Remission Of Proteinuria Research Articles

Long-term outcomes of IgA nephropathy in China.

The long-term prognosis of IgA nephropathy (IgAN) and the optimal target for proteinuria treatment remain controversial. This study, utilizing a large prospective cohort from China, aims to assess the long-term outcomes of IgAN and to explore the definition of proteinuria remission. We enrolled 2 141 patients with biopsy-proven IgAN, all with at least 12 months of follow-up, from a prospective IgAN cohort at Peking University First Hospital. We utilized Kaplan-Meier analysis, Cox regression, and an eGFR slope calculated via a linear mixed model to investigate kidney outcomes. The median (Q1, Q3) baseline proteinuria was 1.26 (0.65, 2.40) g/d, and the estimated GFR was 80 (52, 103) mL/min/1.73m2. After a mean follow-up of 5.8 (±4.4) years, 509 (24%) patients progressed to end-stage kidney disease (ESKD). The median kidney survival time was 12.4 years, the annual event rate of ESKD was 41.1 per 1000 person-years, and the 15-year kidney survival rate was 40%. Time-averaged proteinuria level was strongly associated with kidney failure (adjusted HR: 1.76, 95%CI: 1.65 to 1.88). Restriction cubic spline analysis indicated that the risk of ESKD increases rapidly when time-average proteinuria exceeded 0.5g/d. There was no significant difference in long-term kidney survival between patients with proteinuria<0.3g/d and those with 0.3-0.5g/d, with both groups demonstrating a better prognosis. The long-term outcomes for patients with IgAN under current treatment strategies remain poor, with most progressing to ESKD within 15 years. Patients with time-averaged proteinuria≥0.5g/d experience worse kidney outcomes, challenging the previous view that proteinuria<1.0g/d was associated with a low risk of kidney failure.

The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and leads to end-stage kidney disease. The proteinuria selectivity index (PSI) has been used to assess the prognosis in nephrotic syndrome, but its predictive value in patients with IgAN remains unclear. This single-center retrospective cohort study included patients who diagnosed with IgAN between March 2012 and March 2020. The PSI was calculated at the time of kidney biopsy. Patients were followed up from the time of kidney biopsy to kidney replacement therapy, death, transfer to another facility, or study completion. Ninety-four patients with a median age of 51 years were enrolled and divided according to the cutoff value of PSI determined by the receiver operating characteristic curve analysis into low-PSI (PSI <0.243, n = 39) and high-PSI groups (PSI ≥0.243, n = 55). The median follow-up duration was 70 months. Rates of remission of proteinuria and survival without a two-fold increase in serum creatinine were significantly better in the low-PSI group (both p < 0.01, log-rank test). Cox regression analysis showed that a low PSI was significantly associated with an increased likelihood of remission of proteinuria and hematuria (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.02–3.85 and HR 1.75; 95% CI 1.01–3.13, respectively), and a decreased risk of a two-fold increase in serum creatinine (HR 0.10; 95% CI 0.01–0.81). In conclusion, The PSI could have the potential to support the assessment of the prognosis of IgAN, in addition to established prognostic markers, by reflecting the overall glomerular permeability.

Changes in urine dipstick proteinuria and its relation to the risk of diabetic retinopathy and neuropathy.

Proteinuria is considered as a predictor for cardiovascular complications in diabetes mellitus (DM). However, no study has examined the association between changes in proteinuria and the risk of diabetic microvascular complications. Study participants were 71,825 DM patients who received urine dipstick test for proteinuria both in 2003-2004 and 2006-2007. They were categorized into four groups according to changes in proteinuria over 3 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1+). Cox-proportional hazard model was used in assessing the adjusted hazard ratios (HR) and 95% confidence interval (CI) for incidence of retinopathy, and neuropathy (adjusted HR [95% CI]). In all of DM patients, risk for comprehensive incidence of retinopathy and neuropathy increased in all types of proteinuria changes. In type 1 DM, HR for retinopathy and neuropathy generally increased in order of negative (reference), resolved (2.175 [1.150-4.114] and 1.335 [0.909-1.961]), incident (2.088 [1.185-3.680] and 1.753 [1.275-2.409]), and persistent proteinuria (1.314 [0.418-4.134] and 2.098 [1.274-3.455]). This pattern of relationship was similarly observed in type 2 DM for retinopathy and neuropathy: negative (reference), resolved (1.490 [1.082-2.051] and 1.164 [0.988-1.371]), incident (1.570 [1.161-2.123] and 1.291 [1.112-1.500]), and persistent proteinuria (2.309 [1.407-3.788] and 1.272 [0.945-1.712]). Risk for diabetic retinopathy and neuropathy generally increased in order of negative, resolved, incident, and persistent proteinuria. Once manifested proteinuria was associated with the increased risk of diabetic retinopathy and neuropathy even after remission of proteinuria.

Single-dose telitacicept therapy for refractory idiopathic membranous nephropathy: A case series.

We report three cases of IMN from our center, where patients received a single dose of telitacicept after showing no response to conventional treatments. Although one case did not respond, the other two cases achieved complete or partial remission of proteinuria. These cases illustrates the telitacicept may offer new hope for the treatment of IMN. Despite the variety of treatment options available, effective therapies for refractory membranous nephropathy remain lacking. Recently, some reports have suggested that telitacicept is a new therapeutic option. However, only a few published studies have documented the use of telitacicept for treating idiopathic membranous nephropathy (IMN). We present three cases of IMN from our center, where patients received a single dose of telitacicept after showing no response to conventional treatments, including glucocorticoids, tacrolimus, mycophenolate mofetil, cyclophosphamide, cyclosporine, and rituximab. Although one case did not respond, the other two cases achieved complete or partial remission of proteinuria. Thus, telitacicept may offer new hope for the treatment of refractory membranous nephropathy.

Functional echocardiography for management of shock in neonates - study protocol for a randomized controlled trial

Background: Shock is common in sick neonates and is associated with a high mortality. Detection and management of shock by monitoring clinical parameters may be inadequate due to inconsistent association with tissue perfusion. We hypothesize that objective assessments of cardiac functions may help to match the pathophysiology of shock with the pharmacological action of a vasoactive drug. This may lead to earlier resolution of shock and reduced incidence of mortality or brain injury. To test this hypothesis, this study aims to evaluate the efficacy of adding functional echocardiography to standard clinical assessment in improving short-term outcome of neonates with clinical features of shock. Methods: This study will be an open-labeled randomized controlled trial, conducted in all inborn neonates born at &gt;27 weeks of gestation who develop clinical signs of shock. Enrolled neonates will be randomized into two groups: the echo group and the control group. Neonates in the echo group will be assessed for management of shock by both standard clinical evaluation and functional echocardiography. Neonates in the control group will be assessed for the management of shock by standard clinical evaluation. Primary outcome will be survival without requirement of inotropic support at 72 hours of randomization. Secondary outcomes include time to hemodynamic stability, duration of inotropic support and incidence of abnormal cranial ultrasound. Results: Among the 154 patients in the Clinical Trial Group, 70/154 (45%) continued to have proteinuria, while 84/154 (55%) had no proteinuria (remission) compared to 41 (28%) in remission and 104 (72%) with continued proteinuria in the Usual Care group (p&lt;0.001). Conclusions: The trial intends to deduce the advantages, if any, of addition of functional echocardiography to standard clinical assessment to guide management of shock among preterm and term neonates. Trial registration: CTRI number: CTRI/2023/08/056672.

A case of de novo glomerulonephritis following COVID-19 in a patient with preexistent IgA vasculitis.

During the unprecedented COVID-19 outbreak, new-onset or relapsing glomerulonephritis, such as ANCA-associated glomerulonephritis and Immunoglobulin A (IgA) nephropathy, following COVID-19 has been reported. However, to date, the association of COVID-19 with preexistent IgA vasculitis (IgAV) remains unclear. Here, we present the case of a 20-something old Japanese woman with preexistent IgAV who newly developed glomerulonephritis following COVID-19. At the diagnosis of IgAV, she had cutaneous purpura, joint pains, and gastrointestinal symptoms, but no signs of kidney involvement. Three months ago, she was tested positive for COVID-19 and subsequently developed hematuria and proteinuria. She was then admitted to our hospital and renal biopsy showed glomerular mesangial expansion and hypercellularity and cellular and fibrocellular crescents, accompanied by diffuse IgA and C3 deposits. With the diagnosis of de novo IgAV nephritis, the patient was treated with intravenous methylprednisolone followed by oral prednisolone. She had favorable responses to this treatment and has achieved and maintained the remission of hematuria and proteinuria after initiation of glucocorticoid therapy. Our case highlights that immune response to SARS-CoV-2 infection could trigger the onset of glomerulonephritis in the IgAV patients who have no renal involvement.

Clinical and genetic analysis of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy

To explore the genetic etiology and clinical outcome of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy. A child who was admitted to Peking University First Hospital on March 2, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples from the child and his parents and sister. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing. This study was approved by the Peking University First Hospital (Ethics No. 2016[1029]). The child, a 7-year-old boy who had developed proteinuria 8 months before, was diagnosed with IgA nephropathy (M1E1S1T1C1). With steroid, cyclophosphamide, cyclosporine and angiotensin-converting enzyme inhibitor therapy, partial remission of proteinuria was achieved. However, his serum creatinine level had increased from 53.8 mol/L at the onset of disease to 86.7 mol/L after 3.9 years, along with massive proteinuria. Kidney biopsy still indicated IgA nephropathy (M0E0S1T0C0). The child was found to harbor a homozygous c.737G>A (p.Ser246Asn) missense variant of the COQ8B gene, for which his parents and sister were heterozygous carriers. The variant was predicted to be pathogenic (PS1+PM2_Supporting+PM3+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics. The child was treated with high-dose coenzyme Q10 in combination with steroid and/or mycophenolate mofetil, though his serum creatinine level still increased to 286 mol/L after 7.3 years, which conformed to a chronic kidney disorder with glomerular filtration rate category of G3b. The homozygous c.737G>A missense variants of the COQ8B gene probably underlay the progressive kidney dysfunction in this child. For children with IgA nephropathy presenting with atypical clinical manifestations, unsatisfactory therapeutic effect, and/or early onset of kidney function decline, coexistence of other diseases should be suspected.

Proteinuria as an Endpoint in Clinical Trials of Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis (FSGS) is a characteristic histopathological lesion that is indicative of underlying glomerular dysfunction. It is not a single disease entity but rather a heterogeneous disorder that is an important cause of nephrotic syndrome and kidney failure in children and adults. The aim of this Kidney Health Initiative project was to evaluate potential endpoints for clinical trials in FSGS. This paper focuses on the data supporting proteinuria as a surrogate endpoint. Available data support the use of complete remission of proteinuria in patients with heavy proteinuria as a surrogate endpoint for progression to kidney failure. While substantial treatment effects on proteinuria that are short of a complete remission may also predict the effect of a treatment on progression to kidney failure, further work is needed to determine how such an endpoint should be defined. Fortunately, efforts are underway to bring together patient-level data from randomized controlled trials, observational studies, and registries to address this issue.

Urinary Proteomics Identify Biomarkers for Predicting Complete Remission of Proteinuria in Pediatric IgA Nephropathy

Urinary Proteomics Identify Biomarkers for Predicting Complete Remission of Proteinuria in Pediatric IgA Nephropathy

Lipidomics Analysis Reveals Biomarkers for Proteinuria Remission and Disease Progression in FSGS/Minimal Change Disease (MCD) from the NEPTUNE Cohort

Lipidomics Analysis Reveals Biomarkers for Proteinuria Remission and Disease Progression in FSGS/Minimal Change Disease (MCD) from the NEPTUNE Cohort

Association of Proteinuria Remission and Its Timing with Kidney Outcomes in Patients with Focal Segmental Glomerulosclerosis

Association of Proteinuria Remission and Its Timing with Kidney Outcomes in Patients with Focal Segmental Glomerulosclerosis

Implications of Proteinuria Remission on Estimated Glomerular Filtration Rate (eGFR) Trajectory in Patients with IgA Nephropathy in the PROTECT Trial

Implications of Proteinuria Remission on Estimated Glomerular Filtration Rate (eGFR) Trajectory in Patients with IgA Nephropathy in the PROTECT Trial

Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials

BackgroundSparsentan has shown positive effects on managing different subtypes of glomerulonephritis. The recent results of trials require a pooled analysis to validate these results.AimWe aim to assess the safety and efficacy of sparsentan versus irbesartan for patients with IgA nephropathy and focal glomerulosclerosis (FSGS).MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials retrieved by systematically searching PubMed, Web of Science, Scopus, and Cochrane through March 2024. We used Review Manager v.5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI).ResultsThree studies with a total of 884 patients were included. Sparsentan was superior to irbesartan in improving urine protein to creatinine ratio (UP/C) (ratio of percentage reduction 0.66, 95% CI [0.58 to 0.74], P < 0.001); as well as the proportion of patients achieved complete and partial remission of proteinuria (RR = 2.57, 95% CI [1.73 to 3.81], P < 0.001) and (RR = 1.63, 95% CI [1.4 to 1.91], P < 0.001) respectively. Regarding the effect on the glomerular filtration rate, the results estimate did not favor either sparsentan or irbesartan (MD = 1.98 ml/min per 1.73mm2, 95% CI [-1.05 to 5.01], P = 0.2). There were no significant differences in adverse events except for hypotension, which showed higher rates in the sparsentan group (RR = 2.02, 95% CI [1.3 to 3.16], P = 0.002).ConclusionSparsentan is effective and has a good safety profile for treating FSGS and patients with IgA nephropathy. However, more well-designed RCTs against ARBs, ACE inhibitors, and steroids with larger sample sizes are needed to get conclusive evidence.

The risk factor for adverse pregnancy outcomes and its impact on clinical effect in IgA nephropathy: A retrospective observational study.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Pregnant IgAN patients are more susceptible to adverse pregnancy outcomes (APO). However, the risk factor for APO and its effects on the long-term renal outcome of pregnant IgAN patients remained unclear. We performed a retrospective observational study covering 2003-2019 that included 44 female IgAN patients with pregnancy history to investigate the risk factor for APO and its impact on clinical outcome in IgAN. Renal function outcome and proteinuria remission were evaluated in pregnant IgAN women with and without APO. In this retrospective and observational study, we found that patients with APO exhibited higher levels of serum creatinine and IgM, and lower haemoglobin levels while other clinical characteristics, pathological characteristics and therapy protocol had no significant difference. We found that anaemia and a higher level of serum IgM were independent risk factors for APO. IgAN pregnant women without APO experienced a higher proportion of proteinuria remission than those with APO, but there is no difference in the renal function outcome. Pregnant IgAN patients with higher risks, including lower haemoglobin levels and higher IgM levels deserve intensive monitoring, and aggressive therapy to reduce proteinuria should be carried out in pregnant IgAN patients with APO.

Prognosis of IgA nephropathy patient with proteinuria remission by supportive therapy: cohort from screening failed Chinese patients in TESTING study

Background During the run-in phase of the TESTING study, approximately half of patients with IgA nephropathy (IgAN) were excluded due to proteinuria below 1 g/24 h after intensive supportive therapy. The long-term prognosis of these patients needs further investigation. Methods 112 screening failed patients in the TESTING study from 10 centers in China were enrolled in this retrospective study. The prognosis of 88 patients, who were excluded because of proteinuria below 1 g/24 h, was analyzed by Landmark Kaplan-Meier analysis. The composite kidney endpoint was defined by a ≥ 50% reduction in eGFR, ESKD (eGFR <15 mL/min per 1.73 m2), chronic dialysis for at least 6 months, or renal transplantation. Results In total, 88 patients were excluded due to proteinuria less than 1 g/24 h. During the follow-up, 73/88 (83.0%) patients received renin-angiotensin system blocker. 72/88 (81.8%) had stable proteinuria remission and did not receive immunosuppressive therapy (IST), and 16/88 (18.2%) received IST because of a relapse of proteinuria. Landmark Kaplan–Meier analysis revealed that, the kidney survival from dialysis or composite kidney outcome of these excluded patients with IST was similar to those without IST during the early stages of follow-up (dialysis, before 60 months, p = 0.778; composite kidney outcome, before 48 months, p = 0.862); whereas the risk for dialysis of patients receiving IST was significantly higher than those without IST after 60 months (OR = 11.3, p = 0.03). Similarly, the risk for the composite kidney outcome of patients receiving IST was also significantly higher than those without IST after 48 months (OR = 5.92, p = 0.029). Conclusions IgAN patients who maintained a persistent remission of proteinuria after intensive supportive therapy had a much better long-term kidney outcome than those who experienced a relapse of proteinuria and needed IST.

Combination Therapy With Rituximab and Low-Dose Cyclophosphamide and Prednisone in Membranous Nephropathy

IntroductionStandard treatment with cyclophosphamide or rituximab is suboptimal. We adapted and used the low dose regimen used in vasculitis (rituximab 2*1000mg; cyclophosphamide 1.5mg/kg/day * 8weeks and prednisone (iv 2* 1gr + 3 weeks oral starting at 1mg/kg). MethodsHigh-risk, anti-PLA2R antibodies (PLA2Rab) positive MN patients were included in this single-arm prospective cohort study. PLA2Rab levels were regularly measured. We report PLA2Rab kinetics and overall immunological and clinical remission (CR) rate. ResultsWe analyzed 26 patients (15 males, age 57 ± 14 years, PLA2Rab titer 176 RU/ml [115-460], Screatinine 128 μmol/l [102-136], Salbumin 18 g/l [14-21] and uPCR 7.1 gram/10 mmol [5.7-10]). Within 8 weeks IR (ELISA < 14RU/ml) was 88 %. Proteinuria remission after initial therapy developed in 21 patients. Seven patients received renewed therapy, which resulted in proteinuria remission in all. IR and CR were associated with baseline PLA2Rab tertile. Five of 7 patients in need of additional therapy were identified at 4 weeks after start of therapy by PLA2Rab T ½> 7 days. Serious adverse events occurred in four patients. Adverse events were mild, leukopenia was most frequent. ConclusionLow-dose triple therapy induced a rapid IR and CR in the majority of patients. Patients with insufficient clinical response were characterized by high baseline PLA2Rab levels and longer PLA2Rab T ½. Assessment of PLA2Rab levels within 2-4 weeks after start of therapy may enable to identify patients who need more intensive therapy.

Clinicopathological features and outcomes of PLA2R-related membranous nephropathy with renal glycosuria.

Membranous nephropathy (MN) is an immune complex-mediated disease. Massive proteinuria can lead to Fanconi syndrome, clinically manifesting as renal glycosuria. The prevalence and prognosis of M-type phospholipase A2 receptor (PLA2R)-related MN with renal glycosuria remain unknown. Patients diagnosed with PLA2R-related MN with renal glycosuria were reviewed, and the control group comprised patients with MN without renal glycosuria who were randomly selected at a ratio of 1:3. 50 patients diagnosed with PLA2R-related MN with renal glycosuria from January 2015 to January 2020 were included, with a prevalence of 2.3%. Compared with patients without renal glycosuria, those with renal glycosuria exhibited greater proteinuria, lower estimated glomerular filtration rate (eGFR), and higher use of diuretics, anticoagulants, antibiotics, traditional Chinese medicine, and tacrolimus within 3 months prior to renal biopsy (all p<0.05). Histologically, patients with renal glycosuria exhibited more severe pathological stages, acute/chronic tubulointerstitial lesions, and tubulointerstitial inflammation (all p<0.05). Of the 10 patients treated with rituximab (RTX), proteinuria remission was maintained in 6 (60%) patients, and urine glucose remission was achieved in 5 of these 6 patients (83.3%). Multivariate Cox regression analysis showed that renal glycosuria and age &gt;50 years were independent risk factors for end-stage renal disease (ESRD) or a 30% reduction in the eGFR in patients with PLA2R-related MN. PLA2R-related MN patients with renal glycosuria presented with more severe clinicopathological manifestations and worse prognoses. Nephrotoxic drugs should be administered rationally, and RTX should be considered as a promising treatment option.

Correlation of Urinary Soluble CD163 Levels With Disease Activity and Treatment Response in IgA Nephropathy

BackgroundThe TESTING trial demonstrated that corticosteroids reduce the risk of kidney failure in IgA nephropathy (IgAN) patients but increase the risk of serious adverse events. Reliable noninvasive biomarkers are needed to identify patients who would benefit most from corticosteroid therapy. Previous studies suggest glomerular macrophage infiltration is associated with the response to immunosuppressive therapy in IgAN and urinary soluble CD163(u-sCD163, a marker of M2c macrophage) is correlated with clinical remission in vasculitis. This study aims to investigate the association between u-sCD163 and response of steroids therapy in IgAN. MethodsWe measured u-sCD163 in patients from a large IgAN cohort including China participants of the TESTING trial. The correlation of baseline or serial u-sCD163 and their response of corticosteroids therapy or kidney outcomes were investigated. ResultsIn cross-sectional analysis, u-sCD163 levels correlated with kidney macrophage infiltration, especially in crescentic areas, and with active lesions. Subgroup analysis of the TESTING cohort showed higher levels u-sCD163 were associated with greater benefits from corticosteroids therapy in proteinuria remission [OR, 35.56 (95% CI, 7.62-292.34) vs 3.94 (95% CI, 1.39-12.93), p for interaction 0.036]. Corticosteroids therapy significantly reduced u-sCD163 levels at 6th month compared to placebo group [79% (IQR 58%,91%) vs 37% (-11%,58%), P<0.001]. There was no difference in the suppressive effects on u-sCD163 by either dosage of corticosteroids (full and reduced-dose). The suppression of u-sCD163 was significantly associated with a reduced risk of kidney progression events (adjusted HR 0.52,95% CI 0.30 to 0.93, P=0.027). ConclusionsU-sCD163 is a reliable noninvasive biomarker associated with active pathological lesions in IgAN and can guide glucocorticoid therapy.

The Immunosuppressive Drug LF15-0195 Acts Also on Glomerular Lesions, by a Change in Cytoskeleton Distribution in Podocyte

Introduction: Buffalo/Mna rats spontaneously develop nephrotic syndrome (NS) which recurs after renal transplantation. The immunosuppressive drug LF15-0195 can promote regression of the initial and post-transplantation nephropathy via induction of regulatory T cells. We investigate if this drug has an additional effect on the expression and localization of podocyte specific proteins. Methods: Buffalo/Mna kidney samples were collected before and after the occurrence of proteinuria, and after the remission of proteinuria induced by LF15-0195 treatment and compared by quantitative RT-PCR, Western blot, electron, and confocal microscopy to kidney samples of age-matched healthy rats. Cytoskeleton changes were assessed in culture by stress fibers induction by TNFα. Results: We observed, by electron microscopy, a restoration of foot process architecture in the LF15-0195-treated Buff/Mna kidneys, consistent with proteinuria remission. Nephrin, podocin, CD2AP, and α-actinin-4 mRNA levels remained low during the active disease in the Buff/Mna, in comparison with healthy rats which increase, while podocalyxin and synaptopodin transcripts were elevated before the occurrence of the disease but did not differ from healthy animals after. No difference in the mRNA and protein expression between the untreated and the LF15-0195-treated proteinuric Buff/Mna were seen for these 6 proteins. No changes were observed by confocal microscopy in the protein distribution at a cellular level, but a more homogenous distribution similar to healthy rats, was observed within the glomeruli of LF15-0195-treated rats. In addition, LF15-0195 could partially restore actin cytoskeleton of endothelial cells in TNFα-induced-cell stress experiment. Conclusion: The effect of LF15-0195 treatment appears to be mediated by 2 mechanisms: an immunomodulatory effect via regulatory T cells induction, described in our previous work and which can act on immune cell involved in the disease pathogenesis, and an effect on the restoration of podocyte cytoskeleton, independent of expression levels of the proteins involved in the slit diaphragm and podocyte function, showed in this article.

Clinical Relevance of Computationally Derived Tubular Features: Spatial Relationships and the Development of Tubulointerstitial Scarring in MCD/FSGS.

Visual scoring of tubular damage has limitations in capturing the full spectrum of structural changes and prognostic potential. We investigate if computationally quantified tubular features can enhance prognostication and reveal spatial relationships with interstitial fibrosis. Deep-learning and image-processing-based segmentations were employed in N=254/266 PAS-WSIs from the NEPTUNE/CureGN datasets (135/153 focal segmental glomerulosclerosis and 119/113 minimal change disease) for: cortex, tubular lumen (TL), epithelium (TE), nuclei (TN), and basement membrane (TBM). N=104 pathomic features were extracted from these segmented tubular substructures and summarized at the patient level using summary statistics. The tubular features were quantified across the biopsy and in manually segmented regions of mature interstitial fibrosis and tubular atrophy (IFTA), pre-IFTA and non-IFTA in the NEPTUNE dataset. Minimum Redundancy Maximum Relevance was used in the NEPTUNE dataset to select features most associated with disease progression and proteinuria remission. Ridge-penalized Cox models evaluated their predictive discrimination compared to clinical/demographic data and visual-assessment. Models were evaluated in the CureGN dataset. N=9 features were predictive of disease progression and/or proteinuria remission. Models with tubular features had high prognostic accuracy in both NEPTUNE and CureGN datasets and increased prognostic accuracy for both outcomes (5.6%-7.7% and 1.6%-4.6% increase for disease progression and proteinuria remission, respectively) compared to conventional parameters alone in the NEPTUNE dataset. TBM thickness/area and TE simplification progressively increased from non- to pre- and mature IFTA. Previously under-recognized, quantifiable, and clinically relevant tubular features in the kidney parenchyma can enhance understanding of mechanisms of disease progression and risk stratification.