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Background Polyomavirus (PyV) nephropathy (PyVN) leads to kidney transplant dysfunction and loss. Since a definitive diagnosis requires an invasive kidney biopsy, a timely diagnosis is often hampered. In this clinical dilemma the PyV haufen-test, centering around the detection of 3-dimensional PyV aggregates in the urine, might provide crucial diagnostic information. Methods A multistep experimental design was used. The hypothesis was that PyV-haufen form within the kidneys under high concentrations of uromodulin, a kidney-specific protein and that PyV-haufen are, therefore, kidney-specific disease biomarkers. Results The first investigative step showed colocalization of uromodulin with aggregated PyV (1) in 10 kidneys with PyVN by immunohistochemistry, (2) in urine samples containing PyV-haufen by electron microscopy/immunogold labeling (n = 3), and (3) in urine samples containing PyV-haufen by immunoprecipitation assays (n = 4). In the in vitro experiments of the next step, only high uromodulin concentrations (≥1.25 mg/mL) aggregated PyV, as is expected to occur within injured nephrons. In contrast, in voided urine samples (n = 59) uromodulin concentrations were below aggregation concentrations (1.2−19.6 µg/mL). In the third investigative step, none of 11 uromodulin−/− knockout mice (0%) with histologic signs of PyVN showed urinary PyV-haufen shedding, compared with 10 of 14 uromodulin+/+ wild-type mice (71%). Conclusions PyV-haufen form within kidneys under high uromodulin concentrations. Thus, PyV-haufen detected in the urine are specific biomarkers for intrarenal disease (ie, definitive PyVN). [ABSTRACT FROM AUTHOR]

Objectives Reportedly, patients with LN and low-level proteinuria have favourable short-term renal outcomes. We aimed to clarify the long-term renal outcomes and overall survival of these patients, and the significance of renal biopsy in the early phase with low-level proteinuria. Methods We included 144 Japanese patients with biopsy-proven LN from 10 hospitals. Low-level proteinuria was defined by a urine protein:creatinine ratio (UPCR) of ≤1 g/gCr based on previous reports. The outcomes were end-stage renal disease (ESRD) and death. Results Compared with patients with high-level proteinuria (UPCR >1 g/gCr), those with low-level proteinuria [ n  = 67 (46.5%)] had significantly improved renal function at the time of renal biopsy, and low activity index and chronicity index while the frequency of class III/IV was similar (79.1% vs 84.4%, P  = 0.409). In patients with low-level proteinuria, CYC usage was less, and the incidences of ESRD (3.0% vs 13.0%, P  = 0.036) and death (3.0% vs 16.9%, P  = 0.006) during the total observation period (median, 72 months) were low. Kaplan–Meier analysis showed significant differences in the incidence of ESRD and death between the groups. Multivariate Cox regression analysis revealed that the significant risk factors for ESRD were high chronicity index and hypertension, whereas those for death were increased age and high-level proteinuria. Conclusion Patients with LN and low-level proteinuria had favourable long-term renal and life outcomes. As these patients have substantial active pathological lesions, renal biopsy in the early phase with low-level proteinuria could enable early diagnosis and treatment and thus improve prognosis. [ABSTRACT FROM AUTHOR]

Objective This retrospective study evaluated tolvaptan's efficacy, safety, and predictive indicators in managing volume overload in chronic kidney disease (CKD) patients. Methods CKD patients with volume overload, treated with loop diuretics alone or with tolvaptan at Zhongda Hospital, Southeast University, from 1 March 2022 to 31 December 2023, were included. Patients were divided into loop diuretic (Group C) and loop diuretic combined with tolvaptan (Group T) cohorts. Primary outcomes included volume control, changes in weight, urine output, and laboratory parameters within 1 week post-medication. Adverse events such as hypernatremia and hyperkalemia, etc. were recorded. We further conducted immunohistochemical staining of renal biopsy tissues to investigate the roles of aquaporin-2 (AQP2) in the collecting duct and plasma albumin in predicting the efficacy of tolvaptan. Results Of 174 CKD patients with volume overload, 108 (67.07%) were male. Group C and Group T each comprised 87 patients. At baseline, no significant differences in urine output and weight were noted. By day 3, Group T exhibited a greater increase in urine output (P  < .001) and weight reduction (P  < .001). At day 7, Group T maintained more significant diuretic effects (P  < .001). More Group C patients required ultrafiltration therapy (P  = .040). Adverse event rates did not significantly differ. Notably, AQP2 expression in the collecting duct may predict tolvaptan responsiveness, while plasma albumin did not affect efficacy. Conclusion Tolvaptan showed efficacy and safety in managing volume overload in CKD patients. The expression of AQP2 in the collecting duct could predict tolvaptan's efficacy. This study protocol was approved by the Ethics Committee of Zhongda Hospital Affiliated to Southeast University (Approval No. 2023ZDSYLL180-P01, Clinical Trial Registration No. ChiCTR2300075274, Trial Registration Link: https://www.chictr.org.cn/guide.html). [ABSTRACT FROM AUTHOR]

The discovery of the target antigen M-type phospholipase A2 receptor (PLA2R) with the possibility to detect anti-PLA2R antibodies in serum as well as the identification of several other antigens, overall accounting for almost all cases of membranous nephropathy, paved the way to a revolutionary change in the classification of membranous nephropathy. Serum anti-PLA2R autoantibody titers have been found to be highly specific diagnostic and prognostic biomarkers. Therefore, a positive test for anti-PLA2R serology in patients who present with nephrotic syndrome, normal kidney function, and no evidence of another process to account for proteinuria is believed to suffice to make a diagnosis of primary membranous nephropathy, thus removing the need for a renal biopsy. While technological advances will likely allow this proposal to prevail in the near future, the reasons why renal biopsy could still remain a critical tool for the management of membranous nephropathy in real life are discussed. [ABSTRACT FROM AUTHOR]

Objectives ChatGPT (OpenAI, San Francisco, CA) has shown impressive results across various medical examinations, but its performance in kidney pathology is not yet established. This study evaluated proficiencies of GPT-4 Vision (GPT-4V), an updated version of the platform with the ability to analyze images, on kidney pathology questions and compared its responses with those of nephrology trainees. Methods Thirty-nine questions (19 text-based questions and 20 with various kidney biopsy images) designed specifically for the training of nephrology fellows were employed. Results GPT-4V displayed comparable accuracy rates in the first and second runs (67% and 72%, respectively, P  =  .50). The aggregated accuracy, however—particularly, the consistent accuracy—of GPT-4V was lower than that of trainees (72% and 67% vs 79%). Both GPT-4V and trainees displayed comparable accuracy in responding to image-based and text-only questions (55% vs 79% and 81% vs 78%, P  =  .11 and P  =  .67, respectively). The consistent accuracy in image-based, directly asked questions for GPT-4V was 29%, much lower than its 88% consistency on text-only, directly asked questions (P  =  .02). In contrast, trainees maintained similar accuracy in directly asked image-based and text-based questions (80% vs 77%, P  =  .65). Although the aggregated accuracy for correctly interpreting images was 69%, the consistent accuracy across both runs was only 39%. The accuracy of GPT-4V in answering questions with correct image interpretation was significantly higher than for questions with incorrect image interpretation (100% vs 0% and 100% vs 33% for the first and second runs, P  =  .001 and P  =  .02, respectively). Conclusions The performance of GPT-4V in handling kidney pathology questions, especially those including images, is limited. There is a notable need for enhancement in GPT-4V proficiency in interpreting images. [ABSTRACT FROM AUTHOR]

Background Kidney involvement is common in anti-neutrophil cytoplasm antibody–associated vasculitis (AAV) and the prognosis is determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV. Methods The dataset included 848 patients with newly diagnosed AAV who participated in seven randomized controlled trials (RCTs) (1995–2012). Follow-up information was obtained from questionnaires sent to the principal investigators of the original RCTs. Results The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared with those with preserved kidney function (hazard ratio 2.8, P  < .001). Comparing patients with AAV and kidney involvement with a matched general population, patients with AAV had poor survival outcomes, even in early stages of chronic kidney disease. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. Some 34% of patients with initial need for dialysis recovered kidney function after treatment. Thirty-five out of 175 in need of kidney replacement therapy (KRT) during follow-up received a kidney transplant with good outcome; there was 86% patient survival at 10 years. In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score and the Mayo Clinic Score. The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P  < .001 and P  = .001, respectively). The Renal Risk Score demonstrated a moderate prediction of kidney survival (area under the curve 0.79; standard error 0.03, 95% confidence interval 0.71–0.83). Conclusions Early diagnosis of AAV is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome. [ABSTRACT FROM AUTHOR]

Background Idiopathic nephrotic syndrome (NS) in children poses treatment challenges, with a subset developing steroid-resistant nephrotic syndrome (SRNS). Genetic factors play a role, yet data on paediatric SRNS genetics in India are scarce. We conducted a prospective study using whole-exome sequencing to explore genetic variants and their clinical correlations. Methods A single-centre prospective study (October 2018–April 2023) enrolled children with SRNS, undergoing renal biopsy and genetic testing per institutional protocol. Clinical, histological, and genetic data were recorded. DNA isolation and next-generation sequencing were conducted for genetic analysis. Data collection included demographics, clinical parameters, and kidney biopsy findings. Syndromic features were evaluated, with second-line immunosuppressive therapy administered. Patient and renal outcomes are presented for patients with and without genetic variants. Results A total of 680 paediatric NS patients were analysed, with 121 (17.8%) having SRNS and 96 consent to genetic analysis. 69 (71.9%) had early SRNS, 27 (28.1%) late. Among participants, 62 (64.58%) had reportable genetic variants. The most common were in COL4A genes, with 20 (31.7%) positive. Renal biopsy showed focal segmental glomerulosclerosis in 31/42 (74%) with variants, 16/28 (57.1%) without variants. Second-line immunosuppressions varied, with CNIs the most common. Outcomes varied, with partial or complete remission achieved in some while others progressed to ESRD. Conclusion The study underscores the importance of genetic analysis in paediatric SRNS, revealing variants in 65.7% of cases. COL4A variants were predominant. Variants correlated with varied renal outcomes, highlighting potential prognostic implications. These findings emphasize the value of personalized approaches and further research in managing paediatric SRNS. [ABSTRACT FROM AUTHOR]

Background In contrast to childhood minimal change disease (MCD), adult-onset MCD frequently recurs and requires prolonged immunosuppressive therapy. Accordingly, an investigation of the pathogenesis of adult MCD is required. MCD is usually accompanied by severe dyslipidaemia. Oxidized low-density lipoprotein (ox-LDL) is known to function in a damage-associated molecular pattern (DAMP) through CD36, triggering the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and programmed cell death called pyroptosis. However, the relationship between MCD pathogenesis and NLRP3 inflammasome/pyroptosis activation via CD36 is not fully understood. Methods We conducted comprehensive histological and clinical evaluations by analysing renal biopsy (RBx) specimens and urine samples obtained from 26 patients with MCD. These samples were compared with control kidneys from 15 transplant donors and urine samples from 15 healthy volunteers. Results The number of podocytes was lower in the MCD group than in the control group. Urinary ox-LDL levels were higher in the MCD group than in the control group. Immunofluorescence staining revealed that NLRP3 and CD36 were upregulated in MCD podocytes. Urinary interleukin (IL)-18 levels increased in patients with MCD. Steroid therapy performed before RBx appeared to maintain the podocyte number and reduce urinary ox-LDL and IL-18 levels. Conclusion In MCD, the NLRP3 inflammasome and pyroptosis cascade seem to be activated via upregulation of CD36 in podocytes, associated with increased urinary ox-LDL. Elevated urinary IL-18 levels suggest that pyroptosis may occur in MCD. Further research is required to confirm the significance of the podocyte NLRP3 inflammasome/pyroptosis in MCD. [ABSTRACT FROM AUTHOR]

Background Genetic variants in SEC61A1 are associated with autosomal dominant tubulointerstitial kidney disease. SEC61A1 is a translocon in the endoplasmic reticulum membrane and variants affect biosynthesis of renin and uromodulin. Methods A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis. Genetic evaluation was performed by whole genome sequencing. Results The patient has a novel de novo heterozygous SEC61A1 variant, Phe458Val. Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low. Kidney biopsy at 2 years exhibited subtle changes suggestive of tubular dysgenesis without tubulocystic or glomerulocystic lesions and with renin staining of the juxtaglomerular cells. The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being. Blood pressure and potassium normalized. Biopsy at 9 years showed extensive glomerulosclerosis and mild tubulointerstitial fibrosis, as well as tubular mitochondrial abnormalities, without specific diagnostic changes. Her GFR improved to 54 ml/min/1.73m2. Conclusions As the renin-angiotensin system promotes aldosterone release, and the patient had repeatedly undetectable aldosterone levels, the SEC61A1 variant presumably contributed to severe hypotension. Treatment with a mineralocorticoid had a beneficial effect and corrected the electrolyte and acid-base disorder. We suggest that the increased blood pressure hemodynamically improved the patient's kidney function. [ABSTRACT FROM AUTHOR]

Background This study validates the application of Systematized Nomenclature of Medicine second edition (SNOMED II) codes used to describe medical kidney biopsies in Denmark in encoded form, aiming to support robust epidemiological research on the causes, treatments and prognosis of kidney diseases. Methods Kidney biopsy reports from 1 January 1998 to 31 December 2018 were randomly extracted from the Danish National Patobank, using SNOMED codes. A 5% sample was selected, and nephrologists assessed the corresponding medical records, assigning each case the applied clinical diagnoses. Sensitivity, specificity, positive predictive values (PPV), negative predictive values and Cohen's kappa coefficient for the retrieved SNOMED codes were calculated. Results A total of 613 kidney biopsies were included. The primary clinical disease groups were glomerular disease (n  = 368), tubulointerstitial disease (n  = 67), renal vascular disease (n  = 51), diabetic nephropathy (n  = 51) and various renal disorders (n  = 40). Several SNOMED codes were used to describe each clinical disease group and PPV for the combined SNOMED codes were high for glomerular disease (94%), diabetic nephropathy (85%) and systemic diseases affecting the kidney (96%). Conversely, tubulointerstitial disease (62%), renal vascular disease (60%) and other renal disorders (17%) showed lower PPV. Conclusions SNOMED codes have a high PPV for glomerular diseases, diabetic nephropathy and systemic diseases affecting the kidney, in which they could be applied for future epidemiological research. [ABSTRACT FROM AUTHOR]

Background Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN. Methods We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n  = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n  = 18) and ATN (n  = 21). The findings were validated in an independent cohort from another institution (n  = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN. Results Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P  = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P  = .021).  In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%.  In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P  = .02). The proportion of patients having >2.64/mm2 PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P  = .034). There was a positive correlation (P  = .009, r  = 0.72) between usPD-1 and the number of PD-L1 positive tubules. Conclusions UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort. [ABSTRACT FROM AUTHOR]

Background Idiopathic nephrotic syndrome (INS) is a heterogenous disease and current classification is based on observational responses to therapies or kidney histology. The National Unified Renal Translational Research Enterprise (NURTuRE)-INS cohort aims to facilitate novel ways of stratifying INS patients to improve disease understanding, therapeutics and design of clinical trials. Methods NURTuRE-INS is a prospective cohort study of children and adults with INS in a linked biorepository. All recruits had at least one sampling visit collecting serum, plasma, urine and blood for RNA and DNA extraction, frozen within 2 hours of collection. Clinical histology slides and biopsy tissue blocks were also collected. Results A total of 739 participants were recruited from 23 centres to NURTuRE-INS, half of whom were diagnosed in childhood [ n  = 365 (49%)]. The majority were white [ n  = 525 (71%)] and the median age at recruitment was 32 years (interquartile range 12–54). Steroid-sensitive nephrotic syndrome (SSNS) was the most common clinical diagnosis [ n  = 518 (70%)]. Of patients diagnosed in childhood who underwent a kidney biopsy, for SSNS (n  =103), 76 demonstrated minimal change disease (MCD), whereas for steroid-resistant nephrotic syndrome (n  =80), 21 had MCD. Almost all patients diagnosed in adulthood had a kidney biopsy [ n  = 352 (94%)]; 187 had MCD and 162 had focal segmental glomerulosclerosis. Conclusions NURTuRE-INS is a prospective cohort study with high-quality biosamples and longitudinal data that will assist research into the mechanistic stratification of INS. Samples and data will be available through a Strategic Access and Oversight Committee. [ABSTRACT FROM AUTHOR]

A study published in the journal Nephrology Dialysis Transplantation examined the effectiveness of obinutuzumab in treating frequently-relapsing/steroid-dependent minimal change disease (MCD) in adults. The study found that obinutuzumab, a type II anti-CD20 monoclonal antibody, was effective in achieving remission in patients with FR/SD MCD. The study included six patients, and the treatment involved a combination of glucocorticosteroids and obinutuzumab. Further research is needed to determine the long-term efficacy and safety of obinutuzumab for MCD. The article also discusses the use of obinutuzumab in the treatment of focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) in adult patients. The study included six patients with FSGS or MCD who were treated with obinutuzumab. After treatment, all six patients achieved complete remission, and there were no relapses during the follow-up period. The study suggests that obinutuzumab may be an effective and safe treatment option for adult patients with FSGS or MCD. However, the study has limitations, including a small sample size and short follow-up time, and further research is needed to fully understand the long-term outcomes and mechanisms of obinutuzumab treatment. [Extracted from the article]

Background Diabetic kidney disease (DKD) poses a significant challenge globally as a complication of diabetes. Hyaluronan (HA), a critical non-sulfated glycosaminoglycan in the extracellular matrix, plays a pivotal role in the progression of DKD. This study assesses the predictive significance of HA's corresponding receptor, RHAMM (receptor for HA-mediated motility), in DKD pathogenesis in type 2 diabetes (T2DM) patients. Methods Enzyme-linked immunosorbent assays were utilized to measure plasma and urine levels of HA, CD44 and RHAMM in 99 diabetic patients. Immunohistochemistry staining was employed to examine HA deposition, CD44 and RHAMM expressions from 18 biopsy-proven DKD patients. Spearman correlation analysis, linear regression and receiver operating characteristic (ROC) analysis were conducted to establish associations between plasma HA, CD44 and RHAMM levels, and clinical parameters in DKD patients with T2DM. Results Elevated plasma and urine HA, CD44 and RHAMM levels were notably observed in the severe renal dysfunction group. Plasma RHAMM exhibited positive correlations with HA (r = 0.616, P  < .001) and CD44 (r = 0.220, P  < .001), and a negative correlation with estimated glomerular filtration rate (eGFR) (r = –0.618, P  < .001). After adjusting for other potential predictors, plasma RHAMM emerged as an independent predictor of declining eGFR (β = –0.160, P  < .05). Increased HA, CD44 and RHAMM levels in kidney biopsies of DKD patients were closely associated with heightened kidney injury. The ROC curve analysis highlighted an area under the curve (AUC) of 0.876 for plasma RHAMM, indicating superior diagnostic efficacy compared to CD44 in predicting DKD pathogenesis. The combined AUC of 0.968 for plasma RHAMM, HA and CD44 also suggested even greater diagnostic potential for DKD pathogenesis. Conclusion These findings provide initial evidence that elevated RHAMM levels predict DKD pathogenesis in T2DM patients. The formation of a triple complex involving HA, CD44 and RHAMM on the cell surface shows promise as a targetable biomarker for early intervention to mitigate severe renal dysfunctions. [ABSTRACT FROM AUTHOR]

Introduction This study aimed to analyze the clinical course of TAFRO syndrome in patients through extended follow-up, focusing on recurrent cases and long-term remission. Methods This was a retrospective case series study. We assessed the clinical course of patients diagnosed with TAFRO syndrome between January 2012 and September 2022 at Toranomon Hospital or Toranomon Hospital Kajigaya, excluding those patients who died during the initial hospitalization. Results Twelve patients were included. Baseline characteristics, laboratory findings, treatment modalities, and outcomes were assessed. During the median follow-up period of 1474 days, two patients experienced recurrence following a reduction in tocilizumab (TCZ) dose, whereas two achieved remission for >400 days without TCZ treatment. The remaining eight patients maintained remission under the continued TCZ therapy. Recurrence diagnosis was complicated by the non-simultaneous presentation of the five manifestations of TAFRO syndrome. The patients who experienced recurrence showed milder manifestations and faster recovery than the initial onset. Glomerular endotheliopathy was evident in kidney biopsies during recurrence, which was similar to the initial presentation. In a case where only inflammation preceded other manifestation, a kidney biopsy was pivotal in distinguishing TAFRO syndrome relapse from other inflammatory conditions such as infection. Pretreatment serum IL-6 levels were within the reference range only in patients who experienced long-term remission without TCZ treatment. Conclusions This is the first study to perform kidney biopsies on recurrent TAFRO cases, highlighting recurrence after TCZ dosage reduction, non-simultaneous manifestation of symptoms, the utility of kidney biopsies in recurrence diagnosis, and potential non-IL-6 pathogenesis factors. Pretreatment serum IL-6 levels may help identify patients suitable for maintenance therapy without TCZ. Further investigation is warranted to identify stratified treatment approaches based on individual etiologic factors. [ABSTRACT FROM AUTHOR]

Objectives Pathologists interpreting kidney allograft biopsies using the Banff system usually start by recording component scores (eg, i, t, cg) using histopathologic criteria committed to memory. Component scores are then melded into diagnoses using the same manual/mental processes. This approach to complex Banff rules during routine sign-out produces a lack of fidelity and needs improvement. Methods We constructed a web-based "smart template" (software-assisted sign-out) system that uniquely starts with upstream Banff-defined additional diagnostic parameters (eg, infection) and histopathologic criteria (eg, percent interstitial inflammation) collectively referred to as feeder data that is then translated into component scores and integrated into final diagnoses using software-encoded decision trees. Results Software-assisted sign-out enables pathologists to (1) accurately and uniformly apply Banff rules, thereby eliminating human inconsistencies (present in 25% of the cohort); (2) document areas of improvement; (3) show improved correlation with function; (4) examine t-Distributed Stochastic Neighbor Embedding clustering for diagnosis stratification; and (5) ready upstream incorporation of artificial intelligence–assisted scoring of biopsies. Conclusions Compared with the legacy approach, software-assisted sign-out improves Banff accuracy and fidelity, more closely correlates with kidney function, is practical for routine clinical work and translational research studies, facilitates downstream integration with nonpathology data, and readies biopsy scoring for artificial intelligence algorithms. [ABSTRACT FROM AUTHOR]

Background Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. Methods We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at 3 and 12 months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores [i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR] were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. Results More than one-third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the 3- to the 12-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 [odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.03–1.18]. Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95% CI 1.19–22.57) could be confirmed in our cohort. Conclusions These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions. [ABSTRACT FROM AUTHOR]

Background The development of chronic kidney disease (CKD) in about 20%–40% of patients with type 2 diabetes (T2D) aggravates cardiovascular morbidity and mortality. Pathophysiology is of increasing relevance for individual management and prognosis, though it is largely unknown among T2D patients with CKD as histologic work-up is not routinely performed upon typical clinical presentation. However, as clinical parameters do not appropriately reflect underlying kidney pathology, reluctance regarding timely histologic assessment in T2D patients with CKD should be critically questioned. As the etiology of CKD in T2D is heterogeneous, we aim to assess the prevalence and clinical disease course of typical diabetic vs atypical/non-specific vs non-diabetic vs coexisting kidney pathologies among T2D patients with mild-to-moderate kidney impairment [KDIGO stage G3a/A1–3 or G2/A2–3; i.e. estimated glomerular filtration rate (eGFR) 59–45 mL/min irrespective of albuminuria or eGFR 89–60 mL/min and albuminuria >30 mg/g creatinine]. Methods The Innsbruck Diabetic Kidney Disease Cohort (IDKDC) study aims to enroll at least 65 T2D patients with mild-to-moderate kidney impairment to undergo a diagnostic kidney biopsy. Six-monthly clinical follow-ups for up to 5 years will provide clinical and laboratory data to assess cardio-renal outcomes. Blood, urine and kidney tissue specimen will be biobanked to identify diagnostic and prognostic biomarkers. Conclusions While current risk assessment is primarily based on clinical parameters, our study will provide the scientific background for a potential change of the diagnostic standard towards routine kidney biopsy and clarify its role for individual risk prediction regarding cardio-renal outcome in T2D patients with mild-to-moderate kidney impairment. [ABSTRACT FROM AUTHOR]

Background [18F] AlF-NOTA-FAPI-04 is a novel positron emission tomography (PET) ligand, which specifically targets fibroblast activation protein (FAP) expression as a FAP inhibitor (FAPI). We analysed the diagnostic value of [18F] AlF-NOTA-FAPI-04 PET/CT for the non-invasive assessment of kidney interstitial inflammation and fibrosis in different renal pathologies. Methods Twenty-six patients (14 males and 12 females; mean age, 50.5 ± 16.5 years) with a wide range of kidney diseases and 10 patients (six males and four females; mean age, 55.4 ± 8.6 years) without known evidence of renal disease as disease controls underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues obtained from kidney biopsies were stained with haematoxylin and eosin, periodic acid-Schiff, Masson's trichome, and periodic acid–silver methenamine. Immunohistochemical staining was also performed to assess the expression of α-smooth muscle actin (αSMA) and FAP. Renal parenchymal FAPI uptake reflected by maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) measurements on PET/CT was analysed against pathohistological findings. Results We found that renal parenchymal FAPI uptake was significantly higher in patients with various kidney diseases than in control patients in this study (SUVmax = 4.3 ± 1.8 vs 1.9 ± 0.4, SUVmean=3.9 ± 1.7 vs 1.5 ± 0.4, respectively; all P  < 0.001). All kidney diseases, both in acute and chronic kidney disease, had increased renal parenchymal uptake to varying degrees. The correlation analysis indicated a positive association between the SUVmax and the tubulointerstitial inflammation (TII), interstitial fibrosis and tubular atrophy (IF/TA), and TII + IF/TA scores (r  = 0.612, 0.681, and 0.754, all P  < 0.05), and between the SUVmean and the TII, IF/TA, and TII + IF/TA scores (r  = 0.603, 0.700, and 0.748, all P  < 0.05). Furthermore, we found significant positive correlations between both SUVmax and the SUVmean with SMA and FAP staining scores (r  = 0.686 and 0.732, r  = 0.667 and 0.739, respectively; both P  < 0.001). Conclusions [18F] AlF-NOTA-FAPI-04 PET/CT is clinically available for the comprehensive and non-invasive assessment of tubular injury in various kidney diseases. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. MN is characterized by subepithelial accumulation of immune complexes along the glomerular basement membrane. The immune complexes are composed of immunoglobulin G and a target antigen. PLA2R is the target antigen in approximately 60% of MN cases, and MN is traditionally classified as PLA2R-positive or PLA2R-negative MN. Over the last 7 years, additional target antigens have been identified, which have specific disease associations, distinctive clinical and pathologic findings, and therapeutic implications. The newly discovered target antigens include NELL1, EXT1/EXT2, NCAM1, SEMA3B, PCDH7, FAT1, CNTN1, NTNG1, PCSK6 and NDNF. To group all these antigens into a generic 'PLA2R-negative' MN group is imprecise and un-informative. We propose a logical approach for detection of the target antigen which includes (i) currently available serology-based testing to detect anti-PLA2R and anti-THSD7A antibodies; and (ii) kidney biopsy testing to detect the target antigens. Determination of the antigen on kidney biopsy can be done by immunohistochemistry or immunofluorescence studies. Alternatively, laser capture microdissection (LCM) of glomeruli followed by mass spectrometry (MS) can be used to identify a target antigen. LCM/MS has the advantage of being a one-stop test and is particularly useful for detection of rare target antigens. At the current time, while it is possible to detect the newer antigens by immunohistochemistry/immunofluorescence/LCM/MS, serology-based tests to detect serum antibodies to the new antigens are not yet available. It is critical that serology-based tests should be developed not just for accurate diagnosis, but as a guide for treatment. We review the current methodology and propose an algorithm for diagnosis and detection of target antigens in MN that may shape the current practice in the future. Membranous nephropathy (MN) results from accumulation of subepithelial immune complexes along the glomerular basement membrane. PLA2R is the most common target antigen, but newly discovered target antigens have filled the void of PLA2R-negative MN. MN associated with the newly discovered target antigens have distinctive clinical and pathologic findings, treatment and prognostic implications. These include NELL1, EXT1/EXT2, NCAM1, PCDH7, SEMA3B, CNTN1, FAT1, NDNF and PCSK6. Immunohistochemistry/immunofluorescence methodology is currently in use for detecting target antigens in kidney biopsy tissue, although we anticipate laser capture microdissection of glomeruli followed by mass spectrometry will become available soon. Serologic testing is currently available for only detecting antibodies to PLA2R and THSD7A. It is critical that serologic tests become available for detecting antibodies to the newly discovered antigens. [ABSTRACT FROM AUTHOR]

Simulation is a technique to replace and amplify real experiences with guided ones that evoke or replicate substantial aspects of the real world in a fully interactive fashion. In nephrology (a particularly complex specialty), simulation can be used by patients, nurses, residents, and attending physicians alike. It allows one to learn techniques outside the stressful environment of care such as central venous catheter placement, arteriovenous fistula management, learning about peritoneal dialysis, or performing a kidney biopsy. Serious games and virtual reality are emerging methods that show promise. Simulation could also be important in relational aspects of working in a team or with the patient. The development of simulation as a teaching tool in nephrology allows for maintaining high-quality training for residents, tailored to their future practice, and minimizing risks for patients. Additionally, this education helps nephrologists maintain mastery of technical procedures, making the specialty attractive to younger generations. Unfortunately, the inclusion of simulation training programmes faces occasional logistical or funding limitations that universities must overcome with the assistance and innovation of teaching nephrologists. The impact of simulation-based teaching on clinical outcomes needs to be investigated in clinical studies. [ABSTRACT FROM AUTHOR]

Background The 2021 clinical guidelines of the Kidney Disease: Improving Global Outcomes emphasize the importance of the histological activity index (AI) in the management of lupus nephritis (LN). Patients with LN and a high AI have poor renal outcomes and high rates of nephritic relapse. In this study we constructed prediction models for the AI in LN. Methods The study population comprised 337 patients diagnosed with LN using kidney biopsy. The participants were randomly divided into training and testing cohorts. They were further divided into high-activity (AI >2) and low-activity (AI ≤2) groups. This study developed two clinical prediction models using logistic regression and least absolute shrinkage and selection operator (LASSO) analyses with laboratory test results collected at the time of kidney biopsy. The performance of models was assessed using 5-fold cross-validation and validated in the testing cohort. A nomogram for individual assessment was constructed based on the preferable model. Results Multivariate analysis showed that higher mean arterial pressure, lower estimated glomerular filtration rate, lower complement 3 level, higher urinary erythrocytes count and anti-double-stranded DNA seropositivity were independent risk factors for high histologic activity in LN. Both models performed well in the testing cohort regarding the discriminatory ability to identify patients with an AI >2. The average area under the curve of 5-fold cross-validation was 0.855 in the logistic model and 0.896 in the LASSO model. A webtool based on the LASSO model was created for clinicians to enter baseline clinical parameters to produce a probability score of an AI >2. Conclusions The established nomogram provides a quantitative auxiliary tool for distinguishing LN patients with a high AI and helps physicians make clinical decisions in their comprehensive assessment. [ABSTRACT FROM AUTHOR]

This article discusses a case of relapsed membranous nephropathy (MN) in a 63-year-old woman who had previously been treated with rituximab. MN is a kidney disease characterized by the presence of autoantibodies against the phospholipase A2 receptor (PLA2R). Typically, relapse is indicated by a rise in PLA2R autoantibody titers, but in this case, the patient experienced a relapse without an increase in PLA2R autoantibodies. The authors suggest that rituximab may have "masked" the patient's PLA2R response and emphasize the importance of repeat kidney biopsies in relapsed MN cases. Further research is needed to better understand this unusual scenario. [Extracted from the article]

A 47-year-old woman developed severe kidney dysfunction after taking a lipid-lowering supplement, Red Yeast Rice Cholestehelp, for approximately 7 months. The patient developed sudden nausea and had an elevated serum creatinine level of 4.26 mg/dL. A kidney biopsy showed findings consistent with acute tubular necrosis. Kidney dysfunction improved with discontinuation of supplementation, and corticosteroid therapy. Similar kidney involvement has been reported, raising concerns regarding supplements in Japan. An investigation of the nephrotoxic ingredients in the same product batches is currently underway. This report underscores the need for public awareness and warnings of health risk concerns associated with unregulated supplements. [ABSTRACT FROM AUTHOR]

Background The Banff Classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods A total of 215 patients were categorized into three groups. In the Training cohort, glomerular cells and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations vs automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results In the Test cohort, the networks recognized histological structures with Precision, Recall, F-score and Intersection Over Union exceeding 0.92, 0.85, 0.89 and 0.74, respectively. Univariate analysis revealed associations between the estimated glomerular filtration rate (eGFR) at biopsy and relative endothelial area (r = 0.19, P  = .027), endothelial cell density (r = 0.20, P  = .017), mean parietal epithelial cell area (r = –0.38, P  < .001), parietal epithelial cell density (r = 0.29, P  < .001) and mesangial cell density (r = 0.22, P  = .010). Multivariate analysis retained only endothelial cell density as associated with eGFR (Beta = 0.13, P  = .040). Endothelial cell density (r = –0.22, P  = .010) and mean podocyte area (r = 0.21, P  = .016) were linked to proteinuria at biopsy. Over 44 ± 29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% eGFR sustained decline), with relative endothelial area, mean endothelial cell area and parietal epithelial cell density below medians linked to this endpoint [hazard ratios, respectively, of 2.63 (P  = .048), 2.60 (P  = .039) and 3.23 (P  = .019)]. Conclusion This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss. [ABSTRACT FROM AUTHOR]

Background Microangiopathy (MA) lesions are not rare in immunoglobulin A nephropathy (IgAN) and have been suggested to have a potential role in increasing risk in renal function decline. However, this suggestion has not been universally accepted. We aimed to investigate its role in our cohort and in multiple studies through a systematic meta-analysis. Methods This cohort study included 450 IgAN patients, confirmed by renal biopsy, at Tongji Hospital, China, from January 2012 to December 2016. Clinical data were collected and analysed. We systematically searched PubMed and Web of Science for studies investigating the association between MA lesions and IgAN. Results In our cohort, IgAN patients with MA were significantly older and had higher blood pressure, more proteinuria, worse kidney function and increased uric acid levels compared with patients without MA. When comparing pathological features with the non-MA group, the MA group exhibited more global glomerulosclerosis and interstitial fibrosis/tubular atrophy. MA lesions were independently associated with a composite kidney outcome in IgAN patients {adjusted hazard ratio 2.115 [95% confidence interval (CI) 1.035–4.320], P  = .040}. Furthermore, this relationship was validated in a meta-analysis involving 2098 individuals from five independent cohorts. The combined data showed a 187% adjusted risk of poor renal outcome in IgAN patients with MA compared with patients without MA [adjusted risk ratio 2.87 (95% CI 2.05–4.02; I 2 = 53%). Conclusion MA lesions could serve as a valuable predictor for disease progression in patients with IgAN, extending beyond the widely recognized Oxford MEST-C score. [ABSTRACT FROM AUTHOR]

Chronic changes on kidney biopsy specimens include increasing amounts of arteriosclerosis, glomerulosclerosis, interstitial fibrosis and tubular atrophy, enlarged nephron size, and reduced nephron number. These chronic changes are difficult to accurately assess by visual inspection but are reasonably quantified using morphometry. This review describes the various patient populations that have undergone morphometric analysis of kidney biopsies. The common approaches to morphometric analysis are described. The chronic kidney disease outcomes associated with various chronic changes by morphometry are also summarized. Morphometry enriches the characterization of chronicity on a kidney biopsy and this can supplement the pathologist's diagnosis. Artificial intelligence image processing tools are needed to automate the annotations needed for practical morphometric analysis of kidney biopsy specimens in routine clinical care. [ABSTRACT FROM AUTHOR]

Background Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG. Methods Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional ex vivo testing on microvascular endothelial cells. Results Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years (n/N  = 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive ex vivo C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive ex vivo C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA (n/ N = 1/27, 4%). Conclusions MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation. [ABSTRACT FROM AUTHOR]

The N-PATH (Nephrology Partnership for Advancing Technology in Healthcare) program concluded with the 60th European Renal Association 2023 Congress in Milan, Italy. This collaborative initiative aimed to provide advanced training in interventional nephrology to young European nephrologists. Funded by Erasmus+ Knowledge Alliance, N-PATH addressed the global burden of chronic kidney disease (CKD) and the shortage of nephrologists. CKD affects >850 million people worldwide, yet nephrology struggles to attract medical talent, leading to unfilled positions in residency programs. To address this, N-PATH focused on enhancing nephrology education through four specialized modules: renal expert in renal pathology (ReMAP), renal expert in vascular access (ReVAC), renal expert in medical ultrasound (ReMUS) and renal expert in peritoneal dialysis (RePED). ReMAP emphasized the importance of kidney biopsy in nephrology diagnosis and treatment, providing theoretical knowledge and hands-on training. ReVAC centred on vascular access in haemodialysis, teaching trainees about different access types, placement techniques and managing complications. ReMUS recognized the significance of ultrasound in nephrology, promoting interdisciplinary collaboration and preparing nephrologists for comprehensive patient care. RePED addressed chronic peritoneal dialysis, offering comprehensive training in patient selection, prescription, monitoring, complications and surgical techniques for catheter insertion. Overall, N-PATH's strategy involved collaborative networks, hands-on training, mentorship, an interdisciplinary approach and the integration of emerging technologies. By bridging the gap between theoretical knowledge and practical skills, N-PATH aimed to revitalize interest in nephrology and prepare proficient nephrologists to tackle the challenges of kidney diseases. In conclusion, the N-PATH program aimed to address the shortage of nephrologists and improve the quality of nephrology care in Europe. By providing specialized training, fostering collaboration and promoting patient-centred care, N-PATH aimed to inspire future nephrology professionals to meet the growing healthcare demands related to kidney diseases and elevate the specialty's status within the medical community. [ABSTRACT FROM AUTHOR]

Diabetes is the most common cause of chronic kidney disease (CKD), a condition found in 850 million persons and projected to become the fifth global cause of death by 2040. Research is needed that examines kidney tissue to characterize distinct phenotypes in patients with diabetes mellitus (DM) and CKD so as to identify non-invasive biomarker signatures and develop targeted therapeutic approaches. However, from a routine care point of view, kidney biopsy is likely overused in patients with CKD and DM, as most biopsy results are not expected to be associated with a therapeutic approach that differs from standard kidney protection with triple or quadruple therapy (renin–angiotensin system blockade, sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists). Moreover, expanding the kidney biopsy criteria will increase the absolute number of complications from kidney biopsies, which may reach 27 000 to 108 000 deaths of persons that would derive little benefit from kidney biopsy if all people with DM and severe CKD were biopsied globally. Finally, limited resources should be optimally allocated. The cost of one kidney biopsy can fund 7000 semiquantitative urinary albumin:creatinine ratio assessments that could identify earlier stages of the disease and allow treatment that prevents progression to a stage at which kidney biopsy may be considered. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD) represent intricate challenges in diagnosis and treatment within the context of the global diabetes epidemic. As the prevalence of diabetes continues to escalate, effective management of renal complications becomes paramount. Recent advancements in comprehending the multifaceted nature of renal damage, fueled by insights from histopathological investigations, offer unprecedented prospects for refining diagnostic strategies and customizing therapeutic interventions. Renal biopsies have emerged as indispensable tools for unraveling the diverse phenotypes of renal damage in diabetes. The pioneering study by Mazzucco identified three classes of renal damage in type 2 diabetes patients: classical diabetic glomerulosclerosis (DN), vascular and ischemic glomerular changes (NDRD), and other glomerulonephritides in the presence (DN + NDRD, mixed forms) or absence of DN (NDRD). The prevalence of these classes varies widely in published studies, influenced by factors such as ethnicity, geography and selection criteria for renal biopsy. Moreover, the international Renal Pathology Society consensus classification system has stratified the classical diabetic nephropathy into progressive categories of renal impairment, a breakthrough that aids in prognostication. Histopathological scrutiny, particularly the intricate correlation between glomerular and tubulointerstitial lesions, contributes profoundly to enhancing our grasp of the phenotype's heterogeneity. This amplified comprehension holds the potential to steer personalized treatment strategies. Cutting-edge interventions, encompassing sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and anti-endothelin receptor agents, are broadening the arsenal against renal injury in diabetes. When combined with the profound insights garnered from histopathological, omics, imaging and clinical data, these therapeutic avenues promise a transformative shift towards precision-driven care paradigms. Collaborative efforts uniting researchers, clinicians and patients are indispensable for propelling our knowledge of diabetic renal damage and ameliorating patient outcomes. The fusion of histopathological, omics and imaging findings into clinical decision-making harbors the potential to customize interventions and optimize care for individuals grappling with diabetes-associated renal complications. Furthermore, groundbreaking initiatives like the iBeat Study within the BEAt-DKD (Biomarker Enterprise to Attack Diabetic Kidney Disease) project (https://www.beat-dkd.eu/), elucidating distinct phenotypes of renal damage within diabetes, underscore the imperative necessity of integrating histopathological data into the broader framework of diabetic renal management. [ABSTRACT FROM AUTHOR]

The article discusses the use of exome sequencing (ES) as a potential alternative to kidney biopsies in diagnosing undetermined kidney diseases (UKD). While kidney biopsies are invasive and carry risks, recent studies have shown that genetic variants may explain a significant portion of UKD cases. ES involves sequencing the coding regions of all protein-coding genes in the human genome and has been successful in diagnosing certain genetic kidney disorders. However, the study emphasizes that ES does not provide a definitive diagnosis in all cases, and kidney biopsies should still be considered in certain situations. [Extracted from the article]

This narrative review sheds light on the use of transcriptomics in the analysis of kidney biopsies and urinary cell samples from patients with immunoglobulin A nephropathy or lupus nephritis. The conventional methods of examining kidney biopsy through light microscopy, immunofluorescence and electron microscopy provide valuable clinical information for diagnosis and prognosis but have some limitations that transcriptomics can address. Some recent studies have reported that kidney transcriptomics has uncovered new molecular biomarkers implicated in the inflammatory process induced by the deposition of circulating immune complexes in the investigated kidney diseases. In addition, transcriptomics applied to urinary cells mirrors the inflammatory process that occurs in the kidney. This means that we can study urinary cell transcriptomics in clinical practice to diagnose the stage of the inflammatory process. Furthermore, the transcriptomics of urinary cells can be used to make therapy decisions during patient follow-up to avoid the stress of a second kidney biopsy. The studies analyzed in this review have a significant limitation. Biomarkers have been identified in small cohorts of patients but none of them has been validated in independent external cohorts. Further prospective studies in large cohorts of patients are necessary for accurate and complete validation. Only after that can these biomarkers be widely used in clinical practice. [ABSTRACT FROM AUTHOR]

Background According to data from large national registries, almost 20%–25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. Methods ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. Results We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD -associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P  = .02) and in patients with a family history of kidney disease (P  < .0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease. Conclusion Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD. [ABSTRACT FROM AUTHOR]

Background Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. Methods We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. Results The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P  < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. Conclusion We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology. [ABSTRACT FROM AUTHOR]

Background Percutaneous renal biopsy (PRB) may subject patients to emotional distress and pain before and during the biopsy. The aim of this study was to evaluate the effects of complementary/non-pharmacological interventions such as music therapy (MT) on anxiety, pain and satisfaction in renal patients undergoing PRB. Methods A prospective, single-centre, single-blind, randomized controlled two-arm trial was conducted. Patients ≥18 years of age, hospitalized at the Nephrology, Dialysis and Transplantation Unit (Bari, Italy) and scheduled for PRB were screened. Participants were assigned to standard treatment (CG) or to the music therapy (MT) intervention group. Participants in the MT group received standard care and an MT intervention by a certified music therapist qualified in guided imagery and music. The CG patients received the standard of care. MT and CG patients were subjected to identical measurements (pre/post) of the parameters in the State Trait Anxiety Inventory Y1 (STAI-Y1), visual analogue scale for pain (VAS-P) and satisfaction (VAS-S) and heart rate variability. Results A statistically significant difference in the anxiety scores after PRB between MT and CG patients (STAI-Y1 35.4 ± 6.2 versus 42.9 ± 9.0) was observed. MT also had strong and significant effects on VAS-P compared with CG (5.0 ± 1.4 versus 6.3 ± 1.3, respectively; P  < .001) and VAS-S (7.8 ± 1.0 versus 6.0 ± 0.9, respectively; P  < .001). Decreased activity of the sympathetic nervous system and increased activity of the parasympathetic nervous system was observed after PRB in the MT group. Conclusion Our study supports the use of MT to mitigate the psychological anxiety, pain and sympathetic activation associated with PRB. [ABSTRACT FROM AUTHOR]

Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach, and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: (i) infection-related GN require pathogen identification and control; (ii) autoimmunity-related GN, defined by presence of autoantibodies and (iii) alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow; (iv) autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways; and (v) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include disease category, immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and chronicity to trigger standard chronic kidney disease care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. The use of these five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management and teaching by reflecting disease pathogenesis and guiding the therapeutic approach. [ABSTRACT FROM AUTHOR]

Background Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. Methods We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. Results The median age was 69.5 years (range 47–80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. Conclusions The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) has emerged as a significant challenge to human health and economic stability in aging societies worldwide. Current clinical practice strategies remain insufficient for the early identification of kidney dysfunction, and the differential diagnosis of immunoglobulin A nephropathy (IgAN) predominantly relies on invasive kidney biopsy procedures. Methods First, we assessed a case–control cohort to obtain urine samples from healthy controls and biopsy-confirmed CKD patients. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was applied to detect urinary peptide and then these urinary peptide profiles were used to construct diagnostic models to distinguish CKD patients from controls and identify IgAN patients from other nephropathy patients. Furthermore, we assessed the robustness of the diagnostic models and their reproducibility by applying different algorithms. Results A rapid and accurate working platform for detecting CKD and its IgAN subtype based on urinary peptide pattern detected by MALDI-TOF MS was established. Naturally occurring urinary peptide profiles were used to construct a diagnostic model to distinguish CKD patients from controls and identify IgAN patients from other nephropathy patients. The performance of several algorithms was assessed and demonstrated that the robustness of the diagnostic models as well as their reproducibility were satisfactory. Conclusions The present findings suggest that the CKD-related and IgAN-specific urinary peptides discovered facilitate precise identification of CKD and its IgAN subtype, offering a dependable framework for screening conditions linked to renal dysfunction. This will aid in comprehending the pathogenesis of nephropathy and identifying potential protein targets for the clinical management of nephropathy. [ABSTRACT FROM AUTHOR]

Background Proper assessment of donor organ quality is crucial for optimal kidney allocation and best long-term outcomes. The aim of this study was to analyze the association between the Kidney Donor Risk Index (KDRI) and histological parameters in early post-transplant graft biopsy in a Polish cohort of kidney transplant recipients. Methods In 418 consecutive kidney transplant recipients, a histological evaluation of very early [at median 11 (9–13) post-transplant day] protocol core needle biopsy was performed and analyzed according to the Banff classification. Subjects were divided into quartiles of the KDRI value. Kidney graft function, patient and graft survival were also analyzed over a median follow-up period of 44 (26–56) months. Results There was a significant trend toward greater intensity of chronic histology changes along the KDRI quartiles (χ2 = 20.8; P  < .001), including interstitial fibrosis, tubular atrophy, mesangial matrix increase and arteriolar hyalinosis. Stepwise multivariate regression analysis revealed that only higher KDRI value independently increased the severity of chronic graft injury (rpartial = 0.340, P  < .001). KDRI values were valuable in the determination of both early and long-term graft function. Conclusion The KDRI values correlate with chronic histological changes found in early post-implantation kidney biopsies and can also be helpful in the prediction of graft outcome. [ABSTRACT FROM AUTHOR]

Many existing methods for estimating agreement correct for chance agreement by adjusting the observed proportion agreement by the probability of chance agreement based on different assumptions. These assumptions may not always be appropriate, as demonstrated by pathologists' ratings of kidney biopsy descriptors. We propose a novel agreement statistic that accounts for the empirical probability of chance agreement, estimated by collecting additional data on rater uncertainty for each rating. A standard error estimator for the proposed statistic is derived. Simulation studies show that in most cases, our proposed statistic is unbiased in estimating the probability of agreement after removing chance agreement. [ABSTRACT FROM AUTHOR]

Background This study aimed to determine the incidence and prevalence of immunoglobulin A nephropathy (IgAN) in Europe based on high-quality data from national registries. Methods IgAN incidences were obtained from a literature review of European studies of national kidney biopsy registry data in which IgAN diagnosis was biopsy-verified using contemporary techniques. Studies were eligible for the main analysis if published from 1990 to 2020. IgAN point prevalence was defined as the annual IgAN incidence multiplied by the estimated duration of disease. Incidence and prevalence estimates were made for three pooled populations: (i) patients of all ages; (ii) pediatric patients; and (iii) elderly patients. Results Across 10 European countries, the estimated annual IgAN incidence was 0.76 per 100 000 in patients of all ages. The corresponding pooled IgAN point prevalence was 2.53 per 10 000 (95% confidence interval: 2.51–2.55), ranging from 1.14 per 10 000 in Spain to 5.98 per 10 000 in Lithuania. Applied to 2021 population estimates, the number of expected prevalent IgAN cases was 47 027 across all 10 countries and ranged from 577 in Estonia to 16 645 in Italy. Among pediatric patients, IgAN incidence was 0.20 per 100 000 children and IgAN point prevalence was 0.12 per 10 000 children. Among elderly patients, IgAN incidence was 0.30 per 100 000 and IgAN point prevalence was 0.36 per 10 000. Conclusions Based on high-quality data from European national registries, IgAN point prevalence was estimated at 2.53 per 10 000 in patients of all ages. Prevalence was considerably lower in pediatric and elderly populations. [ABSTRACT FROM AUTHOR]

Background Up to 50–60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan–Meier and Cox regression analyses. Results Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P  < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P  < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85–3.31], P  < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26–2.62), P  = .001]. Conclusions DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD. [ABSTRACT FROM AUTHOR]

Background Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are markers of tubular stress and urinary [TIMP-2]*[IGFBP7] is an established biomarker for risk assessment of acute kidney injury. There are no studies of expression profiles or localization of these markers in human renal tissue with confirmed renal disease. Methods We analysed 37 kidney biopsies of patients with renal disease and 10 non-diseased control biopsies for TIMP-2 and IGFBP7 expression using immunohistochemistry. Changes in glomerular morphology were evaluated by a semi-quantitative glomerulosclerosis score (GSI) and tubular interstitial changes were graded by the tubular injury score (TSI) using periodic acid–Schiff-stained paraffin sections. Interstitial fibrosis and tubular atrophy (IF/TA) were graded according to the Banff classification. Urinary [TIMP-2]*[IGFBP7] was collected at the time of biopsy. Results TIMP-2 and IGFBP7 had significantly greater expression in kidney biopsies from patients with renal disease compared with control tissue, especially in the tubular compartment. Here, IGFBP7 was detected in proximal and distal tubules while TIMP-2 was predominantly localized in the collecting ducts. Renal injury significantly correlated with staining intensity for TIMP-2 and IGFBP7: GSI weakly correlated with glomerular TIMP-2 (r  = 0.36) and IGFBP7 (r  = 0.35) and TSI correlated with tubular TIMP-2 (r  = 0.41) and IGFBP7 (r  = 0.43). Urinary [TIMP-2]*[IGFBP7] correlated weakly with the histopathological damage score but not with glomerular and tubular expression. Conclusion Our findings underline the role of TIMP-2/IGFBP7 as an unspecific marker of renal injury that is already in use for early detection of acute kidney injury. [ABSTRACT FROM AUTHOR]

The article discusses a proposed new classification for glomerulonephritis (GN), a type of kidney disease. The authors argue that the current focus on kidney pathology in diagnosing GN should not be downplayed, as kidney biopsies provide important information about the disease. They also highlight the limitations of non-invasive biomarkers in accurately diagnosing GN. The proposed classification categorizes GN into five groups based on the origin of pathogenesis, but the authors raise concerns about discrepancies and the inclusion of certain entities. They acknowledge the need for improvements in the classification of GN and hope that their critique will contribute to its refinement. [Extracted from the article]

Objectives Amyloid light chain (AL)-κ and AL-λ share common histopathologic changes; however, the potential difference in clinical manifestations, histologic findings, and clinical significance between the 2 subtypes remain unclear. Methods In a retrospective study, 94 kidney biopsies for AL amyloidosis were evaluated using the composite scarring injury score (CSIS) and amyloid score (AS). Results were then compared between AL-κ and AL-λ. Results Comparing AS and CSIS between AL-κ and AL-λ, the AS was significantly higher in AL-κ than in AL-λ, with 2 components of AS (capillary wall and vascular amyloid) scoring higher in AL-κ than in AL-λ, while mesangial and interstitial ASs were similar in the 2 cohorts. In addition, the proportion of periodic acid–Schiff strong-staining amyloid in AL-κ was markedly higher than in AL-λ. There was no significant difference in CSIS and its components between the 2 subtypes of AL amyloidosis. Conclusions Overall, AL-κ presents with higher serum creatinine and a higher AS score than AL-λ at biopsy, which may indicate a worse prognosis and be an important reference for clinical management. [ABSTRACT FROM AUTHOR]

Background Nephrosclerosis is one of the histopathological consequences of severe or malignant hypertension (MH), some of the pathophysiology of which has been extrapolated from essential polygenetic arterial hypertension. Despite our recent description of unsuspected ciliopathies with MH, causes of MH in young patients with severe renal impairment are poorly understood. Methods To refine and better describe the MH phenotype, we studied clinical and prognostic factors in young patients receiving a kidney biopsy following their first episode of MH. Patients were identified retrospectively and prospectively from eight centres over a 35-year period (1985–2020). Keywords were used to retrospectively enrol patients irrespective of lesions found on renal biopsy. Results A total of 114 patients were included, 77 (67%) of whom were men, average age 34 years, 35% Caucasian and 34% African origin. An isolated clinical diagnosis of severe nephrosclerosis was suggested in only 52% of cases, with 24% primary glomerulopathies. Only 7% of patients had normal renal function at diagnosis, 25% required emergency dialysis and 21% were eventually transplanted. Mortality was 1% at the last follow-up. Independent prognostic factors significantly associated with renal prognosis (6-month dialysis) and predictive of end-stage renal disease were serum creatinine on admission {odds ratio [OR] 1.56 [95% confidence interval (CI) 1.34–1.96], P  < .001} and renal fibrosis >30% [OR 10.70 (95% CI 1.53–112.03), P  = .03]. Astonishingly, the presence of any thrombotic microangiopathy lesion on renal biopsy was an independent, protective factor [OR 0.14 (95% CI 0.02–0.60), P  = .01]. The histopathological hallmark of nephrosclerosis was found alone in only 52% of study patients, regardless of ethnicity. Conclusions This suggests that kidney biopsy might be beneficial in young patients with MH. [ABSTRACT FROM AUTHOR]

Background Focal segmental glomerular sclerosis (FSGS) is a histologic lesion rather than a specific disease entity and represents a cluster of different conditions affecting both children and adults that includes primary, secondary and genetically mediated forms. These forms can be distinguished by electron microscopy and genetic assessment and show different responsiveness to steroids and immunosuppressants. Despite some promising effects of rituximab in nephrotic syndrome in children, the results in adults with FSGS are disappointing. Our group previously explored the effectiveness of rituximab in eight adult patients with unselected forms of FSGS and achieved a consistent reduction in proteinuria in one case. Following this experience, we developed an alternative therapeutic option intended to enhance the potential of rituximab with the support of other synergic drugs. We herein report the results of this therapeutic protocol (six administrations of rituximab plus two of intravenous cyclophosphamide plus glucocorticoids) in seven prospectively enrolled patients with extensive podocyte effacement and recurrent relapses or steroid dependence. Results Patients had a median baseline serum creatinine level of 2.2 mg/dl (range 1–4.7) that decreased to 1.1 mg/dl (range 0.9–2.2) and 1.1 mg/dl (range 0.75–2.21) after 3 and 6 months, respectively, and remained unchanged at 12 months. Three of five patients with renal failure turned to normal function while the other two patients maintained a stable impairment after 18 and 52 months. The median proteinuria decreased from 6.1 g/24 h to 3.5, 3.5 and 1.9 g/24 h at 3, 6 and 12 months, respectively. Specifically, five of seven patients had a partial response at 12 months and became non-nephrotic. One of them had a complete response at 18 months and was still in complete remission at the last follow-up visit at 36 months. Proteinuria persisted unchanged in two of seven patients with a genetic-related disease. No serious late adverse events were observed. Conclusions Our results show that intensive B-cell depletion therapy is able to reverse the nephrotic syndrome of steroid-dependent or frequently relapsing adult patients with putatively idiopathic FSGS (i.e. with extensive podocyte effacement). [ABSTRACT FROM AUTHOR]

Background End-stage kidney disease (ESKD) from lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Kidney biopsy is the gold standard for diagnosis and prognostication of LN. While interstitial fibrosis and tubular atrophy (IFTA) predict progression to ESKD, the National Institutes of Health (NIH) classification of interstitial inflammation in unscarred cortical parenchyma is not predictive of chronic kidney disease (CKD) progression. The objective of this study was to determine whether total cortical interstitial inflammation that accounts for inflammation in the entire cortical parenchyma could predict CKD progression in patients with LN. Early identification of at-risk patients may improve outcomes. Methods This retrospective cohort study included 125 SLE patients with LN class III, IV, V or mixed (III/V, IV/V) on the index biopsy (2005–2018). Kidney biopsies were reviewed and assigned based on the 2018 NIH Activity Index (AI) and tubulointerstitial lesion categories. Total interstitial inflammation in the entire cortical parenchyma was graded as 0, 1, 2 or 3, corresponding to <10%, 10–25%, 26–50% and >50%, respectively, of the total cortical parenchyma containing an inflammatory infiltrate (similar to the definition used in the Banff total inflammation score). CKD progression was defined as an estimated glomerular filtration rate decrease of ≥30% within 5 years after the index biopsy. Kaplan–Meier survival curves and Cox proportional hazards models were performed to compare the two scoring systems, the total cortical intestinal inflammation score and the NIH interstitial inflammation score as predictors of CKD progression. Results Of 125 patients, 46 experienced CKD progression; 21 of 46 subsequently developed ESKD, 28 (22.4%) had moderate–severe total cortical interstitial inflammation and 8 (6.4%) had moderate–severe NIH interstitial inflammation. There were no differences in baseline characteristics between progressors and nonprogressors. Total cortical interstitial inflammation was associated with CKD progression in time-dependent analyses [hazard ratio 2.45 (95% confidence interval 1.2–4.97)] adjusted for age at biopsy, race, sex, LN class and hypertensive vascular change on kidney biopsy. The NIH interstitial inflammation was not associated with CKD progression. Conclusions In contrast to the current NIH interstitial inflammation classification, accounting for interstitial inflammation in the entire cortical parenchyma allows identification of patients at risk for CKD progression in LN. [ABSTRACT FROM AUTHOR]