Diabetes and its complications have become a public health problem. One of the most important complications is diabetic nephropathy, which is nowadays the main cause of chronic renal failure. In spite of our greater understanding of this complication, the intimate mechanisms leading to the development and progression of renal injury are not well understood. New perspectives in activated innate immunity and inflammation appear to be relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including adipokines, Toll-like receptors, chemokines, adhesion molecules and pro-inflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.

In patients with type 2 diabetes, urinary TNFalpha excretion is elevated and correlates with severity of renal disease in terms of both glomerular and tubulointerstitial damage, suggesting a significant role for TNFalpha in the pathogenesis and progression of renal injury in diabetes mellitus.

Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n ‫؍‬ 30) or to a control group (n ‫؍‬ 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-␣ (R ‫؍‬ 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was ؊16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-␣ also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-␣ in patients who were treated with PTF (R ‫؍‬ 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-␣ excretion.

Results: Patients were classified by tertiles of Ca, phosphorus (P), Ca-P product (Ca x P), and parathyroid hormone (PTH). After adjustment for age, gender, and eGFR, the levels of C-reactive protein (CRP) and IL-6 (IL-6) of the third tertile of P, Ca x P, and PTH were significantly higher than those of the first and second tertiles. Serum P and Ca x P directly correlated with CRP and IL-6, whereas HDL-cholesterol and eGFR inversely correlated with the levels of the inflammatory parameters. After partial correlation analysis, the previous associations between CRP and eGFR, and serum P, as well as the relationship between IL-6 and eGFR, and serum P, remained significant. Multiple regression analysis demonstrated that eGFR and serum P were independently associated with CRP and IL-6. Finally, logistic regression analysis using the presence/absence of an inflammatory state as the dependent variable showed that eGFR was a protective factor, whereas serum P was an independent risk factor for the presence of an inflammatory state.Conclusions: Elevated serum P might play a role in the development of inflammation in CKD.