Glomerular diseases最新文献

Introduction: MYH9-related disease (MYH9-RD) is a rare genetic cause of proteinuric kidney disease. It typically manifests as a syndromic condition, presenting with macrocytic thrombocytopenia, sensorineural hearing loss (SNHL), chronic glomerulopathy, elevated liver enzymes, and early-onset bilateral cataracts. In accordance with CARE guidelines, we present a case report of a father and daughter with renal-predominant MYH9-RD due to a recently described missense variant affecting the head domain of non-muscle myosin heavy chain IIA.

Case presentations: Patient 1 was an 18-year-old woman with childhood proteinuria who presented with severely advanced kidney failure. Dialysis was initiated as a bridge to a living unrelated renal transplant (LURT). Family history was notable for proteinuric kidney disease in her father (patient 2). Eight years later, genetic testing identified a likely pathogenic missense variant in the head domain of the MYH9 gene (c.1271G>A, p.R424Q). A predictive structural model was obtained via AlphaFold Protein Structure Database, in which the mutation interrupts hydrogen bonding and π-cation interactions, likely leading to protein misfolding. Subsequent clinical screening revealed persistent mild thrombocytopenia and elevated liver enzymes, without cataracts or SNHL. Patient 2 was a 53-year-old man with childhood proteinuria who eventually presented with stage 4 chronic kidney disease and soon after underwent LURT. After patient 1's genetic diagnosis, he was confirmed to have the same mutation by genetic testing. Subsequent screening revealed mild thrombocytopenia and elevated liver enzymes with hepatic steatosis progressing to cirrhosis, without cataracts or SNHL.

Conclusion: The finding of this MYH9 p.R424Q variant confirmed a diagnosis of MYH9-RD in these patients. MYH9 variants affecting the head domain typically result in severe thrombocytopenia. This recently reported head domain variant caused severe renal manifestations with mild thrombocytopenia and no manifestations of SNHL or cataracts in both patients, suggesting that this variant causes a renal-predominant form of MYH9-RD.

Introduction: Systemic lupus erythematous (SLE) is known to be associated with cardiovascular events (CVEs). However, the incidence of CVE has not been thoroughly investigated in lupus nephritis (LN) patients. In this meta-analysis, we aimed to assess the incidence of CVE in patients with LN.

Methods: We performed a literature search in PubMed, Scopus, and Web of Science database for studies reporting CVE (myocardial infarction [MI], heart failure, cerebrovascular accident [CVA] [i.e., ischemic or hemorrhagic stroke or transient ischemic attack], any cardiovascular- or cerebrovascular-related disease or death) in patients with LN. In addition, subgroup analyses were conducted according to geographical locations and kidney disease status. We also separately reported the incidence rate of MI, CVA, and cardiovascular- or cerebrovascular-related deaths, with CVE and MI risk in patients with LN.

Results: Twenty-one records, encompassing 29,489 subjects, were included. The overall CVE incidence was 9% (95% confidence interval [CI]: 6-12%). Specifically, the incidence of MI (8 studies, n = 5,735), CVA (9 studies, n = 6,053), and mortality attributed to any cardiovascular or cerebrovascular disease (10 studies, n = 26,511) were 4% (95% CI: 2-7%), 4% (95% CI: 2-7%), and 5% (95% CI: 3-7%), respectively. Geographically, patients residing in Asia exhibited a lower incidence of CVE (2.3%, 95% CI: 1.6-3.3%) compared to those residing in North America (10.1%, 95% CI: 5.7-17.2%) and Europe (13.3%, 95% CI: 7.6-22.4%). Patients with LN had higher risk of CVE compared to SLE subjects (odds ratio: 1.18, 95% CI: 1.03-1.34, p = 0.014).

Conclusion: CVE occurrence among individuals with LN is significant, and this disease entity increases CVE risk, highlighting the importance of implementing early therapeutic interventions to prevent poor outcomes.

Background: Renal pathologists face a number of challenges in evaluating kidney biopsies: one that is sometimes overlooked is the presence of multiple pathological processes in a single biopsy. Figuring out the interrelatedness (or lack thereof) of more than one form of renal abnormality can difficult. Several pitfalls in biopsy evaluation also await the unprepared diagnostician. This communication will examine these problems with illustrations from a single nephropathology practice dating back more than 3 decades.

Summary: Paired processes in a biopsy can be related in many ways, including 2 lesions with a single root cause, 1 lesion that is a direct consequence of another, 1 lesion that results from the treatment of another, 2 lesions for which circumstantial evidence suggests a connection, and finally, 2 lesions occurring together entirely by chance. Failure to recognize a second lesion after a first has been identified can result from overintense focus on the first lesion, subtlety of the second lesion, unusual situations where the second lesion involves the absence rather than presence of something, instances where the first lesion obscures the second, and disease pairs where the findings for the second are a subset of those for first.

Key messages: Detection and understanding of multiple pathological processes in a biopsy and avoiding pitfalls in their analysis requires the use of all available diagnostic modalities and thorough examination of all tissue received. Careful attention should be paid to the clinical record, but with the recognition that it may not always be entirely accurate or predictive of what will be found in the biopsy. Above all, pathologists must resist the temptation to think that their work is done when they find the first abnormality.

Introduction: Familial kidney disease is common in Cyprus and previous studies have found that the majority of families have mutations in Alport syndrome genes COL4A3/4/5. We have collected data from over 50 Turkish Cypriot families in whom kidney disease appears to follow an autosomal dominant pattern, and looked for pathological variants in these genes.

Methods: Probands from 55 families underwent massive parallel DNA sequencing using a glomerular gene panel for familial hematuria, and whole-exome sequencing (WES) was also performed in 22 of them. Clinical records were reviewed.

Results: Likely pathogenic variants were identified in 7 of the 55 families (COL4A3 [3], COL4A4 [2], and COL4A5 [2]), leaving 48 unsolved families. Among the latter a common missense variant of uncertain significance (COL4A4:p.G545A), was present in 5 families (9.1%). In contrast to families with a pathogenic variant in COL4A3/4 and a clear glomerular phenotype the 5 families (54 patients with clinical and genetic data), manifested near dominant susceptibility with incomplete penetrance, presenting with hypertension, variable and intermittent microscopic hematuria, and minimal proteinuria, <1 g/day until the estimated glomerular filtration rate (eGFR) fell below 30 mL/min, after which it increased in some individuals. Of those over age 50, 20% had reached end-stage by median age of 66 (48-80) years.

Conclusions: We describe a kidney disease with mild hypertension that is more characteristic of a tubulointerstitial disease and phenocopies hypertensive nephropathy. While the variant COL4A4:p.G545A is not responsible for a Mendelian CKD phenotype, it appears to increases the susceptibility, acting as a hypomorphic variant contributing to Alport spectrum nephropathy. Early detection and treatment with ACE inhibitors should prolong kidney survival to an age where hemodialysis is avoided.

Introduction: New equations developed in the USA for estimating glomerular filtration rate (GFR) eliminated race for adults and widened the age range for children and young adults. The European Kidney Function Consortium (EKFC) equation was also validated and updated for a US adult population. The aftereffects of adopting these new equations on previous research results among patients with glomerular disease are unknown. This study compared eGFR using old and new estimating equations and their impacts on eGFR-based outcomes.

Methods: Longitudinal serum creatinine measurements from children and adults enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were used to calculate eGFR using old bedside Schwartz and CKD-EPI 2009 equations, new U25 and race-free CKD-EPI 2021 equations, and the EKFC equation. Time to disease progression (40% eGFR decline or kidney failure) outcomes were compared using Kaplan-Meier curves and Cox models and longitudinal eGFR outcomes were compared using linear mixed-effects models to assess effects of demographics, clinical characteristics, pathology descriptors, a serum and urine biomarker, and the APOL1 genetic trait.

Results: N = 756 NEPTUNE study participants were included (median age 21 years, 41% female, and 25% who reported Black race). Disease progression outcomes were similar between using old versus new age-specific equations, whereas event rates were lower using EKFC. Survival curves were largely overlapping, and selected risk factor effects on disease progression were similar. Only sex and race effects on longitudinal eGFR differed between old versus new age-specific equations, whereas larger differences were observed for disease diagnosis effects when using EKFC.

Conclusion: New U25 and race-free CKD-EPI 2021 equations had little impact on estimated GFR values and results of survival and longitudinal regression analyses. EKFC results differed and were likely driven by those with very high eGFR.

Introduction: Reports on the performance of glomerular hematuria for the diagnosis of glomerulonephritis (GN) show heterogeneity in the results and used urological pathologies as controls. We hypothesized that identification of urinary acanthocytes (uACANTHO) and/or urinary red blood cell casts (uRBCCs) by comprehensive microscopic examination of the urinary sediment (uMICRO) can differentiate glomerular disease from non-glomerular renal pathology.

Methods: Records of patients seen for consultation for acute kidney injury or proteinuria/hematuria who had specimens examined by uMICRO and a kidney biopsy performed within 2 weeks of uMICRO were extracted. We assessed the sensitivity (SENS), specificity (SPEC), and positive and negative predictive value (PPV, NPV) of uACANTHO and/or uRBCC for the diagnosis of biopsy-proven GN or for any glomerulopathy (GP).

Results: Of 915 patients who completed uMICRO, 276 patients were included (mean age 53, 54% women). Median serum creatinine was 3.5 mg/dL. A total of 219 (79%) were categorized as GP, whereas 57 (21%) had non-GP diagnosis (e.g., tubular). Within the GP category, 114 (41%) had GN (e.g., IgA nephropathy, pauci-immune GN), whereas 105 (38%) had non-GN GP (e.g., podocytopathies). The SENS, SPEC, PPV, and NPV of uACANTHO for diagnosing GN were 68%, 86%, 78%, and 79%, respectively, whereas for GP SENS, SPEC, PPV, and NPV were 45%, 100%, 100%, and 32%, respectively. For GN, combining uACANTHO and/or uRBCC resulted in improvement of the SENS, SPEC, PPV, and NPV to 75%, 86%, 79%, and 83%, respectively. Either uACANTHO or uRBCC were found in 47/51 (92%) cases of crescentic/necrotizing GN.

Conclusion: Identification of glomerular hematuria by uMICRO aids in the diagnosis of GN. Combining the identification of uACANTHO and uRBCC enhances the diagnostic yield of uMICRO for GN and offers good NPV for crescentic/necrotizing GN. uACANTHO are pathognomonic for GP.

Introduction: Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with IgA nephropathy remain at risk for kidney failure. The effect of steroids on kidney outcomes in IgA nephropathy with different renal pathologic lesions has been uncertain.

Objective: This study aimed to evaluate the efficacy of steroid treatment in IgA nephropathy patients classified according to the Oxford-MEST-C classification.

Methods: We retrospectively studied 67 patients with biopsy-proven IgA nephropathy who were receiving optimized RAAS inhibitor therapy and had persistent proteinuria >1 g/day between January 2016 and December 2020. Clinical parameters, including estimated glomerular filtration rate (GFR) decline, were compared between the corticosteroid and supportive treatment groups.

Results: Overall, 68.7% of patients received treatment with corticosteroids. The median estimated GFR decline was significantly lower in the steroid group compared to the controls {-0.65 (interquartile range [IQR] -3.45 to 7) vs. -5.75 (IQR -10.65 to -0.7) mL/min/1.73 m²/year, p = 0.025}. The slope of estimated GFR was also significantly different between the steroid and control groups in patients with a baseline GFR >50 mL/min/1.73 m² (3.90 ± 11.42 vs. -9.31 ± 5.08 mL/min/1.73 m²/year, p = 0.011), mesangial hypercellularity M0 score (4.69 ± 11.37 vs. -2.63 ± 6.42 mL/min/1.73 m²/year, p = 0.049), and C0 score (2.48 ± 12.63 vs. -5.58 ± 8.4 mL/min/1.73 m²/year, p = 0.026). Additionally, rapid GFR decline (>5 mL/min/1.73 m²/year) occurred in 9 patients (19.6%) in the steroid group compared with 11 participants (52.4%) in the control group (p = 0.006).

Conclusion: Corticosteroid therapy, in addition to optimized RAAS inhibition, lowers the risk of kidney disease progression in patients with IgA nephropathy, particularly those with a baseline GFR >50 mL/min/1.73 m² and those classified with Oxford scores M0 and C0.

Background: The analysis of a renal biopsy is made complex by multifactorial etiologies involving different renal compartments. Recent proteomic data, pattern-based classification, and a better understanding of various glomerular renal diseases have underscored the importance of immunohistology as an integral part of the diagnostic evaluation of renal biopsies. These include immunofluorescence on formalin-fixed paraffin-embedded renal tissue (IF-P), IgG subclass staining, typing of amyloid, and other organized deposits, classification of membranous nephropathy, etc.

Summary: We describe the recent immunohistological markers on immunofluorescence (IF) and immunohistochemistry (IHC) on fresh and formalin-fixed paraffin-embedded renal native biopsies for proper evaluation and classification of glomerular diseases. The article also provides information on the diagnostic utility, interpretation, and established antibody clones described in the literature for various glomerular diseases. The indications of IF-P in renal biopsies are also outlined.

Key messages: Immunohistology has become integral to diagnosing and classifying various glomerular renal diseases. A specific protein or antigen-based classification has prognostic and therapeutic implications. Additionally, it provides clue for screening the patient for an underlying etiology.