Jorge R. Ferraris

A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Prophylactic Theophylline on Renal Function in Term Neonates With Perinatal Asphyxia

Background. The kidney is the most damaged organ in asphyxiated full-term infants. Experiments in rabbits and rats have shown that renal adenosine acts as a vasoconstrictive metabolite in the kidney after hypoxemia and/or ischemia, contributing to the fall in glomerular filtration rate (GFR) and filtration fraction. Vasoconstriction produced by adenosine can be inhibited by the nonspecific adenosine receptor antagonist, theophylline. Gouyon and Guignard performed studies in newborn and adult rabbits subjected to normocapnic hypoxemia. Their results clearly showed that the hypoxemia-induced drop in GFR could be avoided by the administration of low doses of theophylline. Objective. This study was designed to determine whether theophylline could prevent and/or ameliorate renal dysfunction in term neonates with perinatal asphyxia. Setting. Buenos Aires, Argentina. Study Design. We randomized 51 severe asphyxiated term infants to receive intravenously a single dose of either theophylline (8 mg/kg; study group: n = 24) or placebo (control group: n = 27) during the first 60 minutes of life. The 24-hour fluid intake and the urine volumes formed were recorded during the first 5 days of life. Daily volume balances (water output/input ratio and weights) were determined. Severe renal dysfunction was defined as serum creatinine elevated above 1.50 mg/dL, for at least 2 consecutive days after a fluid challenge, or rising levels of serum creatinine (.3 mg/dL/day). The GFR was estimated during the second to third days of life by endogenous creatinine clearance (mL/minute/1.73 m2) and using Schwartzs formula: GFR (mL/minute/1.73 m2) = .45 × length (cm)/plasma creatinine (mg/100 mL) during the first 5 days of life. Tubular performance was assessed as the concentration of β2-microglobulin (β2M) determined by enzyme immunoassay, on the first voided urine 12 hours after theophylline administration. The statistical analysis for the evaluation of the differences between the groups was performed with Studentst and χ2 tests as appropriate. Results. During the first day of life, the 24-hour fluid balance was significantly more positive in the infants receiving placebo compared with the infants receiving theophyline. Over the next few days, the change in fluid balance favored the theophyline group. Significantly higher mean plasma values were recorded in the placebo group from the second to the fifth days of life. Severe renal dysfunction was present in 4 of 24 (17%) infants of the theophylline group and in 15 of 27 (55%) infants of the control group (relative risk: .30; 95% confidence interval: .12–.78). Mean endogenous creatinine clearance of the theophylline group was significantly increased compared with the creatinine clearance in infants receiving placebo (21.84 ± 7.96 vs 6.42 ± 4.16). The GFR (estimated by Schwartzs formula) was markedly decreased in the placebo group. Urinary β2M concentrations were significantly reduced in the theophylline group (5.01 ± 2.3 mg/L vs 11.5 ± 7.1 mg/L). Moreover, 9 (33%) patients of the theophylline group versus 20 (63%) infants of the control group had urinary β2M above the normal limit (<.018). There was no difference in the severity of the asphyxia between infants belonging to the theophylline and control groups in regards of Portmans score. Except for renal involvement, a similar frequency of multiorganic dysfunction, including neurologic impairment, was observed in both groups. The theophylline group achieved an average serum level of 12.7 μg/mL (range: 7.5–18.9 μg/mL) at 36 to 48 hours of live versus traces (an average serum level of .87 μg/mg) in the placebo group. Conclusions. Our data suggest that prophylactic theophylline, given early after birth, has beneficial effects on reducing the renal dysfunction in asphyxiated full-term infants. A single dose of 8 mg/kg of theophylline within the first postnatal hour in term neonates with severe perinatal asphyxia results in a significant decrease in serum creatine and urinary β2M, together with a significant increase in the creatine clearance. The potential clinical relevance of the data would be the avoidance of the contributory role of hypoxemia in the development of acute renal failure. Additional studies will be necessary before the use of theophylline in asphyxiated newborns can be considered for clinical practice.

Conversion from azathioprine [correction of azathioprina] to mycophenolate mofetil in pediatric renal transplant recipients with chronic rejection.

BACKGROUND Chronic rejection is the leading cause of graft failure. Both nonimmunological and immunological mechanisms contribute to this pathology. METHODS We studied changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, serum HLA class I antigens, cytotoxic antibodies, and lymphocyte population before and after 6 months of follow-up in 22 pediatric renal transplanted patients. The immunosuppressive protocol used was: cyclosporine, azathioprine, and corticosteroids. Eight patients demonstrated chronic graft rejection (by biopsy), group I; and eight patients had no clinical evidence of chronic and/or acute rejection, group II. Substitution of mycophenolate mofetil (MMF) (600 mg/m2 bid for azathioprine was done in patients of groups I and II. Another six patients with chronic rejection, did not receive MMF, group III. RESULTS Creatinine clearance increased in group I (44+/-5 vs. 51.1+/- ml/min/1.73 m2, P<0.03) but it decreased in group III (30+/-3 vs. 25+/-2, P<0.01). Urinary protein excretion decreased only in group I (0.3+/-0.03 to 0.06+/-0.03 g/24 hr, P<0.03). During MMF therapy antidonor mixed lymphocyte culture decreased 62 and 70% (P<0.05) in group I and II. Cell-mediated lympholysis against lymphocyte of the donor decreased 65% (P<0.05) in group I. Cell-mediated lympholysis toward control cells decreased 54% (P<0.01) in group II. Serum HLA class I antigens, only decreased from 0.7+/-0.1 to 0.5+/-0.1 microl/ml, P<0.05, in group I. CD19+ decreased from 7.9+/-1.1 to 5.6+/-0.8%, P<0.05, and 7.8+/-1.2 to 5.5+/-0.9%, P<0.05, in groups I and II, respectively. CD16+ increased from 5.7+/-1.1 to 8.6+/-1.3 (P<0.05) only in group I. CONCLUSIONS Our data suggest that substituting MMF for azathioprine therapy leads to an improvement in the immunosuppression and renal function in children with on-going chronic rejection.

Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids.

Ferraris JR, Argibay PF, Costa L, Jimenez G, Coccia PA, Ghezzi LFR, Ferraris V, Belloso WH, Redal MA, Larriba JM. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: Age dependency and pharmacological interaction with steroids. 
Pediatr Transplantation 2011: 15: 525–532.

ABPM vs. office blood pressure to define blood pressure control in treated hypertensive paediatric renal transplant recipients

Abstract:  While 24‐h ambulatory blood pressure monitoring (ABPM) is an established tool for monitoring antihypertensive therapy in adults, data in children are scarce. We retrospectively analysed whether office blood pressure (BP) is reliable for the diagnosis of BP control in 26 treated hypertensive paediatric renal transplants. Controlled office BP was defined as the mean of three replicate systolic and diastolic BP recordings less than or equal to the 95th age‐, sex‐ and height‐matched percentile on the three‐outpatient visits closest to ABPM. Controlled ABPM was defined as systolic and diastolic daytime BP ≤95th distribution adjusted height‐ and sex‐related percentile of the adapted ABPM reference. Eight recipients (30%) with controlled office BP were in fact categorized as having non‐controlled BP by ABPM criteria. Overall, when office BP and ABPM were compared using the Bland and Altman method, the 95% limits of agreement between office and daytime values ranged from −12.6 to 34.1 mmHg for systolic and −23.9 to 31.7 mmHg for diastolic BP, and the mean difference was 10.7 and 3.9 mmHg respectively. Office readings miss a substantial number of recipients who are hypertensive by ABPM criteria. Undertreatment of hypertension could be avoided if ABPM is applied as an adjunct to office readings.

Mycophenolate mofetil and reduced doses of cyclosporine in pediatric liver transplantation with chronic renal dysfunction: Changes in the immune responses

Abstract:  The aim of this study was to study the incidence of chronic renal dysfunction in patients with more than 5 yr of follow‐up following liver transplantation and to evaluate the benefit of decreasing cyclosporine A (CsA) dose combined with mycophenolate mofetil (MMF) on renal function and immune response in these patients. Between 1988 and 1994, 60 children were transplanted, and 86% survived >5 yr post‐liver transplantation. Fourteen patients developed chronic renal dysfunction secondary to CsA toxicity as evaluated by renal biopsy. In 11 patients CsA dose was decreased to 40–90 mg/ml target levels and MMF 600 mg/m2 twice daily was added to the immunosuppressive regimen. Plasma creatinine decreased (from 1.0 ± 0.03 to 0.8 ± 0.03 ng/dl, p < 0.007), creatinine clearance increased (from 66.8 ± 3.0 to 99.2 ± 6.3 ml/min/1.73 m2, p < 0.002) and microalbuminuria decreased (from 21.0 ± 8.6 to 3.6 ± 1.1 mg/24 h, p < 0.05) after 12 months of CsA combined with MMF therapy. During combined therapy the proliferative, cytolytic response and cytotoxic antibodies showed no significant changes, whereas CD4/CD8 ratio increased (from 1.2 ± 0.2 to 1.4 ± 0.1, p < 0.05). Tumor necrosis factor‐α secretion increased (p < 0.005) during MMF therapy. The release of interleukin‐10 was strikingly augmented under both immunosuppressive regimens, but the release of transforming growth factor‐β and interferon‐γ did not change. Our findings indicate that initiation of MMF combined with reduced doses of CsA allowed the recovery of renal function with minor changes in the immune response.

Conversion from cyclosporine A to tacrolimus in pediatric kidney transplant recipients with chronic rejection: changes in the immune responses.

Background. Tacrolimus (Tac) has immunosuppressant properties similar to those of cyclosporine A (CsA), but it is more potent. At present, however, its immunosuppressive activity in renal transplant recipients with ongoing chronic rejection has not been clarified. Methods. We studied changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, cytotoxic antibodies, lymphocyte population, and cytokine response before and after the conversion from CsA to Tac in 14 pediatric renal transplant recipients with chronic rejection. CsA (5.9±0.2 mg/kg/d) was replaced by Tac (0.1±0.004 mg/kg/d). Results. Serum creatinine decreased (2.3±0.2–1.9±0.2 mg/dL, P <0.005), creatinine clearance increased (36.8±2.5–46.1±4.4 mL/min/1.73m2, P <0.005), and urinary protein excretion decreased (0.4±0.01–0.2±0.04 g/24 hr, P <0.03) after 6 months, and these values were maintained after 2 years with Tac treatment. During Tac therapy, anti-donor and anti-control mixed lymphocyte culture decreased 38% and 31% (P <0.05), respectively. Cell-mediated lympholysis did not change. CD3+ decreased from 87%±2% to 80%±2% (P <0.005), and CD8+ decreased from 34%±3% to 27%±2% (P <0.005). The switch to Tac decreased the interferon-&ggr; production in vitro (P <0.05) and increased tumor necrosis factor-&agr; levels (P <0.05). The release of interleukin-10 was strikingly augmented with CsA or Tac therapy (P <0.01), but transforming growth factor-&bgr; secretion was similar. Conclusions. Our data indicate that conversion from CsA to Tac therapy leads to an improvement in renal function without altering key elements of the immunosuppression in children with ongoing chronic rejection.

Twenty-four-hour ambulatory blood pressure profiles in liver transplant recipients

Abstract:  Twenty‐four‐hour ambulatory blood pressure monitoring (ABPM) has proven to have better reproducibility than office blood pressure (BP) and is increasingly used for the study of hypertension in children and adolescents. The aim of our study was to assess 24‐h BP profiles and to compare the results of office BP measurements with ABPM in stable liver transplant recipients transplanted before the age of 18 yr. ABPM was performed in 29 patients (nine males, 20 females), aged 3.9–24.8 yr (median 10.8 yr). The investigation was conducted 1.1–11.5 yr (median 5.1 yr) following transplantation. ABPM confirmed hypertension in one out of three office hypertensive patients. Seven patients (24%), whose office BP recordings were within the normotensive range, were reclassified as hypertensive. Non‐dippers (n = 17), arbitrarily defined as patients with less than 10% nocturnal fall in BP, were similarly distributed among patients with ambulatory normotension and ambulatory hypertension (χ2, p = 0.79). In addition, non‐dippers showed a negative correlation between 24‐h total urinary albumin excretion and both systolic and diastolic nocturnal decline in BP (Rho = −0.48, p < 0.05 and Rho = −0.86, p < 0.01, respectively). Our study found office BP readings to be poorly representative of 24‐h BP profile. Larger studies are needed to confirm our observations as well as to determine whether routine BP measurements in the follow‐up of paediatric liver transplant recipients should be based solely on office BP.

Hyperhomocysteinemia In Stable Pediatric, Adolescents, And Young Adult Renal Transplant Recipients

Background. High total plasma homocysteine (tHcy) levels are accompanied by an increased risk for premature development of atherosclerosis and atherothrombosis. Adult renal transplant recipients have elevated tHcy levels. Corresponding data in pediatric, adolescent, and young adult renal transplant recipients are scarce. We investigated whether tHcy levels were elevated in stable renal transplant recipients who received kidney grafts before age 18. Methods. This cross-sectional study was conducted during routine posttransplantation follow-up. Fasting tHcy levels, serum creatinine, and lipoprotein profile were measured in 38 clinically stable renal transplant recipients with different degrees of renal function. No patient was receiving B vitamin or folic acid supplementation. Estimated glomerular filtration rate (GFR) was assessed according to Schwartz’s formula. All patients followed a triple-drug immunosuppressive regimen, with the exception of three patients (deflazacort and azathioprine). Forty-one apparently healthy subjects constituted the control group. tHcy levels were determined by fluorescence polarization immunoassay in an IMx analyzer. Results. Mean tHcy levels in transplant recipients were significantly higher than in controls (16.8±8.7 &mgr;mol/L and 9.5±2.3 &mgr;mol/L, respectively;P <0.01). A significant positive correlation between tHcy and serum creatinine levels was observed for both transplant recipients (rS=0.70, P <0.01) and controls (rS=0.54, P <0.01). In transplant recipients, tHcy correlated negatively with estimated GFR (rS=[minus]0.47, P <0.05). Fasting tHcy levels in excess of 14.6 &mgr;mol/L (>95th percentile in controls) were present in 19 (50%) patients; 14 of these patients had an estimated GFR<60 ml/min per 1.73 m2. When the renal transplant recipients were analyzed by renal function, mean tHcy was significantly higher in patients with an estimated GFR<60 ml/min per 1.73 m2 compared with patients with an estimated GFR≥60 ml/min per 1.73 m2 (20.5±9.9 vs. 13.2±5.8 &mgr;mol/L, P <0.01). Both groups were significantly different from controls (P <0.01). No relationship was found between tHcy level and either cumulative cyclosporine or cumula-tive methylprednisone doses. No differences were observed in tHcy levels or lipoprotein profile between patients who were receiving deflazacort and those on methylprednisone. Conclusions. Hyperhomocysteinemia in renal transplant recipients is a common condition. Testing for fasting tHcy level might be a useful tool to identify patients at increased risk for development of vascular disease.

Ambulatory blood pressure monitoring after recovery from hemolytic uremic syndrome.

Abstract. The outcome of acute renal failure due to diarrhea-associated hemolytic uremic syndrome (D+ HUS) is generally predicted to be good. However, there are only a few long-term observations with detailed reports on long-term sequelae. Specifically, adequate long- term blood pressure (BP) evaluations are scarce. The present study evaluated BP in pediatric patients after childhood D+ HUS. The study group comprised 28 patients (20 males) aged 6–23.5 years (median 10.1 years). All patients had a history of D+ HUS at a median age of 1.1 years (range 0.5–6 years). Based on the duration of oliguria and/or anuria, the primary disease was classified as mild (n=6), moderate (n=6), or severe (n=16). The BP in these patients was studied at a median time of 8.4 years (range 2.3–22.9 years) after manifestation of D+ HUS by means of office BP measurements and 24-h ambulatory BP monitoring (ABPM) using a Spacelabs 90207 oscillometric monitor. Measurements were compared with normal values of published standards for healthy children and adolescents. Conventional office BP measurements were above the 95th percentile in 1 patient. By ABPM, 2 patients were diagnosed to have mean systolic daytime and nighttime values in the hypertensive range, and systolic and diastolic hypertension was confirmed in the first patient. All these patients had a severe form of D+ HUS in the past. By applying ABPM, BP anomalies were detected in 5 additional patients. Elevated systolic BP loads were found in 4 patients, and daytime systolic and diastolic hypertension in the other 1. At the time of the study, 2 of them were classified as ”recovered.” The late outcome of D+ HUS may be worse than anticipated. BP anomalies as long-term sequelae of D+ HUS could be identified by ABPM but not by office BP measurements. These findings may repre- sent an isolated sign of residual renal disturbance.

Latin American Registry of Pediatric Renal Transplantation 2004-2008

Latin American Pediatric Nephrology Association (ALANEPE) and Latin American Pediatric Renal Transplant Cooperative Study. Latin American Registry of Pediatric Renal Transplantation 2004–2008.
Pediatr Transplantation 2010: 14:701–708.