Juan F. Macías-Núñez

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.

Dysfunction of the thick loop of Henle and senescence: from molecular biology to clinical geriatrics.

The sodium-potassium-2 chloride bumetanide–sensitive transporter (NKCC2), a protein coded by gene SLC12A1, allows salt reabsorption in the thick ascending loop of Henle (TALH). The functional and clinical exploration of the TALH can be carried out using the Chaimowitz’s test, which is based on the exploration of the tubular response to an acute overload of a hypotonic sodium chloride solution. Since this segment is normally responsible for the generation of free water clearance, its function can be assessed via the calculation of such clearance from the parameters obtained during this test. By applying the Chaimowitz’s test, the presence of incompetence for sodium reabsorption in TALH in healthy old people was documented. Additionally, it was documented that in water-restricted old rats, a situation that normally induces an increase in the number of NKCC2 in young rats is absent in old ones.In the clinical setting, the increased urinary sodium loss usually found in healthy old people predisposes them to dehydration, hypotension and or hyponatremia when they are on low-sodium diet or under treatment with diuretics. These are commonly found in elderly people with geriatric syndromes such as delirium, gait disorders and incontinence.ConclusionThe NKCC2 transporter decrease in the thick ascending loop of Henle secondary to the ageing could explain the reduced sodium reabsorption of this segment in the healthy elderly and its potential clinical consequences of dehydration and serum sodium abnormalities.

Priority topics for European multidisciplinary guidelines on the management of chronic kidney disease in older adults.

PurposeTo identify and prioritize potential topics to be addressed in the development of European multidisciplinary guidelines on the management of chronic kidney disease stage 3b–5 in older patients.MethodsWe composed a list of 47 potential guideline topics by reviewing the literature, consulting online 461 nephrologists and 107 geriatricians, and obtaining expert input. A multidisciplinary panel of twelve experts then prioritized the topics during a face-to-face consensus meeting, following a nominal group technique structure with two voting rounds. Topics were rated on a 9-point scale ranging from 1 (‘not at all important’) to 9 (‘critically important’).ResultsThe highest rating (median; range) was assigned to ‘Screening and referral’ (8.5; 2.0). Eight topics shared the second highest rating with a median priority score of 8.0 (2.0) and included ‘Starting dialysis or not’ and ‘Accurate assessment of renal function.’ ‘Targets for and treatment of diabetes’ received the lowest rating with (3.0; 6.0).ConclusionsThis joint initiative of the European Renal Association–European Dialysis Transplant Association (ERA–EDTA) and the European Union Geriatric Medicine Society (EUGMS) prioritized the development of guidance on interdisciplinary referral of older patients with chronic kidney disease stage 3b–5. Future guidance will therefore focus on identifying prognostic scores to predict death and progression to end-stage renal disease, as well as accurate tests for assessment of renal function in older kidney patients. This will contribute to more informed treatment decision making in this growing patient population.

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.

Manejo de agua y sodio por el riñón senescente. Interpretación de una técnica de aclaramiento para su estudio funcional

Hydroelectrolytic disorders, especially hyponatremias, are frequent in the elderly and are generally due to a syndrome of inappropriate antidiuretic hormone secretion. Although this is the most common cause in young adults, the most frequent cause in the elderly is Na depletion due to impaired competence of the thick ascending limb of Henle’s loop. Localization was performed through hyposaline loading and clearance study using Chaimowitz’s technique, which we describe and discuss in the present article.

Verapamil reverts acute renal functional impairment induced by angiotensin II converting enzyme inhibitors.

Angiotensin converting enzyme inhibitors (ACEI) reduce blood pressure (BP) and provide end-organ protection, but may induce renal function deterioration. In these cases, serum creatinine (SCr) can be normalized by ACEI withdrawn. In some patients, it could be desirable to maintain the ACEI for the protection of the kidney and heart. The objective of the study was to evaluate the effect of Verapamil (V) on renal function added to patients with elevated SCr due to ACEI treatment. In 46 hypertensive patients without previous renal failure, in which ACEI treatment induced an acute increase in SCr (≥20% or 0.5 mg/dL), ACEI treatment was maintained and 180 mg/day of V was added for 12 weeks. Those patients showing further SCr increase or no BP control at four weeks were withdrawn. Patients under BP control were moved on the combination V 180 + Trandolapril 2 mg/day for eight weeks more. SCr decreased from 136 ± 49 µmol/L at baseline to 126 ± 49 at 12 weeks after adding V (p<0.001) and to 111 ± 31 µmol/L at 20 weeks (p<0.01). Creatinine clearance increased from 62 ± 22 mL/min at baseline to 68 ± 28 after 12 weeks of V (p<0.001). This article demonstrates than in patients with acute renal function impairment secondary to ACEI treatment, the addition of 180 mg/day of verapamil to ACEI reverses SCr towards previous values.

Glomerular filtration rate equations: a comprehensive review

Since evaluation of glomerular filtration rate (GFR) is very important in daily medical care, and reliable methods for measuring GFR are too complicated, there has been along decades an enormous effort for developing accurate GFR equations. In the present review article, we performed a comprehensive analysis of the mainly described GFR equations, and we concluded that although MDRD, CKD-EPI, DRA and Gregori–Macías equations are valid to monitor renal function as well as to stage and follow up renal patients, the clinical nephrological evaluation still remains the best alternative for diagnosing renal health and disease.

Perindopril Stimulates Cultured Mesangial Cell Activation via Bradykinin Accumulation

Angiotensin I converting enzyme inhibitors have become important drugs for the treatment of hypertension, preventing angiotensin II generation. We have studied the effect of an angiotensin I convertin

Reduction of renal function by angiotensin-converting enzyme inhibitors: effect of verapamil.

Prof. Juan Florencio Macías-Nuñez, Servicio de Nefrología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58182, E-37007 Salamanca (Spain) Dear Sir, There is a large corpus of papers claiming a beneficial effect of ACEI in renal function in hypertensive patients, particularly in diabetic hypertensives [1]. A recent meta regression analysis of 100 clinical trials in patients with IDDM and NIDDM suggests that ACEI exhibits a specific renoprotective effect independent of the antihypertensive effect [2]. There are studies giving evidence that ACEI (lisinopril) and non-dihydropy-ridine calcium channel blockers are superior in lowering blood pressure, albuminuria, and reducing the rate of decline of GFR than the combination of diuretics and beta-block-ers [3]. Enalapril is more effective than ate-nolol in preserving GFR in spite of a similar reduction in blood pressure and urinary albumin excretion [4]. On the other hand, a worsening of renal function in some patients treated by ACEI has recently been communicated [5], particularly in patients with some degree of renal deterioration. Until now this side effect has been overcome by discontinuation of ACEI [5]. We present data concerning the influence of ACEI on serum cre-atinine in 11 patients aged 68.45 ± 1.46 years (range 23-82), 5 females and 6 males with mean serum creatinine before ACEI of 110.5 ± 41.5 μmolH. In a period of 5.87 ± 0.51 months the serum creatinine was raised to 396.03 ± 25.6 μmol l-1, (p < 0.05). ACEI were withdrawn and serum creatinine reverted towards values previous to ACEI treatment (120.22 ± 41.5 μmol H)· Thus, we confirm the data of Gotloib et al. [5] suggesting that ACEI can induce renal failure in some hypertensive patients, and that this effect can be reverted by discontinuation of ACEI. However, if ACEI are discontinued, the possible beneficial effects of these drugs on renal function are also eliminated. Because of this, the aim of the present paper is to show the effect of adding nondi-hydropyridine calcium channel blockers while maintaining the same dose of ACEI instead of withdrawing it in patients in whom serum creatinine increases with ACEI treatment. We have performed this study in 4 patients. The first patient is a 68-year-old woman with IDDM and serum creatinine 294.37 μmol H, BP 200/80 mm Hg and urinary albumin excretion (UAE) 1.05 g/day. She started on enalapril 10 mg b.i.d. to control BP and to reduce proteinuria. After 18 days serum creatinine raised to 381.89 μmol H, with a BP of 170/75 mm Hg. Maintaining the same dose of enalapril, verapamil at a dose of 80 mg b.i.d. was introduced. Seven days later serum creatinine was 327.97