Management of diabetic nephropathy in older patients: a need for flexible guidelines.

As the population ages and diabetes mellitus increases in prevalence, the incidence of diabetic nephropathy (DN) is becoming a disease of older people (aged ≥ 75 years). As the epidemiology of diabetes mellitus and DN shifts toward this patient population, the pathogenesis of DN in old age is changing: the pathologic findings suggest ischemia and hypertension, and the classic Kimmelstiel-Wilson lesions may be absent. The demographic shift in the epidemiology and the associated changes in pathology because of aging and atherosclerosis will have a significant impact on various aspects related to the disease in old age. This article reviews the authors' current understanding of DN and its implications on clinical management relevant to current guidelines.

Urinary matrix metalloproteinase activity in diabetic kidney disease: a potential marker of disease progression.

BACKGROUND: Progressive kidney fibrosis, associated with chronic kidney disease (CKD), results from an imbalance in extracellular matrix (ECM) homeostasis. Reduced matrix metalloproteinases (MMP) activity causing lower clearance of ECM proteins has been implicated mainly through an overproduction of tissue inhibitors of metalloproteinases (TIMP), but also by reduced MMP synthesis. We tested the hypothesis that MMP activity can be measured in human urine and can be used as a potential biomarker of the progression of diabetic kidney disease (DKD). METHODS: An observational prospective study was performed on 102 DKD patients using 21 diabetic patients without kidney disease and 21 healthy volunteers as controls. The Molecular Probes EnzChek Gelatinase/Collagenase Assay Kit were used to determine urinary MMP activity using DQ™ Gelatin (total MMPs), DQ™ Collagen I (interstitial collagenases) and DQ™ Collagen IV (gelatinises) substrates. A broad-spectrum synthetic inhibitor of all MMP, 1,10-phenanthroline, was used to confirm that the proteolytic activity is due to MMP activity. All MMP values were expressed per unit of urine creatinine. RESULTS: Overall urinary MMP activity (DQ Gelatin substrate) was significantly elevated in DKD patients (14.76 ± 3.65 Δ fl/h/mmol creatinine) compared to diabetes mellitus controls (7.09 ± 2.12 Δ fl/h/mmol creatinine) and healthy volunteers (1.87 ± 0.74 Δ fl/h/mmol creatinine) (ANOVA p = 0.01). Within the DKD cohort, there was an approximate threefold higher urinary MMP activity in nonprogressive DKD patients compared to those with progressive disease (p = 0.002). The urinary MMP activity:creatinine ratio was significantly higher in normoalbuminuric and microalbuminuric DKD compared to macroalbuminuric DKD. Positive correlations were observed between the rate of total MMP activity and interstitial collagenases (r = 0.75, p < 0.0001) and gelatinases (r = 0.59, p = 0.0001). The accuracy of MMP activity to predict the rate of annual eGFR decline (ROC analysis) was 77% compared to 64% for albuminuria. CONCLUSIONS: Total MMP activity can be easily measured in human urine. Surprisingly and in contrast to MMP activity in the kidney, urine MMP activity is elevated in DKD. However, there is a significantly lower MMP activity in patients with progressive DKD. ROC analysis demonstrates that single urine MMP activity estimation is superior to albuminuria in predicting DKD patients with progressive disease.

Natural history and predictors of faster glomerular filtration rate decline in a referred population of older patients with type 2 diabetes mellitus.

AIM: To study the natural history and predictors of faster glomerular filtration rate (GFR) decline in a referred population of older patients (aged ≥ 65 years) with type 2 diabetes mellitus. METHODS: A retrospective medical record analysis in an outpatient diabetes clinic for older patients. Baseline characteristics and blood pressure readings for each clinic visit were recorded. All laboratory results were downloaded from the central database of the pathology laboratory. Annual rate of GFR decline was calculated by linear regression analysis as the slope per year for each individual. Patients were then divided into 2 groups on either side of the mean GFR decline. Group 1 had a slower GFR decline (below the mean value) and group 2 had a faster GFR decline (above the mean value). Five variables were investigated as predictors of faster decline in GFR: cardiovascular disease (CVD), hypertension, diabetes control, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and albuminuria. RESULTS: The study included 100 patients with a mean age of 69.5 (standard deviation [SD], 3.9) years on referral, and 54 patients were men. The mean duration of study was 14.4 (SD, 2.0) years. A total of 3908 GFR results were downloaded during the study. The mean annual rate of GFR decline was 1.5 (SD, 1.2) mL/min/1.73 m2. Glomerular filtration rate values were comparable in both groups on first referral. Mean annual rate of GFR decline was 2.6 (SD, 0.9) mL/min/1.73 m2 in group 2 compared with 0.7 (SD, 0.5) mL/min/1.73 m2 (P < 0.001) in group 1. Development of CVD was the only independent predictor of faster renal function decline (odds ratio, 2.9; 95% CI, 1.1-7.6; P = 0.03). CONCLUSION: Cardiovascular disease is an independent risk factor for faster decline in GFR in older patients with type 2 diabetes mellitus.

Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. METHODS: Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. RESULTS: The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. CONCLUSION: These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.