De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation.

The number of acute rejections and infections after pediatric kidney transplantation (KTX) could not be reduced in the last years. To reduce these events, we investigated a new immunosuppressive protocol in a prospective trial. After KTX, 20 children (median age 12 years, range 1-17) were initially treated with Basiliximab, ciclosporine A (CsA) (trough-level = C0 200-250 ng/mL) and prednisolone. After 2 weeks, CsA dose was reduced to 50% (C0 75-100 ng/mL, after 6 months: 50-75 ng/mL) and everolimus (1.6 mg/m²) /day) was started (C0 3-6 ng/mL). Six months after KTX prednisolone was set to alternate dose and stopped 3 months later. All 20 protocol biopsies 6 months after KTX showed no acute rejection or borderline findings. Indication biopsies resulted in no acute rejections and two borderline findings. Mean glomerular filtration rate (GFR) 1 year after KTX was 71 ± 25 mL/min/1.73 m². Without cytomegalovirus (CMV)-prophylaxis, only two primary CMV infections were seen despite a donor/recipient-CMV-constellation pos./neg. in 10/20 children. In pediatric KTX, de novo immunosuppression with low-dose CsA, everolimus and steroid withdrawal after 9 months led to promising results according to numbers of acute rejections and infections. Further follow up is needed. Future larger trials will have to confirm our findings.

[Pediatric kidney transplantation]. / Nierentransplantation bei Kindern.

Kidney transplantation is the first line treatment for children with terminal renal failure. In addition to the survival rate of children and transplanted kidneys, the overall condition of the child with respect to growth and development is particularly important. The aims of pediatric renal transplantation are treatment strategies which minimize the side effects of immunosuppression and permit normal growth and development.

[Concept to improve adherence in adolescents following renal transplantation: vision or reality?]. / Konzept zur Verbesserung der Adhärenz bei jugendlichen Erwachsenen nach Nierentransplantation : Vision oder Realität?

Transition to adult care is a generic issue for subspecialties dealing with chronic illness and has received little attention to date. The transition from pediatric to adult care for renal transplant recipients is recognized as a high-risk period for poor graft outcome associated with more than 20% graft loss. Non-adherence to immunosuppressive medications is one of the most important factors contributing to graft loss during this period. Transition is, therefore, a concern of both pediatric and adult providers, and medical improvements in this area will require more effective collaboration at this interface. This report explores medical and psychological risk factors and barriers during the transition process. In addition, a specially developed coaching concept for young adults is presented intended to assist adolescents with early childhood end-stage renal disease in the transition from pediatric to adult care.

Superior long-term graft function and better growth of grafts in children receiving kidneys from paediatric compared with adult donors.

BACKGROUND: Organs from paediatric donors are often not accepted for paediatric recipients because previous reports suggested inferior graft function for small kidneys transplanted in children. On the other hand, studies have shown that kidneys of adult donors transplanted into children down-regulate filtration after transplantation and may not increase their function to the need of the growing child. METHODS: We assessed 64 male and 35 female (total n = 99) white children aged <10 years (male: mean 5.1 years, SD 2.8; female: mean 5.8 years, SD 3.4) who had received cadaveric kidney transplants at our centre between 1990 and 2005. Mean observation time was 5.9 years, SD 4.0. The children were divided into two groups depending on the kidney donor age: 63 children (mean age 5.0 years, SD 2.9) received an organ of an adult, and 39 (mean age 6.4 years, SD 3.4) of a paediatric donor. Immunosuppression was performed with prednisolone, cyclosporin A microemulsion+/-mycophenolate mofetil. RESULTS: Three to five years after transplantation the calculated glomerular filtration rate corrected to body surface was significantly higher in recipients of paediatric organs. The size of paediatric grafts doubled in the first years after transplantation while adult grafts had a stable size. Graft survival was comparable in both groups during observation time. CONCLUSIONS: We conclude that paediatric donor kidneys should be given preferentially to paediatric recipients due to better long-term function.

Kidney transplantation without prior dialysis in children: the Eurotransplant experience.

Kidney transplantation without prior dialysis may prevent dialysis-associated morbidity. We analyzed the outcome of 1113 first kidney transplants in children performed between 1990 and 2000 in the Eurotransplant community. Enlistment for a deceased donor kidney before start of dialysis (127/895, 14%) made dialysis redundant in 55% of cases. Mean residual creatinine clearance at transplantation of these patients was 8 mL/min/1.73 m(2). Pre-emptive transplantations of deceased donor kidneys showed less acute rejections (52% vs. 37% rejection-free at 3 years, p = 0.039), compared to transplantations following dialysis. The difference in graft survival between non-dialyzed and dialyzed patients (82% vs. 69% at 6 year) did not reach statistical significance (p = 0.055). No differences were noted after living donor transplantation. Multivariate analysis showed that the period of transplantation was the strongest predictor of graft survival (p < 0.001). Congenital structural abnormalities such as primary kidney disease predominated in nondialyzed patients as compared to dialyzed patients (p < 0.001); this factor did not influence graft survival. Based on our conclusion that pre-emptive transplantation is at least as good as post-dialysis transplantation, as well as on quality of life arguments, we recommend to consider pre-emptive transplantation in children with end-stage renal failure.

Living related kidney donation as an advantage for growth of children independent of glomerular filtration rate.

Seventy-two pediatric kidney recipients of living related donors (LRD) and 145 of cadaveric donors (CAD) were analyzed for height standard deviation scores (Ht-SDS) and glomerular filtration rates (GFR) directly after transplantation and over the following 5 years. GFR was significantly higher immediately after transplantation in LRD compared with CAD recipients; however, GFR was not different during the 5-year follow-up period. Although Ht-SDS was comparable at the time of transplantation in both groups, it was significantly higher among LRD recipients over the next 5 years. Multivariate and covariate analyses showed that Ht-SDS after 5 years was mainly influenced only by CAD vs LRD and not by GFR or other factors, namely, donor age, rejections, time of dialysis, preemptive transplantation, age at transplantation, or immunosuppression. Thus, children receiving grafts from LRD showed a better catch-up growth independent of the GFR than those after CAD transplantation. We concluded that the period of donor death and prolonged cold ischemia in CAD grafts may lead to changes in gene expression of cytokines and other mediator molecules that affect bone metabolism. Better growth seems to be an additional factor supporting the policy of LRD kidney transplantation as the best option in children.

Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab.

Acute rejection episodes leading to treatment refractory early graft loss are increasingly rare events in living related renal transplantation today. Pathophysiologic pathways often remain unsolved. We report on tubulointerstitial and vascular rejection developing within 2 weeks after transplantation in a 12-year-old boy treated with cyclosporine, mycophenolate, steroids and double blinded basiliximab. Despite steroid pulses, switch to tacrolimus and ATG serum creatinine peaked at 347 micromol/L with imminent graft loss and ongoing C4d negative cellular vascular rejection. Permanent gain of function was only achieved after a single dose of rituximab. Retrospectively CD20+ nodular B-cell aggregates could be demonstrated in all three biopsies obtained prior to rituximab and resolved concomitantly with functional improvement. Our case for the first time demonstrates resolution of nodular CD20+ infiltrates and decline of OX40, NF-kappaB and CTL transcription shortly after rituximab indicating a B-cell facilitated C4d negative pathway. Single dose rituximab may effectively reverse even long-lasting refractory rejection.

Growth in children after kidney transplantation with living related donor graft or cadaveric graft.

The extent to which growth after renal transplantation differs between children with a living related donor graft (LRD) and those with a cadaveric donor graft (CAD) is unclear. We retrospectively studied growth in the 5 years after transplantation in 30 boys who received LRD and 21 who received CAD. Height was similar in both groups after transplantation but was greater in LRD than in CAD recipients during follow-up. LRD recipients were taller at all ages, and had greater growth velocity in infancy and during puberty. Glomerular filtration rate (GFR) was higher immediately after transplantation in LRD than in CAD recipients, but did not differ between the groups during follow-up. GFR and other factors did not affect height 5 years after transplantation. These findings support use of LRD as the preferred option in children.

Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function.

BACKGROUND: Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long-term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long-term monitoring of MPA in children have yet been published. METHODS: MMF therapy with a dose of 600 mg/m2 twice daily was initiated in 42 children (median age 9.4 yr, range 1.4-15.1) after a median period of 3.8 yr (range 1.0-10.6) post-transplantation-- according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA-C0-levels, measured by high-pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later. RESULTS: After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = -0.07, p > 0.05). The mean MPA trough level was 2.8 +/- 1.3 ng/mL. The intra-individual coefficient of variation was 2.6 +/- 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05). CONCLUSIONS: Drug monitoring of MPA trough levels had no impact on long-term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA-AUC whereas C0-levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.

[Bacterial pathogens, resistance patterns and treatment options in community acquired pediatric urinary tract infection]. / Bakterielle Erreger, Resistenzentwicklung und Behandlungsoptionen beim ambulant erworbenen Harnwegsinfekt im Kindesalter.

BACKGROUND: Epidemiology and resistance patterns of bacterial pathogens in pediatric UTI show large interregional variability and rates of bacterial resistances are changing due to different antibiotic treatment. We intended to evaluate data from northern Germany. PATIENTS AND METHODS: In 100 children (53 female, 47 male, mean age 4.4 +/- 4.2 years) with community acquired UTI, who presented in the emergency department of our medical school from 2000 - 2002, urine cultures were performed. Inclusion criteria were: acute voiding symptoms, significant bacteriuria with growth of at least 10 (5) colony-forming units/ml urine, leukocyturia > 50/ micro l. Exclusion criteria were underlying renal diseases, anatomic abnormalities of the urinary tract, age < 2 months and recurrent UTI. RESULTS: Patients presented with a mean rectal temperature of 38.6 +/- 1.3 degrees C, mean CRP of 66 +/- 68 mg/dl, mean WBC 13 500 +/- 5 600/ micro l and mean urinary leukocytes of 425 +/- 363/ micro l. In urine cultures E. coli was found in 47 % of the cases, Enterococcus faecalis 23 %, Proteus mirabilis 8 %, Klebsiella oxytoca 4 %, Pseudomonas aeruginosa 5 % and others 13 %. In 76 % one and in 24 % two different bacterial species (60 % Enterococcus faecalis) were cultured. Mean resistance rates were in all bacteria (in E. coli): Ampicillin 53 % (69 %), Ampicillin and Sulbactam 51 % (61 %), Cefalosporin 1 (st) generation (Cefaclor) 48 % (24 %), Cefalosporin 2 (nd) generation (Cefuroxim) 40 % (3 %), Cefalosporin 3 (rd) generation (Cefuroxim) 33 % (0 %), Tobramycin 30 % (2 %), Ciprofloxacine 0 %, Cotrimoxazole 40 % (42 %), Nitrofurantoin 12 % (0 %). CONCLUSION: The resistance rates to Ampicillin (+/- Sulbactam) did not increase as compared to previous analyses (1990 - 1995), however, resistance rates to Cotrimoxazole and 1 (st) generation Cefalosporines increased about 20 %. We conclude that the policies for treatment of UTI in children should be re-evaluated every 5 years according to local resistance rates.

Cyclosporine in pediatric kidney transplantation.

Before the era of cyclosporine (CsA), immunosuppression with azathioprine and steroids resulted in high rejection rates and severe growth retardation in pediatric renal transplant recipients. In the early 1980s, immunosuppression with CsA was introduced for children. Because of differences in metabolism rates and relation of weight and body surface area, special pediatric dosing regimens and monitoring strategies had to be developed. Use of CsA led to a decreased number of acute rejections and, consequently, to a marked increase in graft survival rates. The growth rates of transplanted children were significantly higher under CsA-based immunosuppression than with classical regimens. This was due to a decreased need of steroid co-administration. Main side effects of CsA in children were nephrotoxicity and hirsutism. The introduction of CsA microemulsion in the 1990s led to more reliable absorption profiles and to a lower interindividual variability of CsA area-under-the-curve concentrations and thus to another improvement in rejection rates. New monitoring strategies, based on CsA levels taken 2 hours' postdose, seem promising. In pediatric transplantation, CsA is often successfully combined with an antibody-induction therapy in order to reduce the number of early acute rejections. Combination with mycophenolate mofetil reduces the appearance of chronic rejection. Additional therapy with ToR inhibitors might enforce a reduction of CsA doses and therefore lead to a reduction of CsA toxic effects.

A single center clinical experience in intensive care management of 104 pediatric renal transplantations between 1998 and 2002.

Only a few publications about the treatment in the intensive care unit (ICU) after pediatric renal transplantation have been published yet. As there are no guidelines, we hereby describe the results and recommendations of our transplant unit. A total of 104 renal transplantations have been performed in 96 children at our center since 1998. The age of the children has ranged from 6 months to 18 yr and their body weight from 6 kg to 110 kg. A special fluid management was performed in order to avoid hypotension and hypoperfusion of the graft. Systolic arterial pressure was kept at elevated levels above 100 mmHg during the first day after transplantation. The children remained on the respirator for 4-8 h after transplantation. Anticoagulation was performed using low dose heparin because of the size mismatch of the anastomosed vessels. The mean time in the ICU for the pediatric patients aged <3 yr was 2 days and for children older than 3 yr was 1 day. The main complications after renal transplantation in the ICU were disorders of electrolytes, acute renal failure because of a non-functioning graft (12%), bleeding from the anastomoses (4%), arterial or venous thrombosis (1%), arterial hypertension and pulmonary edema, defined as radiographic evidence (1%). In case of non-function peritoneal- or hemodialysis were performed in the ICU. Young children were more frequently affected than older children. From 1998-2002 one patient died during the ICU time. The 3 yr graft survival rate was 90%. To sum up, children undergoing renal transplantation should be treated in a specialized unit postoperatively to avoid early non-functioning of the graft and extrarenal complications. General guidelines for postoperative care should be established.

Pro-inflammatory cytokines up-regulate MUC1 gene expression in oral epithelial cells.

The membrane-bound mucin MUC1 is expressed ubiquitously on epithelial surfaces and is thought to provide protection from bacterial and chemical injury. The present study was undertaken to determine whether MUC1 was expressed in cultured oral epithelial cells and whether expression is modulated by pro-inflammatory mediators released as part of the host response to infection by oral pathogens. Northern and Western blotting experiments showed that KB cells express MUC1 mRNA and protein. When cells were treated with interleukins (IL-1beta, IL-6), tumor necrosis factor-alpha (TNF-alpha), or interferon-gamma (IFN-gamma), or combinations of these, real-time PCR demonstrated that MUC1 mRNA increased 1.4- to 3.2-fold. Interestingly, a significant increase in levels of MUC1 protein was also observed. While no effect was observed when KB cells were incubated with LPS from Porphyromonas gingivalis, infection of KB monolayers with this oral pathogen caused a 2.85-fold increase in MUC1 transcript levels. These results suggest that increased MUC1 synthesis may be a key element in the host response to infection with oral pathogens.

Alterations of cyclosporin A metabolism induced by mycophenolate mofetil.

Unexpectedly lower CsA 2-h levels were found in patients who received additional immunosuppression by MMF in our center. The aim of this study is to prove whether there are differences in CsA metabolization when MMF is added to treatment. In 33 children who received an immunosuppression of prednisolone and CsA as well as in 15 children who were treated with additional MMF, C2 and C0 were taken. In 11 children, full AUC of CsA were obtained. C2 levels differed significantly (p < 0.05) between patients treated with (617 +/- 230 ng/mL) and without MMF (750 +/- 271 ng/mL) but with similar CsA dosages. C2 correlated better with the AUC than CsA levels at other time points with r = 0.95. The equation AUC = 139 + 6.17 x C2 was calculated to match best in a C2-limited sampling strategy. This formula proved to be safer than equations that had been published before. According to our findings, we suspect that MMF alters the CsA metabolism. When MMF is used in pediatric transplant recipients, either target values of CsA have to be changed or patients may require higher doses of CsA.

MG2 and lactoferrin form a heterotypic complex in salivary secretions.

Protein-protein interactions are necessary for homeostasis to be maintained and for biological systems to be integrated. Heterotypic complexes occur in saliva, and a complex between MG2 and SIgA has been suggested to promote microbial clearance from the oral cavity. In this study, we used a peptide display library to investigate previously unrecognized heterotypic complexes involving MG2 and other proteins. The library was panned with MG2 12 times, and analyses of clones identified the sequence Ala-Leu-Leu-Cys-, which occurs in salivary lactoferrin. Blotting experiments confirmed that MG2 and lactoferrin form a heterotypic complex in vitro and in vivo. Periodate treatment of MG2 did not affect the interaction. A synthetic lactoferrin peptide containing the motif Ala-Leu-Leu-Cys-blocked the interaction between MG2 and lactoferrin, confirming the specificity of the interaction identified by panning. This complex may enhance the properties of these salivary components in the oral environment.

Cyclosporin A monitoring by 2-h levels: preliminary target levels in stable pediatric kidney transplant recipients.

Clinical trials in adults have shown that management of transplanted patients with cyclosporin A (CsA) 2-h levels (C2) lead to superior outcome compared with monitoring of 12-h trough levels (C0). In both adults and children, C2 levels enabled a better estimation of the area under the curve concentration than C0 levels. Therefore, it can be suspected that C2 monitoring might also lead to a better outcome in children. Until now C2 target levels for children have not been defined. We measured C2 levels in 101 stable pediatric kidney recipients with a minimum time of 1 yr after transplantation. C2 levels were compared with changes in glomerular filtration rate (GFR) 6 months later. Median C2 levels in children after renal transplantation were 714 ng/mL (95% confidence interval 654-774). Patients with C2 levels below 750 ng/mL had a significantly higher percentage of decline in GFR than patients with C2 levels above 750 ng/mL (p < 0.05). In children with C2 levels below 500 ng/mL three acute rejections occurred in comparison with no rejection in the remaining patients (p < 0.05). We conclude that the lower C2 target level should be above 750 ng/mL in stable pediatric transplant recipients. An upper target level above 1000 ng/mL should be avoided. The question, whether C2 monitoring in pediatric kidney recipients is superior to C0 monitoring, is yet to be answered.

The beta2-microglobulin/cystatin C ratio--a potential marker of post-transplant lymphoproliferative disease.

BACKGROUND: As a consequence of more intensified immunosuppression, post-transplant lymphoproliferative disease (PTLD) is increasingly observed in patients after solid-organ transplantation. Beta2-microglobulin, a low-molecular weight protein (MW 11.8 kDa), is produced by all nucleated cells as part of the HLA complex. Its serum concentration is directly correlated with prognosis in patients with lymphatic neoplasms. Like other low-molecular weight proteins, beta2-microglobulin is eliminated by glomerular filtration. This complicates its use as a tumor marker in renal insufficiency. Cystatin C, a low-molecular weight protein of 13.3 kDa, is a new marker of kidney function largely unaffected by extrarenal disease. We, therefore, sought to assess the potential of the beta2-microglobulin/cystatin C ratio (beta2M/Cys) as a marker of lymphoproliferation. PATIENTS AND METHODS: Beta2M/Cys was determined by particle-enhanced immunonephelometry in sera from 132 children with different degrees of renal insufficiency, 5 of whom had lymphoproliferative disease. Renal function was assessed using the Schwartz formula. RESULTS: Beta2M/Cys was constant between 1.2 and 2.4 mg/mg for Schwartz GFR > or = 40 ml/min x 1.73 m2. With lower GFR, beta2M/Cys rose progressively, maximum values being found in the hemodialysis patients (4.85-11.73). Healthy renal transplant recipients had beta2M/Cys comparable to controls. With acute lymphoproliferative disease, all but one patient had significantly elevated beta2M/Cys between 2.68 and 3.68 mg/mg, which returned to normal in remission (1.67-2.35 mg/mg). The sensitivity of a beta2M/Cys ratio > 2.4 mg/mg for the detection of PTLD was 80%, the specificity 100%, positive predictive value 100%, negative predictive value 90%. CONCLUSION: The beta2-microglobulin/cystatin C ratio is a promising parameter of lymphoproliferation in patients with normal or mildly impaired renal function.