Impact of renal aging on drug therapy.

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.

Effects of deferasirox on renal function and renal epithelial cell death.

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.

Effect of different antihypertensive treatments on Ras, MAPK and Akt activation in hypertension and diabetes.

Ras GTPases function as transducers of extracellular signals regulating many cell functions, and they appear to be involved in the development of hypertension. In the present study, we have investigated whether antihypertensive treatment with ARBs (angiotensin II receptor blockers), ACEi (angiotensin-converting enzyme inhibitors) and diuretics induce changes in Ras activation and in some of its effectors [ERK (extracellular-signal-regulated kinase) and Akt] in lymphocytes from patients with hypertension without or with diabetes. ACEi treatment transiently reduced Ras activation in the first month of treatment, but diuretics induced a sustained increase in Ras activation throughout the 3 months of the study. In patients with hypertension and diabetes, ARB, ACEi and diuretic treatment increased Ras activation only during the first week. ACEi treatment increased phospho-ERK expression during the first week and also in the last 2 months of the study; however, diuretic treatment reduced phospho-ERK expression during the last 2 months of the study. In patients with hypertension and diabetes, antihypertensive treatments did not induce changes in phospho-ERK expression in lymphocytes. ACEi treatment reduced phospho-Akt expression in patients with hypertension and diabetes only in the first month of treatment. In conclusion, these findings show that antihypertensive treatments with ACEi, and diuretics to a lesser extent, modify Ras activation and some of its signalling pathways, although in different directions, whereas ARBs do not appear to have any influence on Ras signalling pathways.

Effect of adenosine in extracellular matrix synthesis in human and rat mesangial cells.

Adenosine (ADO) is an intermediary metabolite of adenosine trisphosphate degradation and a vasoactive mediator. We showed previously that ADO induces contraction and proliferation in rat mesangial cells by a mechanism involving A1 and A2 receptors. The studies concerning the effect of ADO on extracellular matrix (ECM) accumulation in mesangial cells are scarce. The purpose of our study was to evaluate the effect of ADO and the effect of the selective stimulation of A1 and A2 ADO receptors on the expression of ECM components fibronectin and collagen type I, in human and rat renal mesangial cells. Cultured human and rat renal mesangial cells were subjected to selective stimulation of A1 and A2 ADO receptors for 24 and 48 h. Fibronectin and collagen type I expression was evaluated by Western blot; total collagen synthesis was measured by [3H]-proline incorporation into collagen proteins. ADO, A1 and A2 receptor stimulation induce increases in fibronectin expression in rat mesangial cells, and A1 receptor stimulation partially inhibits fibronectin expression in serum-stimulated rat mesangial cells, without any effect in human mesangial cells. A2 receptor stimulation reduces collagen type I expression in serum-stimulated mesangial cells. Neither ADO nor A1 or A2 receptor stimulation induce significant changes in total collagen synthesis. These data suggest that ADO is not a major regulator of ECM synthesis in rat and human mesangial cells.