Influence of therapeutic plasma exchange treatment on short-term mortality of critically ill adult patients with sepsis-induced organ dysfunction: a systematic review and meta-analysis.

INTRODUCTION: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review. METHODS: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model. RESULTS: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery. CONCLUSIONS: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.

Lipid and Bone Effects of Heparin Use During Hemodialysis.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are commonly prescribed anticoagulants for chronic hemodialysis (HD). The dialysis population comprises a unique group that receives heparin three times per week for a long period, with potential long-term cumulative metabolic effects such as osteoporosis and worsening lipid profile. HD patients have approximately half the number of lipases as healthy individuals, and their lipid metabolism is limited because of this decrease as well as partially inhibited function. Administration of UFH or LMWHs for anticoagulation can lead to metabolic starvation despite high triglyceride levels at the end of HD. In vitro studies indicate that UFH and LMWHs inhibit osteoblasts and promote osteoclasts. In patients on HD, long-term use of UFH or LMWHs did not worsen chronic kidney disease-mineral bone disease. Further investigation is needed to elucidate the underlining mechanisms of UFH and LMWHs and their possible influences on maintenance HD patients.

Myocardial markers are highly altered by higher rates of fluid removal during hemodialysis.

INTRODUCTION: Although hemodialysis is lifesaving in patients with kidney failure extensive interdialytic weight gain (IDWG) between dialyses worsens the prognosis. We recently showed a strong correlation between IDWG and predialytic values of cardiac markers. The aim of the present study was to evaluate if the cardiac markers N-terminal pro-B-type natriuretic peptide (proBNP) and troponin T were influenced by IDWG and speed of fluid removal (ultrafiltration-rate). METHODS: Twenty hemodialysis patients performed in total 60 hemodialysis (three each). Predialytic values of proBNP and troponin T and changes from predialysis to 180 min hemodialysis (180-0 min) were compared with the IDWG calculated in percent of body weight. The ultrafiltration-rate was adjusted (UF-rateadj ) to IDWG: (100 × weight gain between dialysis [kg])/(estimated body dry weight [kg] × length of hemodialysis session [hours]). RESULTS: UF-rateadj correlated (Spearman) with (1) predialytic values of IDWG (r = 0.983, p < 0.001), proBNP (r = 0.443, p < 0.001), and troponin T (r = 0.296, p = 0.025); and (2) differences in proBNP180-0min (r = 0.572, p < 0.001) and troponin T180-0min (r = 0.400, p = 0.002). UF-ratesadj above a breakpoint of 0.60 caused more release of proBNP180-0min (p = 0.027). Remaining variables in multiple regression analysis with ProBNP180-0min as dependent factor were predialytic proBNP (p < 0.001) and the ultrafiltration-rate (p < 0.001). CONCLUSION: Higher UF-rateadj during dialysis was correlated to increased levels of cardiac markers. Data support a UF-rateadj lower than 0.6 to limit such increase. Further studies may confirm if limited fluid intake and a lower UF-rateadj should be recommended to prevent cardiac injury during dialysis.

Sex-specific time trends of long-term graft survival after kidney transplantation - a registry-based study.

BACKGROUND: Sex-specific trends over time with respect to kidney graft survival have scarcely been described in earlier studies. The present study aimed to examine whether kidney graft survival differs between women and men over time. METHODS: This study was based on prospectively collected data extracted from a quality registry including all kidney transplant patients between January 1965 and September 2017 at the transplantation center of a university hospital in Sweden. The transplantation center serves a population of approximately 3.5 million inhabitants. Only the first graft for each patient was included in the study resulting in 4698 transplantations from unique patients (37% women, 63% men). Patients were followed-up until graft failure, death, or the end of the study. Death-censored graft survival analysis after kidney transplantation (KT) was performed using Kaplan-Meier analysis with log-rank test, and analysis adjusted for confounders was performed using multivariable Cox regression analysis. RESULTS: Median age at transplantation was 48 years (quartiles 36-57 years) and was similar for women and men. Graft survival was analyzed separately in four transplantation periods that represented various immunosuppressive regimes (1965-1985, 1986-1995, 1996-2005, and 2006-2017). Sex differences in graft survival varied over time (sex-by-period interaction, p = 0.026). During the three first periods, there were no significant sex differences in graft survival. However, during the last period, women had shorter graft survival (p = 0.022, hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.1-2.7, adjusted for covariates). Biopsy-proven rejections were more common in women. CONCLUSIONS: In this registry-based study, women had shorter graft survival than men during the last observation period (years 2006-2017).

The world apheresis association registry, 2023 update.

The WAA apheresis registry contains data on more than 140,000 apheresis procedures conducted in 12 different countries. The aim is to give an update of indications, type and number of procedures and adverse events (AEs). MATERIAL AND METHODS: The WAA-registry is used for registration of apheresis procedures and is free of charge. The responsible person for a center can apply at the site www.waa-registry.org RESULTS: Data includes reported AEs from 2012 and various procedures and diagnoses during the years 2018-2022; the latter in total from 27 centers registered a total of 9500 patients (41% women) that began therapeutic apheresis (TA) during the period. A total of 58,355 apheresis procedures were performed. The mean age was 50 years (range 0-94). The most common apheresis procedure was stem cell collection for which multiple myeloma was the most frequent diagnosis (51%). Donor cell collection was done in 14% and plasma exchange (PEX) in 28% of patients; In relation to all performed procedures PEX, using a centrifuge (35%) and LDL-apheresis (20%) were the most common. The main indication for PEX was TTP (17%). Peripheral veins were used in 56% as the vascular access. The preferred anticoagulant was ACD. AEs occurred in 2.7% of all procedures and were mostly mild (1%) and moderate 1.5% (needed supportive medication) and, only rarely, severe (0.15%). CONCLUSION: The data showed a wide range of indications and variability in apheresis procedures with low AE frequency.

Dynamics of urine proteomics biomarker and disease progression in patients with IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) frequently leads to kidney failure. The urinary proteomics-based classifier IgAN237 may predict disease progression at the time of kidney biopsy. We studied whether IgAN237 also predicts progression later in the course of IgAN. METHODS: Urine from patients with biopsy-proven IgAN was analyzed using capillary electrophoresis-mass spectrometry at baseline (IgAN237-1, n = 103) and at follow-up (IgAN237-2, n = 89). Patients were categorized as "non-progressors" (IgAN237 ≤0.38) and "progressors" (IgAN237 >0.38). Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio slopes were calculated. RESULTS: Median age at biopsy was 44 years, interval between biopsy and IgAN237-1 was 65 months and interval between IgAN237-1 and IgAN237-2 was 258 days (interquartile range 71-531). IgAN237-1 and IgAN237-2 values did not differ significantly and were correlated (rho = 0.44, P < .001). Twenty-eight percent and 26% of patients were progressors based on IgAN237-1 and IgAN237-2, respectively. IgAN237 inversely correlated with chronic eGFR slopes (rho = -0.278, P = .02 for score-1; rho = -0.409, P = .002 for score-2) and with ±180 days eGFR slopes (rho = -0.31, P = .009 and rho = -0.439, P = .001, respectively). The ±180 days eGFR slopes were worse for progressors than for non-progressors (median -5.98 versus -1.22 mL/min/1.73 m2 per year for IgAN237-1, P < .001; -3.02 vs 1.08 mL/min/1.73 m2 per year for IgAN237-2, P = .0047). In multiple regression analysis baseline progressor/non-progressor according to IgAN237 was an independent predictor of eGFR180days-slope (P = .001). CONCLUSION: The urinary IgAN237 classifier represents a risk stratification tool in IgAN also later in the course of the dynamic disease. It may guide patient management in an individualized manner.

Factors associated with time to first dialysis-associated peritonitis episode: Data from the Peritonitis Prevention Study (PEPS).

INTRODUCTION: Peritonitis remains a potentially serious complication of peritoneal dialysis (PD) treatment. It is therefore important to identify risk factors in order to reduce the incidence of peritonitis. The aim of the present analysis was to identify factors associated with time to first peritonitis episode. METHODS: Incident PD patients from 57 centres in Europe participated in the prospective randomised controlled Peritonitis Prevention Study (PEPS) from 2010 to 2015. Peritonitis-free, self-care PD patients ≥18 years were randomised to a retraining or a control group and followed for 1-36 months after PD initiation. The association of biochemical, clinical and prescription data with time to first peritonitis episode was studied. RESULTS: A first peritonitis episode was experienced by 33% (223/671) of participants. Univariable Cox proportional hazard regression showed a strong association between the time-updated number of PD bags connected per 24 h (PD bags/24 h) and time to first peritonitis episode (HR 1.35; 95% confidence interval (CI) 1.17-1.57), even after inclusion of PD modalities in the same model. Multivariable Cox regression revealed that the factors independently associated with time to first peritonitis episode included age (HR 1.16 per 10 years; 95% CI 1.05-1.28), PD bags/24 h (HR 1.32; 95% CI 1.13-1.54), serum albumin <35 versus >35 g/L (HR 1.39; 95% CI 1.06-1.82) and body weight per 10 kg (HR 1.10; 95% CI 1.01-1.19). CONCLUSION: This study of incident PD patients indicates that older age, greater number of PD bags connected/24 h, higher body weight and hypoalbuminaemia are independently associated with a shorter time to first peritonitis episode.

Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Microemboli induced by air bubbles may be deposited in organs as a consequence of contamination during medical care.

Background: Larger volumes of accidental air infused during medical care may end up as emboli while microbubbles of air are supposed to be absorbed and cause no harm. The aim of this autopsy study was to investigate if microbubbles of air accidently entering the bloodline may be detected as microemboli (ME) in tissue such as lungs, brain and heart. If so, do differences in prevalence exist between haemodialysis (HD) and amyotrophic lateral sclerosis (ALS) patients. Methods: Included were data from 44 patients treated by medical healthcare before death. Twenty-five cases had been treated with chronic HD and 19 cases died from ALS. Since air in the bloodline activates coagulation, ME could appear. To discriminate between microbubbles caused by artificial contamination during autopsy versus microbubbles deposited in vivo, tissues were stained with a polyclonal fluorescent antibody against fibrinogen, fibrin and fragments E and D. Fluorescence staining was used to visualize ME counted within 25 microscopic fields (600×) of a tissue preparation. One tissue preparation was used if available from the lung, heart and frontal lobe of the brain and in five cases also the cerebellum. Results: Microbubbles can be verified at autopsy as ME in the lung, heart and brain in tissue from patients exposed to more extensive medical care. There were significantly more ME in the lungs versus the heart or brain. Women had fewer ME than men. The HD group had a higher median of ME per section than the ALS group (lung: 6 versus 3, P = .007; heart: 2.5 versus 1, P = .013; brain: 7.5 versus 2, P = .001) and had more sections with ME findings than the ALS group (P = .002). A correlation existed between the time on HD (months) and ME in the lungs. Conclusions: More ME were present in HD patients compared with those who suffered from ALS. Minimizing air contamination from syringes, infusions and bloodlines will decrease ME and subsequent tissue injury.

Venous chambers in clinical use for hemodialysis have limited capacity to eliminate microbubbles from entering the return bloodline: An in vitro study.

BACKGROUND: During hemodialysis (HD), blood passes through an extracorporeal circuit (ECC). To prevent air administration to the patient, a venous chamber (chamber) is located before the blood return. Microbubbles (MBs) may pass through the chamber and end up as microemboli in organs such as the brain and heart. This in vitro study investigated the efficacy of various chambers in MB removal. MATERIALS AND METHODS: The in vitro recirculated setting of an ECC included an FX10 dialyzer, a dextran-albumin solution to mimic blood viscosity and chambers with different flow characteristics in clinical use (Baxter: AK98 and Artis, Fresenius: 5008 and 6008) and preclinical test (Embody: Emboless®). A Gampt BCC200 device measured the presence and size of MBs (20-500 µm). Percentage change of MBs was calculated: ΔMB% = 100*(outlet-inlet)/inlet for each size of MB. Blood pump speed (Qb) was 200 (Qb200) or 300 (Qb300) ml/minute. Wilcoxon paired test determined differences. RESULTS: With Qb200 median ΔMB% reduction was: Emboless -58%, AK98 -24%, Fresenius 5008 -23%, Artis -8%, and Fresenius 6008 ± 0%. With Qb300 ΔMB% was: Emboless -36%, AK98 ± 0%, Fresenius 5008 ± 0%, Artis +25%, and Fresenius 6008 + 21%. The Emboless was superior to all other chambers with Qb200 and Qb300 (p < 0.001). Further, the Emboless with Qb300 still eliminated more MBs than all other chambers with Qb200 (p ≤ 0.003). CONCLUSION: The results from the present study indicate that flow characteristics of the chamber and the Qb are important factors to limiting exposure of MB to the return bloodline. The Emboless chamber reduced MBs more effective than those chambers in clinical use investigated.

Wearable and implantable artificial kidney devices for end-stage kidney disease treatment: Current status and review.

BACKGROUND: Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. OBSERVATION: Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. CONCLUSIONS: Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.

Glomerular macrophage index (GMI) in kidney transplant biopsies is associated with graft outcome.

BACKGROUND: Macrophages in renal transplants have been shown to participate in antibody-mediated rejection and are associated with impaired renal function. We calculated the glomerular macrophage index (GMI) in a large transplant biopsy cohort, studied its quantity in different diagnostic groups, to clarify its possible impact on graft survival. METHODS: GMI, defined as the mean number of macrophages in 10 glomeruli, was prospectively quantified in 1440 renal transplant biopsies over a 10-year period. The main histopathological diagnoses were grouped into eight disease entities, and GMI was compared to normal transplant biopsies as the reference group. The impact of GMI on graft survival was analyzed. RESULTS: GMI was highest in chronic (mean 9.4) and active (9.7) antibody mediated rejections (ABMR), mixed rejections (7.6), and recurrent or de novo glomerulonephritis (7.5) and differed significantly from normal transplants (1.3) in almost all diagnostic groups. Hazard ratios for graft loss were significantly increased for all biopsies with GMI ≥1.9 compared to GMI < .5 (reference group) in an adjusted Cox regression model and increased with higher GMI levels. Biopsies with GMI ≥ 4.6 had < 60% 10-year graft-survival, compared to > 80% with GMI ≤ 1.8. CONCLUSION: GMI levels were predictive of graft loss independent of histological diagnoses and may guide clinicians to decide follow-up and therapy.

Kidney function in patients with bipolar disorder with and without lithium treatment compared with the general population in northern Sweden: results from the LiSIE and MONICA cohorts.

BACKGROUND: The clinical relevance of lithium nephropathy is subject to debate. Kidney function decreases with age and comorbidities, and this decline might lead to attribution bias when erroneously ascribed to lithium. We aimed to investigate whether patients with bipolar or schizoaffective disorder had faster decline in estimated glomerular filtration rate (eGFR) compared with the general population, whether observed differences in the steepness of the decline were attributable to lithium, and whether such changes depended on the length of lithium exposure. METHODS: In this cross-sectional cohort study, we used clinical data from the Lithium-Study into Effects and Side-effects (LiSIE) retrospective cohort study, which included patients with bipolar disorder or schizoaffective disorder whose medical records were reviewed up to Dec 31, 2017, and the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, covering a representative sample of the general population in northern Sweden aged 25-74 years. The primary outcome was the age-associated decline of creatinine-based eGFR, assessed using linear regression. We adjusted for sex and grouped for different lengths of lithium exposure (never or <1 year, 1-5 years, >5-10 years, and >10 years). For patients with moderate-to-severe kidney disease we identified the underlying nephropathy in the case records. FINDINGS: From LiSIE, we included 785 patients (498 [63%] female and 287 [37%] male), with a mean age of 49·8 years (SD 13·2; range 25-74). From MONICA, we included 1549 individuals (800 [52%] female and 749 [48%] male), with a mean age of 51·9 years (13·8; 25-74). No ethnicity data were collected. Adjusted for duration of lithium exposure, eGFR declined by 0·57 mL/min/1·73 m2/year (95% CI 0·50-0·63) in patients with bipolar disorder or schizoaffective disorder and by 0·57 mL/min/1·73 m2/year (0·53-0·61) in the reference population. Lithium added 0·54 mL/min/1·73 m2 (0·43-0·64) per year of treatment (p<0·0001). After more than 10 years on lithium, decline was significantly steeper than in all other groups including the reference population (p<0·0001). Lithium nephropathy was judged to be the commonest cause of moderate-to-severe chronic kidney disease, but comorbidities played a role. The effect of lithium on eGFR showed a high degree of inter-individual variation. INTERPRETATION: Steeper eGFR decline in patients with bipolar disorder or schizoaffective disorder can be attributed to lithium, but the trajectory of kidney function decline varies widely. Comorbidities affecting kidneys should be treated assertively as one possible means to affect the trajectory. In patients with a fast trajectory, a trade-off is required between continuing lithium to treat mental health problems and discontinuing lithium for the sake of renal health. FUNDING: Norrbotten County Research and Learning Fund Sweden, Visare Norr (Northern County Councils Regional Federation Fund), Swedish Kidney Foundation (Njurfonden), Swedish Kidney Association (Njurförbundet), Norrbotten section. TRANSLATION: For the Swedish translation of the Summary see Supplementary Materials section.

Oral Microbiota Profile in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

Microbiota has been associated with autoimmune diseases, with nasal Staphylococcus aureus being implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Little is known about the role of oral microbiota in AAV. In this study, levels of IgG antibodies to 53 oral bacterial species/subspecies were screened using immunoblotting in plasma/serum in pre-symptomatic AAV-individuals (n = 85), matched controls, and established AAV-patients (n = 78). Saliva microbiota from acute-AAV and controls was sequenced from 16s rDNA amplicons. Information on dental status was extracted from a national register. IgG levels against oral bacteria were lower in established AAV versus pre-AAV and controls. Specifically, pre-AAV samples had, compared to controls, a higher abundance of periodontitis-associated species paralleling more signs of periodontitis in established AAV-patients than controls. Saliva microbiota in acute-AAV showed higher within-sample diversity but fewer detectable amplicon-sequence variants and taxa in their core microbiota than controls. Acute-AAV was not associated with increased abundance of periodontal bacteria but species in, e.g., Arthrospira, Staphylococcus, Lactobacillus, and Scardovia. In conclusion, the IgG profiles against oral bacteria differed between pre-AAV, established AAV, and controls, and microbiota profiles between acute AAV and controls. The IgG shift from a pre-symptomatic stage to established disease cooccurred with treatment of immunosuppression and/or antibiotics.

Histological diagnosis from kidney transplant biopsy can contribute to prediction of graft survival.

AIM: The primary aim of this study was to in depth examine if the histological findings in a transplanted kidney biopsy can predict the prognosis for the graft and the patient. The secondary aim was to extend knowledge of the impact of time elapsed on biopsy findings. METHODS: Data from 1462 patients were merged from a kidney transplantation registry and a biopsy registry during 1 January 2007 and 30 September 2017. Kaplan-Meier analysis and multivariate Cox-regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were presented. RESULTS: Compared to normal biopsy findings, graft survival after biopsy (gsaBiopsy) was shorter for patients with glomerular diseases (HR 8.2, CI:3.2-21.1), rejections (HR 4.2, CI:1.7-10.3), chronic changes including IFTA (HR 3.2, CI:1.3-8.0), acute tubular injuries (HR 3.0, CI:1.2-7.8), and borderline changes (HR 2.9, CI:1.1-7.6). Sub-analysis of rejections showed shorter gsaBiopsy for chronic TCMR (HR 4.7, CI:1.9-11.3), active ABMR (HR 3.6, CI:1.7-7.7) and chronic ABMR (HR 3.5, CI:2.0-6.0). Patients with TCMR Banff grade II (HR 0.35, CI:0.20-0.63) and grade I (HR 0.52, CI:0.29-0.93) had a better gsaBiopsy compared to all other types of rejections. CONCLUSION: Shorter gsaBiopsy was noted in kidneys with glomerular diseases, rejections, acute tubular injuries and borderline changes. TCMR Banff rejections grade I and II were associated with a better prognosis.

Establishing Cell Models to Understand Cellular Toxicity: Lessons Learned from an Unconventional Cell Type.

The syndrome of uremic toxicity comprises a complex toxic milieu in-vivo, as numerous uremic substances accumulate and harm the organ systems. Among these substances, toxic and non-toxic players differently interfere with human cells. However, results from animal experiments are not always compatible with the expected reactions in human patients and studies on one organ system are limited in capturing the complexity of the uremic situation. In this narrative review, we present aspects relevant for cellular toxicity research based on our previous establishment of a human spermatozoa-based cell model, as follows: (i) applicability to compare the effects of more than 100 uremic substances, (ii) detection of the protective effects of uremic substances by the cellular responses towards the uremic milieu, (iii) inclusion of the drug milieu for cellular function, and (iv) transferability for clinical application, e.g., hemodialysis. Our technique allows the estimation of cell viability, vitality, and physiological state, not only restricted to acute or chronic kidney toxicity but also for other conditions, such as intoxications of unknown substances. The cellular models can clarify molecular mechanisms of action of toxins related to human physiology and therapy. Identification of uremic toxins retained during acute and chronic kidney injury enables further research on the removal or degradation of such products.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

CD99 and polymeric immunoglobulin receptor peptides deregulation in critical COVID-19: A potential link to molecular pathophysiology?

Identification of significant changes in urinary peptides may enable improved understanding of molecular disease mechanisms. We aimed towards identifying urinary peptides associated with critical course of COVID-19 to yield hypotheses on molecular pathophysiological mechanisms in disease development. In this multicentre prospective study urine samples of PCR-confirmed COVID-19 patients were collected in different centres across Europe. The urinary peptidome of 53 patients at WHO stages 6-8 and 66 at WHO stages 1-3 COVID-19 disease was analysed using capillary electrophoresis coupled to mass spectrometry. 593 peptides were identified significantly affected by disease severity. These peptides were compared with changes associated with kidney disease or heart failure. Similarities with kidney disease were observed, indicating comparable molecular mechanisms. In contrast, convincing similarity to heart failure could not be detected. The data for the first time showed deregulation of CD99 and polymeric immunoglobulin receptor peptides and of known peptides associated with kidney disease, including collagen and alpha-1-antitrypsin. Peptidomic findings were in line with the pathophysiology of COVID-19. The clinical corollary is that COVID-19 induces specific inflammation of numerous tissues including endothelial lining. Restoring these changes, especially in CD99, PIGR and alpha-1-antitripsin, may represent a valid and effective therapeutic approach in COVID-19, targeting improvement of endothelial integrity.