confirmed on laboratory investigation was 47.2% (95% CI, 43.9%-50.5%) based on a dipstick result ≥1+ and 27.1% (95% CI, 25.1%-29.2%) based on a trace or higher result. LIMITATIONS: Isolated urine samples precluded assessment of test reproducibility. Urine specific gravity and pH were not recorded; therefore, the effect of urine concentration on test performance was not assessed. CONCLUSIONS: A dipstick test result <1+ or less than trace has a high negative predictive value in the general community setting, with minimal risk of a missed diagnosis of macroalbuminuria. High false-positive rates emphasize the need for laboratory confirmation of positive results.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.

BACKGROUND: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. STUDY DESIGN: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. SETTING & PARTICIPANTS: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. INTERVENTION: The study drug was sulodexide, 200 mg/d. OUTCOME & MEASUREMENTS: The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR. RESULTS: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. LIMITATIONS: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. CONCLUSION: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Proteinuria in type 2 diabetic patients with renal impairment: the changing face of diabetic nephropathy.

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of <500 mg/g. Therapy with ACEi and/or ARB at the time of screening was recorded in 94%, where prior medication data was available. In patients with type 2 DN and advanced renal impairment, levels of proteinuria below that which traditionally defines overt diabetic nephropathy, are found in more than one fifth of patients. We suggest that the high prevalence of ACEi and ARB usage in patients with type 2 DN may be effecting the traditional clinical paradigm of type 2 DN.

Physical inactivity and chronic kidney disease in Australian adults: the AusDiab study.

BACKGROUND AND AIMS: Physical inactivity is associated with cardiovascular risk however its relationship to chronic kidney disease is largely unknown. We examined the association between leisure-time physical activity and risk of chronic kidney disease in a prospective, population-based cohort of Australians aged ≥ 25 years (AusDiab). METHODS AND RESULTS: The baseline sample included 10,966 adults (4951 males and 6015 females). From this sample, 6318 participants with complete baseline and 5-year follow-up urinalysis and serum creatinine measurements formed the study population for longitudinal analysis. Self-reported leisure-time physical activity was measured using a validated, interviewer-administered questionnaire. Compared with sufficiently active individuals (≥ 150 min physical activity per week), those who were inactive (0 min/week) were more likely to have albuminuria at baseline (multivariate-adjusted OR=1.34, 95% CI 1.10-1.63). Inactivity (versus sufficient physical activity) was associated with increased age- and sex-adjusted odds of an estimated glomerular filtration rate <3rd percentile (OR=1.30, 95% CI 1.02-1.65), although this was not significant after multivariate adjustment (OR=1.17, 95% CI 0.91-1.50). Obese, inactive individuals were significantly more likely to have albuminuria at baseline (multivariate-adjusted OR=1.74, 95% CI 1.35-2.25), compared with sufficiently active, non-obese individuals. Baseline physical activity status was not significantly associated with longitudinal outcomes. CONCLUSIONS: Physical inactivity is cross-sectionally associated with albuminuria prevalence, particularly when combined with obesity. Future studies are needed to determine whether this association is causal and the importance of physical activity in CKD prevention.

Comparison of the prevalence and mortality risk of CKD in Australia using the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study GFR estimating equations: the AusDiab (Australian Diabetes, Obesity and Lifestyle) Study.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is more accurate than the Modification of Diet in Renal Disease (MDRD) Study equation. We applied both equations in a cohort representative of the Australian adult population. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 11,247 randomly selected noninstitutionalized Australians aged >or= 25 years who attended a physical examination during the baseline AusDiab (Australian Diabetes, Obesity and Lifestyle) Study survey. PREDICTORS & OUTCOMES: Glomerular filtration rate (GFR) was estimated using the MDRD Study and CKD-EPI equations. Kidney damage was defined as urine albumin-creatinine ratio >or= 2.5 mg/mmol in men and >or= 3.5 mg/mmol in women or urine protein-creatinine ratio >or= 0.20 mg/mg. Chronic kidney disease (CKD) was defined as estimated GFR (eGFR) >or= 60 mL/min/1.73 m(2) or kidney damage. Participants were classified into 3 mutually exclusive subgroups: CKD according to both equations; CKD according to the MDRD Study equation, but no CKD according to the CKD-EPI equation; and no CKD according to both equations. All-cause mortality was examined in subgroups with and without CKD. MEASUREMENTS: Serum creatinine and urinary albumin, protein, and creatinine measured on a random spot morning urine sample. RESULTS: 266 participants identified as having CKD according to the MDRD Study equation were reclassified to no CKD according to the CKD-EPI equation (estimated prevalence, 1.9%; 95% CI, 1.4-2.6). All had an eGFR >or= 45 mL/min/1.73 m(2) using the MDRD Study equation. Reclassified individuals were predominantly women with a favorable cardiovascular risk profile. The proportion of reclassified individuals with a Framingham-predicted 10-year cardiovascular risk >or= 30% was 7.2% compared with 7.9% of the group with no CKD according to both equations and 45.3% of individuals retained in stage 3a using both equations. There was no evidence of increased all-cause mortality in the reclassified group (age- and sex-adjusted hazard ratio vs no CKD, 1.01; 95% CI, 0.62-1.97). Using the MDRD Study equation, the prevalence of CKD in the Australian population aged >or= 25 years was 13.4% (95% CI, 11.1-16.1). Using the CKD-EPI equation, the prevalence was 11.5% (95% CI, 9.42-14.1). LIMITATIONS: Single measurements of serum creatinine and urinary markers. CONCLUSIONS: The lower estimated prevalence of CKD using the CKD-EPI equation is caused by reclassification of low-risk individuals.

Television viewing time and risk of chronic kidney disease in adults: the AusDiab Study.

BACKGROUND: Television viewing time independent of physical activity is associated with a number of chronic diseases and related risk factors; however, its relationship with chronic kidney disease is unknown. PURPOSE: The purpose of this study is to examine the cross-sectional and prospective relationships of television viewing time with biomarkers of chronic kidney disease. METHODS: Participants of the Australian Diabetes, Obesity and Lifestyle Study attended the baseline (n = 10,847) and 5-year follow-up (n = 6,293) examination. RESULTS: Television viewing was significantly associated with increased odds of prevalent albuminuria and low estimated glomerular filtration rate. In the gender-stratified analyses this pattern was seen for men, but not for women. In the longitudinal analyses, odds of de novo albuminuria and low estimated glomerular filtration rate were increased only in unadjusted models. CONCLUSIONS: Television viewing time may be directly related to markers of chronic kidney disease and through intertwined associated risk factors such as diabetes, hypertension, and obesity.

Nephrotic syndrome in diabetic kidney disease: an evaluation and update of the definition.

BACKGROUND: Nephrotic syndrome is defined as urine total protein excretion greater than 3.5 g/d or total protein-creatinine ratio greater than 3.5 g/g, low serum albumin level, high serum cholesterol level, and peripheral edema. These threshold levels have not been rigorously evaluated in patients with diabetic kidney disease or by using urine albumin excretion, the preferred measure of proteinuria in patients with diabetes. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Adults with type 2 diabetes, hypertension, and urine total protein level greater than 0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial. INDEX TEST: Baseline measures of proteinuria (total protein and albumin excretion and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures. REFERENCE TEST: Other signs and symptoms of nephrotic syndrome at baseline (serum albumin < 3.5 g/dL, serum total cholesterol > 260 mg/dL or use of a statin, and edema or use of a loop diuretic); progression of chronic kidney disease during follow-up (doubling of baseline serum creatinine level or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests. RESULTS: In 1,608 participants, total urine protein level of 3.5 g/d was equivalent to urine albumin level of 2.2 g/d (95% confidence interval, 1.4 to 3.5). Of 1,467 participants, 641 (44%) had urine total protein level of 3.5 g/d or greater at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline, and 385 (26%) had progression of kidney disease during a mean follow-up of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. Threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes. LIMITATIONS: Study population limits generalizability; inability to adjust for several variables known to affect serum albumin levels; lack of spot urine samples. CONCLUSIONS: The historical definition of nephrotic-range proteinuria appears reasonable in patients with diabetic kidney disease. Equivalent thresholds for nephrotic-range albuminuria and albumin-creatinine ratio are 2.2 g/d and 2.2 g/g, respectively.

Alcohol consumption and 5-year onset of chronic kidney disease: the AusDiab study.

BACKGROUND: Excessive alcohol consumption is a risk factor for hypertension and stroke; however, evidence for an association with chronic kidney disease is conflicting. METHODS: A total of 6259 adults >or=25 years of age, without a history of alcohol dependence, participating in baseline (1999-2000) and follow-up (2004-2005) phases of an Australian population-representative study (AusDiab) were the subject of this analysis. Alcohol consumption status and volume/frequency were collected by standardized interviewer administered questionnaires and self-administered food frequency questionnaires. The outcomes were as follows: (i) 5-year decline in estimated glomerular filtration rate (eGFR) >or=10%, with baseline eGFR >or= 60 and final eGFR <60 mL/min/1.73 m(2), and (ii) 5-year doubling of albumin to creatinine ratio (ACR) with final ACR >or= 2.5 (males)/>or= 3.5 (females) mg/mmol, in the absence of albuminuria at baseline. RESULTS: Self-identification as a moderate or heavy, versus light, drinker was associated with elevated risk of albuminuria in males and females <65 years of age (OR, 95% CI: males 1.87, 0.99-3.52; females 2.38, 1.37-4.14). Odds of de novo eGFR <60 mL/min/1.73 m(2) were 0.34 (95% CI 0.22-0.59) and 0.68 (95% CI 0.36-1.27) in males and females, respectively, who were moderate-heavy drinkers. Alcohol intake of >or=30 g/day was associated with an increased risk of albuminuria after adjustment for age, sex and baseline kidney function (OR = 1.59, 95% CI 1.07-2.36), but a reduced risk of eGFR <60 mL/min/1.73 m(2) (OR = 0.59, 95% CI 0.37-0.95), compared with consumption of <10 g/day. CONCLUSIONS: Moderate-heavy alcohol consumption may be an important modifiable risk factor for albuminuria in the general population. The natural history of alcohol-induced kidney damage and how this relates to markers of kidney function in the general population warrant further research.

Predictive value of nephelometric and high-performance liquid chromatography assays of urine albumin for mortality in a high-risk Aboriginal population.

BACKGROUND: Urine albumin assays by high-performance liquid chromatography (HPLC) yield greater values than immunoassays at lower albumin levels. We compared predictive values of albumin-creatinine ratios (ACRs) by these 2 techniques for mortality in Aboriginal people. STUDY DESIGN & SETTING: This was a longitudinal study of 741 adults in a remote Aboriginal community who participated in a baseline health survey between 1992 and 1998 at ages ranging from 18 to 84 years (mean, 34 years). All natural deaths were documented on follow-up until 2006. Urine albumin concentrations were measured simultaneously by using both nephelometric and HPLC techniques on baseline urine samples retrieved from -70 degrees C storage, as well as creatinine concentrations, and ACRs were derived. Age- and sex-specific tertiles of ACR were compiled. Cox regression analyses were used to evaluate the predictive value of ACR for natural deaths by ACR tertiles and again by z score changes in ACRs as continuous variables. RESULTS: Participants were followed up for a median of 11 years, during which a total of 119 natural deaths were documented. ACRs on baseline urine samples were greater by HPLC than immunoassay at lower ACR ranges, but were fairly concordant at levels greater than 100 mg/mmol. Levels of ACR by both techniques were strong predictors of death, but correlations of death with ACR tertiles and with ACR levels on a continuum were similar for the 2 techniques. LIMITATIONS: The age- and sex-specific tertiles used might introduce some risk of bias in the assessment of predictive value. In addition, assays were performed on urine after more than 10 years of cold storage. CONCLUSION: Despite different absolute values, this study did not show that ACR level by either technique was superior in predicting deaths.

Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney.

AIM: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. METHODS: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). RESULTS: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of alpha-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. CONCLUSION: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway.

HPLC-detected albuminuria predicts mortality.

Albuminuria is a risk factor for all-cause mortality. Urinary albumin is traditionally measured with an immunochemical method such as immunonephelometry (IN). High-performance liquid chromatography (HPLC) detects additional albumin that is missed by IN, but it is unknown if HPLC-detected albuminuria also predicts mortality in the general population. We measured urinary albumin at baseline with both IN and HPLC in 10,175 participants in the longitudinal Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Over 5.2 yr of follow-up, 319 participants died. In a Cox proportional hazards regression model, participants with albuminuria measured by IN or HPLC were approximately twice as likely to die as participants who were normoalbuminuric on both assays. Receiver-operator characteristic curve analyses suggest that each test has a similar ability to predict mortality. However, the HPLC assay provided information on mortality risk that the IN assay did not capture. We conclude that albuminuria, detected by either IN or HPLC, independently predicts mortality in a community-based sample. HPLC identifies some people at increased risk of mortality that IN would not detect.

Risk of renal allograft loss from recurrent glomerulonephritis.

BACKGROUND: Recurrent glomerulonephritis is a known cause of renal allograft loss; however, the incidence of this complication is poorly defined. We determined the incidence, timing, and relative importance of allograft loss due to the recurrence of glomerulonephritis. METHODS: A total of 1505 patients with biopsy-proved glomerulonephritis received a primary renal transplant in Australia from 1988 through 1997. Recurrence was confirmed by renal biopsy. The Kaplan-Meier method was used to estimate the 10-year incidence of allograft failure due to recurrent glomerulonephritis, and this incidence was compared with the incidence of acute rejection, chronic rejection, and death with a functioning allograft. Characteristics of the recipients and donors were examined as potential predictors of recurrence. RESULTS: Allograft loss due to the recurrence of glomerulonephritis occurred in 52 recipients, with a 10-year incidence of 8.4 percent (95 percent confidence interval, 5.9 to 12.0). The type of glomerulonephritis, the sex of the recipient, and the peak level of panel-reactive antibodies were independent predictors of the risk of recurrence. Recurrence was the third most frequent cause of allograft loss at 10 years, after chronic rejection and death with a functioning allograft. Despite the effect of recurrence, the overall 10-year incidence of allograft loss was similar among transplant recipients with biopsy-proved glomerulonephritis and among those with other causes of renal failure (45.4 percent [95 percent confidence interval, 40.9 to 50.2] vs. 45.8 percent [95 percent confidence interval, 42.3 to 49.3], P=0.09). CONCLUSIONS: Recurrence is an important cause of allograft loss for those with renal failure due to glomerulonephritis. No risk factors for recurrence were identified that warrant altering the approach to transplantation. However, accurate estimates of risk can now be provided to potential recipients of renal allografts.

A quarter of a century of adult peritoneal dialysis-related peritonitis at an Australian medical center.

BACKGROUND: Peritonitis remains one of the major complications of peritoneal dialysis (PD) and results in reduced technique survival and increased patient morbidity and mortality. METHODS: We prospectively recorded comprehensive data on all episodes of PD peritonitis over a 25-year period, including organisms isolated and antibiotic sensitivities. Data on 1588 PD patient-years with 2073 episodes of peritonitis were analyzed; 2089 organisms were isolated in 608 patients. Peritoneal dialysis technique and patient survival were also recorded. RESULTS: There was a significant decline over the years in the incidence of peritonitis, from 6.5 to 0.35 episodes/patient-year, with the decline in the post twin-bag era from 2.3 to 0.47 (p < 0.001) due primarily to a decrease in gram-positive organisms. The most common isolates (68.9%) were gram-positive organisms; gram-negative organisms comprised 26.8% and fungi 4.1%. Coagulase-negative staphylococci were the most common pathogen isolated (35.3%). Culture-negative peritonitis was seen in 13.4% of episodes. CONCLUSION: This is the largest series of PD peritonitis reported, demonstrating a dramatic reduction over a 25-year period and also detailing the changing trends of organisms isolated in association with improved technique and patient survival. Although rates have improved, peritonitis remains a major complication and further research needs to be done to improve both PD technique and patient survival.

Blood pressure lowering for the prevention and treatment of diabetic kidney disease.

The current pandemic of diabetes mellitus will inevitably be followed by an epidemic of chronic kidney disease. It is anticipated that 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes will ultimately develop diabetic kidney disease. The control of blood pressure represents a key component for the prevention and management of diabetic nephropathy. There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes in diabetes. Hypertension is closely linked to insulin resistance as part of the 'metabolic syndrome'. Diabetic nephropathy may lead to hypertension through direct actions on renal sodium handling, vascular compliance and vasomotor function. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. In patients with normoalbuminuria, transition to microalbuminuria can be prevented by blood pressure reduction. This action appears to be significant regardless of whether patients have elevated blood pressure or not. The efficacy of ACE inhibition appears to be greater than that achieved by other agents with a similar degree of blood pressure reduction; although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction, regardless of modality. In patients with established microalbuminuria, ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) consistently reduce the risk of progression from microalbuminuria to macroalbuminuria, over and above their antihypertensive actions. The clinical utility of combining these strategies remains to be established. In patients with overt nephropathy, blood pressure reduction is associated with reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease. In addition to actions on systemic blood pressure, it is now clear that ACE inhibitors and ARBs also reduce proteinuria in patients with diabetes. This anti-proteinuric activity is distinct from other antihypertensive agents and diuretics. Although there is a clear physiological rationale for blockade of the renin angiotensin system, which is strongly supported by clinical studies, to achieve the optimal lowering of blood pressure, particularly in the setting of established diabetic renal disease, a number of different antihypertensive agents will always be needed. In the end, the choice of agents should be individualised to achieve the maximal tolerated reduction in blood pressure and albuminuria. Ultimately, no matter how it is achieved, so long as it is achieved, renal risk can be reduced by agents that lower blood pressure and albuminuria.