Kidney replacement and conservative therapies in rhabdomyolysis: a retrospective analysis.

BACKGROUND: Toxic renal effects of myoglobin following rhabdomyolysis can cause acute kidney injury (AKI) with the necessity of kidney replacement therapy (KRT). Fast elimination of myoglobin seems notable to save kidney function and intensify kidney repair. Clinical data regarding efficacy of KRT in critical care patients with rhabdomyolysis and AKI are limited. This retrospective analysis aimed to identify differences between conservative therapy and different modalities of KRT regarding myoglobin elimination and clinical outcome. METHODS: This systematic, retrospective, single-center study analyzed 328 critical care patients with rhabdomyolysis (myoglobin > 1000 µg/l). Median reduction rate of myoglobin after starting KRT was calculated and compared for different modalities. Multivariate logistic regression models were established to identify potential confounder on hospital mortality. Filter lifetime of the various extracorporeal circuits was analyzed by Kaplan-Meier curves. RESULTS: From 328 included patients 171 required KRT. Health condition at admission of this group was more critical compared to patient with conservative therapy. Myoglobin reduction rate did not differ between the groups (KRT 49% [30.8%; 72.2%] vs. conservative treatment (CT) 61% [38.5%; 73.5%]; p = 0.082). Comparison between various extracorporeal procedures concerning mortality showed no significant differences. Hospital mortality was 55.6% among patients with KRT and 18.5% with CT (p < 0.001). Multivariate logistic regression model identified requirement for KRT (OR: 2.163; CI: 1.061-4.407); p = 0.034) and the SOFA Score (OR: 1.111; CI: 1.004-1.228; p = 0.041) as independent predictive factors for hospital mortality. When comparing specific KRT using multivariate regression, no benefit was demonstrated for any treatment modality. Life span of the extracorporeal circuit was shorter with CVVH compared to that of others (log-Rank p = 0.017). CONCLUSIONS: This study emphasizes that AKI requiring KRT following rhabdomyolysis is accompanied by high mortality rate. Differences in myoglobin reduction rate between various KRTs could not be confirmed, but CVVH was associated with reduced filter lifetime compared to other KRTs, which enable myoglobin elimination, too.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

The Genetic Cross-Talk between Periodontitis and Chronic Kidney Failure Revealed by Transcriptomic Analysis.

Periodontitis and chronic kidney failure (CKF) are potentially related to each other. This bioinformatics analysis aimed at the identification of potential cross-talk genes and related pathways between periodontitis and CKF. Based on NCBI Gene Expression Omnibus (GEO), datasets GSE10334, GSE16134, and GSE23586 were extracted for periodontitis. A differential expression analysis (p < 0.05, |log2(FC)| > 0.5) was performed to assess deregulated genes (DEGs). CKF-related genes were extracted from DisGeNET and examined regarding their overlap with periodontitis-related DEGs. Cytoscape was used to construct and analyze a protein-protein interaction (PPI) network. Based on Cytoscape plugin MCODE and a LASSO regression analysis, the potential hub cross-talk genes were identified. Finally, a complex PPI of the hub genes was constructed. A total of 489 DEGs for periodontitis were revealed. With the 805 CKF-related genes, an overlap of 47 cross-talk genes was found. The PPI network of the potential cross-talk genes was composed of 1081 nodes and 1191 edges. The analysis with MCODE resulted in 10 potential hub genes, while the LASSO regression resulted in 22. Finally, five hub cross-talk genes, CCL5, FCGR3B, MMP-9, SAA1, and SELL, were identified. Those genes were significantly upregulated in diseased samples compared to controls (p ≤ 0.01). Furthermore, ROC analysis showed a high predictive value of those genes (AUC ≥ 73.44%). Potentially relevant processes and pathways were primarily related to inflammation, metabolism, and cardiovascular issues. In conclusion, five hub cross-talk genes, i.e., CCL5, FCGR3B, MMP-9, SAA1, and SELL, could be involved in the interplay between periodontitis and CKF, whereby primarily inflammation, metabolic, and vascular issues appear to be of relevance.

Delta weight loss unlike genetic variation associates with hyperoxaluria after malabsorptive bariatric surgery.

The risk of enteric hyperoxaluria is significantly increased after malabsorptive bariatric surgery (MBS). However, its underlying determinants are only poorly characterized. In this case-control study, we aimed at identifying clinical and genetic factors to dissect their individual contributions to the development of post-surgical hyperoxaluria. We determined the prevalence of hyperoxaluria and nephrolithiasis after MBS by 24-h urine samples and clinical questionnaires at our obesity center. Both hyperoxaluric and non-hyperoxaluric patients were screened for sequence variations in known and candidate genes implicated in hyperoxaluria (AGXT, GRHPR, HOGA1, SLC26A1, SLC26A6, SLC26A7) by targeted next generation sequencing (tNGS). The cohort comprised 67 patients, 49 females (73%) and 18 males (27%). While hyperoxaluria was found in 29 patients (43%), only one patient reported postprocedural nephrolithiasis within 41 months of follow-up. Upon tNGS, we did not find a difference regarding the burden of (rare) variants between hyperoxaluric and non-hyperoxaluric patients. However, patients with hyperoxaluria showed significantly greater weight loss accompanied by markers of intestinal malabsorption compared to non-hyperoxaluric controls. While enteric hyperoxaluria is very common after MBS, genetic variation of known hyperoxaluria genes contributes little to its pathogenesis. In contrast, the degree of postsurgical weight loss and levels of malabsorption parameters may allow for predicting the risk of enteric hyperoxaluria and consecutive kidney stone formation.

Extended genomic HLA typing identifies previously unrecognized mismatches in living kidney transplantation.

Introduction: Antibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort. Methods: 103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as "donor-specific". Results: By two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10). Conclusion: Our results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors.

Prevalence of Dental Caries in Patients on Renal Replacement Therapy-A Systematic Review.

Patients under renal replacement therapy (RRT) often show oral problems, including dry mouth, periodontal and dental diseases. This systematic review aimed to evaluate the caries burden in patients on RRT. Therefore, a systematic literature search based on the databases PubMed, Web of Science and Scopus was performed by two independent individuals in August 2022. Search terms were: "caries" AND "dialysis", "caries" AND "renal replacement therapy", "caries" AND "kidney". The systematic process was complemented by manual search. Studies on adult patients (age ≥ 18 years), treated by any form of RRT and explicitly reporting caries prevalence or incidence were checked for their eligibility and subsequently analyzed qualitatively. For all included studies, a quality appraisal was applied. From the systematic search, 653 studies were identified, of which 33 clinical investigations were included in the qualitative analysis. The majority (31 studies) of all included patients underwent hemodialysis (HD), with a sample size between 28 and 512 participants. Eleven studies investigated a healthy control group. Oral examinations were heterogeneous across studies; the caries burden was primarily assessed by decayed-(D-T), missing- and filled-teeth index (DMF-T). The number of decayed teeth ranged between 0.7 and 3.87 across studies. Only six out of these 11 studies found significant differences in caries prevalence/incidence between RRT and controls, whereby only four studies confirmed worse caries burden in RRT individuals. No information was provided on caries stadium (initial caries, advanced caries, invasive treatment need), caries activity or location (e.g., root caries) across studies. Most of the included studies were assessed to be of moderate quality. In conclusion, patients on RRT suffer from a high prevalence of dental caries. Alongside a need for further research in the field, improved, multidisciplinary, patient-centered dental care concepts are required to support dental and overall oral health in individuals on RRT.

Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.

Background & Aims: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma. PLD most commonly develops in females, either as an extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) or as isolated autosomal-dominant polycystic liver disease (ADPLD). Despite known genetic causes, clinical variability challenges patient counselling and timely risk prediction is hampered by a lack of genotype-phenotype correlations and prognostic imaging classifications. Methods: We performed targeted next-generation sequencing and multiplex ligation-dependent probe amplification to identify the underlying genetic defect in a cohort of 80 deeply characterized patients with PLD. Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints. Results: Monoallelic diagnostic variants were identified in 60 (75%) patients, 38 (48%) of which pertained to ADPKD-gene variants (PKD1, PKD2, GANAB) and 22 (27%) to ADPLD-gene variants (PRKCSH, SEC63). Disease severity defined by age at waitlisting for liver transplantation and first PLD-related hospitalization was significantly more pronounced in mutation carriers compared to patients without genetic diagnoses. While current imaging classifications proved unable to differentiate between severe and moderate courses, grouping by estimated age-adjusted total liver volume progression yielded significant risk discrimination. Conclusion: This study underlines the predictive value of providing a molecular diagnosis for patients with PLD. In addition, we propose a novel risk-classification model based on age- and height-adjusted total liver volume that could improve individual prognostication and personalized clinical management. Lay summary: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe. However, it is currently difficult to predict clinical outcomes such as hospitalization, symptom burden, and need for transplantation in individual patients. In the current study, we aimed to investigate the clinical value of genetic confirmation and an age-adjusted total liver volume classification for individual disease prediction. While genetic confirmation generally pointed to more severe disease, estimated age-adjusted increases in liver volume could be useful for predicting clinical outcomes.

The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: A retrospective cohort study.

BACKGROUND: In nephrotic range proteinuria of adult-onset, kidney biopsy is the diagnostic gold standard in determining the underlying cause of disease. However, in low grade or subnephrotic proteinuria the diagnostic value of kidney biopsy as first-line diagnostics is less well established. METHODS: We conducted a retrospective analysis of all native kidney biopsies at our institution (n = 639) between 01/2012 and 05/2021 for comparison of histological diagnoses and clinical outcomes stratified by amount of proteinuria at the time of kidney biopsy: A: <300mg/g creatinine (low grade), B: 300-3500mg/g creatinine (subnephrotic), C >3500mg/g creatinine (nephrotic). RESULTS: Nephrotic range proteinuria was associated with the highest frequency (49.3%) of primary glomerulopathies followed by subnephrotic (34.4%) and low grade proteinuria (37.7%). However, within the subnephrotic group, the amount of proteinuria at kidney biopsy was linearly associated with renal and overall survival (HR 1.05 per Δ100mg protein/g creatinine (95% CI: 1.02-1.09, p = 0.001)) independent of present histological diagnoses and erythrocyturia. CONCLUSION: Frequency of primary glomerulopathies supports to perform kidney biopsy in patients with subnephrotic proteinuria. These patients have a substantial risk of ESKD and death upon follow-up. Therefore, diagnostic accuracy including histopathology is essential to guide personalized treatment and avert detrimental courses.

Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics.

BACKGROUND: Autosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance. METHODS: Next-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping. RESULTS: Three unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance. CONCLUSION: By this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

Myoglobin clearance with continuous veno-venous hemodialysis using high cutoff dialyzer versus continuous veno-venous hemodiafiltration using high-flux dialyzer: a prospective randomized controlled trial.

BACKGROUND: Myoglobin clearance in acute kidney injury requiring renal replacement therapy is important because myoglobin has direct renal toxic effects. Clinical data comparing different modalities of renal replacement therapy addressing myoglobin clearance are limited. This study aimed to compare two renal replacement modalities regarding myoglobin clearance. METHODS: In this prospective, randomized, single-blinded, single-center trial, 70 critically ill patients requiring renal replacement therapy were randomized 1:1 into an intervention arm using continuous veno-venous hemodialysis with high cutoff dialyzer and a control arm using continuous veno-venous hemodiafiltration postdilution with high-flux dialyzer. Regional citrate anticoagulation was used in both groups to maintain the extracorporeal circuit. The concentrations of myoglobin, urea, creatinine, ß2-microglobulin, interleukin-6 and albumin were measured before and after the dialyzer at 1 h, 6 h, 12 h, 24 h and 48 h after initiating continuous renal replacement therapy. RESULTS: Thirty-three patients were allocated to the control arm (CVVHDF with high-flux dialyzer) and 35 patients to the intervention arm (CVVHD with high cutoff dialyzer). Myoglobin clearance, as a primary endpoint, was significantly better in the intervention arm than in the control arm throughout the whole study period. The clearance values for urea and creatinine were higher in the control arm. There was no measurable albumin clearance in both arms. The clearance data for ß2-microglobulin and interleukin-6 were non-inferior in the intervention arm compared to those for the control arm. Dialyzer lifespan was 57.0 [38.0, 72.0] hours in the control arm and 70.0 [56.75, 72.0] hours in the intervention arm (p = 0.029). CONCLUSIONS: Myoglobin clearance using continuous veno-venous hemodialysis with high cutoff dialyzer and regional citrate anticoagulation is better than that with continuous veno-venous hemodiafiltration with regional citrate anticoagulation. TRIAL REGISTRATION: German Clinical Trials Registry (DRKS00012407); date of registration 23/05/2017. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012407 .

Tuberculosis in Pregnancy - a Summary.

In recent years, the incidence of tuberculosis in pregnancy in the industrialised countries has increased. Tuberculosis in pregnancy is associated with an increased risk for the mother and child. Even if no figures are available for Germany, an increase in the number of tuberculosis cases among pregnant women can be assumed due to the migratory flows; current data from the USA, for example, also show an increasing incidence of tuberculosis in pregnant women in recent years. The physiological and immunological changes that occur during pregnancy are likely to have a negative impact on the course of the disease and may make it more difficult to confirm the diagnosis. There are no internationally standardised recommendations for diagnosing latent tuberculosis infections. When screening for TB is performed in specific risk populations, an Interferon-γ Release Assay (IGRA) should preferably be carried out according to the current study data. If corresponding symptoms are present and an IGRA test is positive, further diagnostics are indicated, also in pregnancy. If tuberculosis is confirmed, the fact that a woman is pregnant must not delay the initiation of anti-tuberculosis therapy, as an early start of therapy is associated with a more favourable outcome for both mother and child. The common first-line therapeutic drugs may also be used during pregnancy and are considered safe. The treatment of latent tuberculosis during pregnancy is disputed.

Middle molecule clearance with high cut-off dialyzer versus high-flux dialyzer using continuous veno-venous hemodialysis with regional citrate anticoagulation: A prospective randomized controlled trial.

BACKGROUND: Regional anticoagulation with citrate during renal replacement therapy (RRT) reduces the risk of bleeding, extends dialyzer lifespan and is cost-effective. Therefore, current guidelines recommend its use if patients are not anticoagulated for another reason and if there are no contraindications against citrate. RRT with regional citrate anticoagulation has been established in critically ill patients as continuous veno-venous hemodialysis (CVVHD) to reduce citrate load. However, CVVHD is inferior regarding middle molecule clearance compared to continuous veno-venous hemofiltration (CVVH). The use of a high cut-off dialyzer in CVVHD may thus present an option for middle molecule clearance similar to CVVH. This may allow combining the advantages of both techniques. METHODS: In this prospective, randomized, single-blinded single-center-trial, sixty patients with acute renal failure and established indication for renal replacement therapy were randomized 1:1 into two groups. The control group was put on CVVHD using regional citrate anticoagulation and a high-flux dialyzer, while the intervention group was on CVVHD using regional citrate anticoagulation and a high-cut-off dialyzer. The concentrations of urea, creatinine, ß2-microglobulin, myoglobin, interleukin 6 and albumin were measured pre- and post-dialyzer 1, 6, 12, 24 and 48 hours after initiating CVVHD. RESULTS: Mean plasma clearance for ß2-microglobulin was 19.6±5.8 ml/min in the intervention group vs. 12.2±3.6 ml/min in the control group (p<0.001). For myoglobin (8.0±4.5 ml/min vs. 0.2±3.6 ml/min, p<0.001) and IL-6 (1.5±4.3 vs. -2.5±3.5 ml/min, p = 0.002) a higher mean plasma clearance using high-cut-off dialyzer could be detected too, but no difference for urea, creatinine and albumin could be observed concerning this parameter between the two groups. CONCLUSION: CVVHD using a high cut-off dialyzer results in more effective middle molecule clearance than that with high-flux dialyzer. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00005254, registered 26th November 2013).