Gregory P. Marelich, M.D., FACP, FCCP

• Assistant Professor of Clinical Internal Medicine
• Division of Pulmonary and Critical Care
• Medicine
• University of California Davis Medical Center
• Sacramento, CA

There were more pronounced gastrointestinal side effects associated with sevelamer use compared to calcium binders erectile dysfunction natural cure buy generic silagra 100 mg online. Lanthanum carbonate resulted in similar end-of-treatment phosphorus levels compared to other binders but is reported to require a lower pill burden compared to sevelamer erectile dysfunction and marijuana purchase cheap silagra line. This study found no difference in the progression of calcification between the calcium binder and sevelamer groups provided that serum lipid levels were kept within the same range erectile dysfunction doctor maryland buy generic silagra 100 mg line. Currently available oral phosphate binders vary in cost erectile dysfunction psychological treatment techniques purchase silagra without a prescription, phosphate-binding efficacy impotence zoloft discount 100 mg silagra mastercard, and side effect profiles yohimbine treatment erectile dysfunction cheap silagra 100 mg with visa, but available data from limited randomized controlled trials do not show the superiority of any one binder over the other with regard to control of serum phosphate level or effects on mortality or other outcomes. Calcium carbonate costs considerably less than calcium acetate, and no study has demonstrated a clinical advantage of one over the other. A major concern regarding use of calcium binders is the potential for cumulative positive calcium balance and soft tissue calcifications. The use of very large oral doses of calcium as a phosphate-binding agent has been associated with evidence of soft tissue and vascular calcification among patients undergoing long-term dialysis. Based on these observations, alternative phosphatebinding strategies that limit total calcium intake to 1500 to 2000 mg/day from both dietary and medicinal sources have been proposed. When used, the duration of treatment is typically limited to periods of 2 to 3 months, the doses kept as low as possible, and concurrent administration of citrate-containing compounds avoided. Lanthanum carbonate is a potent phosphate-binding agent available for clinical use among patients undergoing dialysis. Histologic studies of bone in biopsy specimens obtained after 1 year of treatment with lanthanum carbonate show no adverse effects on skeletal mineralization or on bone remodeling. In longer-term studies, total daily doses averaging 5 to 6 g were sufficient to maintain serum phosphorus levels at approximately 5. Plasma bicarbonate concentrations decrease modestly during treatment with sevelamer hydrochloride, a biochemical change that is probably caused by the release of protons from the resin during phosphate binding57; the carbonate compound ameliorates this problem. A trial comparing sucroferric oxyhydroxide with sevelamer carbonate found equal efficacy in reducing serum phosphate concentrations, but differences in side effect profiles, with sucroferric oxyhydroxide associated with diarrhea and discolored stools, and sevelamer carbonate associated with nausea and constipation. Nevertheless, concern remains regarding the potential of calcium overload and consequent exacerbation of vascular calcification with the use of calcium-based binders. Although no survival advantage has been demonstrated with the use of the resin binder sevelamer compared to calcium-based binders in randomized clinical trials, and all phosphate binders may increase intestinal calcium absorption to some degree,67 most treatment regimens minimize the use of calcium-based binders. The limitation of phosphate binders has led to new ways to prevent gastrointestinal phosphate absorption. Thus the current practice is to limit the amount of calcium supplementation, although little is known about whether calcium supplementation alone, in the absence of concomitant therapy with vitamin D analogs, can be safely administered to correct abnormalities in bone and mineral metabolism. While oral and intravenous administrations appear to be equally effective, there may be a trend for induction of less hypercalcemia and hyperphosphatemia by some of the newer analogs at low doses. Calcitriol thus serves as an important modifier of gene transcription even in tissues that are not involved directly in maintaining calcium homeostasis. These nonclassical actions are important in regulating cell proliferation and differentiation, as well as other functions, such as innate immunity, insulin sensitivity, and bone and cardiovascular health. Such findings are notable and potentially important, but they are limited by residual confounding (indication bias). For example, intravenous synthetic vitamin D analogs administered three times a week are commonly used in the United States, whereas oral vitamin D analogs are more commonly used in other countries. First, increased frequency of dialysis results in a greater cumulative phosphate removal, possibly reducing the need for phosphate binders to maintain neutral phosphate balance. For example, a standard dialysis treatment removes approximately 900 mg of phosphate. Among patients undergoing maintenance hemodialysis, intravenous doses given three times a week during each dialysis session are used most often. Parenteral vitamin D therapy is generally started using small initial doses, assuming that serum calcium and phosphate concentrations are not elevated. Values often increase during treatment, and these biochemical changes often necessitate a reduction in the dose of vitamin D analogs. As such, the use of dialysis solutions containing calcium concentrations lower than 2. Such an approach thus provides biochemical information similar to that used in published clinical trials to guide decisions about dosage adjustments and to judge therapeutic efficacy. Reductions in serum calcium concentration are thus a predictable, physiologic response to treatment with calcimimetic agents. To minimize the effects of hypocalcemia, the initial dose of cinacalcet is 30 mg/day, and subsequent doses are increased every 2 to 3 weeks in 30-mg increments until a maximum dose of 180 mg/day is achieved. The primary analysis of the trial-an unadjusted intention-to-treat approach-showed no significant effect of cinacalcet on mortality or a composite end point of death or major cardiovascular events. Analyses adjusting for baseline factors (there was an imbalance in age across randomized groups) showed nominally significant reductions in the primary composite end point as well as mortality. Finally, successful treatment involves patient education and a multidisciplinary approach involving nephrologists, dietitians, and nurses. There are currently no recommendations to prescribe phosphate binders or vitamin D supplements or analogs in the absence of hyperphosphatemia or documented vitamin D deficiency. Efforts to control serum phosphate concentrations with dietary phosphate restriction (with adequate protein intake) and phosphate binders to maintain serum phosphate between 3. Because there are no prospective outcome studies to separate the different binders, one can choose from among calcium-, resin-, lanthanum-, or iron-based binders. Phosphorus-restricted diets mandate that the intake of dairy products be limited substantially. In addition, oral doses of calcium in such patients may thus serve to maintain serum calcium concentrations, correct overt hypocalcemia, and avert compensatory secretory responses by the parathyroid glands to maintain calcium homeostasis as kidney function declines. Calcium excretion in the urine should be measured periodically among patients treated with oral calcium supplements, and doses should be adjusted to avoid hypercalciuria. Although there is some data that ergocalciferol is less bioactive, these differences are not clinical relevant. After initiating treatment, serum calcium and phosphorus levels should be monitored quarterly to test for possible overtreatment. In addition, treatment should continue for 6 months, and continued need for supplementation with ergocalciferol should be reevaluated annually. The opposing effects of cinacalcet and vitamin D sterols on serum calcium concentrations may permit the use of cinacalcet in patients receiving therapy with active vitamin D analogs. Cinacalcet may also be used in kidney transplant recipients with hypercalcemia caused by persistent, posttransplantation hyperparathyroidism. In this population, treatment with cinacalcet corrected hypercalcemia and increased serum phosphate concentration. Krajisnik T, Bjorklund P, Marsell R, et al: Fibroblast growth factor23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. Zhang Q, Li M, Lu Y, et al: Meta-analysis comparing sevelamer and calcium-based phosphate binders on cardiovascular calcification in hemodialysis patients. Krajisnik T, Bjorklund P, Marsell R, et al: Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. Block G: Association of serum phosphorus and calcium x phosphorus product with mortality risk in chronic hemodialysis patients: a national study. Yamada S, Tokumoto M, Tatsumoto N, et al: Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. Martinez I, Saracho R, Montenegro J, et al: the importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Reichel H, Deibert B, Schmidt-Gayk H, et al: Calcium metabolism in early chronic renal failure: implications for the pathogenesis of hyperparathyroidism. Teng M, Wolf M, Lowrie E, et al: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. Nishi H, Nii-Kono T, Nakanishi S, et al: Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Tokmak F, Quack I, Schieren G, et al: High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients. Gallieni M, Cozzolino M, Brancaccio D: Transient decrease of serum bicarbonate levels with sevelamer hydrochloride as the phosphate binder. Locatelli F, Dimkovic N, Spasovski G: Efficacy of colestilan in the treatment of hyperphosphataemia in renal disease patients. Mucsi I, Hercz G, Uldall R, et al: Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Bacchini G, Fabrizi F, Pontoriero G, et al: "Pulse oral" versus intravenous calcitriol therapy in chronic hemodialysis patients. Sanchez C, Lopez-Barea F, Sanchez-Cabezudo J, et al: Low vs standard calcium dialysate in peritoneal dialysis: differences in treatment, biochemistry and bone histomorphometry. Fernandez E, Borras M, Pais B, et al: Low-calcium dialysate stimulates parathormone secretion and its long-term use worsens secondary hyperparathyroidism. Drueke T, Martin D, Rodriguez M: Can calcimimetics inhibit parathyroid hyperplasia Tu Q, Pi M, Karsenty G, et al: Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. Russo D, Miranda I, Ruocco C, et al: the progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Di Iorio B, Bellasi A, Russo D, et al: Mortality in kidney disease patients treated with phosphate binders: a randomized study. Ishimura E, Nishizawa Y, Inaba M, et al: Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Przedlacki J, Manelius J, Huttunen K: Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure. Tonelli M, Sacks F, Pfeffer M, et al: Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Weber K, Goldberg M, Stangassinger M, et al: 1Alphahydroxyvitamin D2 is less toxic but not bone selective relative to 1alpha-hydroxyvitamin D3 in ovariectomized rats. Rix M, Andreassen H, Eskildsen P, et al: Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Evenepoel P, Cooper K, Holdaas H, et al: A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism. Although regulatory authorities now require a pediatric investigation plan as a routine part of drug development, they have not yet responded to the challenge of ensuring robust data for patients with impaired kidney function. In the 1970s, with the advent of specific and sensitive analytic techniques, the pharmaceutical industry began to investigate the relationship of kidney function to the pharmacokinetics and pharmacodynamics of the drugs they had in development. These resulted in the publication of inconsistent and, in some cases, conflicting recommendations regarding adjustments in drug dose or frequency of administration. The role of pharmacodynamic measures alone or in combination with pharmacokinetics, as well as pharmacogenetic testing in drug dosage regimen design, is discussed. This decrease occurs as the drug distributes from the plasma into the extravascular space and beyond. The terminal elimination half-life of a drug is the time required for the plasma concentration to decline by 50%; this it can be determined from the slope of the elimination phase of the plot of serum or plasma drug concentration versus time after the drug is ingested or injected. Drugs given by other routes must first pass through important organs of elimination before entering the systemic circulation; thus, a smaller proportion of the drug reaches the systemic circulation. Ammonia forms from urea in the presence of gastric urease and buffers gastric acid, increasing gastric pH. The gastric alkalinizing effect of this internal urea-ammonia cycle decreases the absorption of drugs that are best absorbed in an acidic environment. Drug malabsorption may be further aggravated by the increased use of various therapies to reduce gastric acidity and/or reduce phosphate absorption, especially in patients who are dialysis-dependent. Conversely, diarrhea decreases gut transit time (Tmax is shortened and diminishes drug absorption by the small bowel). Failure to detect a reduction in body cell mass may lead to inappropriate maintenance of the same dry weight and drug dosage regimen, despite a real increase in total body water32 (and thus the distribution volume of several drugs). Finally, the method used to calculate the volume of distribution may be influenced by impaired kidney function. The Vc for many drugs approximates extracellular fluid volume and thus may be increased or decreased by acute changes. V is affected by distribution characteristics and by the terminal elimination rate constant. Because Vss has the advantage of being independent of drug elimination, it is the most appropriate volume term to use when it is desirable to compare drug distribution volumes between patients with renal insufficiency and those with normal renal function. The volume of distribution of a drug, quantity of unbound drug available for action, and degree to which the agent is eliminated by hepatic or renal excretion are all influenced by protein binding. Whereas organic acids bind to a single binding site, organic bases probably have multiple sites of attachment. Even when the plasma albumin concentration is normal, the proteinbinding defect of some drugs correlates directly with the level of azotemia and may be corrected with dialysis. Toxicity can occur if the total plasma concentration of these drugs is pushed into the therapeutic range by increasing the dose, wherein the free (active) concentration may be in the supratherapeutic range. More unbound drug is available for metabolism and excretion, which increases the clearance and decreases the halflife of the drug in the body. Drugs with decreased protein binding in patients on dialysis are listed in Table 64. For example, although the liver usually rapidly metabolizes morphine, it is excreted mainly in the urine because its active metabolites, morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G) readily cross the blood-brain barrier and bind to opiate receptors, exerting strong analgesic effects. Normeperidine has little to no analgesic activity but lowers the seizure threshold. Drug elimination by filtration occurs by a pressure gradient, whereas tubular secretion and reabsorption are bidirectional processes that involve carrier-mediated renal transport systems. Genotypic characterization now serves as the basis for dosing recommendations for some drugs,74-77 and more than 120 U. We need to continue to uncover variants within the genome that can be used to predict disease onset, affect progression, and modulate drug response. Physicians and other health care professionals will need support in interpreting genomic data, integrating it into clinical decision making, and applying the results to individual patients.

Normalized protein catabolic rate can be calculated for patients undergoing dialysis erectile dysfunction killing me silagra 50 mg low cost. This requires in some cases concentrating the formula to achieve a higher caloric intake in a smaller volume (80 to 120 kcal/100 mL versus the usual 67 kcal/100 mL) erectile dysfunction vyvanse buy generic silagra online. It may also influence the dialytic modality selected or the frequency of the dialysis sessions erectile dysfunction psychogenic causes 50mg silagra overnight delivery. In countries with population heterogeneity erectile dysfunction causes medications discount generic silagra canada, attempts to construct uniform growth charts for the whole population create inaccuracies erectile dysfunction drugs from india order 50mg silagra visa, which may lead to inappropriate clinical decisions erectile dysfunction hotline silagra 50mg amex. Correcting these abnormalities may improve the likelihood of achieving normal growth. Treatment includes dietary restriction and the use of sodium polystyrene sulfonate. Further reduction in the potassium content of a formula-based diet can be achieved by pretreatment of the food with sodium polystyrene sulfonate. Metabolic acidosis is treated with bicarbonate salts, and the target serum bicarbonate levels are 20 to 22 mEq/L. Patients, including young adults, are often treated as younger than their chronologic age. In the context of chronic illness this leads to overprotection, low expectations, and delayed independence and may subsequently affect socioeconomic status and forming intimate relationships. Ferritin concentrations, on the other hand, may be high because ferritin is an acute phase reactant. Additional data, including mean corpuscular volume, red blood cell width distribution index, reticulocyte count, and a blood smear, may assist in diagnosis. Other assays such as hepcidin and soluble transferring receptor are not in routine clinical use. The physiologic hemoglobin concentrations vary with age and gender as do the recommended target levels: above the fifth percentile of the specific age. Studies in adults receiving dialysis found that excessive correction of anemia (even within the physiologic hemoglobin level) is associated with increased mortality, so it is recommended not to exceed hemoglobin levels of 13 g/dL. The pathophysiology of this phenomenon is unclear and has not been validated in children. Age-adjusted hypophosphatemia should be avoided because it can result in hypophosphatemic rickets, often seen in preterm infants with insufficient phosphorus intake or in children with phosphaturia due to proximal tubulopathy. Sevelamer hydrochloride was associated with increased metabolic acidosis,36 which may impair linear growth. The newer sevelamer carbonate addresses the issue of acidosis, but it is not yet approved by the U. Because abnormal linear growth is attributable to a number of factors whose relative contribution remains to be determined, the consensus is to treat whatever is treatable. Of note, it has been shown that correcting active vitamin D metabolite deficiency alone can increase growth rate. A, Age 1 year: severe rickets, absorption of the metaphyseal edges of the radius and ulna. B, Age 2 years: deformation in the radius and ulna bones, widening of the metaphyseal edges, healing rickets. D, Age 2 years: deformation with angulations of the femur, tibia, and fibula bones, healing phase. For example, in a 2-year-old girl of average height, the ninety-fifty percentile of blood pressure is as low as 104/59 mm Hg. This may be because the patient is not yet accustomed to fluid intake limitation or the follow-up is too short for adequate blood pressure control. Patients with congenital kidney diseases (mostly dysplastic kidneys) tend to be polyuric and thus normotensive. The pathophysiologic factors are complicated and include hypertension, volume overload, anemia, and the uremic milieu per se. Valvular Disease nephrotic syndrome of the Finnish type) or associated with oligohydramnios and hypoplastic lungs and hence possible perinatal hypoxia (autosomal recessive polycystic kidney disease). Uremic toxins, hypertension (or blood pressure fluctuations during hemodialysis), and chronic anemia can cause further damage to the developing brain. Various catheters, feeding tube, or gastrostomy may interfere with rolling over and crawling, and there is less sensory stimulation during hospitalization or dialysis. Muscle tone is diminished, and renal osteodystrophy may be painful and prevent the needed physical activity for normal development. Some pediatric renal diseases are part of a syndrome or systemic disease that may have an effect on the central nervous system and on psychomotor development. All of the studies are inevitably retrospective and depend on reliability of physician reporting. The most frequent cause of death is "cardiac arrest" (25% to 52%), a very nonspecific diagnosis, which may well be the final common pathway of various primary causes of death. There has been a marked reduction not only in the absolute death rate but also in the percentage of deaths attributed to cardiac causes over the years: from 44. This is not merely semantic, because accurate determination of causes of death can help focus efforts aimed at decreasing the death rate. Many routinely used drugs have not been through this process, have never received such formal approval for use in children, and yet are widely used based on clinical experience accumulated and lack of alternatives. Transplantation is the preferred long-term modality, but it is not always possible initially. Blood pressure values above Parents of patients who underwent kidney transplantation (but less so the children themselves) noted a positive impact of transplantation on almost all the domains of healthrelated quality-of-life questionnaire. This was shown in 198489 and later in a longitudinal study90 showing improved mental processing speed and better sustained attention and in comparative studies in which patients after kidney transplantation had better language performances and school grades compared to patients undergoing dialysis. In some developing countries where most people do not have health insurance, dialysis is not a valid option due to its high price as well as the limited professional services. Kidney transplantation remains the only potential option, although at times with catastrophic financial ramifications for the families. There are no comparative studies proving superiority of one mode over the other in the long-term outcome. Caregivers are in continuous need of emotional, psychologic, and financial support. Taken together, the final decision is based upon center experience, patient or family choice, socioeconomic issues, compliance, and treatment availability. The proportion of patients under the age of 1 year at initiation of dialysis has steadily increased29 and doubled from 10% to around 20% of all pediatric patients undergoing dialysis from 1990 to 2010. This is explained by the fact that nephrologists are encouraged to treat younger patients as their survival improved. From the 1996 to 2000 period to the 2006 to 2010 period the percentage of patients at age 0 to 2 years increased from 13. The specialties include pediatric nephrologists, dialysis nurses, dietitians, invasive radiologists, vascular surgeons, pediatric surgeons, a vascular laboratory, and all the subspecialties in pediatrics, as well as social workers, educators, psychologists, and other therapists. Catheter diameter of 8 Fr is the smallest tunneled catheter size available and can be used even in patients as small as 3 kg in weight. Ultrasonographic and fluoroscopic guidance are used to prevent catheter malposition, reducing the primary failure rate to almost zero. Although there are no published data in children, it is recommended to follow the experience in adults, using the internal jugular veins as the preferred access. Infections are more common in younger patients105,106 possibly due to close proximity of the exit site to the infection source: diapers and gastrostomy tubes. Vascular surgeons and invasive radiologists should be available to detect and treat stenosis or thrombosis. Theoretically this may lead to high-output heart failure, although this rarely becomes of clinical significance. Pulmonary hypertension is partially reversible after kidney transplantation, but this may have significant sequelae, including increased mortality. For patients weighing less than 6 kg this goal cannot be achieved with the smallest available tubing, and priming of the extracorporeal system is needed, either with whole blood, or with packed red blood cells diluted with normal saline to an estimated hematocrit of 33% to 36%. Iron overload does not occur because at the end of each session the blood in the extracorporeal system is not routinely washed back to the patient unless the patient requires a transfusion. The procedure of washing back blood at the end of dialysis in any patient deserves special consideration because the blood volume filling the tubing is equivalent to 0. Even with the slowest possible pump speed the whole volume will be washed back within 2 to 3 minutes, which is exceptionally fast. This may cause an abrupt increase in the right atrial pressure, and if the patient has a patent foramen ovale, it would increase the risk for possible microthrombi paradoxical embolism. The latter is crucial because the ultrafiltrate has to be measured directly, and small volumes that are negligible in adults can be removed accurately. Blood flow is determined according to body size and is usually not higher than 10% of blood volume in milliliters per minute. The recommendation states that solute clearance should be greater than that recommended for adults ((Kt/V [dialyzer urea clearance times treatment time divided by body urea volume]) > 1. However, there is little observational information and no randomized studies regarding the correct dose of dialysis for children. However, the true adequacy test is based on clinical grounds, which in children is, in the short term, optimal balance of electrolytes, blood pressure, and volume, and in the long term, adequate weight gain, linear growth, neurodevelopment, and quality of life. Several small studies suggest that delivering more dialysis can improve blood pressure control and hyperphosphatemia, obviate dietary restriction, and improve appetite and general well-being, linear growth, and even school attendance. The theoretical basis for these observations was established in a study by Daugirdas. When these calculations were applied to two of the studies of intensive dialysis,120,122 the patients were indeed found to have a much higher weekly dialysis dose. Despite this, intensive dialysis is still not widely used, and it is premature to recommend a general increase in the dose or frequency of dialysis in all pediatric patients. Widespread changes in clinical practice would have substantial financial ramifications. There is no single reliable marker of the correct dry weight, and thus it is estimated as the lowest weight not causing symptomatic hypovolemia. Sodium profiling, osmotic agents such as mannitol, or lowering dialysate temperature can be helpful in some cases. This is achieved by selection of an appropriately small dialyzer and limiting blood flow and session length for the first few treatments. Mannitol infusion, or in cases of hypertension and hypervolemia, high dialysate glucose or slightly increased dialysate sodium concentration may also be helpful, by preventing the decrease in plasma osmolality. Blood flow rate should be slowed if mild symptoms such as nausea, vomiting, or headache appear, and dialysis stopped if more significant neurologic manifestations appear. Moreover the extracellular volume falls from 52% in infancy to only 18% to 20% in the adult. Hypophosphatemia is attributed to excessive phosphate clearance due to high flow of dialysate relative to patient weight. Infants, especially if catabolic, may be at a higher risk for hypoglycemia, and plasma glucose should be monitored during dialysis if it is suspected. However, in many parts of the world, if dialysis is at all available, this is the only modality used. The advantages are daytime convenience, lower intraperitoneal pressure, lower risk for hernia formation, less glucose absorption, and less membrane exposure to glucose. This makes the dialysis less efficient, but this is partially compensated for by shorter drainage time and thus more possible cycles. Dialysis is satisfactorily performed with standard solutions; however, long-term membrane exposure to lactate-acidic solution and high dextrose concentration are detrimental, leading to peritoneal fibrosis and reduced function. Recommendations by the European Pediatric Dialysis Working Group have been published and include the use of the lowest glucose concentration possible and fluids with reduced glucose degradation products content whenever possible. Dialysate calcium level should be adapted according to individual needs as the child grows, to maintain positive calcium balance. In areas where there is no pediatric data, adult clinical practice guidelines serve as a minimal standard. Clinical and laboratory assessment should be performed at least once a month (more often if clinically necessary). Adequacy is evaluated clinically, seeking signs and symptoms of uremia: hypertension, pulmonary congestion, pericarditis, hyperkalemia, hyperphosphatemia, and worsening school performance and general wellbeing. In addition, laboratory data may indicate inadequacy of dialysis (serum solute concentrations, hemoglobin and albumin levels), and Kt/V is calculated. In another study, including 501 peritonitis events from 44 pediatric dialysis centers in 14 countries,136 significant regional variability was found both for bacteria type and sensitivity. Preventive measures include aseptic handling of the catheter, daily cleansing, immobilization, and applying topical antibiotics. Technical solutions, such as the use of specific types of catheters and omentectomy at the time of catheter insertion, may reduce the incidence. Recurrent hydrothorax is due to pleura-peritoneal connections and the negative pressure produced on inhalation. Because the disease is insidious and progresses slowly, five (36%) were diagnosed when no longer receiving dialysis. In 71% of the patients, high-dextrose solutions were used over the 6 months before diagnosis. A second study found the same rate of encapsulating peritoneal sclerosis but a higher infection rate relative to those without this complication, and no correlation to dialysate type. Only 55% were adherent in all four variables; males and African Americans were less likely to be adherent.

Barbiturates are small molecules with a protein binding usually below 50% impotence treatment devices purchase generic silagra on-line, although long-acting barbiturates are less protein bound than shortacting ones erectile dysfunction treatment psychological buy silagra with a visa. The metabolism of barbiturates is mostly hepatic erectile dysfunction pump hcpc cheap silagra 50 mg line, but there may be renal excretion for those that are less lipophilic new erectile dysfunction drugs 2011 buy 100mg silagra overnight delivery. There may be enzymatic induction and higher barbiturate clearance for patients who are chronically taking these medications erectile dysfunction book silagra 50mg on-line. The following discussion will focus only on phenobarbital erectile dysfunction protocol video cheap 100mg silagra with amex, although it shares many properties similar to other long-acting and short-acting barbiturates. More severe cases present as areflexia, cutaneous bullae, hypotension, hypothermia, and coma. Although positive results of serum screening for barbiturates may confirm recent exposure, a specific level is difficult to interpret as to whether a patient is naive or not to barbiturates and whether the level follows an acute ingestion or not. Specific serum sampling of most barbiturates other than phenobarbital are not systematically available. Patients presenting with severe hepatic and/or renal dysfunction or chronic respiratory disease are particularly susceptible to toxicity. Phenytoin toxicity is relatively frequent considering its narrow therapeutic range, although phenytoinrelated deaths are rare. Phenytoin is available in various forms and has erratic bioavailability,262 especially in overdose. Phenytoin is then eliminated in the bile as an inactive metabolite, reabsorbed from the intestinal tract, and excreted in the urine. Elimination is of the first order at low serum concentration and becomes zero order at higher concentrations. Cardiovascular toxicity is unusual with oral formulations, but atrioventricular delays and bradycardia may be occasionally seen with rapid intravenous infusion,264 possibly due to the diluent propylene glycol. Total serum phenytoin concentration should be obtained in all suspected overdose cases. There are conditions that may alter protein-binding capacity, such as hypoalbuminemia, uremia, extremes of age, or concomitant use of agents that displace phenytoin from its albumin binding site. Free phenytoin fraction should therefore be obtained in such cases, if available (toxicity is apparent at levels above 2. Furthermore, there is a concern that an abrupt lowering of serum phenytoin level may precipitate withdrawal symptoms and rebound seizures in epileptic patients. Metformin improves insulin sensitivity and decreases insulin resistance in patients and is now the most popular antidiabetic drug in the world. The related biguanide, phenformin, was withdrawn in 1978 because of the high incidence of lactic acidosis. It does not undergo hepatic metabolism and is eliminated unchanged by renal tubular secretion (renal clearance 500 mL/min), hence the concern in patients with kidney impairment. The finding of asymptomatic patients who develop toxicity shortly after an acute toxic ingestion of metformin appears to give credence to the latter hypothesis,292-294 which is occasionally named metformin-induced lactic acidosis. Mitochondrial binding of metformin membranes in overdose can shift energy use toward anaerobic metabolism, which in turn yields large quantities of lactate. Because serum metformin measurements are not usually available in a clinically useful time frame, the diagnosis of metformin poisoning must be suspected in every patient presenting with severe metabolic lactic acidosis. There is evidence that the clinical outcome is correlated with the metformin concentration, the lactate concentration, serum pH, or a combination of these. Decontamination with activated charcoal should be considered after a large ingestion of metformin. Patients who develop lactic acidosis, hypoglycemia, or other signs of metformin toxicity should be admitted to an intensive care unit. Dichloroacetate acts by stimulating pyruvate dehydrogenase and has been used to treat type A lactic acidosis. Renal replacement therapies often become necessary to control volume overload and uremia. In fact, the dramatic improvement described in some acutely poisoned patients within moments of dialysis initiation suggests that the benefit might be attributed more to pH correction than metformin removal. It is available in various formulations, is nonselective, and fast acting and becomes biologically inactive on contact with soil, making it an extremely convenient weed killer. Because it is generally not absorbed across intact skin, and because the droplets generated from the aerosol spray are large, toxicity from direct contact or inhalation is rarely problematic. However, accidental or intentional oral ingestion of paraquat is extremely toxic with high rate of morbidity and mortality (50% to 90%). The use of paraquat is restricted in the United States and European countries but remains a major health issue in many Third World and the Asia-Pacific countries. Peak concentrations are generally reached 2 hours after ingestion, but maximal tissue distribution occurs during the next 6 hours. It is reduced by an electron donor such as reduced nicotinamide adenine dinucleotide phosphate and later oxidized by an electron receptor such as dioxygen. Because this process can be sustained by the extensive supply of electrons and oxygen in the lungs, the resultant oxidative stress causes cell injury and a profound inflammatory reaction. Ingestions of less than 20 mg/kg may not cause symptoms other than oral ulceration, vomiting, and diarrhea. Ingestions between 20 and 40 mg/kg will usually cause multiple organ failure with death occurring between 1 week and several weeks after exposure. Other clinical manifestations include severe upper gastrointestinal tract ulcerations, hepatic injury, and shock. Serum paraquat concentration predicts the mortality risk, and nomograms have been validated to correlate with clinical outcome. If the color of urine changes from yellow to blue, it confirms the presence of recent paraquat exposure (the more intense the blue, the higher the paraquat exposure). Any suspected paraquat exposure warrants prompt assessment and aggressive management. After initial stabilization, volume resuscitation should be aggressively provided. Oxygen should be used only if required for hypoxemic patients, because it may promote further cellular damage induced by the oxidation-reduction cycling. Paraquat is absorbed quickly, which limits the efficacy of usual decontamination techniques, especially because there may be paraquat-induced caustic injury present. Many paraquat formulations already contain a pro-emetic and an alginate to reduce its absorption. However, paraquat distributes quickly to tissues, especially lungs, a compartment from which paraquat does not easily diffuse back to the blood. Furthermore, once the toxicodynamic process involving free-radical generation is initiated, it is unlikely that any elimination enhancement could blunt its progression. Of note, the combination of cyclophosphamide and corticosteroids is no longer recommended, because a large randomized controlled trial failed to report a statistical benefit. Its use has dramatically declined over the years in favor of inhaled corticosteroids, anticholinergics, and 2adrenergic agonists. This results in smooth muscle relaxation, catecholamine release, bronchodilation, and peripheral vasodilatation, as well as inotropic and chronotropic activation. The pharmacokinetics and metabolism of theophylline are influenced by age, sex, body weight, concurrent illness. For the same serum theophylline level, symptoms of chronic toxicity are more severe than those following acute intoxication. The therapeutic index is very narrow; even at therapeutic concentrations, nearly one-third of patients may exhibit signs of mild intoxication. Patients with moderate intoxication may be lethargic and disoriented, and they may develop supraventricular tachycardia and frequent premature ventricular contractions. Death is most often the result of cardiorespiratory collapse or hypoxic encephalopathy following cardiac dysrhythmias or generalized seizures. Tachycardia can be corrected by -adrenergic antagonists, such as propranolol or esmolol, but should be used with caution in patients susceptible to bronchospasm. Multiple-dose oral activated charcoal increases clearance of theophylline but is sometimes limited by profound and intractable emesis in severely intoxicated patients. Continuous techniques have also been reported in the management of theophylline intoxication with acceptable results despite the inferior clearances they provide. Because it is available without prescription in various forms and combinations, acetaminophen is a major contributor to acute voluntary poisoning. Patients can remain clinically asymptomatic up to a day after ingestion, and initially only nonspecific symptoms, including nausea, vomiting, anorexia, malaise, or abdominal pain, are evident. Hepatic injury typically occurs approximately 24 hours after ingestion, by which time initiation of antidotal treatment will have diminished efficacy. The severity of the injury can vary and is most commonly detected by elevation of serum transaminase level, which generally peaks 2 to 3 days after ingestion. This nomogram has been validated as such for over 30 years, despite some limitations, which are outside the scope of this chapter. Methotrexate levels in patients being treated for indications other than cancer should not surpass 0. Methotrexate can also cause bone marrow suppression, mucositis and stomatitis, liver damage, and neurotoxicity. Mucositis and pancytopenia will manifest approximately 1 to 2 weeks after exposure. Leucovorin "rescue" is most beneficial when administered promptly after methotrexate exposure and should always be given to patients after high doses. Other supportive measures include transfusion of blood components, antiemetics, and nutritional support for stomatitis. It decreases serum methotrexate concentration within 1 hour following administration. Because it is expensive (>$50,000) and either unavailable or restricted in most countries, its precise application remains uncertain. Intrathecal overdoses of methotrexate may require special measures, including cerebrospinal fluid drainage and exchange, and administration of corticosteroids in addition to leucovorin/glucarpidase. Methotrexate is primarily excreted unchanged (80% to 90%) in the urine by passive glomerular filtration and active tubular secretion; renal clearance varies greatly and decreases at higher doses. Although space restriction does not permit presenting them in detail, there are reports of successful extracorporeal removal of the following poisons: propylene glycol,386 diethylene glycol,387 gabapentin,388 pregabalin,389 isoniazid,390 metronidazole,391 dapsone,392 gentamycin,393 vancomycin,394 cefepime,395 aluminum,396 thallium,397 cibenzoline,398 baclofen,399 bromate,400 Amanita phalloides,401 barium,402 fluoride,403 carambola,404 iodine,405 and dabigatran. We would also thank Andrea Palumbo and Monique Cormier for proofreading this chapter. Mardini J, Lavergne V, Roberts D, et al: Case reports of extracorporeal treatments in poisoning: historical trends. Ghannoum M, Troyanov S, Ayoub P, et al: Successful hemodialysis in a phenytoin overdose: case report and review of the literature. Peters N, Jay N, Barraud D, et al: Metformin-associated lactic acidosis in an intensive care unit. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Lavergne V, Ouellet G, Bouchard J, et al: Guidelines for reporting case studies on extracorporeal treatments in poisonings: methodology. Ozayar E, Degerli S, Gulec H: Hemodiafiltration: a novel approach for treating severe amitriptyline intoxication. Ouellet G, Bouchard J, Ghannoum M, et al: Available extracorporeal treatments for poisoning: overview and limitations. Falkenhagen D, Gottschall S, Esther G, et al: In vitro assessment of charcoal and resin hemoadsorbents. Mydlik M, Derzsiova K, Bucek J, et al: Use of charcoal haemoperfusion in 55 acute poisonings. Tapolyai M, Campbell M, Dailey K, et al: Hemodialysis is as effective as hemoperfusion for drug removal in carbamazepine poisoning. Couriel D, Weinstein R: Complications of therapeutic plasma exchange: a recent assessment. Dichtwald S, Dahan E, Adi N, et al: Molecular adsorbent recycling system therapy in the treatment of acute valproic acid intoxication. Liesivuori J, Savolainen H: Methanol and formic acid toxicity: biochemical mechanisms. Natowicz M, Donahue J, Gorman L, et al: Pharmacokinetic analysis of a case of isopropanol intoxication. Zaman F, Pervez A, Abreo K: Isopropyl alcohol intoxication: a diagnostic challenge. Wollersen H, Erdmann F, Risse M, et al: Oxalate-crystals in different tissues following intoxication with ethylene glycol: three case reports. Hydzik P, Drozdz M, Sulowicz W, et al: Liver albumin dialysis- application in acetaminophen poisoning. Grunbaum A, Kazim S, Ghannoum M, et al: Acetaminophen and N-acetylcysteine dialysance during hemodialysis for massive ingestion. Leblanc M, Fedak S, Mokris G, et al: Blood recirculation in temporary central catheters for acute hemodialysis. Panzer U, Kluge S, Kreymann G, et al: Combination of intermittent haemodialysis and high-volume continuous haemofiltration for the treatment of severe metformin-induced lactic acidosis. Friesecke S, Abel P, Kraft M, et al: Combined renal replacement therapy for severe metformin-induced lactic acidosis. Megarbane B, Baud F: What is the role of bicarbonate in the management of acidosis in the poisoned patient

Details about the use of these agents in pregnancy are discussed in greater detail in the section on chronic hypertension and gestational hypertension erectile dysfunction medications over the counter buy cheap silagra 100 mg line. Because controlled studies on developmental toxicity due to immunosuppressive agents cannot be performed for ethical reasons erectile dysfunction photos purchase silagra 50 mg on line, most immunosuppressive agents fall into category C erectile dysfunction prescription pills proven silagra 100mg. Nevertheless erectile dysfunction band generic silagra 100 mg line, there is a significant amount of published data that can inform decisions to use some of these agents safely in pregnancy (Table 49 erectile dysfunction doctors in memphis tn silagra 100mg with visa. Cyclosporine (or tacrolimus) and steroids psychogenic erectile dysfunction icd-9 silagra 50 mg sale, with or without azathioprine, form the basis of immunosuppression during pregnancy. Corticosteroids at low to moderate doses (5-10 mg/day) are safe and prednisone is classified as pregnancy category B. Hence, close monitoring of blood levels with dosing adjustment are required to maintain optimal levels. Human data are limited to isolated case reports but suggest that mycophenolate mofetil may be associated with spontaneous abortion and with major fetal malformations,390 especially when used in combination with cyclosporine. For a more detailed discussion of data on the effects of these agents on neonatal immunologic function and long-term outcomes, the reader is referred to reviews by Josephson and McKay. Acute rejection should be suspected if fever, oliguria, graft tenderness, or deterioration in renal function is noted. Although high-dose steroid therapy has been associated with fetal malformations and maternal infections, it remains a mainstay of treatment of acute rejection during pregnancy. Investigators from the National Transplantation Pregnancy Registry recommend that breastfeeding should not be discouraged in women taking tacrolimus. Theoretically, mycophenolate mofetil should be safe in breastfeeding because the active metabolite secreted in breast milk, mycophenolic acid, is not gastrointestinally available; however, human evidence of safety is lacking. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy: Hypertension in pregnancy. Soleymanlou N, Jurisica I, Nevo O, et al: Molecular evidence of placental hypoxia in preeclampsia. Sela S, Itin A, Natanson-Yaron S, et al: A novel human-specific soluble vascular endothelial growth factor receptor 1: cell typespecific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Venkatesha S, Toporsian M, Lam C, et al: Soluble endoglin contributes to the pathogenesis of preeclampsia. Villar J, Purwar M, Merialdi M, et al: World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. Asamiya Y, Otsubo S, Matsuda Y, et al: the importance of low blood urea nitrogen levels in pregnant patients undergoing hemodialysis to optimize birth weight and gestational age. Elsheikh A, Creatsas G, Mastorakos G, et al: the renin-aldosterone system during normal and hypertensive pregnancy. Nomura S, Ito T, Yamamoto E, et al: Gene regulation and physiological function of placental leucine aminopeptidase/ oxytocinase during pregnancy. Ananthakrishnan S: Diabetes insipidus in pregnancy: etiology, evaluation, and management. Laivuori H, Lahermo P, Ollikainen V, et al: Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Duckitt K, Harrington D: Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. Rasmussen A, Ravn P: High frequency of congenital thrombophilia in women with pathological pregnancies Tanaka M, Jaamaa G, Kaiser M, et al: Racial disparity in hypertensive disorders of pregnancy in New York State: a 10-year longitudinal population-based study. Eskenazi B, Fenster L, Sidney S: A multivariate analysis of risk factors for preeclampsia. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Hertig A, Watnick S, Strevens H, et al: How should women with pre-eclampsia be followed up Bower S, Schuchter K, Campbell S: Doppler ultrasound screening as part of routine antenatal scanning: prediction of pre-eclampsia and intrauterine growth retardation. Alayed N, Kezouh A, Oddy L, et al: Sickle cell disease and pregnancy outcomes: population-based study on 8. De Wolf F, De Wolf-Peeters C, Brosens I, et al: the human placental bed: electron microscopic study of trophoblastic invasion of spiral arteries. Caniggia I, Mostachfi H, Winter J, et al: Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast 53. Wolf M, Shah A, Jimenez-Kimble R, et al: Differential risk of hypertensive disorders of pregnancy among Hispanic women. Conde-Agudelo A, Villar J, Lindheimer M: Maternal infection and risk of preeclampsia: Systematic review and metaanalysis. Thangaratinam S, Ismail K, Sharp S, et al: Accuracy of serum uric acid in predicting complications of pre-eclampsia: a systematic review. Duley L: Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Altman D, Carroli G, Duley L, et al: Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate Ferrazzani S, De Carolis S, Pomini F, et al: the duration of hypertension in the puerperium of preeclamptic women: relationship with renal impairment and week of delivery. Zhou Y, McMaster M, Woo K, et al: Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Strevens H, Wide-Swensson D, Hansen A, et al: Glomerular endotheliosis in normal pregnancy and pre-eclampsia. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. Robillard P-Y, Perianin J, Janky E, et al: Association of pregnancyinduced hypertension with duration of sexual cohabitation before conception. Hackmon R, Koifman A, Hyobo H, et al: Reduced third-trimester levels of soluble human leukocyte antigen G protein in severe preeclampsia. Chaiworapongsa T, Romero R, Espinoza J, et al: Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Suzuki H, Ohkuchi A, Matsubara S, et al: Effect of recombinant placental growth factor 2 on hypertension induced by full-length mouse soluble fms-like tyrosine kinase 1 adenoviral vector in pregnant mice. Li Z, Zhang Y, Ying Ma J, et al: Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Bergmann A, Ahmad S, Cudmore M, et al: Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. Bdolah Y, Lam C, Rajakumar A, et al: Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia Silasi M, Rana S, Powe C, et al: Placental expression of angiogenic factors in trisomy 13. Cudmore M, Ahmad S, Al-Ani B, et al: Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Wang K, Ahmad S, Cai M, et al: Dysregulation of hydrogen sulfide producing enzyme cystathionine gamma-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Wolf M, Sandler L, Munoz K, et al: First trimester insulin resistance and subsequent preeclampsia: a prospective study. Vicent D, Ilany J, Kondo T, et al: the role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. Xia Y, Wen H, Bobst S, et al: Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. Hirtenlehner K, Pollheimer J, Lichtenberger C, et al: Elevated serum concentrations of the angiogenesis inhibitor endostatin in preeclamptic women. Masuda Y, Shimizu A, Mori T, et al: Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Conde-Agudelo A, Villar J, Lindheimer M: World Health Organization systematic review of screening tests for preeclampsia. Parra M, Rodrigo R, Barja P, et al: Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction. Chafetz I, Kuhnreich I, Sammar M, et al: First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. Verdonk K, Visser W, Russcher H, et al: Differential diagnosis of preeclampsia: remember the soluble fms-like tyrosine kinase 1/ placental growth factor ratio. Perni U, Sison C, Sharma V, et al: Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Caritis S, Sibai B, Hauth J, et al: Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Villar J, Abdel-Aleem H, Merialdi M, et al: World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. American College of Obstetricians and Gynecologists Committee on Obstetric Practice, Society for Maternal-Fetal Medicine: Committee Opinion No. Thadhani R, Kisner T, Hagmann H, et al: Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. American College of Obstetricians and Gynecologists: Practice Bulletin: Chronic hypertension in pregnancy. National Institute of Child Health and Human Development Network of MaternalFetal Medicine Units. Hayashida M, Watanabe N, Imamura H, et al: Congenital solitary kidney with renovascular hypertension diagnosed by means of captopril-enhanced renography and magnetic resonance angiography. Tabesh M, Salehi-Abargouei A, Esmaillzadeh A: Maternal vitamin D status and risk of pre-eclampsia: a systematic review and metaanalysis. Macdonald-Wallis C, Tilling K, Fraser A, et al: Gestational weight gain as a risk factor for hypertensive disorders of pregnancy. Bortolus R, Ricci E, Chatenoud L, et al: Nifedipine administered in pregnancy: effect on the development of children at 18 months. Stratta P, Besso L, Canavese C, et al: Is pregnancy-related acute renal failure a disappearing clinical entity Jungers P, Houillier P, Forget D, et al: Influence of pregnancy on the course of primary chronic glomerulonephritis. Ekbom P: Pre-pregnancy microalbuminuria predicts pre-eclampsia in insulin-dependent diabetes mellitus. Hiilesmaa V, Suhonen L, Teramo K: Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with type I diabetes mellitus. Suhonen L, Hiilesmaa V, Teramo K: Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Day C, Hewins P, Hildebrand S, et al: the role of renal biopsy in women with kidney disease identified in pregnancy. Hoeltzenbein M, Elefant E, Vial T, et al: Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Jefferys A, Wyburn K, Chow J, et al: Peritoneal dialysis in pregnancy: a case series. Biesenbach G, Grafinger P, Stoger H, et al: How pregnancy influences renal function in nephropathic type 1 diabetic women depends on their pre-conceptional creatinine clearance. Chandran V, Aggarwal A, Misra R: Active disease during pregnancy is associated with poor foetal outcome in Indian patients with systemic lupus erythematosus. Erkan D, Sammaritano L: New insights into pregnancy-related complications in systemic lupus erythematosus. Soubassi L, Haidopoulos D, Sindos M, et al: Pregnancy outcome in women with pre-existing lupus nephritis. Fischer-Betz R, Specker C, Brinks R, et al: Low risk of renal flares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Galdo T, Gonzalez F, Espinoza M, et al: Impact of pregnancy on the function of transplanted kidneys. Le Ray C, Coulomb A, Elefant E, et al: Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal Malformations. Krotz S, Fajardo J, Ghandi S, et al: Hypertensive disease in twin pregnancies: a review. The first section reviews the pharmacology of nondiuretic antihypertensive drugs to provide clinicians with a complete overview of how to use these therapies safely in practice (Table 50. The first section also discusses individual drug classes and highlights the class mechanisms of action, members, renal effects, and efficacy and safety. Each drug has a unique structure that determines its potency, tissue receptor binding affinity, metabolism, and prodrug compound, but they have remarkably similar clinical effects (Tables 50. The half-life is 2 hours; with long-term administration, the hemodynamic effects are maintained for 3 to 8 hours. The elimination half-life increases markedly in patients with creatinine clearances of less than 20 mL/min/1. In such patients, the initial dosages should be reduced, and smaller increments should be used for titration. The first antihypertensive drug, hydralazine, was a nonspecific vasodilator discovered in the 1950s. This was followed by blockade of calcium channels on vascular smooth muscle cells, the calcium channel blockers in the 1960s, and blockade of postsynaptic -adrenoceptors on peripheral sympathetic neurons, the alpha blockers in the late 1970s. Benazepril is a prodrug that is rapidly bioactivated in the liver into the active benazeprilat compound, which is 200 times more potent than benazepril. Dialysis does not remove benazepril, but the initial dose should be no more than 10 mg in patients with a creatinine clearance of less than 60 mL/min/1.

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