Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response. STUDY DESIGN: Prospective, multicenter, observational study. STUDY PARTICIPANTS: CureGN participants with proven MCD on biopsy. EXPOSURE: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period. OUTCOME: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure. ANALYTICAL APPROACH: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission. RESULTS: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002). LIMITATIONS: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy. CONCLUSIONS: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response. PLAIN-LANGUAGE SUMMARY: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

Mobility Analysis of the Lumbar Spine with a Dynamic Spine-Correction Device.

According to data, 60-70% of the world's population experience low-back pain (LBP) at least once during their lifetime, often at a young or middle age. Those affected are at risk of having worse quality of life, more missed days at work, and higher medical care costs. We present a new rehabilitation method that helps collect and analyze data on an ongoing basis and offers a more personalized therapeutic approach. This method involves assessing lumbar spine rotation (L1-L5) during torso movement using an innovative dynamic spine correction (DSC) device designed for postural neuromuscular reeducation in LBP. Spinal mobility was tested in 54 patients (aged 18 to 40 years) without LBP. Measurements were made with 12-bit rotary position sensors (AS5304) of the DSC device. During exercise, the mean lumbar spine rotation to the right was greater (4.78° ± 2.24°) than that to the left (2.99° ± 1.44°; p < 0.001). Similarly, the maximum rotation to the right was greater (11.35° ± 3.33°) than that to the left (7.42° ± 1.44°; p < 0.0001). The measurements obtained in the study can serve as a reference for future therapeutic use of the device.

The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study.

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

EBV load is associated with cfDNA fragmentation and renal damage in SLE patients.

BACKGROUND: For long Epstein-Barr virus (EBV) has been suspected to be involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to verify the association between EBV, cell-free DNA (cfDNA) and kidney disease in SLE. METHODS: Blood samples were obtained from 43 SLE patients and 50 healthy individuals. EBV load was measured via real-time PCR assay. Sizing and quantification of plasma cfDNA was performed on Bioanalyzer. We proposed that the uniformity of cfDNA fragmentation can be described using cfDNA fragmentation index. RESULTS: SLE patients with chronic kidney disease (CKD +) had higher EBV load compared to CKD(-) patients (P = 0.042). Patients with high cfDNA level had higher EBV load (P = 0.041) and higher cfDNA fragmentation index (P < 0.001) compared to patients with low cfDNA level. Among patients with high cfDNA level, EBV load was higher in CKD(+) group compared to CKD(-) group (P = 0.035). EBV load was positively correlated with the fragmentation index in all SLE patients (P = 0.028, R2 = 0.13), and the correlation was even more pronounced in CKD (+) patients (P < 0.001, R2 = 0.20). CONCLUSIONS: We showed that EBV load was associated with non-uniform cfDNA fragmentation, higher cfDNA levels, and kidney disease in SLE patients. Although the causality of this relationship could not be determined with the current study, it brings rationale for further investigations on the role of EBV and cfDNA interplay in SLE pathogenesis.

The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study.

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1normal " (N = 129), T cell-mediated rejection (TCMR) "R2TCMR " (N = 37), early injury "R3injury " (N = 61), and fibrosis "R4late " (N = 8). Groups differed in median time posttransplant, for example, R3injury 99 days vs R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR , R3injury , and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.

Cell-free DNA profiling in patients with lupus nephritis.

BACKGROUND: Increased level of cell-free DNA (cf-DNA) is associated with systemic lupus erythematosus (SLE) and might be related to disease activity. The aim of this study was to evaluate whether cfDNA integrity, size distribution and concentration of different cfDNA fractions is associated with lupus activity and kidney involvement. METHODS: Blood samples were collected from 43 SLE patients and 50 healthy controls. Nuclear and mitochondrial fractions of cfDNA and intracellular DNA were quantified by real-time qPCR. Sizing and quantification of total cfDNA level was performed on Bioanalyzer. RESULTS: We determined four parameters that characterized cfDNA profile: fragmentation index, ratio of intra- to extracellular mtDNA copy number, cfDNA concentration, and presence of 54-149 bp and 209-297 bp fragments. Patients with healthy-like cfDNA profile had higher eGFR (P = 0.009) and more often no indications for kidney biopsy or less advanced lupus nephritis (LN) (P = 0.037). In contrary, SLE patients with distinct cfDNA profile (characterized by increased cfDNA concentration and fragmentation, higher discrepancy between intra- to extracellular mtDNA copy number, and the presence of 54-149 bp and 209-297 bp fragments) had lower eGFR (P = 0.005) and more often advanced LN or history of renal transplantation (P = 0.001). CONCLUSIONS: We showed that cfDNA profiling may help to distinguish SLE patients with renal involvement and severe disease course from patients with more favorable outcomes. We suggest cfDNA profile a promising SLE biomarker.

Age-Related Decline in Renal Blood Flow Could Be a Beneficial and Compensatory Mechanism.

Aging is a time-dependent process affecting all organs and tissues in the human body. The process of aging in the kidney is characterized by structural and functional changes, of which the main feature is a reduction in size, a decreased number of functioning glomeruli, and vascular changes. These changes result in functional deterioration, mainly involving a decrease in renal blood flow and the glomerular filtration rate. Additionally, impaired regulation of electrolyte and water homeostasis due to structural changes in the tubulo-interstitial system can occur. A reduced glomerular filtration rate does not necessarily result in serious clinical complications, and other selected parameters of kidney function may remain within reference value ranges in the elderly. Aging is also accompanied by decreased perfusion of other organs, including the heart and brain, which can induce more serious conditions in the elderly, including cardiac insufficiency or impairment of mental function. Thus, the decrease in renal blood flow in the aging kidney could be regarded as a compensatory mechanism to maintain perfusion of other organs and therefore, it could be also treated as being a beneficial reordering of blood-flow allocation.

IL 6 but not TNF is linked to coronary artery calcification in patients with chronic kidney disease.

INTRODUCTION: Patients with chronic kidney disease (CKD) have a high risk of death mainly due to cardiovascular diseases (CVD). Early risk identification may allow interventions and prevention of fatal events. OBJECTIVES: The study aim was to assess the usefulness of selected CVD biomarkers as predictors of 5-year mortality in patients with different CKD stages. PATIENTS AND METHODS: Study included 57 CKD patients: 38 in stage 5 (ESRD), 19 in stage 3 and 4 (CKD3-4), and 19 healthy controls. Blood samples were obtained once to measure fetuin A, adiponectin, leptin, tumor necrosis factor (TNF), interleukin-6 (IL-6), metalloproteinase-9 (MMP9), intracellular-1 (ICAM1) and vascular-1 (VCAM1) adhesion molecules (ELISA or Luminex platform). Computed tomography was performed to assess the calcium score (CS). Patients were prospectively followed for 5 years to evaluate their all-cause mortality. RESULTS: Serum VCAM1, TNF and IL-6 were significantly higher in more advanced CKD stages. VCAM1 correlated significantly with ICAM1, TNF and IL-6. TNF and IL-6 were also significantly correlated with each other. No significant changes were detected for other markers. IL-6 correlated significantly with CS, age, renal function and CRP. Elevated CS and IL-6 increased over 3 times the 5-year all-cause and cardiovascular mortality risks in patients with CKD or ESRD at baseline. CONCLUSIONS: IL-6 and CS were significantly associated with 5-year risk of all-cause mortality in CKD patients. Our study suggests an involvement of chronic inflammation linked to coronary artery calcification that is likely to contribute to the cardiovascular mortality in patients with impaired renal function.

Effects of liver transplantation on health-related quality of life in patients with primary biliary cholangitis.

BACKGROUND: Patients with primary biliary cholangitis (PBC) have decreased health-related quality of life (HRQoL). Here, we investigate HRQoL in two cohorts of transplanted patients with PBC and compare their results to healthy subjects. PATIENTS AND METHODS: We used generic SF-36 and disease-specific PBC-40 questionnaires to evaluate HRQoL in 26 patients with PBC (23 females, age 59.4 ± 5.7 years) before and after liver transplantation (LT), and in 107 patients with PBC (99 females, age 62.8 ± 6.7 years) who were previously transplanted. The control group was comprised of 60 healthy controls (55 females, age 54.6 ± 8.8 years). RESULTS: Health-related quality of life improved after LT in 85% of PBC patients. The SF-36 measure showed significant (all P < 0.05) improvements in the majority of domains after LT, and in the summary scores both physical and mental. We also documented significant improvements in pruritus and fatigue after LT (all P < 0.01). However, liver graft recipients had significantly worse physical functioning, physical role, and emotional role domains, and physical component score (all P < 0.001), as compared to healthy subjects. No differences in HRQoL were detected between patients evaluated after short and prolonged post-LT periods (P > 0.05). CONCLUSION: Liver transplantation substantially improves most aspects of life quality in PBC patients. Nevertheless, their HRQoL remains worse in comparison to healthy individuals, mainly in physical aspects.

The use of nonsteroidal anti-inflammatory drugs and analgesics by liver transplant recipients.

AIMS AND OBJECTIVES: This study aimed to assess the reasons and the frequency of the use of over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) or analgesics by liver transplant recipients (LTR). Patient awareness of possible drug-related side-effects was also assessed. BACKGROUND: NSAIDs and analgesics available without prescription belong to the most commonly used class of drugs. However, use of these drugs might be complicated by toxic adverse effects (AEs). Patients at risk for AEs include the transplant recipients. DESIGN/METHODS: This was a descriptive study. An anonymous survey was carried out in 73 randomly selected LTR, who represented 10% of all LTR at our centre. RESULTS: There were 64% of the patients who confirmed taking NSAIDs or analgesics; 16% of these patients took these drugs at least several times a week and 10% took them daily. For 39% of patients, the only way to manage their pain were OTC NSAIDs or analgesics. As many as 36% of patients were unaware of the risks associated with the use of these drugs. Ninety per cent of LTR consider physicians the most trusted source of drugs information. CONCLUSIONS: Our study shows that two-thirds of LTR take OTC NSAIDs or analgesics and one-third are unaware of the AEs associated with these drugs. Therefore, both transplant nurses and doctors should educate their patients about the use and possible AE of these drugs. RELEVANCE TO CLINICAL PRACTICE: Considering the high NSAIDs consumption rates, the side effects of these drugs should always be suspected. Especially in patients taking these drugs and referring to medical advisors with specific symptoms, such as: abdominal pain, anaemia, elevated serum creatinine concentration or liver enzymes activity. Awareness of the scale of the problem enables health professionals to cooperate in educating patients. Such practices may reduce uncontrolled abuse of these drugs and related health care costs.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹°), with heterogeneity detected only at the PSMB9/TAP1 locus (I²â€Š= 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²8). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

First Successful Pregnancy After Lung Transplantation in Poland-Case Report.

INTRODUCTION: Lung transplantation is well-established treatment for patients with advanced lung dysfunction in cystic fibrosis (CF). Pregnancy in CF lung transplant recipients is feasible, although it still remains challenging for even professionals and demands a multidisciplinary approach. CASE REPORT: We report the case of pregnancy in a 22-year-old woman after lung transplantation (LTx) due to end-stage respiratory failure in the course of CF. The interval from transplant to conception was 2.5 years. In 2019, orthotopic LTx was performed and a 3-drug immunosuppressive scheme was used-tacrolimus, mycophenolate mofetil, and prednisolone. There were no complications in the postoperative course. In April 2022, the patient was confirmed pregnant. All fetotoxic or teratogenic drugs were discontinued. Throughout the whole pregnancy, the patient was regularly monitored in the transplant and obstetrics centers. Due to the vaginal bleeding and irregular contractions at the 33 weeks of pregnancy, the course of steroids was administered. At 38 weeks and 5 days of gestation, she presented premature rupture of membranes. The caesarean section was performed because of breech presentation of the fetus. A live, term daughter was born and according to the screening test she does not have CF. Currently, 12 months after the delivery, the mother's lung function is good. CONCLUSIONS: Getting pregnant and having a safe pregnancy after LTx is possible, but it requires a specialized and individual approach. The patient should be well informed about possible complications and risks including graft failure. The patient's attitude and her cooperation with doctors play a major role.

Uterine Artery Pulsatility Index in Pregnant Kidney or Liver Recipients and Its Impact on Perinatal Outcome.

BACKGROUND: The uterine artery pulsatility index (UtA PI) is associated with blood flow to the placenta. Its increased values imply impaired placentation. This study aimed to evaluate UtA PI measurements in first-trimester ultrasound in pregnancies after kidney (KTx) or liver transplantation (LTx) and its relationship with perinatal outcome. MATERIALS AND METHODS: A retrospective analysis of 72 pregnancies in female kidney (35) or liver (37) transplant recipients between 2017 and 2023 was performed. Data concerning UtA PI were available for 17 kidney and 19 liver recipients. Statistical analysis of variables between KTx and LTx groups and the correlation with perinatal outcomes was performed using Student's t test and Pearson's correlation with P < .05 considered statistically significant. RESULTS: The mean UtA PI results were similar, and there were no statistical differences between the group of pregnant kidney and liver recipients with mean values of 1.46 (SD 0.44] and 1.73 (SD 0.51] respectively (P = .10). The mean neonate birth weight was lower in KTx group (2158 g ([SD 723 g]) compared with the LTx group (2780 g [SD 754g]; P =.02). In the KTx and LTx groups, mean UtA PI was in negative correlation with Apgar score in the first minute (P = .04, P = .01 respectively). CONCLUSIONS: Uterine artery Doppler is useful in predicting perinatal outcomes in the general population and organ recipient pregnancies, even in the early stages of pregnancy, as we observed the correlation between UtA PI and Apgar score. Pregnant kidney recipients remain at higher risk for complications and more unpredictable outcomes than liver recipients.

Anti-HLA and anti-MICA antibodies in liver transplant recipients: effect on long-term graft survival.

OBJECTIVE: Presence of anti-HLA antibodies has a well-known impact on kidney grafts survival; however their role in liver transplantation has not been fully elucidated. We conducted a 7-year prospective study to show correlation between presence of anti-HLA and anti-MICA antibodies and liver graft survival. METHODS: Blood samples from 123 liver transplant recipients were collected during patients routine visits. Time from transplantation to blood sample collection was different for each patient. Blood samples were tested for anti-HLA (separately class I and II) and MICA antibodies using Luminex assays. RESULTS: There were 32 (26%) patients with positive anti-HLA and 37 (30%) with positive anti-MICA antibodies. Graft loss occurred in 7 cases (23%) in anti-HLA positive group compared to 20 (22%) in anti-HLA negative group (P = ns) and in 8 cases (22%) in anti-MICA positive group but 19 (23%) in anti-MICA negative group (P = ns). No correlations were detected between presence of antibodies and acute graft rejection (AGR). Presence of any antibodies (anti-HLA or anti-MICA antibodies) correlated with late graft rejection (P = 0.04). CONCLUSION: Presence of anti-HLA or anti-MICA had no impact on long-term liver graft survival; however, detection of any antibodies was correlated with episodes of late graft rejection.

Results of liver transplantation in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw in patients with chronic hepatitis B and C viruses infection.

INTRODUCTION: Cirrhosis related to hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is the most frequent indication for liver transplantation worldwide. Progress in prophylaxis of posttransplant HBV recurrence has led to major improvements in long-term outcomes of patients after liver transplantation. Conversely, impaired posttransplant survival of patients with HCV infection was reported in several studies, mainly due to recurrence of viral infection. The purpose of this study was to compare long-term results of liver transplantation between patients with HBV monoinfection, HCV monoinfection and HBV/HCV coinfection. MATERIAL AND METHODS: A total of 1090 liver transplantations were performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw between December 1994 and May 2012. After exclusion of patients with cirrhosis of non-viral etiology, patients with malignant tumors, and patients with acute liver failure, the final study cohort comprised 209 patients with HBV (HBV+/HCV- subgroup; n = 56) or HCV (HBV-/HCV+ subgroup; n = 119) monoinfection or HBV/HCV coinfection (HBV+/HCV+; n = 34). These subgroups of patients were compared in terms of long-term results of transplantations, defined by 5-year patient and 5-year graft survival estimates. RESULTS: Overall and graft survival rates after 5-years for the whole study cohort were 74.5% and 72.6%, respectively. Five-year overall survival was 70.4% for patients within the HBV+/HCV- subgroup, 77.8% for patients within the HBV-/HCV+ subgroup, and 68.5% for patients within the HBV+/HCV+ subgroup. The corresponding rates of graft survival were 67.0%, 76.3%, and 68.5% for patients within the HBV+/HCV-, HBV-/ HCV+, and HBV+/HCV+ subgroups, respectively. Observed differences were non-significant, both in terms of overall (p = 0.472) and graft (p = 0.461) survival rates. CONCLUSIONS: Both overall and graft survival rates after liver transplantations performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw in patients with HBV and HCV infection are comparable to those reported by other European and American centers. In contrast to other studies, obtained results do not confirm the negative impact of HCV infection on long-term outcomes of patients.

Lupus Nephritis and Dysbiosis.

Lupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythematosus (SLE). The risk factors for developing LN by SLE patients are not fully understood. They are considered to be a mix of genetic and environmental variables, one of them being dysbiosis, proposed recently to interfere with autoimmunity. As of yet, the relations between the human microbiome, its genetic determinants, individual variability and clinical consequences remain to be established. One of the major obstacles in studying them is the magnitude of confounders, such as diet, drugs, infections or antibiotics use. They also make comparison between the studies extremely complicated. We reviewed the available evidence for the interplay between microbiome, dysbiosis and mechanisms triggering the autoimmune responses and potentially contributing to LN development. One such mechanism is the stimulation of autoimmune responses by bacterial metabolites that can mimic autoantigens and cause antibody production. These mimicking microbial antigens seem to be a promising target for future interventions.

Omics are Getting Us Closer to Understanding IgA Nephropathy.

During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.

Hybrid Immunity Provides the Best COVID-19 Humoral Response in Immunocompromised Patients with or without SARS-CoV-2 Infection History.

Immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly limited the spread of coronavirus disease 2019 (COVID-19) and reduced the associated complications, especially mortality. To prolong immunity, an immune booster was implemented. We evaluated the role of SARS-CoV-2 infection history in the vaccination schedules of kidney and liver transplant recipients and patients with chronic kidney disease (CKD). To this end, we retrospectively analyzed the data of 78 solid organ transplantation (SOT) recipients and 40 patients with immunoglobulin A (IgA) nephropathy as representatives of the CKD group. Patients received two or three doses of the BNT162b2 vaccine. At the follow-up, antibody (Ab) titer, graft function, COVID-19 history, and patients' clinical condition were assessed. Ab level was higher after two doses in patients with a COVID-19 history over three doses in patients with no COVID-19 history. Compared to three doses, subjects who were administered two doses had a longer median time to infection. Positive antibodies, in response to the third dose, were not observed in up to 8.4% of SOT patients. The results show that the vaccination schedule should take into account the vaccine response rate and COVID-19 history. So-called hybrid immunity appears to be most efficient at providing humoral responses against SARS-CoV-2 infection in immunocompromised patients.

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes.

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population.

Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes.

BACKGROUND: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors. METHODS: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation. RESULTS: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups. CONCLUSIONS: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function.