Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy.

CAN is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to CNIs. In the present study, effects of a conversion protocol were investigated in pediatric CAN with declining GFR, defined by a Schwartz formula clearance below 60 mL/1.73 m2/min, steadily increasing SCr and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kgBW, followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. CNIs were reduced to 50% at start of sirolimus and discontinued at median seven days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m2/month, p = 0.025). Individual GFR increased in five of eight patients (p = 0.026), only one child exhibited unaltered progression of graft failure. In the responders, mean SCr improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, nor time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, serum lipids transiently increased. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from CNIs to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy proven CAN.

Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy.

Chronic allograft nephropathy is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to calcineurin inhibitors. In the present study, effects of a conversion protocol were investigated in pediatric chronic allograft nephropathy with declining glomerular filtration rate (GFR), defined by a Schwartz formula clearance below 60 mL/1.73 m(2)/min, steadily increasing serum creatinine and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kg bodyweight (BW), followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. Calcineurin inhibitors were reduced to 50% at the start of sirolimus and discontinued at median 7 days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m(2)/month, p = 0.025). Individual GFR increased in five out of eight patients (p = 0.026), and only one child exhibited unaltered progression of graft failure. In the responders, mean serum creatinine improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, or on time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, and serum lipids increased transiently. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from calcineurin inhibitors to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy-proven chronic allograft nephropathy.

Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion.

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.

[Referral to the pediatric dialysis unit -- the earlier the better?]. / Zuweisung an die Kinderdialyse -- Ist früher besser?

Whereas recent research has demonstrated clear evidence for beneficial effects of early referral to the nephrologist in chronic renal insufficiency in adults, no such data exist for the pediatric population. In this study, we therefore correlated patient age and residual renal function at first presentation to a specialized pediatric nephrologist with the extent of secondary uremic complications and the further course of renal function. From March 2003 until March 2004, 43 children (34 boys, aged 10.1 +/- 6.3 yrs) with congenital-urologic (n = 26), congenital-nephrologic (n = 13) or acquired (n = 4) renal diseases had been followed for 3.9 yrs (14 days to 17.5 yrs) at the Kinderdialyse Wien, with a residual renal function of 35 +/- 20.5 ml/min/1.73 m(2) at first presentation. With regards to uremic secondary complications, the majority of children exhibited involvement of at least two systems at first presentation. Thereafter, children with congenital diseases who were referred to the specialized pediatric nephrology unit within the first year of live demonstrated a significantly better course of residual renal function (1.8% vs -0.7%, p = 0.034) than children who were referred later. These data confirm recent registry reports on chronic renal insufficiency in children. Only about a third of the children of our population were presented to a specialized pediatric nephrology center within their first year of life (despite a congenital disease in 90% of them). Thus, therapeutic interventions might be currently offered at a delayed time point in the majority of children.

ACE inhibition in the treatment of children after renal transplantation.

Currently, there are no data available on long-term effects of angiotensin-converting enzyme inhibitors (ACE-I) on graft function in children after renal transplantation. We therefore analyzed all children who were transplanted at our institution between 1989 and 1998 and followed for at least 2 years. Those treated with ACE-I, mainly because of failure of other antihypertensive medications, were compared to those without ACE-I. The ACE-I-treated children ( n=19) showed significantly better blood pressure control during the 1st year of follow-up ( p<0.05). In children with chronic allograft dysfunction ( n=8), treatment with ACE-I stabilized graft function, with improvement in creatinine clearance in 50% ( p<0.01). Serum potassium and hemoglobin levels remained stable. One patient discontinued ACE-I because of renal artery stenosis. Taken together, ACE-I were effective and safe in the treatment of hypertension in children following renal transplantation. Children with chronic allograft dysfunction experienced a stabilizing effect on graft function.

Management of congenital hydronephrosis with ureteropelvic junction obstruction: the Vienna-AKH experience 1986-2001.

One of the most common causes of congenital hydronephrosis is obstruction of the ureteropelvic junction. The obstruction can be detected with prenatal ultrasonography screening and treated before renal function is reduced; the obstruction may also resolve spontaneously. Currently, there is no test for predicting the outcome of this obstruction. Management guidelines for neonates with asymptomatic obstruction of the ureteropelvic junction are based on expert opinions, but not on evidence-based data. In our retrospective study, we evaluated management and outcome of 26 renal units in 23 infants (15 boys, 8 girls) with congenital obstruction of the ureteropelvic junction treated in our institution between 1986 and 2001. These infants had isolated hydronephrosis on prenatal and postnatal sonography, showed an obstructive curve pattern in the postnatal diuretic nephrogram and had at least one follow-up nephrogram during a follow-up period of at least 1.5 years. Of these renal units, 16 demonstrated normal function (Group I), five moderate function (Group II) and five severely reduced function (Group III). In group I, 6 of 12 primarily conservatively managed kidneys resolved spontaneously and remained normal in function. In group II, all infants were operated and 83% improved their kidney function. In group III, all infants were operated but none demonstrated relevant improvement. These data support the current expert opinion of the Arbeitsgemeinschaft Pädiatrische Nephrologie (APN), that ureteropelvic junction obstruction in neonates with normal renal function can be managed primarily conservatively with close monitoring. In neonates with moderately--but not with severely--reduced renal function, early surgery is effective in the prevention of deterioration.

[Chronic peritoneal dialysis in children. Results of the Vienna Pediatric Dialysis Department]. / Chronische Peritonealdialyse bei Kindern--Ergebnisse der Kinderdialyse Wien.

BACKGROUND: Peritoneal Dialysis (PD) has been increasingly used as primary renal replacement therapy in children over the last 10 years. The aim of this study was to investigate complications of PD and compare the collected data with our own historical data and data from the literature. PATIENTS AND METHODS: 33 children (17 boys, mean age 4.9 years) who underwent PD for the first time due to chronic renal failure between 1994 and 2003 were enrolled in this retrospective survey. RESULTS: 398 months on PD in total, with a mean time of 12 months per patient were investigated. The occurrence rate of peritonitis was one per 14.2 months and for exit-site-infection one per 13.2 months. 23 children underwent renal transplantation, one child was switched to hemodialysis, two children died (one because of PD-unrelated circumstances), reflecting a 1-year survival rate of 94%. CONCLUSIONS: Peritoneal dialysis has become the most frequently used modality of renal replacement therapy in children, with a trend towards smaller children and infants. PD can be managed safely and successfully in children of all age groups, including even newborns.

Serum lipid pattern unifies following renal transplantation in children.

Hyperlipidemia is a common problem in solid organ transplant recipients. In this study we evaluated the role of pre-transplant renal replacement therapy on early and late changes of serum lipid levels in children following renal transplantation. In 46 children with chronic renal failure (median age 10.3 years) and 12 children with heart failure (median age 5.0 years), cholesterol and triglycerides were measured before and during follow-up after transplantation. Children with renal failure had significantly higher serum lipids than controls ( n=34, median age 9.2 years) and patients with heart failure. Pre transplantation, cholesterol and triglycerides were significantly lower in the hemodialysis than in the peritoneal dialysis population, whereas conservatively treated children had intermediate levels. After transplantation, serum cholesterol converged towards a mean level of 208 mg/dl and triglyceride levels converged towards a uniform level of 195 mg/dl at 9 months post transplant. The ratio of cholesterol/high-density lipoprotein significantly decreased from 4.7 to 3.8. The pattern of "post-transplant hyperlipidemia" was similar in both renal and cardiac allograft recipients. Hence, the early post-transplant changes of serum lipid pattern are markedly dependent on the mode of pre-transplant renal replacement therapy. Later, serum lipid levels were no longer influenced by prior renal replacement therapy and showed a new pattern of "post-transplant hyperlipidemia" in all children.

Urinary tract infections beyond the early post-transplant period in pediatric renal graft recipients.

BACKGROUND: Urinary tract infection is a frequent bacterial complication after renal transplantation in adults and children, however there are only very limited data on children beyond the early post-transplant period. In this study we investigated urinary tract infections in pediatric outpatients who had received transplants more than six months previously. Incidence, risk factors and impact on short-term graft function were analyzed. METHODS: 47 children who had received a total of 58 allografts were analyzed between 1997 and 2000. At the time of analysis they had had their transplants for an average of 3.5 years (range 0.5-9.4). Urinary tract infection was defined as the presence of both significant bacteriuria (> 10(5) CFU/ml) and symptoms. RESULTS: Of the 47 patients, 15 (32%) had from 1 to 7 urinary tract infections each. In total 35 infections were recorded. Median age at urinary tract infection was 5.5 years (range 1.8-24.2). Gender, donor source, immunosuppression and underlying disease (urologic vs non-urologic) did not influence the incidence of urinary tract infection. Creatinine but not C-reactive protein rose significantly during the infection. CONCLUSIONS: Our data suggest that urinary tract infection remains a frequent but mostly benign complication in the pediatric transplant population, even beyond the early post-transplant period. More extended studies are needed to assess the long-term effects on graft function.

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.