Osteopontin-A Potential Biomarker for IgA Nephropathy: Machine Learning Application.

Many potential biomarkers in nephrology have been studied, but few are currently used in clinical practice. One is osteopontin (OPN). We compared urinary OPN concentrations in 80 participants: 67 patients with various biopsy-proven glomerulopathies (GNs)-immunoglobulin A nephropathy (IgAN, 29), membranous nephropathy (MN, 20) and lupus nephritis (LN, 18) and 13 with no GN. Follow-up included 48 participants. Machine learning was used to correlate OPN with other factors to classify patients by GN type. The resulting algorithm had an accuracy of 87% in differentiating IgAN from other GNs using urinary OPN levels only. A lesser effect for discriminating MN and LN was observed. However, the lower number of patients and the phenotypic heterogeneity of MN and LN might have affected those results. OPN was significantly higher in IgAN at baseline than in other GNs and therefore might be useful for identifying patients with IgAN. That observation did not apply to either patients with IgAN at follow-up or to patients with other GNs. OPN seems to be a valuable biomarker and should be validated in future studies. Machine learning is a powerful tool that, compared with traditional statistical methods, can be also applied to smaller datasets.

Peroxiredoxins as Markers of Oxidative Stress in IgA Nephropathy, Membranous Nephropathy and Lupus Nephritis.

IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) represent important causes of chronic kidney disease. They belong to the immune-mediated glomerulonephritis (GNs), and have distinct pathogenesis, distinct clinical courses, and variable responses to treatment. Therefore, specific diagnostic procedures are necessary for more effective patient management. Recently, a role for oxidative stress has been proposed in various renal disorders. Thus, molecules related to oxidative stress, such as 2-Cys-peroxiredoxins (PRDXs), may represent plausible candidates for biomarkers in renal pathologies. The aim of this study was to assess whether there are differences between individual GNs and healthy controls in the context of PRDXs serum concentration. We enrolled 108 patients with biopsy-proven IgAN (47), MN (26), LN (35) and 30 healthy age- and sex-matched controls. The serum concentrations of PRDX 1-5 were measured with ELISA assays and correlated with demographic and clinical data. The PRDXs' concentration varied depending on the GN type. We also observed an association of PRDXs with lower estimated glomerular filtration rates, complement, hemoglobin, and body mass index. Our study indicates that individual PRDX can play roles in pathophysiology of selected GNs and that their serum concentrations may become useful as a new supplementary diagnostic markers in IgAN, MN as well as LN. The results of this study open a new avenue for prospective research on PRDXs in renal diseases.

Unexpectedly High Efficacy of SARS-CoV-2 BNT162b2 Vaccine in Liver versus Kidney Transplant Recipients-Is It Related to Immunosuppression Only?

The BNT162b2 vaccine is reportedly effective in preventing severe disease in more than 90% of the general population, but its efficacy in transplant recipients remains controversial. We aimed to determine the immune response to the BNT162b2 vaccine in kidney (KTRs) and liver transplant recipients (LTRs). In this retrospective cohort study, we included randomly 65 KTRs and 65 LTRs, who received two 30 µg doses of BNT162b2 vaccine in 3-to6-week intervals. We analyzed the anti-SARS-CoV-2 spike protein IgG antibody (anti-S1 Ab) titer, biochemical liver and renal tests, immunosuppressive drug trough level, and clinical follow up 4-6 weeks after the first dose and 4-8 weeks after the second dose. The level of protective antibodies was 57.1% in KTRs and 88.9% in LTRs after the second dose. The anti-S1 Ab response was significantly associated with sex, age, and history of COVID-19. A tacrolimus dose at vaccination but not its trough level was significantly correlated with the increase in anti-S1 Ab titer after the second vaccine dose in LTRs. Rejection episodes did not occur after vaccination. Our results showed a higher than previously reported humoral response to the BNT162b2 vaccine in KTRs and LTRs, which was dependent upon age, type of transplanted organ, and immunosuppression.

NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies.

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene (NR3C1) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs-rs6198, rs41423247 and rs17209237-in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN (p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs (p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy (p = 0.013) and IgAN (p = 0.021); and in the same groups treated with steroids (p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings (p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN.

Membranous Nephropathy: From Research Bench to Personalized Care.

Membranous nephropathy is a glomerulopathy that causes nephrotic syndrome and, in at least a third of cases, lasting end-stage kidney disease (ESKD). It is also a rare case of revolutionary changes in our understanding of the disease, that translates from scientific findings to real diagnosis and treatment recommendations in less than ten years. In this review we present: (1) a short history and traditional approach to patients with membranous nephropathy, (2) current recommendations and treatment options that have emerged in recent years, (3) findings of new studies, with a particular focus on serological/immunological methods, genomic and proteomic studies, still requiring validation. With further development in this field, membranous nephropathy may become one of the first nephrological conditions that apply a truly personalized approach with the omission of invasive measures such as kidney biopsy.

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Viruses in transplantology.

The 3 leading causes of death in patients after solid organ transplantation (SOT) include cardiovascular diseases, malignancies, and infections. According to our current understanding, the latter play the key role in the pathogenesis of atherosclerosis. Similarly, infections (mainly viral) are implicated in the pathogenesis of at least 20% of known neoplasms. In other words, the implications of acute and chronic infectious diseases in modern medicine, not only transplantology, are significant and ever­increasing. Immunosuppressive treatment impairs the immune function, which renders the patient more susceptible to infections. Furthermore, treatment of infections in immunocompromised patients poses a challenge and SOT. The current publication provides a brief summary of the key information provided in 20 lectures on viral infections in patients after SOT delivered during the 9th Practical Transplantology Course in Warsaw, Poland on September 15-16, 2017.

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.

Long-term response to sunitinib: everolimus treatment in metastatic clear cell renal cell carcinoma.

AIM: The study aim was to evaluate progression-free survival (PFS) and overall survival (OS) in patients with metastatic clear cell renal cell carcinoma on sunitinib (SU) and SU-everolimus treatment. PATIENTS & METHODS: After 7 years of enrollment and 9 years of follow-up, 193 consecutively presenting patients (151 men and 42 women) were treated. RESULTS: A total of 157 patients (81.3%) died and 36 patients (18.7%) survived. Median PFS in 193 SU-treated patients was 14.7 months and OS was 28.8 months. Median PFS was 13.98 months and median OS was 26.67 months in 175 patients treated with SU only or on SU-everolimus. CONCLUSION: The development of SU-induced hypothyroidism, hypertension, neutropenia and edema was a significant predictive and prognostic factor.

Mechanisms through which diabetes mellitus influences renal cell carcinoma development and treatment: A review of the literature.

Renal cell carcinoma (RCC) comprises 2­3% of all malignant tumors in adults. Many studies have established the key roles of smoking, hypertension and other components of metabolic syndrome in the occurrence of RCC. Diabetes mellitus (DM), one of the main consequences of metabolic syndrome, appears much more often in patients with RCC. The prognosis for patients suffering from both diabetes and RCC is worse than for those with kidney cancer only. Diabetes is linked to higher rate of recurrence and a greater number of distant metastases. These factors contribute to a reduction in overall survival (OS) and cause­specific survival (CSS). Diabetes can also occur as a paraneoplastic syndrome. Tyrosine kinase inhibitors (TKIs), which are agents used in the therapy of metastatic RCC, may have unexpected effects when administered to patients with diabetes. Studies and case reports have shown that they influence blood glucose levels (BGLs) in diabetic patients, sometimes causing dangerous episodes of hypoglycemia. Hyperinsulinemia and hyperglycemia can be considered independent carcinogenic factors, as they increase the amount of pro­inflammatory cytokines, reactive oxygen species and lipid peroxidation. TKIs have yet to be re­evaluated as to their safety of use in patients with diabetes.