Carmen Mora

Inflammatory parameters are independently associated with urinary albumin in type 2 diabetes mellitus

BACKGROUND Data about the relationship of inflammation to nephropathy in type 2 diabetes mellitus are scarce. In the present study, we test the hypothesis that inflammatory parameters are independently related to urinary albumin excretion (UAE) at early stages of nephropathy. METHODS Sixty-five patients with type 2 diabetes with microalbuminuria (MAB) or mild proteinuria (protein < 1 g/d) were included. We analyzed serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-alpha), as well as urinary level of this cytokine. RESULTS Inflammatory parameters were significantly greater in patients with diabetes than controls; furthermore, urinary TNF-alpha levels increased significantly as nephropathy progressed. Median urinary TNF-alpha level was 7 pg/mg in normoalbuminurics, 13 pg/mg in microalbuminurics (P < 0.001), and 18 pg/mg in proteinurics (P < 0.001 versus normoalbuminuria and P < 0.01 versus MAB). Albuminuria was related to hs-CRP (r= 0.68; P < 0.001) and serum (r = 0.45; P < 0.01) and urinary TNF-alpha levels (r = 0.71; P < 0.001), but there was no association between serum and urinary TNF-alpha levels. Partial correlation analysis showed that hs-CRP level, urinary TNF-alpha level, duration of diabetes, and glycated hemoglobin level remained significantly associated with UAE. A stepwise multiple regression analysis showed that UAE was significantly associated with hs-CRP level (P < 0.001), duration of diabetes (P < 0.001), urinary TNF-alpha level (P < 0.01), and glycated hemoglobin level (P < 0.05; adjusted R2 = 0.73; P < 0.001). CONCLUSION Inflammatory parameters in patients with type 2 diabetes at an early stage of nephropathy are independently associated with UAE. In addition to traditional metabolic and hemodynamic factors, it is possible to hypothesize on the participation of inflammation in the pathogenesis of diabetic nephropathy.

Renal Pro-Inflammatory Cytokine Gene Expression in Diabetic Nephropathy: Effect of Angiotensin-Converting Enzyme Inhibition and Pentoxifylline Administration

Background: Recent studies have shown a role for inflammation in the pathogenesis of diabetic nephropathy (DN). Tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 are cytokines with a prevalent pro-inflammatory activity. Our objective was to study the renal gene expression of TNF-α, IL-1 and IL-6 in DN and their relationship with renal damage assessed by urinary albumin excretion (UAE). In addition, we also investigated the effect of angiotensin-converting enzyme inhibition and pentoxifylline (PTF) administration on these parameters. Methods: After streptozotocin-induced diabetes, rats received either no treatment or therapy with enalapril (EN) or PTF for 8 weeks. Renal expression of pro-inflammatory cytokines was evaluated by real-time polymerase chain reaction. Urinary cytokine excretion and albuminuria were also evaluated. Results: Renal cortical mRNA expression for TNF-α, IL-1 and IL-6 in untreated diabetic rats was 2.4-, 1.2- and 3.4-fold higher than in non-diabetic rats. Kidney weight and UAE were significantly associated with renal mRNA expression of TNF-α and IL-6. Both EN and PTF administration virtually abrogated the overexpression of TNF-α, IL-1 and IL-6, which was associated with a reduction in kidney weight and urinary albumin excretion. Conclusion: The renal expression of the main pro-inflammatory cytokines TNF-α, IL-1 and IL-6 is increased in DN, which is significantly associated with UAE. EN and PTF administration prevented this enhanced expression, leading to a decrease in urinary cytokine excretion and a reduction in albuminuria. These findings provide novel insight into the pathogenic mechanisms of DN, supporting the hypothesis that inflammatory mechanisms play a role in the renal injury secondary to diabetes mellitus.

Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.

In 24 diabetic patients with advanced renal failure (creatinine clearance [C(Cr)] < 35 mL/min), we prospectively studied serum tumor necrosis factor-alpha (TNF-alpha) levels, the possible relationship with urinary protein excretion, and the effects of pentoxifylline (PTF) administration. PTF (400 mg daily) was administered for 6 months to 14 patients, and the results were compared with data from a control group (n = 10). Baseline parameters were similar in both groups. At the end of the study, urinary protein excretion and serum TNF-alpha decreased in the active group from 2.7 (1.2 to 5.8) g/d and 569 +/- 285 pg/mL to 1.1 (0.3 to 4.0) g/d and 329 +/- 232 pg/mL, respectively (P < 0.001). By contrast, proteinuria and TNF-alpha did not change in the control group. Regression analysis showed a significant correlation between proteinuria and serum TNF-alpha both at basal (r = 0.55) and at the sixth month (r = 0.57). Furthermore, the reduction of urinary protein excretion was strongly correlated with the decrease of TNF-alpha (r = 0.72, P < 0.01). Serum Cr and C(Cr) remained stable in both groups during the study. Our findings suggest that cytokines might play a role in renal damage in diabetic nephropathy. PTF is effective in reducing proteinuria in diabetic patients with advanced renal failure. The anticytokine activity of PTF may be a further explanation for this antiproteinuric effect.

Pathogenic perspectives for the role of inflammation in diabetic nephropathy

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.

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade: A Short-Term, Randomized, Controlled Trial

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-alpha (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-alpha 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-alpha 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-alpha excretion.

Relationship between serum magnesium and parathyroid hormone levels in hemodialysis patients

Acute magnesium (Mg) infusion decreases patathyroid hormone (PTH) secretion. However, the effect of chronic hypermagnesemia on PTH levels in dialysis patients is not well established. We studied 110 hemodialysis patients (mean age, 55 +/- 14 years; time on dialysis, 35 +/- 28 months) not receiving vitamin D and undergoing dialysis with an Mg dialysate concentration of 1.2 mg/dL. The primary phosphate binder was calcium carbonate, and 43% of the patients also needed aluminum hydroxide. During a 6-month period, calcium (Ca), phosphorus (P), and total serum Mg were measured every 2 months; intact PTH and aluminum (Al) were measured every 6 months. The mean value of each parameter was computed. Hypermagnesemia (serum Mg > 2.47 mg/dL) was observed in 73% of the patients. Mg and Ca were inversely correlated with PTH levels (r = -0.48; P < 0.001 and r = -0.21; P < 0.05, respectively). After adjusting for Ca and P (partial correlation analysis), Mg and PTH were inversely correlated (r = -0.58; P < 0.001). A stepwise multiple regression analysis showed that PTH levels were predicted by Mg (P < 0.001), alkaline phosphatase (P < 0.01), and P levels (P< 0.05; multiple R = 0.57; P < 0.001), whereas Ca level, sex (dummy variable), diabetes (dummy variable), time on dialysis, and Al level were not predictive. Patients with inadequately low PTH levels (relative hypoparathyroidism, PTH < 120 pg/mL; n = 52) showed greater serum Mg concentrations than the rest (n = 58; 3.01 +/- 0.33 v 2.63 +/- 0.38 mg/dL; P < 0.001). In conclusion, serum Mg concentrations in dialysis patients are independently associated with PTH levels, suggesting that chronic hypermagnesemia may decrease PTH secretion and/or synthesis. In addition, chronic hypermagnesemia of dialysis patients may have a role in the pathogenesis of adynamic bone disease.

Tumor necrosis factor-α as a therapeutic target for diabetic nephropathy

Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-alpha (TNF-alpha). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-alpha inhibition with the use of soluble TNF-alpha receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-alpha might be an efficacious treatment for renal disease secondary to diabetes mellitus.

Diabetes, inflammation, proinflammatory cytokines, and diabetic nephropathy.

Diabetes and its complications have become a public health problem. Diabetic nephropathy is the main cause of renal failure. In spite of our higher knowledge on this complication, the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, inflammation, and more specifically proinflammatory cytokines and other molecules with a relevant role within the inflammatory process, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective may lead to important new therapeutic considerations and new therapeutic goals for the treatment of diabetic nephropathy.

Nephrogenic diabetes insipidus and renal tubular acidosis secondary to foscarnet therapy.

Foscarnet is used as therapy of cytomegalovirus (CMV) infection in immunosuppressed subjects. We present a patient with human immunodeficiency virus infection under treatment with foscarnet for CMV retinitis who complained of thirst and polyuria. Laboratory data showed hypernatremia with increased plasma osmolality and metabolic hyperchloremic acidosis. A water deprivation test demonstrated a nephrogenic diabetes insipidus. Other laboratory studies, including urine pH, anion gap, titratable acidity, and bicarbonate, showed a distal tubular acidification defect. All abnormalities were transient, with recovery a few days after foscarnet withdrawal. No cases of renal acidosis, and only one case of nephrogenic diabetes insipidus, has been previously reported as a complication of foscarnet treatment. Our patient developed both nephrogenic diabetes insipidus and renal tubular acidosis with a temporal pattern that demonstrated a link between foscarnet therapy and these abnormalities.

Association of tumor necrosis factor-α with early target organ damage in newly diagnosed patients with essential hypertension

Objectives To investigate the relationship between inflammatory parameters [high-sensitivity C-reactive protein (hs-CRP), serum tumor necrosis factor-α (TNF-α) and urinary TNF-α] with subclinical cardiac and renal markers of early target organ damage (TOD) in essential hypertension. Methods Preclinical TOD [left ventricular hypertrophy (LVH) and microalbuminuria (MAB)] was evaluated in 40 newly diagnosed never-treated patients with essential hypertension. Serum and urinary TNF-α and hs-CRP were measured as inflammatory parameters. Twenty-one BMI-matched and sex-matched normotensive, healthy individuals were included as control group. Results The serum levels of hs-CRP and the urinary TNF-α excretion were higher in hypertensive patients with MAB, whereas patients with LVH presented higher levels of urinary TNF-α. The only difference between hypertensive patients without TOD and healthy controls was the higher urinary excretion of TNF-α. Partial correlation analysis showed a significant association between urinary albumin excretion (UAE) and systolic blood pressure (r = 0.62, P < 0.0001), hs-CRP (r = 0.64, P < 0.001), urinary TNF-α (r = 0.55, P = 0.001) and Cornell product (r = 0.33, P < 0.05), whereas the Cornell product was related to UAE (r = 0.34, P < 0.05), urinary TNF-α (r = 0.45, P < 0.01), and hs-CRP (r = 0.32, P < 0.05). Multiple regression analysis demonstrated that the parameters independently correlated with UAE were mean blood pressure, Cornell product, hs-CRP and urinary TNF-α (adjusted R2 = 0.77, P < 0.001), whereas UAE, urinary TNF-α and hs-CRP were independently correlated with Cornell product (adjusted R2 = 0.66, P < 0.001). Multiple logistic regression analysis with TOD as the dependent variable showed that hs-CRP [2.24 (1.17–4.28), P < 0.05] and urinary TNF-α [1.21 (1.02–1.44), P < 0.05] were independently related to TOD. Conclusion Urinary TNF-α is independently correlated with UAE and Cornell product in essential hypertension, suggesting that inflammation may participate in the development of TOD. In addition, urinary excretion of TNF-α might be an early marker of preclinical TOD in hypertensive patients. Finally, these results may be a basis to study the effect of the blockade of TNF-α activity on the development and progression of TOD in essential hypertension.