CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children.

BACKGROUND: CYP3A5 gene polymorphism rs776746 has been associated with lower tacrolimus dose requirements and bioavailability in both adults and children. This variant causes a loss of CYP3A5 activity owing to a splice site variant leading to a truncated inactive enzyme. The aim of this study was to determine if the rs776746 gene polymorphism is related to the time to reach tacrolimus therapeutic levels in renal transplant children. METHODS: A prospective study was performed in renal transplant children receiving tacrolimus as part of their immunosuppressive regime. CYP3A5 genotype was determined by direct sequencing. Tacrolimus trough levels and serum creatinine at 1 week and 1 month after renal transplantation was obtained from clinical chart. RESULTS: A total of 42 patients were included; 19 (45.2%) were female, 23 (54.8%) received living-donor transplants, and 21 patients expressed CYP3A5*1/*1 or CYP3A5*1/*3. Tacrolimus dose was higher in expressers at week 1 (0.13 vs 0.10 mg/kg/d; P = .011), and week 4 after transplantation (0.17 vs 0.09 mg/kg/d; P < .0001). At 4 weeks after renal transplantation, only 9 patients from the expressers group (42.8%) had levels ≥7 ng/mL, in contrast to 18 in the nonexpressers group (85.7%; Fisher exact P = .008). CONCLUSIONS: Tacrolimus dose was significant higher in functional CYP3A5 expressers. Only 42.8% of such expressers had tacrolimus trough levels ≥7 ng/mL at 1 month after transplantation despite dose adjustments. Long-term follow up is needed to address the consequences of early post-transplantation bioavailability differences due to CYP3A5 genotype.

Serum soluble interleukin 2 receptor (sIL-2R) as a marker of acute rejection in renal transplant children.

The aim of the study was to evaluate whether or not serum levels of soluble interleukin 2 receptor (sIL-2R) predict acute rejection in pediatric recipients. We studied 51 pediatric renal transplant recipients divided into three groups: Group 1) Biopsy-proven cellular acute rejection (n = 19), Group 2) Graft dysfunction with histological diagnosis other than acute rejection (n = 8) and Group 3) Patients with stable graft function, no biopsy (n = 24). Serum samples for sIL-2R measurement by sandwich ELISA were obtained at the time of renal transplant and at the time of renal biopsy due to graft dysfunction (Groups 1 and 2) or at six months post-transplant in the case of Group 3. The mean ± s.e. serum values of sIL-2R were higher in patients during acute rejection (6539 ± 1802 pg/mL) compared to patients with other causes of graft dysfunction (2217 ± 256 pg/mL) or stable graft function at six months (2183 ± 283 pg/mL) (Kruskal-Wallis p = 0.004). When the sIL2-R levels at the time of transplant were compared to those at the time of biopsy (Groups 1 and 2) or at six months post-transplant in Group 3, there was no significant difference between baseline and biopsy in the acute rejection group (paired t-test = 0.07), whereas there was a significant reduction in Groups 2 and 3.

Usefulness of fractional excretion of sodium in critically ill pre-term newborns.

The purpose of this prospective study was to measure the fractional excretion of sodium (FENa) in critically ill pre-term newborns (PTNB) in order to determine its cut point in the diagnosis of acute renal failure (ARF). This study included 52 newborns and was conducted from May, 1994 to May, 1995. Patients were divided in two groups: patients without ARF in group A (n = 47) and patients with ARF in group B (n = 5). No statistically significant differences were found in birth weight, extrauterine life span, serum sodium levels, urine creatinine and urinary volumes between the two groups, but there was a difference in gestational age, urinary sodium concentration and serum creatinine levels. Sensitivity and specificity were determined, and the critical level of FENa was 4% or greater for ARF diagnosis. The average FENa value for Group A was 1.4 +/- 1.4% with a median of 0.92%. In Group B, average FENa was 6.9 +/- 2.9% with a median of 8.5% (P < 0.001). We conclude that FENa is a valuable tool for the assessment of renal function in critically-ill PTNB, in spite of all other factors present in this population that could modify its values.

[Acute renal insufficiency]. / Insuficiencia renal aguda.

The incidence of acute renal failure in children is higher due to the prevalence of diarrheal dehydration, use of nephrotoxic substances and sepsis. The occurrence in the newborn has increased, probably due to the large number of seriously sick infants maintained in neonatal intensive care units. Various laboratory examinations have been proposed as diagnostic indices of acute renal failure in children. Among these are the urine-to-plasma concentrations of urea and creatinine and the urine-to-plasma osmolality ratio. The fractional excretion of sodium and the so-called renal failure index are the most reliable of the diagnostic tests. The functional abnormalities and complications of acute renal failure include reduced glomerular filtration rate, retention of nitrogenous wastes, hyponatremia, hyperkalemia, metabolic acidosis, hypocalcemia, hyperphosphatemia and hypermagnesemia. The principles of management and treatment of complications are discussed.

[IgA nephropathy (Berger's disease) in children]. / Nefropatía IgA (enfermedad de Berger) en niños.

IgA nephropathy, also called Berger's disease, is characterized by recurrent gross hematuria or persistent microscopic hematuria, together with mesangial glomerular deposits of IgA found in the renal biopsy. Seven children with IgA nephropathy were studied. Most of them presented initially with recurrent macroscopic hematuria and low or moderate-grade proteinuria, without hypertension or renal function impairment. Only one patient presented with a rapidly progressive glomerulonephritis. Four patients did not receive any treatment; one of them is in remission, one has improved and two remain with moderate proteinuria and hematuria. One patient with significant proteinuria improved after prednisone and azathioprine treatment. The patient with rapidly progressive glomerulonephritis improved his renal function after oral prednisone and intravenous boluses of methylprednisolone and cyclophosphamide.

[Nephrotic syndrome associated with AIDS in children]. / Síndrome nefrótico asociado al síndrome de inmunodeficiencia adquirida en niños.

Several renal and renal-related disturbances have been described in patients with AIDS (acquired immune deficiency syndrome), in adults and children as well. These are mainly electrolyte and acid-base imbalance, acute renal failure and nephrotic syndrome. The latter is usually steroid non-responder. The renal histopathological lesions described more commonly are minimal change, mesangial hyperplasia and focal segmental glomerulosclerosis. Herein, we describe a 5 year-old with AIDS, that developed nephrotic syndrome, characterized by edema, ascites, hypoalbuminemia and massive proteinuria. A percutaneous renal biopsy showed mesangial proliferation. She did not respond to a 6 week treatment with prednisone. She died with sepsis after several viral and bacterial infections.

[Fever of unknown origin. Presentation of 180 pediatric cases]. / Fiebre de origen obscuro. Presentación de 180 casos pediátricos.

Fever of unknown origin (FUO) is a frequent disorder in pediatric age. FUO is defined as the presence of fever over 38.4 centigrades in a patient for more than three weeks in which the etiology remains undetermined. From 30.736 consecutive admittances into our hospital, 180 patients with FUO were detected, and studied in a systematized way and according to a predetermined protocol. FUO was commonly found in children under six years of age. Our patients presented fever from three weeks to six and a half years of evolution; however, in the vast majority of the cases (n = 115) fever had a three weeks course. Several symptoms and physical manifestations other than fever were observed in our patients but they were widely variable and nonspecific. Infectious diseases were the commonest etiological factor encountered; among them, thyroid fever, and urinary tract infections were the most frequent infectious disorder found; in four children fever was associated to ampicillin administration; in 19 patients, fever was no demonstrated. A large number of laboratory investigations were done in the diagnosis of neoplastic diseases. We think that the study of a patient with FUO requires of a systematized approach.

[Acute kidney failure due to stings by Africanized bees]. / Insuficiencia renal aguda por picadura de abejas africanizadas.

Africanized bees are unique in their aggressive behavior, characterized by massive attacks during which the victims are injected an important amount of venom. For this reason, Africanized bees are extremely dangerous. Their venom contains biological toxic substances, mainly mellitin, phospholipases, histamine, hyaluronidase and apamin. Non-sensitized persons that survive a massive attack may develop acute renal failure, as a consequence of the severe hemolysis, rhabdomyolysis and shock. These complications may lead to acute renal tubular necrosis. Also, the clinical pattern and treatment of the acute renal failure secondary to bee stings are discussed.

Rice solution and World Health Organization solution by gastric infusion for high stool output diarrhea.

We sought to determine the efficacy of three different types of treatment in children with acute diarrhea who, during the oral rehydration period, had high stool output (greater than 10 mL/kg per hour). Sixty-six children, aged 1 to 18 months, with an average stool output of 22.6 mL/kg per hour were randomly distributed into three groups: group 1 received a rice flour solution, group 2 received the World Health Organization rehydration solution by gastric infusion, and group 3 continued to receive this solution orally. In all three groups, a decrease in stool output was observed, with the higher decrease observed in group 1 patients. Such a decrease facilitated rehydration of all 22 patients in group 1 (100%) in 3.3 +/- 1.5 hours, 16 (73%) in group 2 in 4.3 +/- 2.1 hours, and 15 (69%) in group 3 in 4.9 +/- 2.0 hours. No complications were observed. These data indicate that the rice flour solution is effective in children with high stool output diarrhea.

[Oral rehydration solutions with 60 or 90 nmol/L of sodium for infants with acute diarrhea in accord with their nutritional status]. / Soluciones de rehidratación oral con 60 ó 90 mmol/L de sodio en niños con diarrea aguda de acuerdo a su estado nutricional.

A total of 186 infants suffering from dehydration due to acute diarrhea were studied and divided into two groups: 84 children were placed in group A and received the oral rehydration solution (ORS) recommended by the World Health Organization (WHO), know as ORS-90 and those placed in group B were given an ORS with 60 and 90 mmol/L of sodium and glucose, respectively, with an osmolality of 240 mOsm/kg (ORS-60). Seven patients from group A (8.3%) and two from group B (2.5%) could not be orally rehydrated and required intravenous rehydration. The children were divided according to their weight for their age into eutrophics, grade I malnutrition (10 to 25% deficit), grade II (26 to 40% deficit) and grade III (more than 40% deficit). In those patients who evolved favorably, the average rehydration time was 4.5 to 5.3 hours, independently from their nutritional state. In the same way, no important variations were seen in the average sodium and potassium serum levels once the dehydration was corrected, in either of the groups. Yet, both groups showed a persistence in hypokalemia and hyperkalemia seen when admitted, once the dehydration was corrected, demonstrating that the short time needed for the correction of the dehydration was insufficient to completely corrected the changes in serum potassium. Closer studies must be conducted on the hydric balance to adequately demonstrate if the new ORS-60 induces lesser losses through vomiting and feces when compared to the ORS-90 recommended by the WHO.

[Comparative study of 2 oral rehydration solutions containing 60 or 90 mmol/L of sodium and with different osmolalities]. / Estudio comparativo de dos soluciones de hidratación oral conteniendo 60 ó 90 mmol/L de sodio y con diferente osmolalidad.

A total of 186 infants, suffering from acute diarrhea were studied and divided into two groups: 84 children were placed in group A and given the ORS recommended by the World Health Organization which contains sodium and glucose at concentrations of 60 and 90 mmol/L respectively and an osmolality of 311 mOsm/kg (mmol/kg) (ORS-90). Group B included 82 children who received an ORS containing sodium and glucose at concentrations of 60 and 90 mmol/L respectively and with an osmolality of 240 mOsm/kg (mmol/kg) (ORS-60). Seven belonging to group A (8.3%) required intravenous rehydration due to the severity of the diarrhea (three cases), persistent vomiting (three cases) and paralytic ileus (one case), while only two cases belonging to group B (2.5%) required intravenous rehydration due to severe losses through feces (one case) and another due to paralytic ileus (one case). No differences were observed due to the variations in sodium concentrations among either of the groups of patients, whether that be in the natremias when admitted or once rehydrated, with a general tendency towards the correction of the hypernatremia or hyponatremia seen during admittance with both types of ORS. A similar situation was observed with the variations in serum potassium. The results obtained from this study show the different advantages of using an ORS with lesser sodium and glucose concentrations as well as minor osmolality with those from using the solution recommended by the World Health Organization, when a lesser index of failures is observed in the treatment of children with acute diarrhea with oral rehydration therapy. Yet before widely recommending its' use, it should be demonstrated that the new ORS induces lesser losses through feces during the rehydrating period in children dehydrated due to acute diarrhea.

[Water-electrolyte and acid-base imbalance. IX. Respiratory alkalosis]. / Alteraciones hidroelectrolíticas y ácido-base. IX. Alcalosis respiratoria.

Respiratory alkalosis is the consequence of primary hypocapnia of divergent etiologies. Any pathologic process that increases ventilation to levels beyond that required to excrete the CO2 byproduct of metabolism, will result in an inappropriately low systemic pCO2 and a tendency to an alkaline systemic pH. The increased drive to ventilation may be due predominantly to a primary increase in central nervous system activity, either within the respiratory center itself or from more centrally placed areas with neural projections that extend to and control the respiratory center. Alternatively, an increased drive to ventilation may result from an "appropriate" physiologic response to another more important stimulus that overrides the human's needs to protect pCO2 and pH. Hypoxia (of different causes), is the most important and most commonly encountered such stimulus.

[Oral rehydration in newborns with dehydration caused by diarrhea]. / Hidratación oral en recién nacidos deshidratados por diarrea.

The clinical experience obtained while treating 43 dehydrated newborns due to diarrhea with oral rehydration solution (ORS) using the formula recommended by the World Health Organization is reported. Of the 43 patients, 26 were severely dehydrated (greater than equal to 10% of weight recovery once rehydrated). The averaged time need to correct the dehydration was 4.7 +/- 2.7 hours, with a average intake of ORS of 26.5 +/- 7.5 mL/kg/hour. Children who were being breastfed continued so during the rehydration period. Two of the patients were hospitalized for intravenous treatment, one was due to persistent vomiting during rehydration and probably due to sepsis, and the other due to necrosing enterocolitis. The oral rehydration therapy was successful in 95% of the newborns included in the study, which proved the method to be safe and adequate for the correction of dehydration due to diarrhea among these patients. Similar experiences are reported in Mexico as well as from other countries, which also suggest the use of this therapeutic procedure in children of this age.

[Water-electrolyte and acid-base disorders. VIII. Respiratory acidosis]. / Alteraciones hidroelectrolíticas y ácido-base. VIII. Acidosis respiratoria.

Acute respiratory acidosis will result from many processes that acutely interfere with the excretion of CO2 by the lungs. CO2 excretion by the lungs can be interfered with by processes that inappropriately decrease minute ventilation, processes that impair the transport of CO2 from the site of production to the lungs for export, and by processes that impair the transfer of CO2 from the blood through the alveolar space to the atmosphere. The underlying clinical syndrome generating the primary hypercapnia will determine the duration of the acidosis as well as the anticipated clinical manifestations attributable to the acidosis.

[Effect of a new amino acid solution in the oral hydration of nursing infants with acute diarrhea. A prospective study]. / Efecto de una nueva solución con aminoácidos en la hidratación oral de lactantes con diarrea aguda. Un estudio prospectivo.

Thirty-two one- to 12-month-old male infants with diarrheal dehydration treated with either the oral rehydration solution recommended by the World Health Organization (WHO), or the same solution modified by the addition of glycerine (60 mmol/L) and glycil-glycine (30 mmol/L), with a total osmolality of 379 mOsm/kg. The patients belonging to the latter group exhibited greater stool losses (10.3 +/- 8.3 vs 8.0 +/- 6.4 mL/kg/hour) and a greater urine volume (10.4 +/- 14.2 vs 4.6 +/- 4.0 mL/kg/6 hours), during the first four to six hours of the rehydration period. The results of this study show, that in contrast with those of other series, the addition of glycine and glycil-glycine to the WHO solution, at the concentrations used in the study, produces greater fecal water losses in children with dehydration due to acute diarrhea.

[Water-electrolyte and acid-base disorders. VII. Metabolic alkalosis]. / Alteraciones hidroelectrolíticas y ácido-base. VII. Alcalosis metabólica.

Metabolic alkalosis is defined as a primary increase in plasma bicarbonate concentration. As a consequence of this increase, systemic alkalemia and secondary hypercapnia develop. In most instances metabolic alkalosis arises from loss of acid through the kidney or gastrointestinal tract. The causes of metabolic alkalosis can be separated into two groups. Those forms of alkalosis responsive to chloride salt administration (e.g., vomiting), are associated with extracellular fluid volume and chloride depletion. In contrast, alkalosis resistant to administration of chloride salt (e.g., primary aldosteronism), is usually associated with extracellular fluid volume expansion and a urine chloride above 20 mEq/L (mmol/L). Metabolic alkalosis; causes; diagnosis; clinical manifestations.

[Water-electrolyte and acid-base imbalance. VI. Metabolic acidosis]. / Alteraciones hidroelectrolíticas y ácido-base. VI. Acidosis metabólica.

Metabolic acidosis results from a disequilibrium between production and excretion of acid. Loss of base from the body through the gastrointestinal tract or in the urine or an increase in metabolic acid production are the three major mechanisms from which metabolic acidosis is generated. Uncomplicated metabolic acidosis is manifested by an increase in blood acidity, hypobicarbonatemia, and hypocapnea. The magnitude of these changes defines the severity wf the acidosis. It is convenient to divide metabolic acidosis into two general categories (hyperchloremic and normochloremic), based on the observed anion gap, as this serves to narrow the differential diagnosis. The normal anion gap is that amount of plasma anion not measure by routine laboratory screening that accounts for the difference between the measured sodium cation (Na+) and anions (Cl +/- HCO3-). Metabolic acidosis; causes; diagnosis; clinical manifestations.