Dietlinde Fuchs

Renal function in long-term survivors of stem cell transplantation in childhood. A prospective trial

The aim of this prospective study was to assess glomerular and tubular renal function before, and 1 and 2 years after hematological stem cell therapy (HSCT) in children and adolescents. 137 consecutive patients undergoing HSCT, for malignant diseases, were included in a prospective trial. Forty-four patients were followed for up to 1 year after HSCT and 36 for up to 2 years, without relapse. Ninety healthy school children were used as a control group. The following parameters were investigated: inulin clearance (GFR), urinary excretion of albumin, α1-microglobulin (α1-MG), calcium, β-N-acetylglucosaminidase (β-NAG) and Tamm–Horsfall protein (THP), tubular phosphate reabsorption (TP/Clcr) and percent reabsorption of amino acids (TAA). Significantly lower GFR was found 1 and 2 years after HSCT but within the normal range in the period before HSCT. There was no correlation between GFR within the first month after HSCT and long-term outcome of GFR. Tubular dysfunction was found in 14–45% of patients 1 and 2 years after HSCT depending on the parameter investigated. Pathological values 1 and 2 years after HSCT were found for α1-MG excretion in 40% and 39%, respectively, for TP/Clcr in 44% and 45%, for β-NAG in 26% and 19%. Median TP/Clcr was significantly lower 2 years after HSCT than before. TAA was mildly impaired in 7/14 patients before, in 5/29 one and in 9/29 2 years after HSCT, but median TAA was within normal range at all times. The median excretion of albumin, THP and calcium was within the normal range at all investigations. No influence of ifosfamide pre-treatment on the severity of tubulopathy was found. The investigation of tubular renal function should be part of a long-term follow-up in children after HSCT. Bone Marrow Transplantation (2001) 27, 319–327.

Procalcitonin, C-reactive protein, and endotoxin after bone marrow transplantation: identification of children at high risk of morbidity and mortality from sepsis

Summary:We prospectively evaluated the capacity of serum procalcitonin (PCT), compared with serum levels of C-reactive protein (CRP) and endotoxin, to identify children at high risk for mortality from sepsis after BMT. Of 47 pediatric bone marrow transplantation patients studied, 22 had an uneventful course post-transplant (Group 1), 17 survived at least one septic event (Group 2), and eight died from multiorgan failure (MOF) following septic shock (Group 3). Median concentrations of PCT over the course of the study were 1.3, 15.2, and 102.8 ng/ml, respectively, in each of the three groups (P<0.002 for each comparison). Median concentrations of CRP were 91, 213, and 260 mg/l, respectively (P<0.001 for Group 1 vs Group 2 and Group 3; P=NS for Group 2 vs Group 3). Median concentrations of endotoxin were 0.21, 0.30, and 0.93 U/l, respectively (P=NS for each comparison). Median concentrations of PCT, in contrast to serum CRP and endotoxin, correlated with the severity of sepsis (8.2 ng/ml in ‘sepsis’ and 22.3 ng/ml in ‘severe sepsis’, P=0.028) and provided useful prognostic information during septic episodes.

US and MRI of gastrointestinal graft-versus-host disease

Abstract. Abdominal problems often complicate the clinical course after bone marrow transplantation. Graft-versus-host disease occurs as a complication of allogenic bone marrow transplantation. In this report, the findings of intestinal involvement are described and correlated with histopathological findings. Increased bowel-wall thickness and increased vascularity were shown by US. MRI demonstrated generalised increased bowel-wall thickness associated with bowel-wall enhancement after administration of IV gadolinium.

Renal function after conditioning therapy for bone marrow transplantation in childhood

The knowledge of renal function in the course of BMT is poor. We prospectively investigated glomerular and tubular function in 42 children who underwent BMT because of malignancy. Seventeen children were transplanted autologously. Investigations were performed before and immediately after the conditioning regimen. Inulin and creatinine clearance, albuminuria, urine excretion of alpha 1-microglobulin, beta-N-acetylglucosaminidase, alanine-aminopeptidase, intestinal alkaline phosphatase, and Tamm-Horsfall-Protein as well as sodium- and phosphatreabsorption were measured. The patients were classified regarding use of total body irradiation (tTBI) in the conditioning regimen. BEFORE CR: Glomerular filtration rate (GFR) was not influenced by the underlying diagnosis or previous treatment. Mean GFR was elevated compared with the reference group. Microalbuminuria was elevated in 15% of patients, and mean levels were higher than in the reference group. Proximal tubular dysfunction was indicated by an elevated excretion of alpha 1-MG in 54%, of beta-NAG in 66%, of AAP in 40%, and of IAP in 47%. Fractional sodium excretion was abnormal in 21%, phosphate reabsorption in 5% and THP-excretion in 7% of the patients. AFTER CR: Creatinine clearance was not affected by CR. After CR alpha 1-MG, beta-NAG, FENa, AAP, and IAP were increased compared with values before CR. TP/Clcr was decreased. Excretion of THP was not altered by CR. In patients without fTBI there was a greater increase in alpha 1-MG excretion and decrease in phosphate reabsorption after CR compared with patients conditioned with fTBI. We conclude that significant proximal tubular dysfunction is present in about 50-60% of patients before and in nearly all alter CR. Distal tubular function was less severely affected. Severity of nephrotoxicity after CR did not correlate with pre-existing abnormalities.

Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML

Insulin-like growth factor binding protein (IGFBP)-2 has mitogenic effects in normal and neoplastic cells. The purpose of this study is to examine the diagnostic and prognostic significance of elevated IGFBP-2 levels in children with AML after hematopoietic stem cell transplantation (HSCT) at relapse and continuous complete remission (CCR). In 27 children with AML (mean age 13.6±5.3 years; patients in remission n=15 with relapse n=12) serum parameters of IGFBP-2, IGFBP-3, IGF-I and IGF-II were analyzed up to 18 months after HSCT by RIA. AML-patients with evidence of relapse demonstrated a continuous increase of IGFBP-2 levels during the follow-up. At day 100 after HSCT, IGFBP-2 concentrations were significantly higher in patients with relapse than in children without relapse (7.4±4.0 standard deviation score (SDS) vs 3.9±1.7 SDS; P=0.01). Serum IGFBP-2 was identified as an independent factor for the prediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 >4.5 SDS at day 100 after HSCT was 31% compared to patients with IGFBP-2 <4.5 SDS was 72% (P=0.004). Patients with IGFBP-2 concentration up to 4.5 SDS more likely developed a relapse and had a poorer outcome. Identification of these patients allows a more individualized and aggressive adjuvant treatment and follow-up.

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Cyclosporin A (CsA) can induce graft-versus-host disease (GVHD) following autologous bone marrow transplantation (ABMT) and autologous peripheral blood stem cell transplantation (APBSCT) in adults. We investigated whether GVHD can be induced following ABMT and APBSCT in childhood, and which cells are involved in the pathogenesis of this syndrome. We conducted a prospective study of 20 children and adolescents with hematological malignancies receiving CsA after ABMT and APBSCT. Skin biopsies were obtained on day 21 after transplantation or in the event of a rash. Immunophenotypic analysis of peripheral blood lymphocytes was performed on days 14, 21, 28 and 60 after transplantation. Clinical GVHD of the skin, confirmed by histological criteria, occurred in five patients. Five patients had no clinical GVHD but had acute GVHD alterations on routine skin biopsy. In all 10 patients with a positive skin biopsy for GVHD, CD4+ lymphocytes were the predominant cells in the epidermis. Immunophenotypic analysis of peripheral blood lymphocytes revealed a significantly increased CD4/CD8 ratio in patients with a positive skin biopsy (P < 0.01). our findings indicate that it is possible to induce acute gvhd following abmt and apbsct in childhood. in addition, cd4+ lymphocytes play an important role in the pathogenesis of CsA-induced GVHD.

Blutselengehalte nach Konditionierung sowie im Verlauf der Knochenmarktransplantation bei Kindern mit malignen Erkrankungen

Summary□Patients and Results: Prior to bone marrow transplantation (BMT), at the end of the conditioning phase, we found in 42 investigated children with malignant diseases subnormal lowered plasma- and blood selenium levels. Parallel to the diminished selenium status the plasma glutathione peroxidase activity (Gpx) was not reduced as it is in selenium deficiency, but markedly elevated and probably reflecting cytolytic processes. In the group of combined conditioning (fractionated total body irradiation plus chemotherapy) we found significantly more elevated plasma Gpx values in comparison to the only-chemotherapy group. The renal selenium excretion was elevated during the whole observation and could be caused by disturbed tubular function.□ Conclusion: We conclude, that in the situation of BMT a selenium substitution in a dosage of at least 1 to 2 µg Se/kg/d is necessary. Patients’ selenium status should be monitored by analyses of plasma-and blood selenium contents.

Complete Recovery of Renal Fuction in a Wilms’ Tumor Patient After Acute Renal Failure Caused by Autologous Bone Marrow Transplantation (ABMT)

An autologous bone marrow transplantation (ABMT) was carried out on a 4-year-old boy following the second pulmonary relapse of a nephroblastoma. Glomerular and tubular function of the remaining kidney before ABMT was normal. Etoposide, carboplatin, and melphalan were used in the conditioning regimen. The patient developed acute renal failure (ARF), and hemodialysis was required for 3 weeks. The situation was further complicated by his requiring mechanical ventilation for 12 days. Today, the patient is in good general health and in stable remission 32 months after bone marrow transplantation. This report shows that even serious tubular and glomerular dysfunction may be completely reversible in children. The background for high-dose chemotherapy with ABMT or stem cell rescue is discussed.

Hämophagozytische Lymphohistiozytose bei 3 Kindern

ZusammenfassungHintergrund. Das klinische Bild der sekundären hämophagozytischen Lymphohistiozytose (HLH) ist geprägt durch hohes Fieber und Hepatosplenomegalie, seltener Lymphknotenvergrößerung, Exantheme, Pleuraerguss oder Aszites. An Laborkriterien finden sich Zytopenien, Hyperferritinämie (>1000 ng/ml), Erhöhung der LDH oder eine Hypertriglyzeridämie und eine Hypalbuminämie. Im Knochenmark werden aktivierte Makrophagen und eine Hämophagozytose gesehen. Das Krankheitsbild wird meist durch Infektionen mit Viren, v. a. Epstein-Barr-Viren, Bakterien oder Protozoen, z. B. Malaria, ausgelöst. Diese führen zu einer Aktivierung von Lymphozyten und Makrophagen und nachfolgend zu einer massiven Ausschüttung von proinflammatorischen Zytokinen (“Zytokinsturm”) und Ferritin. Trotz intensiver Therapie ist die HLH mit einer Letalität zwischen 30 und 50% belastet. Fallbericht. Es wird über 3 Kinder mit einer HLH berichtet. Bei einem 5-jährigen Jungen trat die Erkrankung als Manifestation eines EBV-infizierten, großzellig anaplastischen Lymphoms (so genanntes Ki-1-Lymphom) auf, bei der 2. Patientin als letal verlaufende perakute Sepsis nach korrekt antibiotisch behandelter Harnwegsinfektion durch Enterokokken. Beim 3. Patienten wurde die HLH im Rahmen einer Osteomyelitis beobachtet. Diskussion. Bei der hämophagozytischen Lymphohistiozytose handelt es sich um ein Makrophagenaktivierungssyndrom, an das in allen Fällen von “septischen Zuständen unklarer Genese” unbedingt gedacht werden sollte, v. a., wenn diese mit einem Abfall von Leukozyten oder Thrombozyten einhergehen. Dabei hat sich Ferritin als globaler Marker der Makrophagenaktivierung als nützlicher diagnostischer Parameter erwiesen.AbstractBackground. The clinical presentation of secondary hemophagocytic lymphohistiocytosis (HLH) is characterized by high fever, hepatosplenomegaly and more rarely by lymph node enlargement, exanthema, pleural effusion or ascites. Laboratory studies demonstrate cytopenias, hyperferritinemia (>1000 ng/ml), elevation of LDH or hypertriglyceridemia and hypalbuminemia. Bone marrow examination reveales activated macrophages and hemophagocytosis. The disease is commonly associated with infections caused by viruses, especially Epstein-Barr-virus, bacteria or protozoa, for instance malaria. These infections lead to an activation of lymphocytes and macrophages and afterwards to an excessive release of proinflammatory cytokines (“cytokine storm”) and ferritin. Despite intensive therapy mortality rate of HLH is between 30% and 50%. Case report. We report three children with HLH. A 5-year-old boy developed the disease as manifestation of an EBV-infected large cell anaplastic lymphoma (Ki-1 lymphoma), a second female patient as lethally occurring peracute sepsis after properly treated urinary tract infection by Enterococci with antibiotics. HLH was observed in a third child during osteomyelitis. Discussion- HLH is a macrophage-activation syndrome, that should be seriously considered in all cases of “septic conditions of unknown origin”, especially if associated with reduction of leukocytes and thrombocytes. Ferritin has proved as a global marker of macrophage activation and therefore as a useful and rapid available diagnostic parameter.

Comparison of Allogeneic and Autologous Bone Marrow Transplantation for Treatment of Childhood Acute Myeloblastic Leukemia (AML) in First Complete Remission

The goal of treatment of acute myeloblastic leukemia (AML) in children is cure. Treatment results in AML have considerably improved during the last decade [5]. Remission induction therapy has become increasingly successful, and approximately 70 to 80% of children achieved complete remission (CR). However, despite consolidation, intensification and maintenance therapy, relapses have become, at least for a certain group of children, the limiting factor in the efforts to increase the event-free-survival rate.