2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Crescentic Glomerulonephritis Due to Enterococcal Endocarditis.

Glomerulonephritis following an enterococcal endocarditis is an extremely rare and life-threatening condition. We present the case of a 71-year-old patient with rapidly progressive glomerulonephritis following enterococcal endocarditis after surgical replacement of the aortic valve. The combination of antibiotic therapy, corticosteroid therapy and haemodialysis led to an improvement in renal function; however, the severity of cardiac deterioration resulted in a fatal outcome.

Clinical and histopathological characteristics of COL4A3 c.2881+1G>A variant causing Alport spectrum disorders in Croatian population.

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are part of the spectrum of kidney disorders caused by pathogenic variants in α3, α4, or α5 chains of the collagen type IV, the major structural component of the glomerular basement membrane (GBM). Using targeted next-generation sequencing (NGS), 34 AS/TBMN patients (58.8% male) from 12 unrelated families were found positive for heterozygous c.2881+1G>A variant of the COL4A3gene, that is considered disease-causing. All patients were from the continental or island part of Croatia. Clinical, laboratory, and histopathological data collected from the medical records were analyzed and compared to understand the clinical course and prognosis of the affected patients. At the time of biopsy or first clinical evaluation, the mean age was 31 years (median: 35 years; range: 1 - 72 years). Hematuria was present in 33 patients (97.1%) and 19 (55.9%) patients had proteinuria. There were 6 (17.6%) patients with hearing loss, 4 (11.8%) with ocular lesions, and 11 (32.4%) with hypertension. Twenty-three (67.6%) patients had proteinuria at follow-up, and 5 (14.7%) patients with the median age of 48 years (range: 27-55) progressed to kidney failure, started dialysis, or underwent kidney transplantation. Of the 13 patients who underwent kidney biopsy, 4 (30.8%) developed focal segmental glomerulosclerosis (FSGS), and 8 (66.7%) showed lamellation of the GBM, including all patients with FSGS. It is essential to conduct a detailed analysis of each collagen type IV genetic variant to optimize the prognosis and therapeutic approach for affected patients.

Immune-mediated diseases after coronavirus disease 2019 vaccination: rare but important complication.

Since the beginning of mass vaccination against coronavirus disease 2019 (COVID-19), vaccine-linked immune-mediated diseases have been increasingly reported. The development of these diseases after COVID-19 vaccination may be attributed to the mechanisms of molecular mimicry and cross-reactivity between the viral spike protein and self-antigens. The most frequent vaccine-linked glomerular disease is immunoglobulin A nephropathy (IgAN). Cutaneous vasculitis has also been reported after COVID-19 vaccination. In both diseases, deposition of immune complexes activates the inflammatory response with end-organ damage. We report on a case of de novo IgAN in a young man and a case of severe cutaneous vasculitis in a 68-year-old woman, both after the second dose of Pfizer-BioNTech COVID-19 vaccine. Neither of the patients had a history of autoimmunity or adverse reactions to vaccines. The temporal association between vaccination and disease development in the absence of other possible intercurrent inciting events suggests a causal mechanism, although coincidental co-occurrence cannot be excluded. In both cases, immunosuppressive treatment was warranted to stop disease progression and to partially or completely resolve the disease. A timely reaction is needed if new-onset signs of an immune-mediated disease appear after vaccination.

Resistant and Relapsing Collapsing Glomerulopathy Successfully Treated with Rituximab-A Case Report.

Collapsing glomerulopathy (CG) or collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive disease with a high tendency of progression to end-stage renal disease due to common resistance to conventional immunosuppressants. Rituximab (RTX), a monoclonal antibody against CD20 B cells, showed some benefit in the treatment of CG. We are reporting about female patients with an idiopathic form of CG presenting with nephrotic syndrome (NS) and renal insufficiency resistant to several immunosuppressive agents such as steroids (ST), calcineurin inhibitors (CNI), and cyclophosphamide (CYC). This multidrug-resistant disease responded to RTX with complete remission. Forty-four months after initial RTX administration, a relapse of CG with severe NS and acute renal insufficiency occurred. Repeated application of RTX led to complete remission again. To the best of our knowledge, we are reporting the first case of the relapsing multidrug-resistant form of CG, which responded to RTX. Current data about the treatment of CG with RTX is lacking and is based on rare case reports and small case series. Thus, our report can contribute to determining the role of RTX in the treatment of CG.

PULMONARY HEMORRHAGE AND CRESCENTIC GLOMERULONEPHRITIS IN A PATIENT WITH SEROPOSITIVE ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE AND ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES.

Anti-glomerular basement membrane (anti-GBM) disease is an acute and life-threatening systemic autoimmune disorder. The coexistence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) and anti-GBM disease, the so-called double-positive disease (DPD), is exceptionally rare. We report a unique case of DPD manifesting as pulmonary-renal syndrome (PRS) in a 46-year-old woman who first presented with clinical and radiological suspicion of pneumonia. Chest computed tomography scan later revealed bilateral alveolar hemorrhage. Kidney biopsy showed necrotizing crescentic (100% glomeruli) glomerulonephritis. On immunofluorescence microscopy, glomeruli were global linear positive for IgG, confirming anti-GBM disease. Double positivity was detected for circulating anti-myeloperoxidase ANCA (p-ANCA) and anti-GBM antibodies. Acute renal failure evolved rapidly. Therapeutic plasma exchange (TPE) and hemodialysis (HD) were initiated early in combination with intravenous pulse corticosteroid therapy followed by oral methylprednisolone and cyclophosphamide. Pulmonary hemorrhage resolved, but renal function could not be preserved. The patient remains HD dependent. This case report highlights that pulmonary symptomatology may be the leading clinical presentation of PRS, with initially normal renal function at DPD onset. Early recognition and diagnosis are therefore crucial to timely clinical intervention. The role of prompt kidney biopsy and initiation of TPE and HD in PRS must not be underestimated.

Clinical and pathohistological characteristics of Alport spectrum disorder caused by COL4A4 mutation c.193-2A>C: a case series.

AIM: To present the pathohistological and clinical characteristics of five Croatian families with Alport spectrum disorders caused by splice acceptor pathogenic variant c.193-2A>C in COL4A4 at the genomic position chr2:227985866. METHODS: The study enrolled five probands with kidney biopsy analysis and five family members. Mutation screening was performed with Illumina MiSeq platform. The pathogenic variant was confirmed with standard dye-terminator sequencing. RESULTS: The only homozygous patient, aged two, had proteinuria and hematuria with preserved kidney function and no extrarenal manifestations. This patient had changes characteristic for Alport syndrome observed on electron microscopy of the kidney biopsy. In the heterozygous group, six patients had hematuria, four biopsied probands had proteinuria, and only one had moderately reduced kidney function. Heterozygous probands had variable kidney biopsy findings. Three patients had thin glomerular basement membrane nephropathy visible on electron microscopy and focal segmental glomerulosclerosis on light microscopy, two of them with focal lamellation on electron microscopy. One heterozygous patient had changes characteristic for Alport syndrome on electron microscopy without focal segmental glomerulosclerosis. CONCLUSION: The homozygous patient had hematuria and proteinuria with preserved kidney function. The heterozygous patients presented with reasonably mild clinical phenotype and variable pathohistological findings.

Autosomal recessive Alport syndrome caused by a novel COL4A4 splice site mutation: a case report.

Alport syndrome (AS) is a genetically heterogenic, structural disorder of the glomerular basement membrane (GBM) due to the mutation of COL4A3, COL4A4, or COL4A5 genes, which clinically presents as progressive hematuric nephritis with ultrastructural changes of the GBM, high tone sensorineural hearing loss, and ocular lesions. About 15% of AS cases have autosomal mutations of COL4A3 and COL4A4 genes, including homozygous and compound heterozygous mutations. Here, we present a case of a two-year-old boy with autosomal recessive Alport syndrome (ARAS) caused by a novel c.193-2A>C COL4A4 mutation. The patient had a delayed motor and sensory development coupled with speech and language delay, megalencephaly, hematuria and proteinuria, and normal tonal audiogram and ophthalmology exam. Extensive genetic, metabolic, and neurologic workup performed at the age of 10 months was unremarkable and patient's megalencephaly was described as familial benign megalencephaly. Kidney biopsy analysis showed characteristic signs of AS. Mutations screening with use of Illumina MiSeq platform revealed that the patient was homozygous for a newly discovered splice acceptor pathogenic variant c.193-2A>C found in COL4A4 at the genomic position chr2:227985866 and both parents were heterozygous carriers. The genetic heterogeneity of AS makes the diagnostic process challenging. Although renal biopsy provides information about the characteristic GBM changes and the degree of renal parenchyma damage (interstitial fibrosis and tubular atrophy ratio), genetic testing is a more sensitive and specific method that also gives insight into potential disease severity and clinical course, and provides the basis for genetic counseling.

IgM as a novel predictor of disease progression in secondary focal segmental glomerulosclerosis.

AIM: To determine the role of immunoglobulin M (IgM) deposits in clinical manifestations, disease outcome, and treatment response of idiopathic and secondary focal segmental glomerulosclerosis (FSGS). METHODS: Kidney biopsy specimens of 171 patients diagnosed with FSGS (primary and secondary) and 50 control patients were retrospectively included in the study. For each patient, clinical and outcome data were obtained and compared to morphological parameters, including immunofluorescence analysis of mesangial IgM and complement 3 (C3) deposits analyzed on kidney biopsy samples. RESULTS: There were significant positive correlations between IgM and C3 deposition in secondary FSGS (P<0.001) and between IgM and mesangial deposits detected by electron microscopy in secondary FSGS (P=0.015), which indicated that higher IgM deposition correlated with higher C3 deposition and mesangial deposits only in secondary FSGS. Patients with secondary FSGS and the deposition of IgM showed inferior renal outcomes at earlier time points in comparison with patients with negative IgM expression (P=0.022). CONCLUSIONS: We detected a positive correlation between IgM and C3 in secondary FSGS. The association between IgM deposition and worse renal outcome in secondary FSGS indicates that IgM may play a role in the progression of this disease.

Isolated Tricuspid Valve Libman-Sacks Endocarditis in Systemic Lupus Erythematosus with Secondary Antiphospholipid Syndrome.

Libman-Sacks endocarditis, one of the most prevalent cardiac presentations of systemic lupus erythematosus, typically affects the aortic or mitral valve; tricuspid valve involvement is highly unusual. Secondary antiphospholipid syndrome increases the frequency and severity of cardiac valvular disease in systemic lupus erythematosus. We present the case of a 47-year-old woman with lupus and antiphospholipid syndrome whose massive tricuspid regurgitation was caused by Libman-Sacks endocarditis isolated to the tricuspid valve. In addition, we discuss this rare case in the context of the relevant medical literature.

The accuracy of fine needle aspiration cytology and flow cytometry in evaluation of nodal and extranodal sites in patients with suspicion of lymphoma.

Today lymphomas are defined according to a combination of morphology, immunophenotype, genetic features and clinical presentation, so beside the pure cytomorphologic analysis in diagnosis of lymphoma ancillary techniques such as cytochemistry, immunocytochemistry, molecular diagnosis and flow cytometry (FC) are often used. Our goal was to determinate how is information given by fine-needle aspiration cytology (FNAC) and FC correlated with pathohistologic diagnosis and to evaluate ability to diagnose and subclassify malignant lymphomas by FNAC and FC. This study is a retrospective chart review of patients with suspicion of lymphoma processed at University Hospital Dubrava in Zagreb. After analysis 50 patients fulfilled inclusion criteria for this study (FNAC diagnosis with or without FC and consecutive confirmatory pathohistological diagnosis). When analyzing accuracy of FNAC according to suspicion of lymphoma or NHL and differential diagnosis lymphoma sensitivity was 97.7%, specificity 85.7% and the diagnostic accuracy was 96%. When analyzing accuracy of FNAC according to the subclassification of lymphoma, sensitivity was 74.4%, specificity 85.7% and the diagnostic accuracy 76%. Combined FNAC and FC improved sensitivity, positive predictive value, negative predictive value and diagnostic accuracy. Sensitivity was 79.1% and the diagnostic accuracy 80%. We have shown that these methods can distinguish benign lymphadenopaties from lymphomas and also subclassify lymphomas and quickly provide clinicians with that information.