Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls.

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.

Use of a renal-specific oral supplement by haemodialysis patients with low protein intake does not increase the need for phosphate binders and may prevent a decline in nutritional status and quality of life.

BACKGROUND: Protein-energy wasting is a frequent and debilitating condition in maintenance dialysis. We randomly tested if an energy-dense, phosphate-restricted, renal-specific oral supplement could maintain adequate nutritional intake and prevent malnutrition in maintenance haemodialysis patients with insufficient intake. METHODS: Eighty-six patients were assigned to a standard care (CTRL) group or were prescribed two 125-ml packs of Renilon 7.5(R) daily for 3 months (SUPP). Dietary intake, serum (S) albumin, prealbumin, protein nitrogen appearance (nPNA), C-reactive protein, subjective global assessment (SGA) and quality of life (QOL) were recorded at baseline and after 3 months. RESULTS: While intention to treat analysis (ITT) did not reveal strong statistically significant changes in dietary intake between groups, per protocol (PP) analysis showed that the SUPP group increased protein (P < 0.01) and energy (P < 0.01) intakes. In contrast, protein and energy intakes further deteriorated in the CTRL group (PP). Although there was no difference in serum albumin and prealbumin changes between groups, in the total population serum albumin and prealbumin changes were positively associated with the increment in protein intake (r = 0.29, P = 0.01 and r = 0.27, P = 0.02, respectively). The SUPP group did not increase phosphate intake, phosphataemia remained unaffected, and the use of phosphate binders remained stable or decreased. The SUPP group exhibited improved SGA and QOL (P < 0.05). CONCLUSION: This study shows that providing maintenance haemodialysis patients with insufficient intake with a renal-specific oral supplement may prevent deterioration in nutritional indices and QOL without increasing the need for phosphate binders.

Pioglitazone improves fat distribution, the adipokine profile and hepatic insulin sensitivity in non-diabetic end-stage renal disease subjects on maintenance dialysis: a randomized cross-over pilot study.

BACKGROUND: Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity. TRIAL DESIGN: This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects. METHODS: At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored. RESULTS: Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10-3 to 0.76×10-3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP. CONCLUSIONS/LIMITATIONS: Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation. TRIAL REGISTRATION: ClinicalTrial.gov NCT01253928.

Hyperresponders vs. nonresponder patients after renal denervation: do they differ?

BACKGROUND: Blood pressure (BP) response after renal denervation (RDN) is highly variable. Besides baseline BP, no reliable predictors of response have been consistently identified. The differences between patients showing a major BP decrease after RDN vs. nonresponders have not been studied so far. AIM AND METHODS: We identified extreme BP responders (first quintile) and nonresponders (fifth quintile) to RDN defined according to office or 24-h ambulatory BP in the European Network COordinating research on Renal Denervation database (n = 109) and compared the baseline characteristics and BP changes 6 months after RDN in both subsets. RESULTS: In extreme responders defined according to ambulatory BP, baseline BP and BP changes 6 months after RDN were similar for office and out-of-the office BP. In contrast, extreme responders defined according to office BP were characterized by a huge white-coat effect at baseline, with dramatic shrinkage at 6 months. Compared with nonresponders, extreme responders defined according to office BP were more frequently women, had higher baseline office--but not ambulatory--BP, and higher estimated glomerular filtration rate (eGFR). In contrast, when considering ambulatory BP decrease to define extreme responders and nonresponders, the single relevant difference between both subsets was baseline ambulatory BP. CONCLUSION: This study suggests a major overestimation of BP response after RDN in extreme responders defined according to office, but not ambulatory BP. The association of lower eGFR with poor response to RDN is consistent with our previous analysis. The increased proportion of women in extreme responders may reflect sex differences in drug adherence.

Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

Renal protection with calcium antagonists: the role of lercanidipine.

Abstract Background: Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date. Scope: This review will discuss available evidence on the renal effects of two calcium channel blockers: amlodipine and lercanidipine, on the basis of clinical data. Methods: MEDLINE and EMBASE were searched for inclusion of relevant studies. No limitations in time were considered. Results: Results from preclinical and clinical studies suggest that amlodipine is overall less effective in terms of renal protection when compared with other antihypertensive tested agents. Its beneficial effect in retarding the progression of renal disease is achievable only when combined with a blocker of the renin-angiotensin system. Conversely lercanidipine seems to provide renal protection in a similar way to ACE inhibitors, probably thanks to its mechanism of action which acts directly on the afferent and efferent renal arterioles. Conclusions: Treatment of hypertension with CCBs should take into consideration the special effects of each single agent at different levels; lercanidipine for example may play a useful role in the management not only of hypertension but also in renal protection of hypertensive patients.

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers.

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.

Prevalencia,evolución y factores de riesgo asociados a insuficiencia renal en pacientes infectados por VIH de nuestro medio

El objetivo es Establecer la prevalencia de insuficiencia renal en pacientes infectados por el VIH de nuestro medio, factores de riesgo asociados y evolución de esta función renal. Estudio descriptivo prospectivo de 1596 pacientes VIH +. 2 cortes transversales de la muestra: Nov´08-Feb´09 y Jul–Sept´10. Datos sobre múltiples variables disponibles en cada corte. Se dividió la muestra en GRUPO 1: FG ≤ 60 ml/min/1,73 m2 y GRUPO 2: FG & 60 ml/min/1,73 m2. Prevalencia de insuficiencia renal 4-5%. Deterioro de función renal relacionado con: Edad, fibrinógeno, albúmina, carga viral, CD4%, tratamiento con Tenofovir, dislipemia, Hipertensión y diabetes.

Corte de prevalencia del fracaso renal agudo y análisis de la lipocalina asociada a la gelatinasa de neutrófilos en el paciente crítico

En aquest estudi es pretén ampliar el coneixement del fracàs renal agut (FRA) en els pacients crítics i analitzar si el biomarcador lipocalina associada a la gelatinasa de neutròfils (NGAL) és una bona prova diagnòstica de lesió renal. Vàrem realitzar dos talls de prevalença incloent 46 pacients i es va analitzar la creatinina sèrica i el NGAL. El 28,26% dels pacients van presentar FRA, la mortalitat global va ser del 28,26%, el 37% dels pacients van presentar un NGAL alt. El valor predictiu positiu de NGAL per diagnosticar FRA va ser del 36,1% mentre que el valor predictiu negatiu va ser del 92,6%.

Importancia de la cirugía aorto-ilíaca previa o simultánea en la evolución del trasplante renal

La malaltia renal crònica terminal, el tractament substitutiu d'elecció és el trasplantament renal, és un problema de salut pública mundial en augment. L'envelliment de la població i la major prevalença de diabetis i hipertensió arterial en aquests pacients, s'associa a una major incidència de malaltia aorto-ilíaca i possible fracàs del ronyó trasplantat. En aquest treball es va analitzar l'evolució del filtrat glomerular en pacients trasplantats renals amb patologia aorto-ilíaca que van requerir cirurgia arterial prèvia o simultània al trasplantament renal, comparada amb un grup control sense patologia aorto-ilíaca. No es van trobar diferències estadísticament significatives entre ambdós grups.

Association of CYP3A5 genotypes with blood pressure and renal function in African families.

OBJECTIVE: Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associated with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. METHODS: Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles (*1, *3, *6 and *7) and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. RESULTS: CYP3A5*1 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5*1 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P = 0.003/0.045, respectively] and this effect was modified by age (CYP3A5*1 x age interactions, P = 0.017/0.018). For night-time ABP, the effect of CYP3A5*1 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5*1 carriers had a 7.6(3.8) ml/min lower GFR (P = 0.045) than non-carriers. Proximal sodium reabsorption decreased with age in non-carriers, but not in CYP3A5*1 carriers (P for interaction = 0.02). CONCLUSIONS: These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5*1 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.

La fonction rénale sous inhibition de l'enzyme de conversion de l'angiotensine [Renal function after administration of angiotensin-converting enzyme inhibitors]

Angiotensin converting enzyme (ACE) inhibitors are widely used today for the management of hypertension and congestive heart failure. These agents inhibit angiotensin II synthesis. In some particular circumstances they may be responsible for deterioration of renal function, e.g. in hypertensive patients with bilateral renal artery stenosis or with stenosis of the artery supplying a single kidney, or in patients with severe congestive heart failure or marked nephroangiosclerosis. In these patients renal perfusion pressure may become too low to maintain adequate glomerular filtration as there remains no angiotensin II to increase the tone of the efferent arteriole. In high risk patients it is therefore recommended that serum creatinine be checked after initiating therapy with an ACE inhibitor.

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.