Blood pressure management in children on dialysis.

Hypertension is a leading cause of cardiovascular complications in children on dialysis. Volume overload and activation of the renin-angiotensin-aldosterone system play a major role in the pathophysiology of hypertension. The first step in managing blood pressure (BP) is the careful assessment of ambulatory BP monitoring. Volume control is essential and should start with the accurate identification of dry weight, based on a comprehensive assessment, including bioimpedance analysis and intradialytic blood volume monitoring (BVM). Reduction of interdialytic weight gain (IDWG) is critical, as higher IDWG is associated with a worse left ventricular mass index and poorer BP control: it can be obtained by means of salt restriction, reduced fluid intake, and optimized sodium removal in dialysis. Optimization of peritoneal dialysis and intensified hemodialysis or hemodiafiltration have been shown to improve both fluid and sodium management, leading to better BP levels. Studies comparing different antihypertensive agents in children are lacking. The pharmacokinetic properties of each drug should be considered. At present, BP control remains suboptimal in many patients and efforts are needed to improve the long-term outcomes of children on dialysis.

A comprehensive cooperative project for children with renal diseases in Nicaragua.

In low-income countries renal diseases generally and chronic kidney disease (CKD) in particular represent a wide-spread and often underdiagnosed clinical problem. The aim of the cooperative project between the pediatric nephrology units of Milan, Italy, and Managua, Nicaragua was to improve the diagnosis and treatment of renal diseases and CKD in Nicaraguan children. When the project started, in 2000, there were many constraints in human and material resources in the Children's Hospital in Managua. Since 2001, a specialized Unit of Pediatric Nephrology and Urology has developed, offering free of charge basic clinical assistance to hospitalized children, and training abroad of the whole staff. Shared protocols, renovation of infrastructure and an information technology (IT) program were implemented. In 2003, renal replacement therapy (RRT) for selected children was initiated, along with a network of six department hospitals in 2005 and, in 2007, a CKD prevention program in the most peripheral Health Units, so that 61% of the Nicaraguan pediatric population is now covered by the project. To ensure implementation of the project, applications for funds to Italian private and public institutions were made and a Nicaraguan charity foundation was activated. The Nicaraguan Ministry of Health and the hospital directors were always involved in the plans of the development of the project and accepted the progressive transfer of the costs to the government, throughout the 9-year duration of the project. The IT program, inclusive of a database of children with kidney and other urinary tract (UT) diseases and a web connection between Milan and Managua, was crucial in monitoring the activities and providing epidemiological data, in order to better allocate resources. The clinical activities and the number of children managed in Managua in 2008 are similar to those of pediatric nephrology units worldwide and depict the level of clinical autonomy achieved. The sister-center model of cooperation and the top-down strategy we applied, along with the careful consideration of all the economic, logistic and political issues, were and are the key factors which explain the favorable results of this cooperative project.

Assessment of nutritional status in children with chronic kidney disease.

The achievement of a normal nutritional status, that is a normal body composition and a normal pattern of growth, is a cornerstone in the management of children with chronic kidney disease (CKD). Protein-energy wasting (PEW) which indicates the state of decreased body protein mass and fuel reserves (body protein and fat mass), is a common condition in this population, and a source of morbidity and mortality. For the diagnosis of this condition, a lot of methods have been proposed, but due to the clinical characteristics of children with CKD, the intrinsic limits of the available indices and some methodological issues concerning published pediatric studies, none of these parameters could be considered as the gold standard. Given these limitations, a general consensus exists according to which only the combination of more indices integrated in a multidisciplinary approach can give the idea of the individual nutritional status. Among these indices, recent guidelines recommend dietary intake (by means of 3-day diary or 24-hour recall), anthropometric parameters (weight, height, height velocity, body mass index, head circumference) and, only for adolescent on hemodialysis, normalized protein catabolic rate as the most accurate ones. Other methods, such as mid-arm anthropometry, bioimpedance analysis, biochemical indices, and dual-energy X-ray absorptiometry could certainly help in the nutritional evaluation, taking into account the advantages and drawbacks of each method.

Pediatric kidney transplantation: a snapshot 10 years later.

Herein we report the outcomes of pediatric kidney recipients who underwent transplantation at least 10 years prior. A cohort of 36 patients (mean age, 26.4+/-6 years) with a mean follow-up time of 14.2+/-4 years was selected for the study. Immunosuppression consisted of cyclosporine and steroids. Actuarial patient and graft survivals 15 years after the transplantation were 97% and 86%, respectively. Only 1 patient died due to a complicated sclerosant peritonitis. Graft function was good with a mean serum creatinine of this selected cohort of 1.5+/-0.6 mg/dL. Eighteen percent were class 1, 33% class 2, and 49% chronic kidney disease. Hypertension was treated in almost 80% of the patients. The majority of patients were smaller than the average population with a final height (between 0 and -2) standard deviation score (HSDS) but only 27% had a severe growth impairment (HSDS>-2). Regarding nutritional status, fewer than 30% were overweight and only 1 patient was obese with a body mass index (BMI) >30. The majority of patients, except 2 mentally retarded individuals, are or have been attending normal school and achieved full-time employment. In conclusion, long-term survivors of a kidney transplant received during childhood reached a high degree of rehabilitation despite a long period of immunosuppression.

[Diagnostic and therapeutic criteria of arterial hypertension in childhood]. / Criteri diagnostici e terapeutici dell'ipertensione arteriosa in età pediatrica.

Arterial hypertension (AH), either primary or secondary, is an important issue in childhood for its short- and long-term cardiovascular morbidity. Renal diseases are the most frequent causes of AH in children, but essential hypertension can also be detected early in life. It is important for blood pressure (BP) to be checked regularly (at least once every 5 years) in healthy children and adolescents and every year in those belonging to at-risk categories (family history of AH, low birth weight, obesity, etc). In children, AH is defined as BP recorded in three non-consecutive measurements with an appropriate device and cuff size > or = 95th centile for age, gender and height. Ambulatory BP monitoring is a valuable diagnostic tool and once AH is confirmed, a specific primary cause should always be ruled out (renovascular, cardiac, vascular, endocrine, pharmacologic, other). In case of border-line or significant AH (between 90th and 99th centile) a non-pharmacological treatment should be considered, whereas severe hypertension (>99th centile for height and age) will require pharmacological treatment (Diuretics, Angiotensin Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, beta - and Calcium blockers).

Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines.

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol(2)/l(2). The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

Hemodialysis in children: general practical guidelines.

Over the past 20 years children have benefited from major improvements in both technology and clinical management of dialysis. Morbidity during dialysis sessions has decreased with seizures being exceptional and hypotensive episodes rare. Pain and discomfort have been reduced with the use of chronic internal jugular venous catheters and anesthetic creams for fistula puncture. Non-invasive technologies to assess patient target dry weight and access flow can significantly reduce patient morbidity and health care costs. The development of urea kinetic modeling enables calculation of the dialysis dose delivery, Kt/V, and an indirect assessment of the intake. Nutritional assessment and support are of major importance for the growing child. Even if the validity of these "urea only" data is questioned, their analysis provides information useful for follow-up. Newer machines provide more precise control of ultrafiltration by volumetric assessment and continuous blood volume monitoring during dialysis sessions. Buffered bicarbonate solutions are now standard and more biocompatible synthetic membranes and specific small size material dialyzers and tubing have been developed for young infants. More recently, the concept of "ultrapure" dialysate, i.e. free from microbiological contamination and endotoxins, has developed. This will enable the use of hemodiafiltration, especially with the on-line option, which has many theoretical advantages and should be considered in the case of maximum/optimum dialysis need. Although the optimum dialysis dose requirement for children remains uncertain, reports of longer duration and/or daily dialysis show they are more effective for phosphate control than conventional hemodialysis and should be considered at least for some high-risk patients with cardiovascular impairment. In children hemodialysis has to be individualized and viewed as an "integrated therapy" considering their long-term exposure to chronic renal failure treatment. Dialysis is seen only as a temporary measure for children compared with renal transplantation because this enables the best chance of rehabilitation in terms of educational and psychosocial functioning. In long term chronic dialysis, however, the highest standards should be applied to these children to preserve their future "cardiovascular life" which might include more dialysis time and on-line hemodiafiltration with synthetic high flux membranes if we are able to improve on the rather restricted concept of small-solute urea dialysis clearance.

Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients.

This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300-400 mg/m2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC(0-12)) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 +/- 0.6 and 1.9 +/- 1.1 microg/mL (P < .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC(0-12) at 6 and 180 days after transplantation was 23.3 +/- 10.8 and 40 +/- 11.6 mg*h/L (P = .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r = 0.8 and 0.79; P < .001). The abbreviated MPA AUC (0-4 hours) correlated reasonably with the full AUC (r = 0.87; P < .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P < .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.

C2 is an age-independent parameter for optimal cyclosporine exposure in long-term kidney transplant recipients.

The argument for therapeutic drug monitoring (TDM) of cyclosporine (Cya) has been discussed for the last two decades. So far, a generalized consensus has been reached for TDM of Cya microemulsion in adult transplant recipients, being Cya blood levels obtained 2 hours after the administration (C2), the most reliable in reflecting the overall Cya exposure. However, clear guidelines are not available for the pediatric population because of the distinct metabolism of the drug in this patient population. Therefore, adult data do not necessarily apply to children. In this retrospective analysis, the authors sought to define a universal parameter for pharmacokinetic clinical monitoring of Cya in long-term kidney transplant recipients, regardless of their age. Lower C2 levels were observed in all patients, adult and pediatric, who eventually developed chronic allograft dysfunction (CRAD) compared with patients who maintained stable kidney function throughout the entire follow-up (pediatric CRAD, 933 +/- 455 ng/mL; vs Stable, 1236 +/- 347 ng/mL, P = .0001; and adult CRAD, 781 +/- 518 ng/mL; vs Stable, 1088 +/- 452 ng/mL, P = .009). On the other hand, the risk of Cya underexposure was not highlighted by trough level monitoring (C0) because all patients have been maintained steadily on therapeutical C0 levels for the entire follow-up. In conclusion, for Cya maintenance therapy, C2 appears to be a superior strategy to C0 monitoring in both adult and pediatric kidney transplant recipients.

Conversion from tacrolimus to cyclosporine for a non-dose-dependent tacrolimus-induced toxicity, a pediatric kidney transplant recipient case report.

Tacrolimus-induced toxicity is considered a dose-related side effect largely due to a direct action of this potent calcineurin inhibitor on its targets including the kidney and the pancreas. This paper describes a case of tacrolimus systemic toxicity that appeared in a pediatric kidney transplant recipient who received a low drug dose. The kidney biopsy was a crucial aid toward the correct diagnosis, which reversed upon conversion to cyclosporine-based immunosuppression. A review of the literature suggests a chance of systemic toxicity even when the patient is maintained on therapeutic levels of tacrolimus. Because idiosyncratic reactions to the drug have not yet been postulated, we conclude that this suspicion may be addressed by a safe conversion to cyclosporine in pediatric patients.

Cyclosporine monitoring in stable, long-term, pediatric kidney transplant recipients: the value of C2 determination.

Although a generalized consensus has been reached for therapeutic drug monitoring of cyclosporine microemulsion in adult transplant patients, clear guidelines are recently not available for the pediatric population. In this retrospective analysis of pharmacokinetic data obtained from stable, long-term, pediatric kidney transplant recipients, we sought to define a possible approach to manage cyclosporine therapy in a pediatric setting. The 2-hour postdose cyclosporine blood concentration, C(2), rather than trough levels, was the best single time point predictor of the area under the concentration curve. We concluded that therapeutic drug monitoring of cyclosporine-based immunosuppressive regimens should be tailored based on C(2) determinations for pediatric kidney transplant recipients.

[Genetic basis for malformation-associated uropathy and renal dysplasia]. / Basi genetiche delle uropatie malformative e della displasia renale.

The wide association between urinary tract malformations and dysplastic kidneys, known as CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), could be caused by a single disorder of the embryonic development of the kidney and urinary tract. These complex patterns of development are under genetic control. A positive family history strongly suggests a genetic origin of these conditions. Linkage studies show an extreme genetic heterogenicity and an important phenotypic and clinical variability of the same mutation. Some urinary tract malformations have been investigated in the context of clinical syndromes. The renal-coloboma syndrome is an autosomal dominant human disease, secondary to mutation of the PAX2 transcription factor, characterized by optic nerve coloboma, renal anomalies and vesicoureteral reflux. However, most of the urinary tract anomalies can occur in isolation. Studies have shown the association of hereditary hydronephrosis with HLA antigens on chromosome 6 and the association of VUR with the mutations in a locus of chromosome 1. The higher frequency and severity of some uropathies in the male gender may be explained by a linkage-disequilibrium phenomenon or a X-linked transmission pattern. For example, the mutations in the AGTR2 gene on chromosome X were observed in animal models but not yet confirmed in human subjects. Finally, the ACE gene polymorphism is associated with a higher incidence of congenital hypo-dysplastic kidneys and represents a significant risk factor for the development of progressive renal damage.

Lipid profile during rhGH therapy in pediatric renal transplant patients.

To evaluate the effect of recombinant human growth hormone (rhGH) treatment on the lipid profile of pediatric renal transplant patients, we studied nine children treated with rhGH for 1 yr and a control group of 12 untreated patients matched in terms of age, renal transplant function and post-transplant follow-up. The levels of lipoprotein (a [Lp(a)], cholesterol, triglycerides, apolipoprotein A (APO A) and apolipoprotein B (APO B), and the APO B/APO A ratio, were determined at baseline and after 6 and 12 months of follow-up. RhGH therapy had no effect on cholesterol, triglycerides or apolipoproteins. Mean serum Lp(a) levels increased from 6.7 +/- 5.7 mg/dL at baseline to 11.8 +/- 10.7 after 6 months (p = 0.018) and 13.6 +/- 15.1 after 12 months of rhGH treatment (p = 0.04), but did not change in the control group. Lp(a) is a risk factor for cardiovascular morbidity, and increased Lp(a) levels may be a side-effect of rhGH treatment in renal transplant patients. Although long-term follow-up of a large number of patients is needed to establish the duration and extent of the effects of rhGH treatment on Lp(a) levels in transplanted children, serum Lp(a) levels should be carefully monitored in those receiving rhGH therapy.

A multicenter survey on automated peritoneal dialysis prescription in children.

Automated peritoneal dialysis (APD) is considered the first-choice chronic peritoneal dialysis modality for pediatric patients. Nighttime APD courses reduce the impact of PD treatment on a patient's and family's way of life, and the wide range of prescription options permit the dialysis schedule to be tailored to the needs of children of varying age and body size. We registered data concerning the dialytic regimens adopted in 12 pediatric dialysis centers for the treatment of 110 children on APD. Of the 110 children, 64 (aged 7.6 +/- 5.1 years) were on nightly intermittent peritoneal dialysis (NIPD); 29 (aged 9.2 +/- 4.3 years) were on tidal peritoneal dialysis (TPD); and 17 (aged 8.2 +/- 4.9 years) were on continuous cycling peritoneal dialysis (CCPD). The main prescription parameters for the various regimens (mean +/- standard deviation) were these: NIPD--exchanges: 13.0 +/- 5.8; duration: 10.0 +/- 1.1 hours; dwell volume: 36.5 +/- 6.2 mL/kg body weight (BW); glucose concentration: 1.69% +/- 0.41%. TPD--exchanges: 23.3 +/- 8.1; duration: 10.0 +/- 1.0 hours; dwell volume: 36.1 +/- 5.9 mL/kg BW; glucose concentration: 1.63% +/- 0.37%. CCPD--exchanges: 13.0 +/- 4.7; duration: 10.1 +/- 1.3 hours; dwell volume: 37.7 +/- 5.2 mL/kg BW; glucose concentration: 1.65% +/- 0.28%. Tidal volume was 52.2% +/- 9.0% of initial fill volume. Daytime dwell volume was 54.8% +/- 17.3% of night volume in CCPD patients, and 56.6% +/- 13.3% in 9 patients on continuous TPD. Because the patient population in this report varied in age, body size, and metabolic needs, the resulting range in prescription parameters was quite wide. Nevertheless, the duration of nightly PD sessions averaged 10 hours, fill volume averaged 36 mL per kilogram body weight, and daytime volume averaged 50% of nighttime fill volume.

Prevalence of malnutrition assessed by bioimpedance analysis and anthropometry in children on peritoneal dialysis.

OBJECTIVE: To evaluate the sensitivity of anthropometry and bioelectrical impedance analysis (BIA) in detecting alterations in body composition of children treated with peritoneal dialysis (PD), and to determine the prevalence of malnutrition in this population, in short- and long-term PD duration, using anthropometric and BIA-derived indices. PATIENTS: Eighteen children treated with automated PD (11 males, 7 females; mean age 8.7 +/- 4.7 years). DESIGN: Eighteen patients were studied using anthropometry and BIA at the start (t0) and after 6 months (t1) of PD, 15 of these patients at 12 months (t2), and 8 at 24 months (t3) of PD. Midarm muscle circumference (MAMC), arm muscle area (AMA), and arm fat area (AFA) were calculated from anthropometric measures according to Frisancho (FrisanchoAR. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 1981; 34:2540-5.). The bioelectrical measures of resistance (R) and reactance (Xc) were obtained directly from the impedance signal; phase angle (PA) and distance (D) were calculated using mathematical formulas. Nutritional status was assessed by anthropometric measurements and BIA-derived indices, expressed as standard deviation scores (SDS), and by a score system based on BIA and anthropometric parameters. The percentage of children with values of anthropometric and BIA-derived indices below the 3rd percentile or between the 3rd and 25th percentiles, and the percentage of children with scores of 7-12 and 4-6 were calculated in order to detect patients with severe or moderate derangement of nutritional status. RESULTS: The mean SDS values of Xc, PA, and D significantly improved (p = 0.05, p = 0.001, p = 0.02) during the first 6 months of PD and remained almost stable during the following months. The SDS values of the anthropometric indices were less compromised than those of the BIA-derived indices, particularly at the start of dialysis. By 6 months, the percentages of children with values of BIA and anthropometric indices below the 3rd percentile had decreased. The percentages of patients with moderate and severe derangement of BIA and anthropometric indices remained substantially unchanged after 12 months. However, at 24 months, the percentage of patients with moderate derangement of BIA indices increased. All these findings were confirmed by the nutritional score system. CONCLUSION: BIA is more sensitive than anthropometry in detecting alterations in body composition of children on PD. The prevalence of malnutrition, high at the commencement of PD, decreases during the first year of treatment but not over the long term.