Immunosuppressive strategies for renalfunction preservation in IgA nephropathy with partial crescent formation: A retrospective cohort study.

Introduction: There are conflicting opinions regarding the use of immunosuppressant treatment in IgA nephropathy (IgAN) patients with an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2 and persistent proteinuria with a daily excretion of ≥1.0 g. Methods: This retrospective study involved 110 IgAN patients for whom clinical data were available; of these, 90 had complete follow-up data. Patients were grouped based on whether they received immunotherapy during follow-up, their renal function, proteinuria levels, and the percentage of crescentic glomeruli observed at the time of renal biopsy. Results: The mean eGFR for the participants was 32.0 ± 10.2 mL/min/1.73 m2. The average follow-up duration was 46.1 ± 37.9 months. The mean rate of decline in eGFR was 3.6 mL/min/1.73 m2 per year. There were 43 (47.8%) composite kidney endpoints occurred in these patients. In the group that received immunotherapy, the incidence of kidney endpoint events was lower than in the untreated group (45.1% vs. 57.9%), but the difference was not statistically significant (p = 0.320). Among patients with stage CKD 3b, the incidence of endpoint events was lower than in those with stages CKD 4 and 5 (36.8% vs. 66.7%, p = 0.006). Conversely, the high proteinuria group saw a higher incidence of endpoint events compared to the low proteinuria group (51.9% vs. 23.1%), although this difference was not statistically significant (p = 0.054). Meanwhile, there was no significant difference in the incidence of endpoint events between the two crescent glomerular ratio groups (48.7% vs. 41.7%, p = 0.649). Kaplan-Meier survival analysis indicated that renal function level (p < 0.001) and proteinuria (p = 0.023) were associated with renal survival in IgAN patients. In contrast, the administration of immunosuppressive therapy (p = 0.288) and the prevalence of C lesions (p = 0.982) did not show a significant association with renal survival. Further, Cox regression analysis identified systolic blood pressure, fibrinogen, and CKD stage as risk factors for eGFR decline in IgAN patients (all p < 0.05). Conclusion: IgAN patients with stages 3b-5 CKD exhibited a poor prognosis. It appears that in this specific cohort of IgAN patients, immunosuppressive therapy may not provide significant advantages over supportive care therapeutic regimens in terms of disease management.

Non-immunosuppressive treatment for IgA nephropathy.

Objective and designImmunoglobulin A nephropathy (IgAN) is a kidney disease characterized by the accumulation of IgA deposits in the glomeruli of the kidney, leading to inflammation and damage to the kidney. The inflammatory markers involved in IgAN remain to be defined. Gene expression analysis platforms, such as the NanoString nCounter system, are promising screening and diagnostic tools, especially in oncology. Still, their role as a diagnostic and prognostic tool in IgAN remains scarce. In this study, we aimed to validate the use of NanoString technology to identify potential inflammatory biomarkers involved in the progression of IgAN.SubjectsA total of 30 patients with biopsy-proven IgAN and 7 cases of antineutrophil cytoplasmic antibody (ANCA)-associated pauci-immune glomerulonephritis were included for gene expression measurement. For the immunofluorescence validation experiments, a total of 6 IgAN patients and 3 controls were included.MethodsTotal RNA was extracted from formalin-fixed paraffin-embedded kidney biopsy specimens, and a customized 48-plex human gene CodeSet was used to study 29 genes implicated in different biological pathways. Comparisons in gene expression were made between IgAN and ANCA-associated pauci-immune glomerulonephritis patients to delineate an expression profile specific to IgAN. Gene expression was compared between patients with low and moderate risk of progression. Genes for which RNA expression was associated with disease progression were analyzed for protein expression by immunofluorescence and compared with controls.ResultsIgAN patients had a distinct gene expression profile with decreased expression in genes IL-6, INFG, and C1QB compared to ANCA patients. C3 and TNFRSF1B were identified as potential biomarkers for IgAN progression in patients early in their disease course. Protein expression for those 2 candidate genes was upregulated in IgAN patients compared to controls. Expression of genes implicated in fibrosis (PTEN, CASPASE 3, TGM2, TGFB1, IL2, and TNFRSF1B) was more pronounced in IgAN patients with severe fibrosis compared to those with none.ConclusionsOur findings validate our NanoString mRNA profiling by examining protein expression levels of two candidate genes, C3 and TNFRSF1B, in IgAN patients and controls. We also identified several upregulated mRNA transcripts implicated in the development of fibrosis that may be considered fibrotic markers within IgAN patients.

Background and Aims Increased activity of the complement alternative pathway (AP) contributes to the pathogenesis of primary IgA nephropathy (IgAN). Factor B (FB), a key protein of the AP, is elevated in IgAN patients and is associated with proteinuria and poorer renal function. Approved complement inhibitors involve either IV administration or frequent dosing, presenting challenges to adherence for patients. As the complement system is important for host defense against pathogens, an unmet need remains for a convenient therapeutic approach that selectively targets the disease-associated AP in IgAN. Sefaxersen (IONIS-FB-LRx, RO7434656), an antisense oligonucleotide (ASO) against FB, is the first AP mRNA-targeting therapy in late-stage development for the treatment of IgAN. We previously reported that subcutaneous (SC) administration of sefaxersen every 4 weeks (Q4W) resulted in proteinuria reduction in IgAN patients. Here, we further describe the PK profile and mechanism of action of sefaxersen using data from Phase 2 clinical studies in patients with IgAN and geographic atrophy (GA) secondary to age-related macular degeneration. Method Sefaxersen is a second-generation GalNAc-conjugated ASO for enhanced stability and targeted delivery to the liver as the main site of FB production. Sefaxersen 40, 70, or 100 mg was administered Q4W in 223 participants with GA (NCT03815825), and 70 mg in 23 participants with IgAN (NCT04014335). An additional dose was administered 2 weeks after the first dose in the majority of participants. Complement proteins were serially measured in plasma (FB, Bb) and urine (Factor Ba, IgAN patients only). Classical pathway and alternative pathway functional activity in serum were measured by the Wieslab WCP and WAP assays, respectively. Results The plasma concentration (PK) profile of sefaxersen following SC injection shows rapid absorption, a sharp decline post-Cmax due to tissue distribution, and a slower terminal elimination phase driven by re-distribution from tissue, with apparent half-lives ranging from approximately 5 to 8 weeks. Q4W dosing with sefaxersen rapidly and durably reduced complement proteins FB and Bb in plasma, as well as Ba in urine. Near maximum suppression of FB, Bb, and Ba levels was reached by the earliest assessments of Week 5 and Week 9 and maintained over the dosing intervals in GA and IgAN patients, respectively. Plasma levels of FB and Bb were reduced by 69% and 73%, respectively, from baseline to inferred steady-state in patients with GA at the 70 mg dose. Plasma FB levels were reduced by a mean of 69%, Factor Bb by 79%, and urine Factor Ba levels by 78% from baseline to inferred steady-state in IgAN patients. The activity of the alternative pathway was reduced by 34% at inferred steady-state in patients with GA at the 70 mg dose, and reduced by 39% after 9 weeks in IgAN patients, whereas classical pathway activity was maintained. Conclusion Sefaxersen, a novel complement Factor B mRNA-targeting therapy, demonstrates a PK profile supporting Q4W subcutaneous administration and provides durable reduction in AP complement components in both blood and urine. Substantial reduction in AP functional activity was achieved while complement classical pathway activity was maintained, potentially maintaining host defense against pathogens. Taken together, sefaxersen is a convenient therapeutic approach for the treatment of IgAN, providing durable control of the alternative complement pathway that may translate into improvements in proteinuria. Currently, the effect of sefaxersen 70 mg on proteinuria reduction and eGFR stabilization is being evaluated in IgAN patients in a phase 3 study (IMAgINATION, NCT05797610).

Background: The significance of segmental glomerular necrosis (SGN) was not evident in immunoglobulin A nephropathy (IgAN) patients. Especially, there were a number of patients who presented with slight histopathological damage except SGN. We, therefore, conducted a study to highlight the occurrence of these cases and to define their clinical characteristics and outcomes at our centre. Methods: The clinical, laboratory and pathological manifestations and outcomes of these IgAN patients were collected and compared with IgAN patients with simily histopathological background but without SGN. Survival curves were constructed according to the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify independent factors for the development of endpoint. Results: Eighty-two patients with SGN but without crescents were found in Haas grades I-III. Macroscopic hematuria and prodromal infection were more popular and the mean daily proteinuria was significantly higher in patients with SGN. More patients had high serum IgA in the ecrotizing IgAN group. At last follow-up, there were no differences in hypertension, proteinuria, serum creatinine, estimated GFR and the incidence of end-point events between 2 groups. SGN was not an independent predictor for the prognosis of IgAN. Corticosteroid treatment could decrease proteinuria significantly. The outcomes of the 2 populations of necrotizing IgAN patients with or without corticosteroid treatment were not different. Conclusions: SGN can be found in mild pathological damage patients and is not always associated with crescent formation. Heavier proteinuria was found in these IgAN patients. SGN was not an independent predictor for the prognosis of IgAN.

BACKGROUND AND AIMSSeveral models have been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN) and, among them, the multihit model where the gut-microbiota may play an important role. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed that further predisposing factors are present, including immunological, genetic, environmental or nutritional factors.Recently, the role of IL-6 in IgAN pathogenesis is becoming increasingly important. It is essential for the deposition of glomerular immunoglobulin A and the development of renal disease in Cd37-deficient mice, although the pathogenetic mechanisms that determine its increase are not well known.A possible hypothesis emerges from our recent work on genome-wide DNA methylation screening in patients with IgAN, which identified, among other findings, a hypermethylated region comprising Vault 2–1 RNA (VTRNA2-1), a non-RNA coding also known as a precursor of miR-886 (pre-mi-RNA). Consistently, VTRNA2-1 expression was found downregulated in IgAN patients.Here we studied the involvement of the VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN.METHODTotal RNA were isolated from PBMCs of IgAN patients, transplanted IgAN patients (TP-IgAN), non-IgAN transplanted patients (TP) and healthy subjects (HS). VTRNA2-1, CREB and PKR transcripts were evaluated by RT-PCR. Total and phosphorylated PKR, CREB and Il-6 proteins were evaluated by ELISA. Poly (I: C), a synthetic analogue of dsRNA and Pfizer-BioNTech COVID-19 COMIRNATY vaccine were used to transfect patient PBMCs. PKR inhibitor imoxin (C16) 1 µM was used to stimulate patient PBMCs.RESULTSHere we confirm that VTRNA2-1 transcript was down-regulated in native and transplanted IgAN subjects compared to HS and non IgAN transplanted patients, with a decrease of 30- and 100-folds, respectively (P < 0.05, and P < 0.0001). IgAN patients with downregulated VTRNA2-1 showed a PKR overactivation (fold increase of phosphorilation of 2.6- in IgAN and 2-folds in TP-IgAN patients; P < 0.05), coherently with the role played by VTRNA2-1 that binds to PKR and inhibits its phosphorylation. Then, we found that PKR causes the activation of CREB, a classical cAMP-inducible CRE-binding factor (fold increase of phosphorilation of 3- in IgAN and 2.67-folds in TP-IgAN patients; P < 0.01). CREB, interacting with a region of the IL-6 promoter, led to IL-6 production. Indeed, in IgAN patients we showed a IL-6 mean increase to 120 pg/mL compared to the respective controls (P < 0.05). Moreover, the IL-6 levels correlated with CREB and PKR phosphorylation (r = 0.97; P = 0.0006 and r = 0.89; P = 0.0064, respectively, for IgAN and TP-IgAN patients).Since PKR is normally activated by bacterial and viral RNA, we hypothesized that these microorganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production. This may explain both the high levels of IL-6, and infection involvement in the disease, and cases of IgAN associated with COVID-19 infection or with COVID-19 RNA-vaccination, and recent data showing microbiota involvement in IgAN. Effectively, we found that IgAN PMBCs stimulated with RNA poly(I: C) or the COVID-19 RNA-vaccine showed a significant increase in IL-6 levels compared to not-stimulated PBMCs (P < 0.05), supporting the pathogentic role played by viral RNA in IgAN pathogenesis and explaining the cases of IgAN patients developing episodes of macrohematuria after a COVID-19 infection or vaccination.Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin (fold decrease of 5-folds in IgAN and TP-IgAN patients; P < 0.05).CONCLUSIONIn conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a new pathogenic mechanism in IgAN and may be useful for the development of novel therapeutic approaches, likely by modulating the VTRNA2-1 methylation level in IgAN patients.

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study

Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcomes and with nephroprotection independent of diabetes status. Recent data suggest that SGLT2i significantly reduce proteinuria in patients with IgA nephropathy (IgAN). However, they often cause an initial decline in estimated glomerular filtration rate (eGFR). The aim of our study was to assess the degree of proteinuria reduction after SGLT2i treatment in IgAN and its possible association with the initial functional dip in eGFR. Method 63 adult patients with biopsy-proven IgA nephropathy, eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi), and total urine protein of &amp;gt;0.5 grams/day at screening were included. Patients with secondary IgAN were excluded. All receiving maximally tolerated RASi for at least 12 weeks. All patients started dapagliflozin 10 mg once per day after baseline data were registered. The total follow-up was 12 months. The main outcome was the decline in eGFR and the reduction in 24-hour proteinuria from SGLT2i initiation to 1,3, 6, 9, 12 months, end-stage renal disease, or kidney or cardiovascular death. Results 55 patients (38/17 M/F), with mean age of 44,2±18,3 years, completed follow up. 8 patients discontinued treatment due to adverse events attributed to dapagliflozin. At baseline eGFR was 66.17±19,7 ml/min/1.73 m2 and Upr: 2356±1023 mg/24H. There was a transient decline in eGFR, 30 days after initiation of dapagliflozin (66.17±19,7 min/1.73 m2 at baseline to 57 ml/min/1.73 m2) but then, there was an improvement at month 3 from baseline. The Upr/24H difference for dapagliflozin was −25.1% (95% CI −27.5, −23.2; p &amp;lt; 0.001) at the end of follow-up (month 12). Proteinuria reduction was similar across all eGFRs. Notably, a significant correlation was found between the initial eGFR dip and percentage proteinuria reduction in the 12th month. (R = –0.23; p = 0.03). Consistent results of dapagliflozin treatment on proteinuria were found in all analysis subgroups including sex, baseline proteinuria, systolic blood pressure, and body mass index. No hypoglycaemic events were reported and no deaths occurred. Conclusion In the present study, the use of SGLT2i was associated with a significant reduction of proteinuria in patients with IgA nephropathy in patients with maximally tolerated RASi. Higher initial eGFR dip after treatment initiation was a predictor of a significantly higher reduction in proteinuria at the end of follow-up. The correlation between eGFR dip and proteinuria reduction perhaps reflects the intraglomerular pressure reduction, mediated by tubuloglomerular feedback, one of the numerous.

Background and Aims Sparsentan (SPAR) is a non-immunosuppressive, dual endothelin angiotensin receptor antagonist (DEARA) approved in the US and Europe for adults with immunoglobulin A nephropathy (IgAN). In patients with IgAN, SPAR showed sustained proteinuria reduction and preservation of kidney function in the phase 3 PROTECT trial. In a subgroup analysis from DAPA-CKD and EMPA-KIDNEY, sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduced proteinuria and the risk of progression to kidney failure in patients with IgAN. The combination of SPAR added to stable SGLT2i treatment led to further reductions in proteinuria in patients with IgAN in an interim analysis of the phase 2 SPARTACUS trial. Here we report results from the final analysis of SPARTACUS. Method SPARTACUS was a 28-week, open-label, multicenter study of the efficacy and safety of SPAR added to a stable SGLT2i in patients with IgAN at risk of disease progression. Patients had biopsy-proven IgAN, a urine albumin-to-creatinine ratio (UACR) of ≥0.3 g/g, and an estimated glomerular filtration rate (eGFR) of ≥25 mL/min/1.73 m2 despite a stable SGLT2i and maximum tolerated dose of renin-angiotensin-system inhibition (RASi) for ≥12 weeks. Endpoints included change in UACR from baseline to week 24 (primary); achievement of UACR of &amp;lt;0.2 g/g, or a ≥50% or ≥30% reduction in UACR at week 24 (secondary); change from baseline in UACR, eGFR, and blood pressure (BP) at each visit (secondary); and adverse events. Results A total of 48 patients (mean [SD] age, 48.9 [13.9] y) received ≥1 dose of SPAR, of whom 41 completed the study. At baseline, patients (male, n = 28 [58%]; female, n = 20 [42%]) had a median (IQR) UACR of 0.70 (0.49–1.01) g/g, median (IQR) urine protein-to-creatinine ratio of 1.24 (0.88–1.74) g/g, and mean (SD) eGFR of 57 (26) mL/min/1.73 m2. At week 24, SPAR added to a stable SGLT2i led to a 56% reduction in UACR (median [IQR] UACR at week 24, 0.33 [0.16–0.72] g/g) (Figure and Table); 12 patients (31%) reached a UACR of &amp;lt;0.2 g/g, and 20 (51%) and 30 (77%) patients showed a ≥50% or ≥30% reduction in UACR from baseline, respectively. eGFR remained relatively stable through week 24, with slight decreases in BP (Table). Thirty (63%) patients had a treatment-emergent adverse event, the most common of which was hypotension (15%). No patients experienced abnormal liver function test results &amp;gt;3 × the upper limit of normal. Conclusion Switching from RASi to SPAR treatment on a background of an SGLT2i allowed for further reduction in proteinuria in adult patients with IgAN, lowering their risk for disease progression. SPAR combined with an SGLT2i was generally well tolerated, with no unexpected safety signals.

Background Immunoglobulin A nephropathy (IgAN) has been well studied among young people, but few data on clinicopathological characteristics, treatment response and outcomes for elderly IgAN patients are available. Methods A cohort study of elderly IgAN patients was performed. The combined endpoints of renal outcome were a 50% decline in eGFR compared with the time of renal biopsy, end-stage kidney disease and/or death. Risk factors associated with poor renal outcomes were then determined. The benefits of immunosuppressant therapies were also evaluated by Kaplan-Meier survival curve analysis. Results This study ultimately included 126 elderly patients with IgAN. Comparison between the endpoint and non-endpoint groups indicated that patients with poor outcomes had more severe clinical features, such as worse kidney function, severe hematuria and lower albumin levels. Cox regression analysis indicated that age (HR 1.15, 95% CI 1.02–1.29, p = 0.021), male gender (HR 9.71, 95% CI 1.00–97.56, p = 0.050), and urine red blood cells (HR 1.003, 95% CI 1.000–1.006, p = 0.029) were independent risk factors for poor renal outcome in elderly IgAN patients. To explore possible reasons accounting for the predictive value of age and sex, patients were divided into two groups based on these two variables. Patients in the geriatric group had lower serum albumin, estimated glomerular filtration rate, hemoglobin and aspartate aminotransferase levels than those in the quinquagenarian group. Male patients tended to have higher hemoglobin, higher alanine aminotransferase, and lower triglycerides and cholesterol levels than female patients. To investigate different treatment responses, patients were classified into two groups depending on treatment strategies (renin-angiotensin system inhibitors and immunosuppressive therapy), and the survival analysis indicated no significant difference in kidney outcome between the two groups (p > 0.05). This result still holds after adjusting for age, sex, eGFR, hematuria, and proteinuria. Conclusion Advanced age, male, and hematuria might be independently associated with poor kidney outcomes in elderly patients with IgAN. Immunosuppressive therapy might confer no overall benefit to older IgAN patients.

Objective To analyze the clinicopathological features of IgA nephropathy (IgAN) patients with anemia and the influencing factors of prognosis. Methods The clinical and pathological data of patients diagnosed with primary IgAN at the First Affiliated Hospital of Fujian Medical University from January 1, 2006 to December 31, 2016 were retrospectively analyzed. The patients were divided into anemia group and non-anemia group according to whether the patient was anemia or not. The clinical and pathological data of the two groups were collected. All of them were followed up from the date of renal biopsy to January 1, 2018. Survival curves of the two groups were drawn by Kaplan-Meier method, and compared by Log-rank test. Multivariate Cox proportional hazards regression model was adopted to explore the influencing factors of prognosis in IgAN patients. Results A total of 231 subjects were enrolled, including 122 males (52.8%), and the male-female ratio was 1.12∶1. Their age was (34.8±10.1) years (15-68 years). There were 70 patients (30.3%) in anemia group, 161 cases (69.7%) in non-anemic group. Compared with non-anemia group, anemia group had higher proportion of females, lower serum albumin, higher proportion of tubular atrophy/interstitial fibrosis (T1/2), endothelial cell proliferation (E1) and crescent formation (C1/2), which were statistically significant (all P<0.05). The patients had a median follow-up time as 6.3 years (0.3-12.9 years). Survival analysis showed that patients in anemia group had lower cumulative renal survival rate than that in non-anemia group (χ2=15.234, P<0.001). Multivariate Cox hazards regression analysis revealed that anemia (HR=3.820, 95%CI 1.674-8.719, P=0.001), tubular atrophy/interstitial fibrosis (T1/2) (HR=3.770, 95%CI 1.026-13.852, P=0.046), glomerular segmental sclerosis/adhesion (S1) (HR=4.211, 95%CI 1.139-15.576, P=0.031), hypertension (HR=2.988, 95%CI 1.276-6.999, P=0.012), increased 24 h urinary protein (HR=1.103, 95%CI 1.046-1.163, P<0.001) and estimated glomerular filtration (eGFR)<60 ml·min-1·(1.73 m2)-1 (HR=3.725, 95%CI 1.639-8.462, P=0.002) were the independent risk factors for poor renal prognosis in patients with IgAN. Conclusions The clinicopathological features of IgAN patients with anemia are relatively serious, and the renal cumulative survival rate is lower. Anemia, tubular atrophy/interstitial fibrosis (T1/2), glomerular segmental sclerosis/adhesion (S1), hypertension, increased urinary protein and eGFR<60 ml·min-1·(1.73 m2)-1 are the independent risk factors for poor renal prognosis in patients with IgAN. Key words: Glomerulonephritis, IgA; Anemia; Pathology, clinical; Prognosis

IgA Nephropathy

To investigate the clinicopathologic features of IgA nephropathy (IgAN) patients with different levels of proteinuria and its clinical significance. This was a single-center retrospective cohort study. Patients with biopsy-proven primary IgAN were enrolled from January 2006 to December 2011 in The First Affiliated Hospital of Sun Yat-sen University, divided into six groups based on proteinuria at biopsy (≤ 0.30 g/d, 0.31 - 0.50 g/d, 0.51 - 1.00 g/d, 1.01 - 2.00 g/d, 2.01 - 3.00 g/d, and > 3.00 g/d). Demographic and clinicopathologic data were collected and analyzed. 1,413 patients were enrolled in this study, with the median proteinuria being 0.61 g/d (interquartile range 0.30 - 1.29). Patients with proteinuria > 0.50 g/d showed significant differences in their clinicopathologic characteristics with higher prevalence of hypertension, hypoalbuminemia, hyperuricemia, hypercholesterolemia and hypertriglyceridemia, worse renal function, higher proportions of segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and interstitial inflammation. Even the patients with proteinuria 0.31 - 0.50 g/d exhibited higher uric acid, lower total serum protein and albumin, higher proportions of crescents, and global glomerulosclerosis. Furthermore, multiple risk factors linear regression analysis has shown that there were significant associations between proteinuria and serum albumin, uric acid, total cholesterol, triglyceride, systolic blood pressure, degrees of segmental glomerulosclerosis, proportions of crescents, and global glomerulosclerosis. Clinicopathologic features were significantly worse in IgAN patients with increasing of proteinuria.

Background and Aims Rare proteinuric kidney diseases are associated with clinical and economic burden, however, the humanistic burden associated with these conditions has not been directly evaluated. HONUS is a multi-national, cross-sectional survey study designed to evaluate the humanistic burden associated with two rare kidney diseases, immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), from the patient and caregiver perspectives in the United States and Europe. The current analysis presents preliminary results from adults with IgAN or FSGS and their care-partners in Spain, Germany, France, or the United Kingdom. Method The study recruited adult patients (≥ 18 years old) with IgAN or FSGS and their adult care-partners. Participants completed an online survey including demographic and clinical characteristics, health-related quality of life (HRQoL) (i.e., Kidney Disease Quality of Life Instrument [KDQoL] including 12-Item Short Form Survey [SF-12]), anxiety and depression (i.e., Generalized Anxiety Disorder Assessment [GAD-7], Patient Health Questionnaire [PHQ-9]), and disease impact on work productivity (i.e., Work Productivity and Activity Impairment [WPAI]). Descriptive analyses were conducted. Results From Europe, 26 IgAN patients, 9 FSGS patients, and their care-partners (4 IgAN and 2 FSGS patients did not report having a care-partner) participated in the survey before November 2023. Mean age for IgAN and FSGS patients was 42.2 years and 51.4 years, with 61.5% and 44.4% being female, respectively. Over two-fifths of both IgAN (42.3%) and FSGS patients (44.4%) were in chronic kidney disease (CKD) stage 3, 4 or 5 (on dialysis), while over one-quarter had received a kidney transplant (IgAN: 26.9%; FSGS: 44.4%). Most patients had worse CKD status since diagnosis (IgAN: 61.5%; FSGS: 77.8%). Hypertension and anemia were the most common comorbidities in both groups. In terms of HRQoL, mean (SD) SF-12 physical and mental component scores (PCS, MCS) indicated IgAN patients were more impacted on the mental component (PCS: 47.3 [11.6], MCS: 43.2 [10.9]), with FSGS patients more impacted on the physical component (PCS: 40.6 [6.0], MCS: 43.8 [9.1]), reflecting generally worse HRQoL (lower scores) than previously published European general population scores (50.0 for PCS and MCS). Moderate to severe anxiety was reported by 30.8% of IgAN and 33.3% of FSGS patients, and moderate to severe depression by 30.8% of IgAN and 44.4% of FSGS patients. Among employed IgAN patients (69.2%), mean percent absenteeism (work time missed) was reported at 13.3%, presenteeism (impairment while working) at 17.7%, and overall work productivity loss at 17.7% due to IgAN-related reasons (only 3 FSGS patients [33.3%] were employed; outcomes not shown). Mean percent activity impairment was reported at 27.3% in IgAN and 43.3% in FSGS patients. Most paired care-partners were partners of patients (IgAN: 81.8%, FSGS: 71.4%), with a mean age of 46.6 years (IgAN) and 50.1 years (FSGS). Mean (SD) SF-12 PCS and MCS of IgAN care-partners were 53.3 (8.8) and 47.9 (10.8), respectively (FSGS: 47.0 [10.6], 49.4 [9.5]). Mild to moderate anxiety was reported in 31.8% (IgAN) and 42.9% (FSGS) of care-partners, with one IgAN care-partner (4.6%) reporting severe anxiety. Mild to moderate depression was reported in 27.3% (IgAN) and 71.4% (FSGS) of care-partners, with two IgAN care-partners (9.1%) reporting moderately severe or severe depression. Among employed IgAN care-partners (86.4%), mean percent absenteeism was reported at 14.2%, presenteeism at 9.3%, and overall work productivity loss at 9.9% due to IgAN-related reasons. Mean percent activity impairment was reported at 18.6% in IgAN and 17.1% in FSGS care-partners. Conclusion Patients with IgAN and FSGS in Europe experience impaired HRQoL compared to previously published European population estimates, as well as anxiety, depression, and impaired productivity. Care-partners of these patients also experience impaired HRQoL, in terms of mental components, and reduced overall productivity.