Acute kidney injury in children.

Acute kidney injury (AKI) affects 5% of critically ill hospitalized children and is a risk factor for increased morbidity and mortality. The current review focuses on new definitions of acute kidney injury, standardized to reflect the entire spectrum of the disease, as well as on ongoing research to identify early biomarkers of kidney injury. Its also provides an overview of current practice and available therapies, with emphasis on new strategies for the prevention and pharmacological treatment of diarrhea-associated hemolytic uremic syndrome. Furthermore, a decision-making algorithm is presented for the use of renal replacement therapies in critically ill children with AKI.

Hyperlipidemic profiles during remission in childhood idiopathic nephrotic syndrome.

Hyperlipidemia, an important characteristic of idiopathic nephrotic syndrome in children (NS), is usually observed during the active phase of the disease and disappears with the resolution of the proteinuria. However, persisting lipid anomalies during remission have been reported in a few studies and raise the question of the later development of atherosclerosis. Plasma lipid profiles in 25 children with NS at remission, with or without active prednisone treatment, were compared with those of an age-matched population. The results indicate that plasma total and LDL-cholesterol levels were above the 95(th) percentile for age and sex in 12 of the 25 patients (48%) with 7 of them having apolipoprotein B and triglyceride concentrations above the 95(th) percentile. Moreover, frequently relapsing children were more likely to have abnormal lipid profile during the remission. We conclude that close monitoring of lipid levels during the remission of the NS especially in those with frequent relapses, is necessary to select the high-risk patients.

Plasma homocysteine concentration in children with chronic renal failure.

Hyperhomocysteinemia, a risk factor for vascular disease, is commonly found in adult patients with end-stage renal disease. Major determinants of elevated plasma homocysteine levels in these patients include deficiencies in folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) genotype and renal function. Little information is available for children with chronic renal failure (CRF). The prevalence and the factors that affect plasma homocysteine concentration were determined in children. Twenty-nine children with various degrees of CRF (15 were dialyzed, 14 were not dialyzed) were compared with 57 age- and sex-matched healthy children. Homocysteine concentrations were higher in patients than controls (17.3 micromol/l vs 6.8 micromol/l, P<0.0001) and hyperhomocysteinemia (>95th percentile for controls: 14.0 micromol/l) was seen in 62.0% of patients and 5.2% of controls. Folate concentrations were lower in patients (9.9 nmol/l) than controls (13.5 nmol/l), P<0.01. Vitamin B12 was similar in patients (322 pmol/l) and controls (284 pmol/l). Dialyzed patients have a higher prevalence of hyperhomocysteinemia than nondialyzed patients (87% vs 35%). Dialyzed patients with MTHFR mutation have higher plasma homocysteine (28.5 micromol/l) than nondialyzed patients with the mutation (10.7 micromol/l), P<0.002. In our study, differences between controls and patients in plasma homocysteine concentrations are observed when age is greater then 92 months, folate less than 21.6 nmol/l and vitamin B12 less than 522 pmol/l. Our study shows that hyperhomocysteinemia is common in children with CRF and is associated with low folate and normal vitamin B12 status, compared to normal children. Among the patients, the dialyzed patients with the MTHFR mutation are particularly at risk for hyperhomocysteinemia. Further studies are needed to investigate therapeutic interventions and the potential link with vascular complications in these patients.

Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children.

BACKGROUND: Several studies have examined the association of the methylenetetrahydrofolate reductase (MTHFR) genotype with plasma homocysteine in adults, but few studies have been performed in children. OBJECTIVE: We measured the concentrations of plasma total homocysteine, folate, and vitamin B-12 in a group of healthy fasting children and related these to MTHFR genotype. DESIGN: After the subjects fasted, blood samples were collected into EDTA-containing tubes. Plasma, red blood cells, and the buffy coat were immediately stored at -80 degrees C for biochemical and molecular analyses. Plasma total homocysteine was determined by HPLC. Folate and vitamin B-12 were measured by a double-labeled radioimmunoassay, and the genotypic analysis was performed by polymerase chain reaction amplification of genomic DNA extracted from blood leukocytes. RESULTS: Plasma homocysteine concentrations correlated negatively with folate and vitamin B-12(,) but positively with age (P: < 0. 0001). Whereas folate and vitamin B-12 accounted for 27% and 19% of the variation in homocysteine, respectively, age accounted for 48% of the variation. When the cohort was divided into older (>10 y) and younger (10 y. CONCLUSION: Our data show that in a healthy pediatric population, MTHFR genotype played a significant role in determining homocysteine concentrations in older (>10 y), nutritionally stressed children.

Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child.

We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele.

The kidney in children with tyrosinemia: sonographic, CT and biochemical findings.

BACKGROUND: Tyrosinemia relates to a deficiency of fumarylacetoacetate hydrolase and presents early in life with central nervous system and liver abnormalities. Renal function is often impaired. Little is known about the architecture and function of the kidneys. OBJECTIVE: Imaging changes on US and CT are compared to the function of the kidneys in children with tyrosinemia, and followed after liver transplantation. MATERIALS AND METHODS: Renal sonography, CT and renal function tests in 32 children were reviewed. Renal length, volume, echogenicity and nephrocalcinosis were evaluated. Renal function was assessed by glomerular filtration rate, and the presence of aminoaciduria, acidosis and calciuria. Seventeen children had open renal biopsy during time of liver transplantation. Histology was reviewed. Statistical analyses relating renal structure to function were performed, and repeated after transplantation. RESULTS: The kidneys were enlarged (47 %), hyperechogenic (47 %) and showed nephrocalcinosis (16 %). There was delayed excretion of contrast medium at CT in 64 %. Aminoaciduria was present in 82 % of children, hypercalciuria in 67 %, tubular acidosis in 59 %, and low GFR in 48 %. Delayed excretion of contrast was associated with low GFR (P < 0.05). Renal biopsies showed dilated tubules (81 %), interstitial fibrosis (56 %), glomerulosclerosis (56 %) and tubular atrophy (56 %). During a mean observation period of 3 years following liver transplantation, GFR improved in 50 %, tubular acidosis in 50 % and hypercalciuria in 70 %. No change was noted in renal size or sonographic architecture. CONCLUSION: Renal architecture and function are abnormal in the majority of children with tyrosinemia. Liver transplantation improves renal function in about 50 % of patients, but abnormal renal size and architecture persist.

Temporal relationships between hormonal and hemodynamic changes in early human pregnancy.

BACKGROUND: The systemic hemodynamic profile of human pregnancy is characterized by a decrease in mean arterial pressure, a rise in cardiac output and plasma volume in association with an increase in renal plasma flow and glomerular filtration rate. The factors and the time course responsible for the initial hemodynamic changes seen in human pregnancy have not been completely documented. We hypothesize that systemic and renal hemodynamic changes occur early, prior to the presence of the fetal-placental unit. METHODS: Thirteen women were studied prior to and immediately following conception in identical fashion at gestational weeks 6, 8, 10, 12, 24 and 36. Individuals underwent mean arterial pressure, cardiac output, inulin and PAH clearance determinations. RESULTS: Mean arterial pressure decreased by six weeks gestation (mid follicular 81.5 +/- 2.6 vs. six weeks 68.7 +/- 2.0 mm tig, P < 0.001) in association with a significant increase in cardiac output, a decrease in systemic vascular resistance and an increase in plasma volume. Renal plasma flow and glomerular filtration rate increased by six weeks gestation. Plasma renin activity and aldosterone concentration increased significantly by six weeks, whereas norepinephrine levels did not change throughout pregnancy. Atrial natriuretic peptide levels increased later, at 12 weeks gestation. Plasma cGMP levels decreased and cGMP clearance increased by six and eight weeks, respectively. CONCLUSIONS: Peripheral vasodilation occurs early in pregnancy prior to full placentation in association with renal vasodilation and activation of the renin-angiotensin-aldosterone system. Plasma volume expansion occurs early, followed later by increases in ANP concentration, suggesting that ANP increases in response to changes in intravasular volume.

Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy.

Blood pressure decreases during early pregnancy in association with a decrease in peripheral vascular resistance and increases in renal plasma flow and glomerular filtration rate. These early changes suggest a potential association with corpora lutea function. To determine whether peripheral vasodilation occurs following ovulation, we studied 16 healthy women in the midfollicular and midluteal phases of the menstrual cycle. A significant decrease in mean arterial pressure in the midluteal phase of the cycle (midfollicular of 81.7 +/- 2.0 vs. midluteal of 75.4 +/- 2.3 mmHg, P < 0.005) was found in association with a decrease in systemic vascular resistance and an increase in cardiac output. Renal plasma flow and glomerular filtration rate increased. Plasma renin activity and aldosterone concentration increased significantly in the luteal phase accompanied by a decrease in atrial natriuretic peptide concentration. Serum sodium, chloride, and bicarbonate concentrations and osmolarity also declined significantly in the midluteal phase of the menstrual cycle. Urinary adenosine 3',5'-cyclic monophosphate (cAMP) excretion increased in the luteal compared with the follicular phase, whereas no changes in urinary cGMP or NO2/NO3 excretion were found. Thus peripheral vasodilation occurs in the luteal phase of the normal menstrual cycle in association with an increase in renal plasma flow and filtration. Activation of the renin-angiotensin-aldosterone axis is found in the luteal phase of the menstrual cycle. These changes are accompanied by an increase in urinary cAMP excretion indicating potential vasodilating mediators responsible for the observed hemodynamic changes.

Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and cisplatin as compared to cisplatin alone. A prospective study is therefore needed to examine the potential additive toxic effect of the combination of taxol and cisplatin on long-term renal function, including potential preventive interventions.

Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.

Autologous and allogeneic bone marrow grafting both require cytoreductive therapy but only the allogeneic procedure requires immunosuppressive agents. Allogeneic bone marrow transplantation has been reported to be associated with a high incidence of both renal failure and veno-occlusive disease (VOD) of the liver, the combination of which is associated with a high morbidity and mortality. There is less known about the frequency and severity of these complications in patients undergoing autologous bone marrow transplantation. In the present study renal, hepatic and other complications were examined in 232 patients with Stages II/III and IV breast cancer who were treated with high-dose chemotherapy and autologous hematopoietic cell support with either marrow or peripheral blood progenitor cells. The post-treatment severity of the renal dysfunction was classified as follows: Grade 0, normal renal function [< 25% decrement in glomerular filtration rate (GFR)]; Grade 1. mild renal dysfunction (> 25% decrement in GFR but < a twofold increase in serum creatinine); Grade 2, > twofold rise in serum creatinine but no need for dialysis; Grade 3 > than twofold rise in serum creatinine and need for dialysis. There were 102 patients (44%) who were classified as Grade 0 and 81 patients (35%) who were classified as Grade 1 renal dysfunction. Severe renal dysfunction (Grades 2 and 3) was observed in 49 of the 232 patients (21%). This severe renal dysfunction of 21% compares with a previously reported 53% incidence of severe renal dysfunction for allogeneic bone marrow transplantation. Similarly, the frequency of hepatic VOD was less (4.7% or 11 of 232 patients) in this autologous bone marrow transplant study as compared to a reported incidence of hepatic VOD ranging from 22 to 53% in large series of allogeneic bone marrow transplant patients. The severe renal dysfunction (Grades 2 and 3) in the present autologous hematopoietic cell support study correlated most significantly with sepsis, liver and pulmonary dysfunction. The major fall in GFR occurred during chemotherapy but before hematopoietic cell support, thus primarily incriminating the cytoreductive therapy rather than the hematopoietic cell support. The only significant effect of different chemotherapy protocols was, at four weeks, the Taxol-treated group had a significantly lower creatinine clearance as compared to the BCNU treated group.

Focal segmental glomerulosclerosis (FSG) 20 years later. From toddler to grown up.

In 1981, we reported the outcome of 25 children with FSG after a follow-up of 10 years. In 1991, all the living patients were reevaluated. Ten patients are now in sustained remission. Four patients still present heavy proteinuria with a normal glomerular filtration rate, four required dialysis and seven patients have died. The renal survival curve has stabilized at 56%. These data show an overall outcome slightly more favourable than we had initially reported in 1981. The difference probably stems from our referral system which enables us to see the patients at an earlier stage of their disease. The percentage of deaths is important. Among the various clinical or histological factors of predictive prognostic value only the degree of interstitial damage has reached statistical significance (p < 0.02).

[Subarachnoid hematoma and spinal anesthesia]. / Hématome sous-arachnoïdien et rachianesthésie.

Two cases of spinal subarachnoid haematoma occurring after spinal anaesthesia are reported. In the first case, lumbar puncture was attempted three times in a 81-year-old man; spinal anaesthesia trial was than abandoned, and the patient given a general anaesthetic. He was given prophylactic calcium heparinate soon after surgery. On the fourth day, the patient became paraparetic. Radioculography revealed a blockage between T10 and L3. Laminectomy was performed to remove the haematoma, but the patient recovered motor activity only very partially. The second case was a 67-year-old man, in whom spinal anaesthesia was easily carried out. He was also given prophylactic calcium heparinate soon after surgery. On the fourth postoperative day, pulmonary embolism was suspected. Heparin treatment was then started. Twelve hours later, lumbar and bilateral buttock pain occurred, which later spread to the neck. On the eighth day, the patient had neck stiffness and two seizures. Emergency laminectomy was carried out, which revealed a subarachnoid haematoma spreading to a level higher than T6 and below L1, with no flow of cerebrospinal fluid, and a non pulsatile spinal cord. Surgery was stopped. The patient died on the following day. Both these cases are similar to those previously reported and point out the role played by anticoagulants. Because early diagnosis of spinal cord compression is difficult, the prognosis is poor, especially in case of paraplegia.