Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic ...variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood.
We present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings.
We identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1–6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2–6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age.
In patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype.
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We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx).
This registry study collected data up to 10 years ...posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of serum bicarbonate concentration (HCO3−) < 22 mmol/l (metabolic acidosis) and HCO3− < 18 mmol/l (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome.
We report on 1911 patients, of whom 347 reached the composite end point. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio HR, 2.00; 95% confidence interval CI, 1.54–2.60) and severe metabolic acidosis (HR, 2.49; 95% CI, 1.56–3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR, 1.75; 95% CI, 1.32–2.31 and HR, 2.09; 95% CI, 1.23–3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio OR 0.93/yr older; 95% CI, 0.91–0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84–0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54–5.40)
The degree of metabolic acidosis is associated with allograft dysfunction.
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The tyrosine kinase inhibitor imatinib mesylate (STI571) is a potent therapeutic agent for treatment of chronic myeloid leukemia (CML) due to its specific inhibition of bcr-abl kinase. However, ...patients with CML always relapse after withdrawal of imatinib therapy. With CML being the paradigm for a stem cell disease, we sought to investigate the influence of imatinib on the most primitive stem cell compartment.
Imatinib has recently been reported to be a high affinity substrate for the ABC-transporters ABCG2/BCRP (breast cancer resistance protein) and MDR1 (P-Glycoprotein). Given the high expression of these ABC-transporters in Hematopoietic Stem Cells (HSC), we examined the influence of imatinib on ABCG2- and MDR1-activity in human and murine HSC by using Hoechst- and Rhodamine-efflux assays. MDR1-mediated Rhodamine-efflux was only mildly influenced by Imatinib. However, addition of imatinib at therapeutic dosages completely abrogated the SP phenotype of total bone marrow after Hoechst 33342 staining. This effect was even more pronounced in cells of the HSC-phenotype, i.e., lineage-negative/AC133+ or c-kit+/Sca-1+/lin− (KSL) of human and murine marrow, respectively. In order to determine the effect of imatinib on stem cells in vivo, we isolated SP cells from 13 CML patients at various stages of disease using FACS. We employed quantitative RT-PCR-analysis for bcr-abl and demonstrated that the majority of CML patients had bcr-abl-negative SP cells, while peripheral blood mononuclear cells were mostly bcr-abl-positive. However, two patients in complete cytogenetic and molecular-genetic remission proved to be bcr-abl-positive within the SP cell population. This supports the notion that continuous imatinib-therapy may not eradicate the malignant stem cell pool and the leukemic clone may be able to expand even during permanent imatinib-therapy.
Furthermore, these data imply that the detoxifying function of ABC transporters on stem cells may be altered under imatinib treatment. Using HEK-293 cells transfected with ABCG2, we demonstrate that imatinib reverses mitoxantrone-resistance - potentially due to high affinity substrate inhibition.
In summary, our data suggest the novel resistance mechanism of imatinib being actively extruded from primitive leukemic stem cells, and that addition of chemotherapeutic agents to imatinib therapy may facilitate the eradication of bcr-abl-positive stem cells in chronic myeloid leukemia.
Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years ...can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA.
Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES).
Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified.
Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation.
Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University ...Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.
Recently, the CPO Detect panel for the detection of carbapenemase-producing, Gram-negative bacteria was introduced for the Phoenix semi-automated antimicrobial susceptibility testing system. The CPO ...Detect assay aims to detect carbapenemase activity (P/N test) and to type carbapenemase producers according to the Ambler classification (Ambler test). The P/N test-based detection of carbapenemase producers was 100% sensitive and 55.3% specific in the assessment of 57 carbapenemase-producing and 38 non-carbapenemase-producing Enterobacterales. False-positive test isolates in the P/N test arose from carbapenemase-non-producing, but carbapenem-non-susceptible isolates. In contrast, using the Ambler test-based approach for carbapenemase detection resulted in a specificity of 100% and a sensitivity of 79%. In order to improve the overall performance, we established an algorithm that additionally included the colorimetric β-CARBA assay as downstream test for P/N test-positive isolates, which remained un-typed in the Ambler test. This algorithm displayed an overall sensitivity and specificity of 98.3% and 100%, respectively. Our data demonstrate that the combination of the CPO Detect assay with the β-CARBA test allows for rapid detection and classification of carbapenemase-producing Enterobacterales.
•The BD CPO Detect panel is an automated test for detection of carbapenemases.•It detects carbapenemases and additionally provides their Ambler classification.•We tested 57 and 38 Enterobacterales with and without carbapenemase production.•The overall sensitivity and specificity were 100% and 55.3%, respectively.•Applying the β-CARBA assay as downstream test significantly improved specificity.
Ceftazidime-avibactam is one of the last resort antimicrobial agents for the treatment of carbapenem-resistant, Gram-negative bacteria. Metallo-β-lactamase-producing bacteria are considered to be ...ceftazidime-avibactam resistant. Here, we evaluated a semi-automated antimicrobial susceptibility testing system regarding its capability to detect phenotypic ceftazidime-avibactam resistance in 176 carbapenem-resistant, metallo-β-lactamase-producing Enterobacterales and
isolates. Nine clinical isolates displayed ceftazidime-avibactam susceptibility in the semi-automated system and six of these isolates were susceptible by broth microdilution, too. In all nine isolates, metallo-β-lactamase-mediated hydrolytic activity was demonstrated with the EDTA-modified carbapenemase inactivation method. As zinc is known to be an important co-factor for metallo-β-lactamase activity, test media of the semi-automated antimicrobial susceptibility testing system and broth microdilution were supplemented with zinc. Thereby, the detection of phenotypic resistance was improved in the semi-automated system and in broth microdilution. Currently, ceftazidime-avibactam is not approved as treatment option for infections by metallo-β-lactamase-producing, Gram-negative bacteria. In infections caused by carbapenem-resistant Gram-negatives, we therefore recommend to rule out the presence of metallo-β-lactamases with additional methods before initiating ceftazidime-avibactam treatment.
Introduction: Treatment options for infections with carbapenem-resistant Enterobacterales are strongly limited. New antimicrobials are not effective against all types of carbapenemases. Therefore, ...rapid and reliable antimicrobial susceptibility testing and identification of the resistance mechanism are important.
Areas covered: We assess several methods to determine carbapenemase production of Enterobacterales in culture and discuss the value of the novel automated BD Phoenix CPO Detect (BDPCPO) panel for the detection and classification of carbapenemases.
Expert opinion: The meropenem minimum inhibitory concentration (MIC) range used in the BDPCPO panel includes the EUCAST screening breakpoint for the detection of carbapenemase producers. The phenotypic, inhibitor-based assay for detection of carbapenemase activity in the BDPCPO panel displays high sensitivity for carbapenemase detection while its specificity is modest. Therefore, confirmation testing of positive results is warranted. Nevertheless, implementing the BDPCPO panel has the potential to reduce time-to-result for detection and classification of carbapenemase producers.
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