Usefulness of urinary biomarkers to estimate the interstitial fibrosis surface in diabetic nephropathy with normal kidney function.

BACKGROUND: Kidney biopsies of patients with diabetic nephropathy (DN) and normal kidney function may exhibit interstitial fibrosis (IF) without reduction of glomerular filtration rate (GFR) because of hyperfiltration. The aim of our study was to analyse the performance of a set of biomarkers of tubular injury to estimate the extent of IF in patients with DN and normal kidney function. METHODS: This cross-sectional study included 118 adults with DN diagnosed by kidney biopsy and GFR ≥90 mL/min/1.73 m2 and a control group of healthy subjects. We measured the urinary excretion of monocyte chemoattractant protein-1 (MCP-1) neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), ß2-microglobulin and dickkopf-3 protein (DKK-3) at the time of kidney biopsy. GFR was measured by chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA) (measured GFR). IF was quantified using a quantitative morphometric procedure. Predictive multivariate models were developed to estimate the IF surface. RESULTS: Patients with DN showed significantly higher levels of DKK-3, MCP-1 and L-FABP and significantly lower levels of epidermal growth factor (EGF) than healthy controls. There were no significant between-group differences in the levels of ß2-microglobulin, KIM-1 or NGAL. IF was negatively associated with EGF and positively with age, proteinuria, MCP-1, DKK-3 and L-FABP, but not with ß2-microglobulin, KIM-1, NGAL or GFR. The best model to predict IF surface accounted for 59% of its variability and included age, proteinuria, EGF, DKK-3 and MCP-1. CONCLUSIONS: Our study provides a model to estimate the IF in DN that can be useful to assess the progression of IF in patients with normal kidney function.

Microalbuminuria and the Combination of MRI Markers of Cerebral Small Vessel Disease.

BACKGROUND: Kidney function has been related to the presence of individual markers of cerebral small vessel disease (CSVD), as lacunes, white matter hyperintensities (WMH) or microbleeds. We aimed at studying the relationship of kidney dysfunction with the combination of several markers of CSVD. METHODS: Subjects are those included in the ISSYS cohort (Investigating Silent Strokes in hypertensives: a magnetic resonance imaging study). A scale ranging from 0 to 4 points was applied based on the presence (one point each) of lacunes, deep microbleeds, moderate to extensive basal ganglia enlarged perivascular spaces (EPVS), and periventricular or deep WMH. We determined the creatinine-based glomerular filtration rate and the urinary albumin-to-creatinine ratio (UACR) as markers of kidney function and studied their association with the scale of CSVD in univariate and ordinal logistic regression analyses. RESULTS: Among the 975 patients included, 28.2% presented one or more CSVD markers, being the most prevalent marker (either alone or in combination) basal ganglia EPVS. The UACR was elevated at increasing the scores of the CSVD scale and remained as independent predictor of the combination of markers (common OR per natural log unit increase in UACR: 1.23, 1.07-1.41) after controlling per age, gender, cardiovascular risk, antihypertensive treatment and hypertension duration. In contrast, no associations were found between the CSVD scores and the creatinine-based estimated glomerular filtration rate. CONCLUSIONS: A significant proportion of stroke-free hypertensives present at least one imaging marker of CSVD. UACR but not creatinine-based glomerular filtration rate is associated with the combination of markers of CSVD.

Cognitive Impact of Cerebral Small Vessel Disease Changes in Patients With Hypertension.

Hypertension is one of the principal risk factors for cerebral small vessel disease progression and cognitive impairment. We aimed to investigate how changes in cerebral small vessel disease lesions relate to cognitive decline and incident mild cognitive impairment in hypertensive patients. Data were obtained from the ISSYS cohort (Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study)-a longitudinal population-based study on hypertensive patients aged 50 to 70 years without dementia and stroke at baseline. Patients underwent a brain magnetic resonance imaging, a cognitive screening test, and cognitive diagnosis (normal aging or mild cognitive impairment) at baseline and follow-up. We evaluated incident lacunar infarcts and cerebral microbleeds. Changes in the periventricular and deep white matter hyperintensities (WMH) were qualitatively defined as none, minor, or marked. We followed up 345 patients (median age, 65 [61-68]; 55.4% men) for 3.95 (3.83-4.34) years. Incident mild cognitive impairment was diagnosed in 9.1% of the sample. Considering the progression of cerebral small vessel disease, the prevalence of incident infarcts was 6.1% and that of incident cerebral microbleeds was 5.5%; progression of periventricular WMH was 22% and that of deep WMH was 48%. Patients with marked progression of periventricular WMH showed a significant decrease in global cognition compared with patients without progression (adjusted mean [SE], -0.519 [0.176] versus 0.057 [0.044], respectively; P value=0.004) and a higher risk of incident mild cognitive impairment (OR, 6.184; 95% CI, 1.506-25.370; P value=0.011). Therefore, our results indicate that hypertensive patients with progression of periventricular WMH have higher odds of cognitive impairment, even in the early stages of cognitive decline.

Mesangial C4d Deposits in Early IgA Nephropathy.

BACKGROUND AND OBJECTIVES: The prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR≥80 ml/min per 1.73 m2 at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available. RESULTS: In total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; P=0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; P=0.04), had a higher protein-to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; P<0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; P<0.01), and showed a larger reduction in eGFR (-1.6 versus -0.8 ml/min per 1.73 m2 per year; P=0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival. CONCLUSIONS: C4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment.