Biomedical subjects
Publications and source records attributed to Christoph Licht.
Bordetella holmesii is a rare cause of human infection, mainly in the immunocompromised host, and is associated with bacteremia, respiratory tract infection and endocarditis. Herein, we describe a patient with severe relapse of nephrotic syndrome associated with bacteremic B. holmesii pneumonia.
MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease. It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3. Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress.
Atypical hemolytic uremic syndrome (HUS) is a severe disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent evidence has shown that defective complement activation and defective complement control is a cause of HUS. So far, mutations in single genes coding for the cofactor and complement regulator factor H, the membrane cofactor protein (MCP/CD46), the serine protease factor I, and autoantibodies to factor H have been linked to HUS. All of these proteins affect the same enzyme the alternative pathway convertase C3bBb. This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage.
Atypical hemolytic uremic syndrome is a disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations in the complement regulator factor H are associated with the inherited form of the disease, and >60% of the mutations are located within the C terminus of factor H. The C-terminus of factor H, represented by short consensus repeat 19 (SCR19) and SCR20, harbors multiple functions; consequently, this study aimed to examine the functional effects of clinically reported mutations in these SCR. Mutant factor H proteins (W1157R, W1183L, V1197A, R1210C, R1215G, and P1226S) were recombinantly expressed and functionally characterized. All six mutant proteins showed severely reduced heparin, C3b, C3d, and endothelial cell binding. By peptide spot analyses, four linear regions that are involved in heparin, C3b, and C3d binding were localized in SCR19 and SCR20. A three-dimensional homology model of the two domains suggests that these four regions form a common binding site across both domains. In addition, this structural model identifies two types of residues: Type A residues are positioned on the SCR surface and are represented by mutants W1157R, W1183L, R1210C, and R1215G; and type B residues are buried within the SCR structure and affect mutations V1197A and P1226S. Mutations of both types of residue result in the same functional defects, namely the reduced binding of factor H to surface-attached C3b molecules and reduced complement regulatory activity at the cell surfaces. The buried type B mutations seem to affect ligand interaction of factor H more severely than the surface-exposed mutations.
Quantitative or functional deficiency of complement factor H results in uncontrolled complement activation. This leads to thrombotic microangiopathy and finally causes renal failure (atypical hemolytic uremic syndrome [aHUS]). By regular analysis of factor H in patients with aHUS, the authors found a complete factor H deficiency in an infant in whom aHUS developed at 8 months of age. Factor H was quantified by enzyme-linked immunosorbent assay and further analyzed by Western blot using a factor H-specific antibody. Complement activation was determined by measuring total hemolytic activity of the classical (CH50) and alternative (APH50) pathways, C3 and C3d. The sequence of factor H gene was determined. Serial factor H measurements after fresh frozen plasma infusion allowed calculation of a factor H half-life. Factor H was absent in plasma (<1 mug/mL), and the complement system was highly activated (CH50, APH50, C3 decreased; C3d increased). Genetic analysis identified a novel homozygous factor H mutation (T2770A; Y899Stop) in CCP domain 15, most likely causing defective protein secretion. Time course measurements of factor H after plasma infusion established a factor H half-life of about 6 days. By repetitive plasma infusions (20 mL/kg over about 2 to 3 hours) the authors were able to interrupt the vicious circle of thrombotic microangiopathy in a factor H-deficient patient with aHUS. Based on the measured factor H half-life of about 6 days, regular plasma infusions in 2-week intervals were given, which prevented further aHUS episodes and stopped the decline of kidney function.
BACKGROUND: Reactivation of polyomavirus is a known reason for severe renal dysfunction in adult renal transplant recipients. Testing for polyomavirus DNA in plasma has been described as a sensitive and specific method to discover viral nephropathy in adult patients. We were now interested in polyomavirus status in a pediatric patient setting. METHODS: Plasma and urine samples were obtained from 80 children including 38 children after renal transplantation (group 1), 7 children with different kidney diseases receiving immunosuppressive treatment (group 2) and 35 children with different kidney diseases not receiving immunosuppressive treatment (group 3). A nested polymerase chain reaction method was used for amplification of polyomavirus DNA fragments. Differentiation between JC and BK virus was done by digestion with restriction endonucleases. RESULTS: Polyomavirus DNA was detected in the urine sample of 19 of 38 (50%) renal transplant recipients (group 1), of 1 of 7 (14%) patients from group 2 and in none of the 35 patients of group 3. Plasma samples from 3 (8%) of group 1 patients and from 1 child each of group 2 (14%) and group 3 (3%) were tested positive for polyomavirus DNA. CONCLUSION: Urinary polyomavirus excretion seems to be more frequent in pediatric patients with kidney diseases receiving immunosuppressive treatment and after renal transplantation than in children with various kidney diseases without immunosuppressive treatment.
Endothelin-1 (ET-1) plays an important role in tissue remodelling and fibrogenesis by inducing synthesis of collagen I via protein kinase C (PKC). ET-1 signals are transduced by two receptor subtypes, the ETA- and ETB-receptors which activate different Galpha proteins. Here, we investigated the expression of both ET-receptor subtypes in human primary dermal fibroblasts and demonstrated that the ETA-receptor is the major ET-receptor subtype expressed. To determine further signalling intermediates, we inhibited Galphai and three phospholipases. Pharmacologic inhibition of Galphai, phosphatidylcholine-phospholipase C (PC-PLC) and phospholipase D (PLD), but not of phospholipase Cbeta, abolished the increase in collagen I by ET-1. Inhibition of all phospholipases revealed similar effects on TGF-beta1 induced collagen I synthesis, demonstrating involvement of PC-PLC and PLD in the signalling pathways elicited by ET-1 and TGF-beta1. ET-1 and TGF-beta1 each stimulated collagen I production and in an additive manner. ET-1 further induced connective tissue growth factor (CTGF), as did TGF-beta1, however, to lower levels. While rapid and sustained CTGF induction was seen following TGF-beta1 treatment, ET-1 increased CTGF in a biphasic manner with lower induction at 3 h and a delayed and higher induction after 5 days of permanent ET-1 treatment. Coincidentally at 5 days of permanent ET-1 stimulation, a switch in ET-receptor subtype expression to the ETB-receptor was observed. We conclude that the signalling pathways induced by ET-1 and TGF-beta1 leading to augmented collagen I production by fibroblasts converge on a similar signalling pathway. Thereby, long-time stimulation by ET-1 resulted in a changed ET-receptor subtype ratio and in a biphasic CTGF induction.
OBJECTIVE: The main rationale behind the continuous analgesia/sedation currently practiced in the treatment of neonates with severe respiratory failure in intensive care is an attempt at shielding the sick newborn from exogenous stress and pain caused by diagnostic and therapeutic interventions. Until now, however, the factors which influence endogenous, disease-related distress have been largely ignored. METHOD: We retrospectively studied the daily need for analgesics and sedatives (fentanyl, midazolam, pentobarbital, thiopental) of 40 full-term newborns with severe respiratory failure who had been ventilated for at least 48 h over an observational period of 2-5 days. Dosing of the analgesics and sedatives was based on a neonatal sedation score for ventilated infants. These daily amounts were converted to a normative comparative dose (analgesic/sedative need = ASN) and compared with the oxygenation index (OI) as a measure of the degree of pulmonary insufficiency. RESULTS: Depending on the duration of ventilation, an increasingly close correlation between the ASN and the OI was detected: the index of correlation (r) was detected to be 0.65 on the second day, but increased up to 0.94 after 5 days. The subgroup of patients who had been ventilated for more than 3 days (n = 8) consistently showed a very high correlation, ranging from r = 0.86 to r = 0.94. CONCLUSION: Our results indicate a direct relationship between severity of pulmonary failure (expressed as OI) and degree of disease-related distress (reflected by ASN). This supports the hypothesis that in full-term neonates under mandatory intensive care for severe respiratory failure, endogenous distress caused by the primary disease itself, in addition to exogenous distress caused by therapeutic and diagnostic interventions, is key factor for the determination of the required amount of analgesic and sedative drugs.
BACKGROUND: Chronic metabolic acidosis leads to an increase in NHE3 activity that is mediated by endothelin-1 (ET-1) expression and activation of the proximal tubule endothelin B receptor. Chronic metabolic acidosis increases preproET-1 mRNA abundance in kidney cortex, but the cell responsible has not been identified. METHODS: PreproET-1 mRNA abundance was quantified by competitive reverse transcription-polymerase chain reaction (RT-PCR) on tissue harvested from control rats or rats in which chronic metabolic acidosis was induced by addition of NH(4)Cl to the drinking water. RESULTS: Chronic metabolic acidosis leads to an increase in preproET-1 mRNA expression in kidney cortex, proximal tubules, and glomeruli. The increase in preproET-1 expression correlates with the decrease in blood [HCO3(-)]. ET-1 expression is also increased by acidosis in abdominal aorta, but not in cardiac muscle. CONCLUSION: In the renal proximal tubule, chronic metabolic acidosis induces an increase in preproET-1 expression, providing a mechanism for autocrine regulation of proximal tubule NHE3 activity. This response is not unique to the proximal tubule cell, but is also not ubiquitous.
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are now considered to be variants of one single syndrome called thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Key features are thrombocytopenia, hemolytic anemia, and subsequently impaired function of different organs, especially the kidneys and the central nervous system (CNS). One possible reason is the deficiency of von Willebrand factor-cleaving protease (vWF-CP) resulting in persistence of uncleaved, ultralarge von Willebrand factor multimers (ULvWFM). METHODS: We report a patient who was initially diagnosed with Evans syndrome (hemolytic anemia and autoimmune thrombocytopenia) as infant. At 10 years of age he developed HUS-like disease with gastrointestinal tract infection, hemolytic anemia, thrombocytopenia,and acute renal failure. However, enteropathogenic Escherichia coli-like or Shiga-like toxins were not detected. RESULTS: Further investigations revealed severe deficiency (<3%; normal >40%) of vWF-CP activity caused by compound heterozygosity of two novel ADAMTS13 gene mutations (1170 G>C [W390C] and 3735 G>A [W1245X]. vWF-CP autoantibodies were not detected. Periodic (every 2 weeks) treatment with fresh frozen plasma (FFP) maintained both platelet level and kidney function within normal range and prevented new episodes of TTP/HUS. CONCLUSION: Enteropathogenic E. coli- and Shiga-like toxin-negative patients who present with hemolytic or thrombocytopenic episodes and HUS like symptoms should be tested for vWF-CP deficiency and other noninfectious reasons for TTP/HUS since plasma substitution possibly provides an efficient therapeutic option for this subgroup of patients.
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We report a 12-year-old girl suffering from end-stage renal disease due to focal-segmental sclerosis and retardation of statomotoric and mental development of unknown origin. Renal transplantation (TX) was performed 7 months after initiation of peritoneal dialysis at the age of 11 years. Immunosuppressive therapy included cyclosporine A, mycophenolate mofetil and methylprednisolone. The patient developed spiking fever up to 40 degrees C without signs of infection 10 months after TX. Kidney function remained stable but ultrasound examination and CT-scan showed hypodense masses within both liver and spleen. Epstein-Barr virus (EBV) polymerase chain reaction (PCR) results with a high number of copies (20 x 10(6) copies/ml blood) against the background of a previous EBV infection (IgG positive, IgM negative) made the diagnosis of EBV-reactivation likely. Splenectomy was performed. Examination of the spleen showed EBV-associated polymorphic posttransplant lymphoproliferative disease (PTLD) with predominant B cell proliferation and monoclonal VH3-rearrangement of the IgG heavy chain locus. Therapy with acyclovir was introduced and immunosuppression was reduced. No rejection episode occurred. Body temperature normalized and the patient recovered over a 3-month period. EBV-PCR in plasma was negative (0.02 x 10(6) copies/ml blood) 12 weeks after reduction of immunosuppression. The liver masses completely resolved after 27 months. After a total follow-up of 36 months the child remains in good health.
The renal cortical collecting duct (CCD) plays an important role in systemic acid-base homeostasis. The beta-intercalated cells secrete most of the HCO(-)(3), which is mediated by a luminal, DIDS-insensitive, Cl(-)/HCO(-)(3) exchange. The identity of the luminal exchanger is a matter of debate. Anion exchanger isoform 4 (AE4) cloned from the rabbit kidney was proposed to perform this function (Tsuganezawa H et al. J Biol Chem 276: 8180-8189, 2001). By contrast, it was proposed (Royaux IE et al. Proc Natl Acad Sci USA 98: 4221-4226, 2001) that pendrin accomplishes this function in the mouse CCD. In the present work, we cloned, localized, and characterized the function of the rat AE4. Northern blot and RT-PCR showed high levels of AE4 mRNA in the CCD. Expression in HEK-293 and LLC-PK(1) cells showed that AE4 is targeted to the plasma membrane. Measurement of intracellular pH (pH(i)) revealed that AE4 indeed functions as a Cl(-)/HCO(-)(3) exchanger. However, AE4 activity was inhibited by DIDS. Immunolocalization revealed species-specific expression of AE4. In the rat and mouse CCD and the mouse SMG duct AE4 was in the basolateral membrane. By contrast, in the rabbit, AE4 was in the luminal and lateral membranes. In both, the rat and rabbit CCD AE4 was in alpha-intercalated cells. Importantly, localization of AE4 was not affected by the systemic acid-base status of the rats. Therefore, we conclude that expression and possibly function of AE4 is species specific. In the rat and mouse AE4 functions as a Cl(-)/HCO(-)(3) exchanger in the basolateral membrane of alpha-intercalated cells and may participate in HCO(-)(3) absorption. In the rabbit AE4 may contribute to HCO(-)(3) secretion.
OBJECTIVE: Insertion of percutaneous endoscopic gastrostomies (PEG) in patients on chronic peritoneal dialysis (PD) has been reported to be contraindicated due to an increased risk of morbidity and mortality. However, no systematic survey on this topic has yet been published. DESIGN: Retrospective multicenter study. SETTING: 23 pediatric dialysis units associated with the working group Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN). DATA SOURCE: A structured questionnaire on clinical details of PD patients who had undergone PEG insertion or open gastrostomy (OG) since 1994 was distributed to all pediatric dialysis units of the APN. RESULTS: 27 PD patients (20 males) from 12 centers in whom PEG insertion was performed after Tenckhoff catheter introduction were evaluated. Age at intervention ranged from 0.25 to 10.9 years (median 1.3 years). Most patients were malnourished, with standard deviation score (SDS) for body weight between -4.2 and -0.6 (median -2.2). Major complications were early peritonitis < 7 days after PEG in 10/27 (37%) patients, episodes of fungal peritonitis in 7/27 (26%) patients, 4 cessations of PD and change to hemodialysis, and 2 associated deaths. However, in 14 patients, no such problems were encountered and, in 4 patients, early peritonitis effectively treated with intraperitoneal antibiotics was the only major complication. Thus, in 18/27 (67%) patients, PD was successfully reinitiated shortly after PEG insertion. Among all participating centers, only two OG procedures were reported during the study period, illustrating a clear preference for the PEG over the OG procedure among members of the APN. CONCLUSION: PEG insertion following PD initiation carries a high risk for fungal peritonitis and potential PD failure; however, complication rates in this largest reported series were lower than previously described. Antibiotic and antifungal prophylaxis, withholding PD for 2 - 3 days, and gastrostomy placement by an experienced endoscopy team are suggested precautions for lowering the risk of associated complications. When gastrostomy placement does not occur prior to or at the time of initiating PD, the risks and benefits of percutaneous versus open placement must be carefully weighed.