Chronic nitric oxide synthase inhibition and carotid artery distensibility in renal hypertensive rats.

The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n = 53) or sham operation (n = 49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C-L-NAME (197 mm Hg), and sham-L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME- and vehicle-treated 2K1C rats compared with the sham-L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensibility that is not dependent on the synthesis of nitric oxide.

Valoración del daño renal producido durante la nefrectomía parcial abierta, condicionado según el tipo de isquemia y sexo, en cerdos monorrenos

Tradicionalmente la técnica para realizar una nefrectomía parcial ha sido previa inducción de isquemia renal (caliente o fría), habiéndose evidenciado que el daño producido por la isquemia-reperfusión es menor con la hipotermia. En relación al género, estudios experimentales demuestran mayor susceptibilidad de los machos a las lesiones renales de isquemia-reperfusión. El objetivo de este trabajo es comprobar si en cerdos monorrenos, la isquemia fría produce menor daño renal que la caliente, mediante marcadores bioquímicos y análisis anatomo-patológico, y así también valorar la existencia de estas diferencias según el sexo.

Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure.

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.

Severe hypertension and massive proteinuria in a newborn with renal artery stenosis.

Renal vein thrombosis and the congenital nephrotic syndrome have been associated with nephrotic-range proteinuria/nephrotic syndrome and hypertension in the newborn period. We describe a newborn with severe hypertension and proteinuria secondary to unilateral renal artery stenosis. Proteinuria completely disappeared with blood pressure control (with sodium nitroprusside and an angiotensin-converting enzyme inhibitor). Although renin was not measured, we speculate that proteinuria might have been induced by a high renin state, and was controlled by the angiotensin-converting enzyme inhibitor.

WNK3 abrogates the NEDD4-2-mediated inhibition of the renal Na+-Cl- cotransporter.

The serine/threonine kinase WNK3 and the ubiquitin-protein ligase NEDD4-2 are key regulators of the thiazide-sensitive Na+-Cl- cotransporter (NCC), WNK3 as an activator and NEDD2-4 as an inhibitor. Nedd4-2 was identified as an interacting partner of WNK3 through a glutathione-S-transferase pull-down assay using the N-terminal domain of WNK3, combined with LC-MS/MS analysis. This was validated by coimmunoprecipitation of WNK3 and NEDD4-2 expressed in HEK293 cells. Our data also revealed that the interaction between Nedd4-2 and WNK3 does not involve the PY-like motif found in WNK3. The level of WNK3 ubiquitylation did not change when NEDD4-2 was expressed in HEK293 cells. Moreover, in contrast to SGK1, WNK3 did not phosphorylate NEDD4-2 on S222 or S328. Coimmunoprecipitation assays showed that WNK3 does not regulate the interaction between NCC and NEDD4-2. Interestingly, in Xenopus laevis oocytes, WNK3 was able to recover the SGK1-resistant NEDD4-2 S222A/S328A-mediated inhibition of NCC and further activate NCC. Furthermore, elimination of the SPAK binding site in the kinase domain of WNK3 (WNK3-F242A, which lacks the capacity to bind the serine/threonine kinase SPAK) prevented the WNK3 NCC-activating effect, but not the Nedd4-2-inhibitory effect. Together, these results suggest that a novel role for WNK3 on NCC expression at the plasma membrane, an effect apparently independent of the SPAK kinase and the aldosterone-SGK1 pathway.

PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemia.

We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1(+/+) wild-type and 15 male Parp1(0/0) knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp1(0/0) knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

Temsirolimus in overtreated metastatic renal cancer with subsequent use of sunitinib: A case report.

During the last decade, we have been developing new therapeutic strategies for the treatment of renal cancer, based on knowledge derived from molecular biology. We report a case of long-term renal metastatic cancer progression despite therapy with sunitinib and interleukin, which are the most active drugs in renal cancer. Disease stabilization for 58 weeks was achieved upon sequential use of temsirolimus, following the occurrence of disease progression during angiogenic therapy. The patient demonstrated excellent tolerance without marked symptoms for 10 months. Hypothyroidism and mumps-related adverse events were present. The survival time from diagnosis to lung metastasis was 8 years. Thus, this case demonstrates promising therapeutic effects of the sequential use of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors during different stages of the disease.

PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemia.

We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1(+/+) wild-type and 15 male Parp1(0/0) knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp1(0/0) knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

Study of the effectiveness of first-line treatment in renal cell carcinoma.

The emergence of novel drugs corresponds with the determination of the effectiveness of the current treatments used in clinical practice. A retrospective observational study was conducted to evaluate the effectiveness of first-line treatments and to test the influence of the prognostic factors established using the Memorial Sloan-Kettering Cancer Center (MSKCC) and the analysis of Mekhail's study for two or more metastatic sites. The primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS) times. A total of 65 patients were enrolled and the mPFS and mOS of the patients treated with sunitinib (n=51) were 9.0 and 20.1 months, respectively, and for the patients treated with temsirolimus (n=14) these were 3.0 and 6.2 months, respectively. In the poor-prognosis (PP) group, a difference of 1.2 months (P=0.049) was found in mPFS depending on the first-line treatment. A difference of 4.1 months (P=0.023) was also found in mPFS when classified by histology (clear verses non-clear cell) in the sunitinib-treatment group. When stratified by the prognostic group, differences of >7 months (P<0.001) were found between the groups. Therefore, it was concluded that the effectiveness of the treatments was reduced compared to previous studies and differences were found in the PP group when classified by first-line drug and histology. Additionally, the influence of prognostic factors on OS and the value of stratifying patients using these factors have been confirmed.

Estudio longitudinal del peso e índice de masa corporal tras el trasplante renal durante 5 años de evolución.

INTRODUCTION: Gain weight after transplantation is relatively common, also tends to be multifactorial and can be influenced by glucocorticoids and immunosuppressive medications, delayed graft function and cause serious health complications. OBJECTIVES: Assess changes in weight, degree of obesity and body mass index as well as the effect of immunosuppressive treatment over these 5 years after kidney transplantation. METHODS: The samples were 119 kidney transplant recipients, 70 men and 49 women, that attended the query post for five years. All patients were measured Pretransplant and post (from 1st year to the 5th year) weight, height and body mass index calculated by the formula weight/size2 relating it to immunosuppressive treatment taking. RESULTS: There is a considerable increase of body mass index, weight and degree of obesity in the first year after transplantation to increase more slowly in the next four years. The type of immunosuppressive treatment influence the weight and degree of obesity that occurs in this period of time. CONCLUSIONS: A high prevalence there are overweight and obesity after the transplant especially during the first year. A year patients earn an average of 6.6 kg in weight and an average of 2.5 kg/m2 in their BMI. During treatment should minimize doses of steroids and include dietary treatment and adequate physical exercise

Effects of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men.

Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.

Free-breathing renal magnetic resonance angiography with steady-state free-precession and slab-selective spin inversion combined with radial k-space sampling and water-selective excitation.

The impact of radial k-space sampling and water-selective excitation on a novel navigator-gated cardiac-triggered slab-selective inversion prepared 3D steady-state free-precession (SSFP) renal MR angiography (MRA) sequence was investigated. Renal MRA was performed on a 1.5-T MR system using three inversion prepared SSFP approaches: Cartesian (TR/TE: 5.7/2.8 ms, FA: 85 degrees), radial (TR/TE: 5.5/2.7 ms, FA: 85 degrees) SSFP, and radial SSFP combined with water-selective excitation (TR/TE: 9.9/4.9 ms, FA: 85 degrees). Radial data acquisition lead to significantly reduced motion artifacts (P < 0.05). SNR and CNR were best using Cartesian SSFP (P < 0.05). Vessel sharpness and vessel length were comparable in all sequences. The addition of a water-selective excitation could not improve image quality. In conclusion, radial k-space sampling reduces motion artifacts significantly in slab-selective inversion prepared renal MRA, while SNR and CNR are decreased. The addition of water-selective excitation could not improve the lower CNR in radial scanning.

Sistema de Información de la Coordinación Autonómica de Trasplantes de Andalucía (SICATA) : Subsistema de Insuficiencia Renal Crónica : Informe 2013

Coordinación Autonómica de Trasplantes

Osteoporosis e índice de masa corporal en el trasplantado renal.

INTRODUCTION: frequently after kidney transplantation there is an increase in weight with a resulting high percent of obesity in these recipients. This combined with a rapid loss of bone mass, a higher prevalence of osteoporosis and fractures is evident than in normal populations. OBJECTIVES: to explore the relationship between body mass index (BMI) and prevalence of osteoporosis in a population of renal transplant recipients. METHODS: prospective longitudinal study design. The study was conducted on 306 kidney transplant recipients. The relationship between weigh and body mass index with femoral and lumbar osteopenia and osteoporosis prevalence at the moment of transplant and at 12 months post was explored. RESULTS: there was a high prevalence of overweight (35.6%) and obese (14.1%) recipients after renal transplant and 1 year after (42.2% and 24.2% respectively). Significant differences were found(p = 0.049) between the weight at the time of transplant and the presence of osteopenia or osteoporosis at the lumbar level one year after, the highest weights were in recipients with osteoporosis. The mean BMI was higher (p = 0.028) in osteoporotic patients (26.59 kg/m2) than in patients with osteopenia (24.23 kg/m2). CONCLUSION: results seem to be consistent with recent studies in the general population showing excessive weight as a possible factor detrimental to the bone health.