Lower Urinary Albumin Excretion Research Articles

Mitochondria-Derived Reactive Oxygen Species Contribute to Synergistic Interaction of Diabetes and Hypertension in Causing Chronic Kidney Injury.

Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. The combination of DM and HTN significantly accelerates development of renal injury; however, the underlying mechanisms of this synergy are still poorly understood. This study assessed whether mitochondria (MT) dysfunction is essential in developing renal injury in a rat model with combined DM and HTN. Type 1 DM was induced in Wistar rats by streptozotocin (STZ). HTN was induced six weeks later by inter-renal aorta constriction between the renal arteries, so that right kidneys were exposed to HTN while left kidneys were exposed to normotension. Kidneys exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion (UAE). In contrast, kidneys exposed to DM plus 8 weeks HTN had significantly increased UAE and glomerular structural damage with reduced glomerular filtration rate. Marked increases in MT-derived reactive oxygen species (ROS) were also observed in right kidneys exposed to HTN+DM. We further tested whether treatment with MT-targeted antioxidant (MitoTEMPO) after the onset of HTN attenuates renal injury in rats with DM+HTN. Results show that kidneys in DM+AC+MitoTEMPO rats had lower UAE, less glomerular damage, and preserved MT function compared to untreated DM+AC rats. Our studies indicate that MT-derived ROS play a major role in promoting kidney dysfunction when DM is combined with HTN. Preserving MT function might be a potential therapeutic approach to halt the development of renal injury when DM coexists with HTN.

Plasma Calprotectin Levels Associate With New-Onset Hypertension in the General Population: A Prospective Cohort Study.

Low-grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil-mediated inflammation, is associated with developing new-onset hypertension in the general population. Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective population-based cohort study. Plasma calprotectin levels were studied for associations with the risk of new-onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34-0.66) mg/L, and median systolic blood pressure was 117 (109-126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new-onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21-1.41]; P<0.001), also after adjustment for age and sex (HR, 1.26 [95% CI, 1.16-1.37]; P<0.001), but not after additional adjustment for potentially confounding factors, including baseline systolic blood pressure (HR, 1.00 [95% CI, 0.90-1.11]; P=0.996). Stratified analyses showed significant effect modification by sex (Pinteraction=0.023) and urinary albumin excretion (Pinteraction=0.004), with higher HRs in men (compared with women) and in individuals with higher urinary albumin excretion (>9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). Higher plasma calprotectin levels are associated with an increased risk of new-onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.

Trajectories of renal biomarkers and new-onset heart failure in the general population: Findings from the PREVEND study.

Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new-onset HF and all-cause mortality. Using group-based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study and their association with new-onset HF and all-cause death during the 11-years of follow-up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new-onset HF or all-cause mortality, whereas stable serum creatinine trajectories showed a linear association for new-onset HF and no association with all-cause mortality. Our population-based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality.

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

Urinary Markers and Chronic Effect of Physical Exercise.

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. The clinical protocol of CKD forecasts that markers such as serum creatinine, the estimate of the glomerular filtration rate value, microalbuminuria, cystatin c are evaluated as routine markers. In recent years, new studies have identified new markers to diagnose and assess the level of kidney damage.The prevalence of CKD increases in subjects suffering from cardiovascular and metabolic diseases. The highest risk of cardiovascular risk in the CKD patient compared to the general population is related to risk factors such as hypertension, obesity, and specific renal disease factors such as albuminuria.Physical exercise, especially aerobic, has been seen through the analysis of urinary markers, able to mitigate the adverse effect of sedentary, hypertension and interstitial damage in patients with CKD and decrease the urinary levels liver-type fatty acid binding protein (L-FABP) and lower urinary albumin excretion.

Saxagliptin and vildagliptin lowered albuminuria in patients with diabetes and hypertension independent on glycaemic control.

Preclinical data illustrated that the dipeptidyl peptidase-4(DPP-4) inhibitors did lower urinary albumin excretion in diabetes-induced rats. We evaluated the effects of saxagliptin and vildagliptin on albuminuria in patients with diabetic nephropathy on top of the renin-angiotensin-aldosterone system (RAAS) blockade therapy. This study included 120 patients with type 2 diabetes (T2D), hypertension, and prevalent albuminuria [defined as urine albumin-to-creatinine ratio (UACR) 30-3000mg/g creatinine] on a stable dose of olmesartan as a standard RAAS blocker for diabetic nephropathy. Patients were assigned to receive either of saxagliptin 5mg/day (n=40), vildagliptin 100mg/day (n=40), or traditional antidiabetic therapy as control patients (n=40) for 12weeks. Each of saxagliptin and vildagliptin significantly reduced albuminuria after 12weeks, with mean percentage changes (%) of -57.9% [95% confidence interval (CI) -66.1 to -49.8], and -55.2% (95% CI -64.9 to -45.4); P<.001, respectively, compared with the control group. Significantly, saxagliptin shifted higher proportions of patients towards lower albuminuria categories (P<.001) compared with vildagliptin despite a similar UACR rate of changes. Results of binary logistic models confirmed that the change in UACR because saxagliptin was independent of changes in systolic blood pressure (SBP), glycated hemoglobin (HbA1c ), estimated glomerular filtration rate (eGFR), or body weight (overall regression: P=.002, R2 =0.398) vs control. Likewise, vildagliptin reduced UACR independently on other confounders (overall regression: P=.002, R2 =0.388). Furthermore, no significant correlation was observed between the change in UACR and changes in HbA1c, SBP or eGFR with either saxagliptin or vildagliptin (Pearson coefficients: 0.203, 0.143, -0.190; P>.05, and 0.003, 0.241, 0.019; P>.05, respectively). DPP-4 inhibitors, saxagliptin, and vildagliptin, resulted in substantial reductions in albuminuria in patients with T2D and hypertension on top of RAAS blockade after short term therapy independently on glycaemic or hemodynamic changes. Saxagliptin was superior to vildagliptin in albuminuria-categorical shifting.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials

Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. Demographic, clinical, laboratory, and imaging features of participants. Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. Relatively short follow-up of a clinical trial population. Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Radon inhalation suppresses nephropathy in streptozotocin-induced type-1 diabetic mice

In this study, we investigated the suppressive effects of radon inhalation against nephropathy in C57BL/6J mice with type-1 diabetes induced by intraperitoneal injection of streptozotocin (50 mg/kg weight, given five times). Four weeks after diabetes induction, the diabetic mice were continuously treated with inhaled radon-222 of 2000 Bq/m3 or air only (sham) for four weeks. The results showed that radon inhalation did not affect type-1 diabetic symptoms such as body weight loss, hyperglycemia, and hypoinsulinemia. However, diabetic mice treated with radon showed lower urinary albumin excretion and fibrotic change in renal glomeruli compared with diabetic mice not treated with radon. Furthermore, renal superoxide dismutase activity and glutathione content were significantly higher in diabetic mice treated with radon than in diabetic mice not treated with radon. These findings suggested that radon inhalation enhanced renal antioxidants activities, resulting in the suppression of diabetic nephropathy. This study may contribute to the development of a novel approach in the treatment of nephropathy for diabetic patients.

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes.

The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.

Elevated urinary albumin excretion complements the Framingham Risk Score for the prediction of cardiovascular risk — response to treatment in the PREVEND IT trial

BackgroundThe PREVEND IT trial reported on a high cardiovascular (CV) event rate in subjects with a baseline urinary albumin excretion (UAE) rate of ≥ 50 mg/24 h. Here, we report on the observed 10-year CV outcome of this population and compare this with the predicted Framingham Risk Score (FRS). In addition, we evaluated the effect of four years of fosinopril treatment on this relation. Methods and resultsFrom the PREVEND IT cohort, 833 subjects without history of CV disease, randomized to fosinopril (N = 412) or placebo (N = 421), were studied. The primary endpoint included CV mortality and adjudicated hospitalization for CV disease during a 10-year follow-up period. Mean age was 51 ± 12 years and 65% were males, while prevalence of diabetes (2.6%) and use of CV drugs (3.5%) was low. Subjects were categorized to high UAE (≥ 50 mg/24 h) or low UAE (< 50 mg/24 h). After 10 years of follow-up, the event rate in the high UAE group was almost twice as high as predicted by the FRS (29.5% vs. 17.2%). Treatment for four years with fosinopril reduced the event rate to comparable levels of that predicted by FRS. The addition of UAE ≥ 50 mg/24 h to the FRS improved the Integrated Discrimination Improvement (P = 0.033) and increased the area under the curve by 0.54% (P = 0.024). ConclusionsThe 10-year CV risk of subjects with an elevated UAE (≥ 50 mg/24 h) is substantially underestimated by the FRS. Treatment with fosinopril successfully reduced this increased event rate to FRS-predicted CV risk.

Linagliptin Lowers Albuminuria on Top of Recommended Standard Treatment in Patients With Type 2 Diabetes and Renal Dysfunction

OBJECTIVEPreclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials.RESEARCH DESIGN AND METHODSA pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30−3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24.RESULTSUACR at week 24 was reduced by 32% (95% CI −42 to −21; P < 0.05) with linagliptin compared with 6% (95% CI −27 to +23) with placebo, with a between-group difference of 28% (95% CI −47 to −2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% (−6.7 mmol/mol) in favor of linagliptin (95% CI −0.88 to −0.34% [−9.6 to −3.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment.CONCLUSIONSLinagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.

The impact of maternal in utero environment on salt‐induced hypertension in the SS rat

The SS rat is an established model of salt‐sensitive human hypertension. We previously demonstrated that SS animals from parents fed a grain‐based diet are less susceptible to salt‐induced elevations in blood pressure and associated renal damage than SS animals fed a casein‐based protein diet. Others have shown that transfer of SS strain embryos into genetically unrelated recipients can also attenuate salt‐induced blood pressure changes. We hypothesized, therefore, that differences in dietary‐induced susceptibility may be driven by the in utero environment of pregnant females fed these different diets. Using the closely related SS/JrHsdMcwi strain (SS/Mcw), maintained on a purified casein diet, and the SS/JrHsdMcwiCrl (SS/Crl) which is maintained on a grain diet, we addressed this hypothesis by performing embryo transfers between strains and phenotyping the offspring. Compared to control male rats (n=6) generated by the transfer of SS/Mcw embryos into SS/Mcw females, males (n=9) generated by transfer of SS/Mcw embryos into SS/Crl female recipients demonstrated both significantly reduced mean arterial pressure (154 ±7 mmHg vs. 134±6) and lower urinary albumin excretion (200±19 mg/day vs. 74±14 mg/day) following three weeks of a 4.0% NaCl diet. These data demonstrated that the dietary exposure of pregnant SS female rats can impact the susceptibility of their offspring to salt‐induced hypertension.

Targeting albuminuria in arterial hypertension and diabetes

Targeting albuminuria in arterial hypertension and diabetes

Albuminuria within the normal range and ultrasound‐assessed atherosclerosis in the AIR study: a 9‐year follow‐up of 58‐year‐old clinically healthy men

Background:Microalbuminuria, traditionally defined as 30–300 mg urinary albumin/24 h, predicts renal impairment and cardiovascular disease. Studies suggest that also a far lower urinary albumin excretion (UAE) can predict clinical outcome. Intima media thickness (IMT) is an established estimate of atherosclerosis. In this study, we investigated the predictive value of UAE within the normal rate (UAE–n) for the progression of IMT in the carotid and femoral arteries. Methods: We included 325 clinically healthy men with normoalbuminuria. Anthropometrics, urine and blood samples were taken and IMT in the carotid and femoral arteries were assessed by B–mode ultrasound at baseline and after 3 and 9 years. The annual progression rate of IMT (r–IMT) was calculated. Results: UAE–n correlated with carotid IMT at baseline and after 3 and 9 years, but not with r–IMT. In a regression analysis, only HDL and baseline IMT remained as statistically significant co–variates to mean IMT at 9 years. IMT in the femoral artery and r–IMT at any time–point did not correlate to baseline UAE. Conclusion: UAE–n was associated with carotid IMT after 3 and 9 years but not r–IMT or with femoral artery IMT. Carotid IMT after 9 years' follow–up was independently related to baseline IMT and HDL cholesterol. In this cohort of 58–year–old men, our interpretation is that UAE–n is not associated with the increase in carotid and femoral artery IMT observed after 9 years.

Extended Prognostic Value of Urinary Albumin Excretion for Cardiovascular Events

Because urinary albumin excretion (UAE) is a marker of cardiovascular (CV) risk, some have proposed screening the general population; however, it is unknown how the predictive power of a single screening value changes over time. In this study, data of 8496 individuals in a community-based, prospective cohort were used to evaluate this question. For each doubling of baseline UAE, the hazard ratio (HR) for a CV event was 1.36 (95% confidence interval [CI] 1.31 to 1.42). Baseline UAE similarly predicted events occurring >5 yr after baseline, suggesting that it remains a good predictor during at least the first 5 yr after measurement. Approximately 4 yr after baseline, UAE was measured again in 6800 individuals. Once again, high UAE (>75th percentile) predicted subsequent CV events, whether defined using the baseline UAE or follow-up UAE (HR 3.39 [95% CI 2.58 to 4.45] and HR 2.50 [95% CI] 1.90 to 3.29, respectively; P = 0.3 for difference). Finally, compared with individuals with consistently low UAE, individuals who progressed from low to high UAE during follow-up had a significantly higher risk for CV events (HR 3.68; 95% CI 2.45 to 5.53). In conclusion, UAE remains a good predictor of CV events during the first 5 yr after measurement, but repeating the measurement several years later also detects progression of UAE, which is also associated with increased CV risk. Future studies are required to determine the optimal interval of repeat testing and its cost-effectiveness.

Relationship between Urinary Albumin Excretion and Left Ventricular Mass with Mortality in Patients with Type 2 Diabetes

Increased urinary albumin excretion (UAE) has been shown to be associated with increased cardiovascular mortality in patients with type 2 diabetes. This study evaluated whether the association between UAE and cardiovascular mortality in 880 patients with type 2 diabetes was related to an increase in left ventricular mass (LVM). LVM was estimated by electrocardiographic index, namely adjusted Cornell voltage. LVM was significantly different between the stages of albuminuria (8.17 +/- 0.12 in normoalbuminuric, 9.05 +/- 0.21 in microalbuminuric, and 10.30 +/- 0.30 in overt albuminuric patients; P < 0.001). There also was a positive correlation between log UAE and LVM independent of BP. During 5 yr of follow-up, survivors had significantly lower LVM (8.62 +/- 0.11 versus 9.88 +/- 0.45; P = 0.0140) and lower UAE (154.60 +/- 16.53 versus 446.62 +/- 114.11; P = 0.0003) than nonsurvivors. The results indicate that patients with type 2 diabetes and increased UAE should be evaluated for increased LVM as an important and potentially reversible cardiovascular risk factor.

The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study

Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis. We used data from the Prevention of REnal and Vascular ENd-stage Disease Intervention trial (PREVEND-IT) and the PREVEND cohort study. The PREVEND-IT subjects (788 with a UAE 15-300 mg/day) received pravastatin 40 mg/day vs placebo and/or fosinopril 20 mg/day vs placebo in a 2x2 factorial-RCT design. Of the 3440 cohort subjects, 469 used statins during the 4-year follow-up period. Multivariate-regression adjusted for confounding factors and the propensity score was used to estimate the relation between statin use and UAE and GFR. In the RCT, pravastatin did not change UAE or GFR, neither in fosinopril yes/no subgroups. In the observational cohort, statin use was associated with a rise in UAE (+12.1%), compared with statin non-use (+3.6%, P<0.001). This rise was most pronounced in those on statins prior to the first screening [+24.8% (95% CI: 11.9-39.2)], those using statins>3 years [+18.5% (7.3-30.8)] and those with >1 or >2 defined daily doses (+15.7 and +17.3%, respectively). These differences remained significant after adjustment for relevant variables and propensity score. The rise in UAE could not be attributed to a higher dose or a specific statin. GFR fell in 4 years in both statin users and non-users (4.6+/-13.5 and 2.4+/-11.2, respectively). The fall in GFR between groups was not different after adjustment (P=0.11). We conclude from the RCT data that statins do not lower UAE in subjects selected because of an elevated UAE instead of hyperlipidaemia. In the observational cohort study, the use of statins similarly was not associated with a fall in UAE; UAE instead increased. Statin treatment was not associated with a significant change in GFR in these subjects with only modestly impaired GFR.

Very low level of microalbuminuria is associated with increased risk of death in subjects with cardiovascular or cerebrovascular diseases

The original definition of microalbuminuria (20-200 microg min-1 or 15-150 microg min-1 overnight) is based on studies of patients with diabetes, in whom microalbuminuria was associated with increased risk of chronic renal failure. In a recent report an overnight urinary albumin excretion (UAE) above only 5 microg min-1 was strongly predictive of coronary heart disease and death in the general population. The aim of the present study was to investigate if this cut-off level also has prognostic value in a population with cardiovascular or cerebrovascular disease. In The Third Copenhagen City Heart Study in 1992-1994, 491 men and women aged 30-80 years with a history of coronary heart disease or stroke delivered a timed overnight urine sample. They were followed by registers with respect to vital status until 2004. During follow-up, 141 of the 491 participants died. The relative risk of death in subjects with UAE above 5 microg min-1 compared with subjects with lower UAE was 2.0 (1.4-2.8; P<0.001). It was unaffected [RR 1.9 (1.3-2.7); P<0.005] by adjustment for age, sex, blood pressure, diabetes, lipoproteins, renal creatinine clearance, smoking and body mass index. Subjects with cardiovascular or cerebrovascular disease have about 100% higher risk of death if microalbuminuria defined as UAE above 5 microg min-1 is present. Measurements of UAE should be included in the risk assessment in subjects with cardiovascular or cerebrovascular disease. This study supports the definition of microalbuminuria as UAE above 5 microg min-1.

PAI-1 in diabetic nephropathy

To the Editor: The mechanisms by which plasminogen activator inhibitor-1 (PAI-1), the main plasminogen activator inhibitor, promotes fibrosis in a number of experimental models, are still intensely debated. On the one hand, PAI-1 is supposed to inhibit extracellular matrix degradation by preventing plasmin formation. On the other hand, it has been shown to prevent transforming growth factor (TGF) beta activation and, thus, to prevent extracellular matrix production1.Hertig A. Rondeau E. Plasminogen activator inhibitor type 1: The two faces of the same coin.Curr Opin Nephrol Hypertens. 2004; 13: 39-44Google Scholar. Nicholas et al recently provided experimental, in vivo data suggesting that PAI-1 deficiency might be helpful in the prevention of diabetic nephropathy: when compared to wild-type animals, PAI-1 knockout mice have, thus, a lower urinary albumin excretion and a lower synthesis of fibronectin in the kidney after streptozotocin injection2.Nicholas S.B. Aguiniga E. Ren Y. et al.Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.Kidney Int. 2005; 67: 1297-1307Google Scholar. Interestingly, PAI-1 is reported by these authors to enhance TGF beta synthesis by mesangial cells, a finding that is somewhat provocative because TGF beta is itself a potent enhancer of the PAI-1 promoter gene, and because recent works by Luttun et al and our group demonstrated that PAI-1 plays a critical role in the regulation of the TGF beta activation (i.e., PAI-1 inhibits TGF-beta activation)3.Luttun A. Lupu F. Storkebaum E. et al.Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice.Arterioscler Thromb Vasc Biol. 2002; 22: 499-505Google Scholar , 4.Hertig A. Berrou J. Allory Y. et al.Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta.FASEB J. 2003; 17: 1904-1906Google Scholar. Moreover, in Nicholas' study, the induction of TGF-beta synthesis, at the mRNA and at the protein level, in diabetic PAI-1 +/+ mice, is weak when compared with nondiabetic mice (×1.5), and is hardly distinguishable from the induction observed in PAI-1 -/- mice, at least for the eye Figure 3. Another striking result is that the level of TGF-beta expression and production by the kidney is higher in PAI-1 -/- mice than in PAI-1 +/+ mice, in either basal or diabetic conditions. In the absence of pathologic data, including measurements of the glomerular basement membrane thickness, it is therefore difficult to conclude that PAI-1 knockout animals could be protected towards diabetic nephropathy and that this would be related to a lower concentration of TGF-beta.

A major gene locus links early onset albuminuria with renal interstitial fibrosis in the MWF rat with polygenetic albuminuria.

The development of renal interstitial fibrosis (RIF) represents an important step in the progression of chronic proteinuric nephropathies. The Munich Wistar Frömter (MWF) rat represents a valuable model to study the progression in proteinuric renal disease. MWF animals demonstrate a significant increase of urinary albumin excretion (UAE) and RIF compared with the spontaneously hypertensive rat (SHR) with low UAE. The aim of this study was to analyze the genetic basis and the relation between UAE and RIF by genetic linkage and quantitative trait loci (QTL) mapping analysis. The authors generated a backcross population between MWF and SHR including 215 male animals. UAE was determined in young backcross animals at 8 wk, and at 14 and 24 wk of age, respectively. RIF was evaluated by Sirius red staining of kidney sections and quantified by computer-assisted image analysis at 24 wk. Total genome scan analysis identified in total eight QTL linked to UAE and a major locus on chromosome 6. At this locus, homozygosity for the MWF allele exhibited a strong effect on UAE levels (threefold elevation) and displayed significant linkage already at 8 wk (logarithm of odds [LOD] = 4.3) with increasing significance at 14 and 24 wk (LOD = 7.8 and 10.1, respectively). In addition, this was the only QTL that was linked to the amount of RIF (P = 0.0009, LOD = 2.4). These data establish a genetic link between early onset albuminuria and progression of RIF at the QTL on RNO6. This study demonstrates the power of genetic linkage analysis for the dissection of physiologic pathways involved in renal disease progression.