[Experience with sevelamer in peritoneal dialysis]. / Experiencia con sevelamer en diálisis peritoneal.

BACKGROUND: Sevelamer is a non-absorbable phosphorus chelator that is not a source of aluminium, calcium or base. The clinical experience with sevelamer in peritoneal dialysis and in daily clinical practice is scarce. The aim of this study is to evaluate the results of therapy of hyperphosphoremia with sevelamer on serum phosphorus and phosphorus chelators requirements, in a peritoneal dialysis clinical practice. METHODS: Sevalamer 400 mg was prescribed to peritoneal dialysis patients with hyperphosphoremia who were treated with aluminium hydroxide or with calcium salts in the absence of hypocalcemia. Fourteen patients completed 12 months of therapy. RESULTS: The initial sevelamer dose was 2,280 +/- 760 mg/day, and was increased to 2,760 +/- 1,160 mg/day at 12 months. At 12 months no patient was on aluminium salts and calcium salts had been significantly reduced. Phosphoremia (5.9 +/- 0.6 to 5.0 +/- 1.4 mg/dL, p = 0.049), calcium-phosphorus product (59.8 +/- 5.8 to 48.6 +/- 12.5 mg2/dL2, p = 0.01) and serum cholesterol (191 +/- 29 to 167 +/- 33 mg/dL, p = 0.02) decreased at 12 months. No significant changes were observed in serum triglycerides, total CO2 or PTH. Serum alkaline phosphatase increased at 6 months, but values returned to normal at 12 months. No changes were observed in serum gamma-glutamyl-transpeptidase. Five patients were started on 1.25 (OH)2 vitamin D therapy. CONCLUSION: In peritoneal dialysis patients, sevelamer allows a satisfactory control of serum phosphorus levels and calcium-phosphorus product, while decreasing the amount of aluminium and calcium salts prescribed.

[Can we increase phosphate removal with conventional hemodialysis?]. / Se puede aumentar la eliminación de fósforo con la hemodiálisis convencional?

BACKGROUND: The aim of the present study was to investigate the effect of different dialysate buffer and glucose concentrations, membrane surface (S) bigger than 2 m2 and increased dialysate flow (Qd) in phosphate (P) removal. METHODS: A. First phase (5 patients): the following variations in dialysate composition were introduced. A: glucose 1.60 g/L, bicarbonate: 39 mEq/L, acetate 4 mEq/L, B: glucose 1.5 g/L bicarbonate 17 mEq/L, acetate 10 mEq/L; C: glucose 0, bicarbonate: 39 mEq/L, acetate 4 mEq/L; and D: glucose 0, bicarbonate 17 mEq/L, acetate 10 mEq/L. B. Second phase (14 patients): variations in S and Qd were: 1. Qd: 500 mL/min + Hemophan 2 m2, 2. Qd: 500 mL/min + Hemophan 2.6 m2, 3. Qd: 750 mL/min + Hemophan 2 m2, 4. Qd: 750 mL/min + Hemophan 2.6 m2. RESULTS: Comparing HDs performed with low bicarbonate (B and D) respect to current buffer formulations (A and C), total P removal was 997.3 (+/- 237.3) vs 882 (+/- 216.1) mg (p NS). No differences were found by grouping the sessions according to glucose concentration. There were no significant differences in total phosphate removal between the two different S or Qd. The most important predictive factor of total P removal was the initial P and 2 hours serum P concentration, and PTH concentration. CONCLUSIONS: i) Removal of P is better predicted by pre-dialysis P serum concentration; ii) P removal was not affected by the changes in bicarbonate and glucose concentration in the dialysate; iii) the increase of the dialyzer area between 2 and 2.6 m2 augments Kt/V, but without influencing P elimination; iv) a higher Qd does not determine significant differences in P removal and v) higher PTH is associated with a higher P elimination.

Experiencia con sevelamer en diálisis peritoneal / Experience with sevelamer in peritoneal dialysis

Introducción: El sevelamer es un quelante del fósforo no absorbible que no aporta aluminio, calcio ni bases. La experiencia con este nuevo quelante en nuestro medio, en diálisis peritoneal y en la práctica clínica diaria es escasa. El objetivo de este estudio es evaluar los resultados del tratamiento con sevelamer sobre la fosforemia y el uso de quelantes del fósforo en diálisis peritoneal. Métodos: En los pacientes del programa de diálisis peritoneal que recibían hidróxido de aluminio o que recibían sales de calcio sin tener tendencia a la hipocalcemia, la hiperfosforemia se trató con sevelamer. Catorce pacientes completaron 12 meses de tratamiento. Resultados: La dosis inicial de sevelamer fue de 2.280 ñ 760 mg/día, repartidos en dos o tres dosis y a los 12 meses era 2.760 ñ 1.160 mg/día. A los 12 meses el hidróxido de aluminio se había suspendido y la dosis de sales de calcio, la fosforemia (5,9 ñ 0,6 a 5,0 ñ 1,4 mg/dL, p = 0,049), el producto calciofósforo (59,8 ñ 5,8 a 48,6 ñ 12,5 mg2/dL2, p = 0,01) y el colesterol (191 ñ 29 a 167 ñ 33 mg/dL, p = 0,02) disminuyeron. No hubo cambios significativos en los triglicéridos, CO2 total ni la PTH. Se objetivó un aumento de la fosfatasa alcalina a los 6 meses, que se había normalizado a los 12 meses, sin cambios en la GGTY. Cinco pacientes comenzaron tratamiento con 1,25 dihidroxivitamina D. Conclusiones: En diálisis peritoneal el sevelamer permite un adecuado control de la fosforemia, a pesar de un menor uso de sales de calcio y de aluminio, y mejora el producto calcio-fósforo (AU)

Impairment of renal vasodilation with l-arginine is related to more severe disease in untreated hypertensive patients.

Data remain insufficient to place the decreased response to L-arginine in hypertensive patients within a consistent pathophysiological sequence. The aim of the present study in patients with essential hypertension was to assess the relationships between the response to L-arginine and a set of relevant clinical and laboratory parameters. In this prospective, interventional study, we administered L-arginine to untreated hypertensive individuals and healthy control subjects and measured the clearance of inulin and of para-aminohippurate and a set of biochemical and clinical variables. L-Arginine infusion revealed major differences between control subjects and 1 subgroup (group B) of hypertensive individuals. Group B hypertensives (n=18) had no increase in inulin clearance and no decrease in renal vascular resistance with L-arginine; however, in another subset of hypertensive patients (group A, n=27), the insulin clearance increased and renal vascular resistance decreased similar to the control group (group C, n=11). The ambulatory blood pressure monitoring in group B showed both an increased mean diastolic pressure and a "nondipper" pattern in the nocturnal regulation of arterial pressure. These findings in group B were accompanied by significant alterations in optic fundus and left ventricle hypertrophy and increased microalbuminuria (all, P<0.05). Furthermore, group B individuals had significantly lower values of HDL cholesterol and a higher baseline atherogenic index, plasma insulin level, and glucose/insulin index. We disclose a previously undescribed relationship between end organ repercussion and decreased renal hemodynamic response to L-arginine. Our results may help to understand the mechanisms that lead to target organ damage in hypertension.

Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure.

BACKGROUND: Parathyroid hormone (PTH)-related protein (PTHrP) is present in many normal tissues, including the kidney. Current evidence supports that PTHrP is involved in renal pathophysiology, although its role on the mechanisms of renal damage and/or repair is unclear. Our present study examined the changes in PTHrP and the PTH/PTHrP receptor (type 1) in folic acid-induced acute renal failure in rats. The possible role of PTHrP on the process of renal regeneration following folic acid administration, and potential interaction between angiotensin II (Ang II) and endothelin-1, and PTHrP, were examined in this animal model. METHODS: PTHrP, PTH/PTHrP receptor, ACE, and preproendothelin-1 (preproET-1) mRNA levels in the rat kidney were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and/or RNase protection assay. Immunohistochemistry also was performed for PTHrP, the PTH/PTHrP receptor, and Ang II in the renal tissue of folic acid-injected rats. The role of PTHrP on tubular cell proliferation following folic acid injury was investigated in vitro in rat renal epithelial cells (NRK 52E). PTHrP secretion in the medium conditioned by these cells was measured by an immunoradiometric assay specific for the 1-36 sequence. RESULTS: Using RT-PCR, PTHrP mRNA was rapidly (1 hour) and maximally increased (3-fold) in the rat kidney after folic acid, decreasing after six hours. At 72 hours, renal function was maximally decreased in these rats, associated with an increased PTHrP immunostaining in both renal tubules and glomeruli. In contrast, the PTH/PTHrP receptor mRNA (RNase protection assay) decreased shortly after folic acid administration. Moreover, PTH/PTHrP receptor immunostaining dramatically decreased in renal tubular cell membranes after folic acid. A single subcutaneous administration of PTHrP (1-36), 3 or 50 microg/kg body weight, shortly after folic acid injection increased the number of tubular cells staining for proliferating cell nuclear antigen by 30% (P < 0.05) or 50% (P < 0.01), respectively, in these rats at 24 hours, without significant changes in either renal function or calcemia. On the other hand, this peptide failed to modify the increase (2-fold over control) in ACE mRNA, associated with a prominent Ang II staining into tubular cell nuclei, in the kidney of folic acid-treated rats at this time period. The addition of 10 mmol/L folic acid to NRK 52E cells caused a twofold increase in PTHrP mRNA at six hours, without significant changes in the PTH/PTHrP receptor mRNA. The presence of two anti-PTHrP antibodies, with or without folic acid, in the cell-conditioned medium decreased (40%, P < 0.01) cell growth. CONCLUSIONS: Renal PTHrP was rapidly and transiently increased in rats with folic acid-induced acute renal failure, featuring as an early response gene. In addition, changes in ACE and Ang II expression were also found in these animals. PTHrP induces a mitogenic response in folic acid-damaged renal tubular cells both in vivo and in vitro. Our results support the notion that PTHrP up-regulation participates in the regenerative process in this model of acute renal failure and is a common event associated with the mechanisms of renal injury and repair.

Test de equilibrio peritoneal con intercambio hipertónico: aplicación práctica en un programa de diálisis peritoneal / Hypertonic peritoneal equilibration test: application to a peritoneal dialysis program

Recientemente se ha recomendado el test de equilibrio peritoneal (TEP) con intercambio hipertónico (3,86 por ciento/4,25 por ciento glucosa) para evaluar la capacidad de ultrafiltración peritoneal y, mediante el análisis de la concentración de sodio del dializado, estudiar ciertas causas de fallo de ultrafiltración, como la disfunción de acuaporinas. Sin embargo, no existe suficiente información sobre la mejor forma de expresar variaciones de la concentración de sodio del dializado, sobre los valores de la normalidad de este parámetro y sobre los posibles efectos adversos de la aplicación del TEP con intercambio hipertónico en la población general de pacientes en diálisis peritoneal.Realizamos un TEP con intercambio hipertónico en 22 pacientes. Siete pacientes presentaron un defecto de ultrafiltración (ultrafiltración < 0,4 L). Los pacientes con defecto de ultrafiltración tenían un transporte peritoneal de solutos pequeños y una concentración de sodio en el dializado más elevados y habían estado más tiempo en diálisis peritoneal. La concentración de sodio en el dializado a los 60 y 240 minutos se correlacionó directamente con el transporte peritoneal de solutos, calculado como D/PCr240 (r = 0,74, p = 0,0008 y r = 0,84, p < 0,0001) e inversamente con la ultrafiltración (r = 0,64, p = 0,0016 y r = 0,72, p = 0,0002). La ausencia de caída de la concentración de sodio en el dializado, sugerente de defecto de acuaporinas, es infrecuente. La concentración de sodio en el dializado a los 60 minutos discrimina mejor a los pacientes con fallo de ultrafiltración que parámetros como el D/PNa o la caída absoluta de los valores de sodio con respecto al tiempo cero. Como efectos adversos observamos hipotensión sintomática en 2 pacientes con ultrafiltración conservada.En conclusión, aunque el TEP hipertónico permite confirmar el diagnóstico de fallo de ultrafiltración, la medida del sodio en el dializado solo aporta información adicional en los raros casos en que existe un defecto severo en la función de acuaporinas. El empleo rutinario del TEP hipertónico puede provocar efectos adversos en pacientes sin defecto de ultrafiltración. (AU)

[Peritoneal equilibrium test with hypertonic exchange: practical application in a peritoneal dialysis program]. / Test de equilibrio peritoneal con intercambio hipertónico: aplicación práctica en un programa de diálisis peritoneal.

Peritoneal equilibration test (PET) employing a 2.27%/2.5% glucose exchange is the most widely used method of to evaluating peritoneal function and small solute transport. Hypertonic (3.86%/4.25% glucose) PET has been recently recommended for the evaluation of ultrafiltration and to study certain causes of ultrafiltration failure, such as aquaporin dysfunction, through the analysis of dialysate sodium. However, there is not enough information on the optimal way to express the changes in dialysate sodium concentration, the normal range of values for this parameter, and possible adverse effects of hypertonic PET in the general population of peritoneal dialysis patients. A hypertonic PET was performed in 22 patients. Ultrafiltration failure (ultrafiltration < 0.4 L) was present in seven patients. Patients with ultrafiltration failure had higher small solute peritoneal transport and dialysate sodium concentration and had been treated with peritoneal dialysis for longer periods of time. Dialysate sodium concentration at 60 and 240 minutes was directly correlated with small solute peritoneal transport calculated as D/PCr240 (r = 0.74, p = 0.0008 y r = 0.84, p < 0.0001) and inversely correlated with ultrafiltration (r = 0.64, p = 0.0016 y r = 0.72, p = 0.0002). An absence of a dip in dialysis sodium, suggestive of aquaporin dysfunction, was only observed in one patient with a high-average small solute peritoneal transport. Dialysate sodium concentration at 60 minutes is a better discriminator between ultrafiltration failure patients than parameters such as D/PNa or the absolute dip in dialysate sodium with respect to time zero. We observed the following adverse effects: symptomatic hypotension in 2 patients with preserved ultrafiltration. In conclusion, hypertonic PET allows to confirm the diagnosis of ultrafiltration failure, but monitoring dialysate sodium concentration offers additional information only in patients with severe aquaporin dysfunction. Hypertonic PET may have adverse effects in patients without ultrafiltration failure.

Role of vascular endothelial growth factor (VEGF) in endothelial cell protection against cytotoxic agents.

Autocrine expression of VEGF has been detected in endothelial cells under hypoxia or oxidative stress. However, the functional significance of this VEGF autocrine expression remains undefined. To analyze the role of autocrine VEGF in the endothelial response against injury, cultured bovine aorta endothelial cells (BAEC) were challenged with potentially cytotoxic substances with different chemical structure and pharmacologic properties, namely cytochalasin D (CyD), hydrogen peroxide (H2O2) and cyclosporine A (CsA). Our results revealed that: i. In particular conditions, exposure to potentially cytotoxic agents as CyD, H2O2 or CsA results in significant BAEC cytoprotection rather than injury. ii. The response to the 3 agents is shifted to a cell damaging pattern in the presence of a specific anti VEGF monoclonal antibody (mAb). iii. CyD and H2O2 markedly stimulate the autocrine expression of VEGF mRNA and VEGF protein. In conclusion, the present study reveals a protective mechanism of endothelial cells against injury involving autocrine VEGF production. Moreover, the occurrence of a significant increase in VEGF expression accompanying this defensive mechanism is further disclosed.

Hyperkalemia in patients infected with the human immunodeficiency virus: involvement of a systemic mechanism.

BACKGROUND: The appearance of hyperkalemia has been described in human immunodeficiency virus (HIV)-positive patients treated with drugs with amiloride-like properties. Recent in vitro data suggest that individuals infected with HIV have alterations in transcellular K+ transport. METHODS: With the objective of examining the presence of alterations in transmembrane K+ equilibrium in HIV-positive patients, we designed a prospective, interventional study involving 10 HIV-positive individuals and 10 healthy controls, all with normal renal function. An infusion of L-arginine (6%, intravenously, in four 30-min periods at 50, 100, 200, and 300 ml/hr) was administered, and plasma and urine electrolytes, creatinine, pH and osmolality, total and fractional sodium and potassium excretion, transtubular potassium gradient, plasma insulin, renin, aldosterone, and cortisol were measured. RESULTS: A primary disturbance consisting of a significant rise in plasma [K+] induced by L-arginine was detected in only the HIV patients but not in the controls (P < 0.001 between groups). A K+ redistribution origin of the hyperkalemia was supported by its rapid development (within 60 min) and the lack of significant differences between HIV-positive individuals and controls in the amount of K+ excreted in the urine. The fact that the HIV-positive individuals had an inhibited aldosterone response to the increase in plasma K+ suggested a putative mechanism for the deranged K+ response. CONCLUSIONS: These results reveal that HIV-infected individuals have a significant abnormality in systemic K+ equilibrium. This abnormality, which leads to the development of hyperkalemia after the L-arginine challenge, may be related, in part, to a failure in the aldosterone response to hyperkalemia. These results provide a new basis for understanding the pathogenesis of hyperkalemia in HIV individuals, and demonstrate that the risk of HIV-associated hyperkalemia exists even in the absence of amiloride-mimicking drugs or overt hyporeninemic hypoaldosteronism.

Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria.

Persistent proteinuria is considered a deleterious prognostic factor in most progressive renal diseases. However, the mechanisms by which proteinuria induces renal damage remain undetermined. Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II), we approached the hypothesis that proteinuria could elicit the renal activation of the renin-angiotensin system in a model of intense proteinuria and interstitial nephritis induced by protein overload. After uninephrectomy (UNX), Wistar-Kyoto rats received daily injections of 1 g BSA or saline for 8 days. The mean peak of proteinuria was observed at the fourth day (538+/-89 versus 3+/-1 mg/24 h in UNX controls; n=12; P<0.05) and was increased during the whole study period (at the eighth day: 438+/-49 mg/24 h; n=12; P=NS). Morphological examination of the kidneys at the end of the study showed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion. In relation to UNX control rats, renal cortex of BSA-overloaded rats showed an increment in the gene expression of angiotensinogen (2.4-fold) and angiotensin-converting enzyme (ACE) (2.1-fold), as well as a diminution in renin gene expression. No changes were observed in angiotensin type 1 (AT1) receptor mRNA expression in both groups of rats. By in situ reverse transcription-polymerase chain reaction and immunohistochemistry, ACE expression (gene and protein) was mainly localized in proximal and distal tubules and in the glomeruli. By immunohistochemistry, angiotensinogen was localized only in proximal tubules, and AT1 receptor was localized mainly in proximal and distal tubules. In the tubular brush border, an increase in ACE activity was also seen (5. 5+/-0.5 versus 3.1+/-0.7 U/mg protein x10(-4) in UNX control; n=7; P<0.05). Our results show that in the kidney of rats with intense proteinuria, ACE and angiotensinogen were upregulated, while gene expression of renin was inhibited and AT1 was unmodified. On the whole, these data suggest an increase in Ang II intrarenal generation. Since Ang II can elicit renal cell growth and matrix production through the activation of AT1 receptor, this peptide may be responsible for the tubulointerstitial lesions occurring in this model. These results suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.

Effects of LY-117018 HCl on bone remodeling and mineral density in the oophorectomized rat.

OBJECTIVE: LY-117018 HCl is a recently developed, selective estrogen receptor modulator and an analog of raloxifene. Its mode of action on the skeleton is similar to that of estrogens, although it does not have the same side effects. The aim of the current study was to compare the effects produced by the administration of 17alpha-ethinyl estradiol (0.1 mg/kg/day) and LY-117018 HCl (1 mg/kg/day) on bone remodeling, bone mineral density, and body and uterus weight in sham-operated and oophorectomized rats (experimental model of postmenopausal osteoporosis). STUDY DESIGN: Twelve-week-old female Wistar rats were used. Treatment was given for 3 months after oophorectomy or sham operation. Bone mineral density was determined in the lumbar spine (L2, L3, and L4) and in the left femur with use of a Hologic QDR 1000 (S/N 277) densitometer. Bone remodeling was estimated with use of the formation markers osteocalcin (bone gla protein) and alkaline phosphatase and the resorption markers type I collagen carboxyterminal telopeptide and tartrate-resistant acid phosphatase. RESULTS AND CONCLUSIONS: The newly developed derivative of raloxifene, LY-117018 HCl, offsets the reduction in bone mineral density and the accompanying increase in bone remodeling markers observed in oophorectomized rats compared with control animals. 17Alpha-ethinyl estradiol also prevents the loss of bone mass attributed to oophorectomy, but this is accompanied by an increase in body mass and a greater increase in uterus weight than that observed after treatment with LY-117018 HCl.