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.

Serum C3 complement levels in ANCA associated vasculitis at diagnosis is a predictor of patient and renal outcome.

AIM: To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA-associated vasculitis (AAV). METHODS: Our cohort included 75 consecutive patients with AAV diagnosed from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9-1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients. RESULTS: Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079; 95% CI 1.231-7.701; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831; 95% CI 1.093-7.338; p = 0.032). For both end-points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378; 95% CI 2.252-18.065; p < 0.001; on multivariate adjusted analysis HR 4.315 95% CI 1.350-13.799; p = 0.014) and renal survival (HR 3.207; 95% CI 1.040-9.830; p = 0.043; on multivariate adjusted analysis HR 3.679; 95% CI 1.144-11.827; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels. CONCLUSION: Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients.

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.

Clinical, serological and histological determinants of patient and renal outcome in ANCA-associated vasculitis with renal involvement: an analysis from a referral centre.

PURPOSE: To evaluate significance of clinical and histopathological prognostic factors for renal and patient outcome in AAV patient cohort. METHODS: Retrospective study included consecutive patients diagnosed with pauci-immune crescentic glomerulonephritis from January 2003 to December 2013. Primary outcome was combined endpoint patient death or progression to end-stage renal disease (ESRD). Secondary outcomes were patient survival and progression to ESRD (renal survival) singularly and disease relapse. Kaplan-Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between phenotypes and finding significant predictors regarding outcomes. RESULTS: Out of 81 patients, 40.7% patients reached primary endpoint, 22.2% died, 29.6% reached ESRD and 16% relapsed during follow-up. Multivariate Cox proportional hazards regression-adjusted analysis found higher BVAS (HR 1.08, 95% CI 1.01-1.17, p = 0.042), higher baseline maximal serum creatinine (HR 1.02, 95% CI 1.01-1.03, p = 0.04) and lower haemoglobin (HR 0.97, 95% CI 0.95-0.99, p = 0.011) significantly associated with primary endpoint. Higher BVAS (HR 1.25, 95% CI 1.01-1.43, p = 0.001) and lower haemoglobin (HR 0.95, 95% CI 0.91-0.99, p = 0.008) were significantly associated with patient survival, while for renal survival, lower haemoglobin (HR 0.97, 95% CI 0.94-0.99, p = 0.041) and the need for acute haemodialysis (HR 3.15, 95% CI 1.20-8.26, p = 0.02) were significant predictors. On multivariate-adjusted analysis, no significant predictors for disease relapse were found. Kaplan-Meier survival analysis found no difference between clinical, serological and pathohistological phenotypes for all of the endpoints. CONCLUSIONS: Renal function at presentation, anaemia and BVAS should be included in prediction models for the outcomes for the AAV patients.

Ambulatory arterial stiffness index and carotid intima-media thickness in hypertensive rheumatoid patients: a comparative cross-sectional study.

AIM: Rheumatoid arthritis is associated with accelerated atherosclerosis. However, little is known about preclinical atherosclerosis in hypertensive rheumatoid arthritis patients. In this cross-sectional study we assessed the expression of preclinical atherosclerosis in hypertensive rheumatoid arthritis patients in comparison with matched hypertensive non-rheumatoid arthritis patients. METHODS: The study included 52 hypertensive rheumatoid arthritis patients and 42 hypertensive non-rheumatoid arthritis patients. The patients were extensively examined clinically and laboratory tested. The expression of preclinical atherosclerosis was estimated by assessing ambulatory arterial stiffness index and common carotid intima-media thickness. RESULTS: Arterial stiffness index and common carotid intima-media thickness were higher in hypertensive rheumatoid arthritis patients than in hypertensive non-rheumatoid arthritis patients. There was no correlation between arterial stiffness index and common carotid intima-media thickness with markers of inflammation and disease activity in hypertensive rheumatoid arthritis patients. CONCLUSION: The expression of subclinical atherosclerosis is more pronounced in hypertensive rheumatoid arthritis than in hypertensive non- rheumatoid arthritis patients.

[HYPOKALEMIC METABOLIC ALKALOSIS ­ A REPORT OF SIX CASES].

In this article six patients with hypokalemic metabolic alkalosis, classified as Bartter or Gitelman syndrome are presented. Both syndromes result from different gene mutation inducing impaired function of the transporters involved in sodium, chloride and potassium reapsorption in thick ascending limb of the loop of Henle and distal convoluted tubules. These syndromes typically present with hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism without hypertension, polyuria and muscle weakness. Other clinical characteristics may vary considerably, depending on the gene expression. Correct diagnosis is only possible using expensive and not-routinely available genetic testing. Routine laboratory tests, especially those considering serum and urine electrolytes, can help in recognizing these syndromes and therefore in timely beginning of treatment. The most important distinctive laboratory findings are serum magnesium concentration and urine calcium excretion. In Bartter syndrome typically there is hypercalciuria with or without hypomagnesemia, while in Gitelman syndrome typical findings are hypocalciuria and hypomagnesemia. Recognizing and treating these patients is important due to possible increased morbidity and mortality induced by severe electrolyte imbalance.

[GOODPASTURE'S SYNDROME--CASE REPORTS]. / GOODPASTUREOV SINDROM--PRIKAZI BOLESNIKÂ.

Goodpasture's syndrome is a rare clinical entity characterized by rapidly progressive glomerulonephritis, diffuse pulmonary hemorrhage and the presence of circulating autoantibodies to the glomerular basement membrane (GBM). Autoantibodies bind to reactive epitopes of noncollagenous domain of the collagen type IV alpha-3 chain in glomerular and alveolar basement membranes. Autoantibodies activate the complement cascade resulting in tissue injury by the type II hypersensitivity reaction according to the Coombs and Gell classification of antigen-antibody reactions. Prognostic factors include the renal excretory function and the degree of renal and lung damage at the time of presentation. Prompt diagnosis and early and adequate medical treatment is vital for patients. Clinical treatment must be aggressive in order of achieving better outcome. This article describes three patients who clinically presented with renopulmonary syndrome, renal failure, hematuria, proteinuria and hemoptysis. Kidney biopsy diagnosis was crescentic glomerulonephritis due to antibodies against GBM. In all three patients we started therapy with glucocorticoids and cyclophosphamide combined with plasma exchange therapy. In two patients who initially had severe impairment of renal function and high percentage of crescents in the renal biopsy, kidney function recovery was not achieved. In one patient, who at the time of clinical presentation showed milder renal failure and lower percentage of crescents in renal biopsy, the full recovery of renal function was obtained.

Cardiac surgery-associated acute kidney injury: risk factors analysis and comparison of prediction models.

OBJECTIVES: Cardiac surgery-associated acute kidney injury (AKI) is a well-known factor influencing patients' long-term morbidity and mortality. Several prediction models of AKI requiring dialysis (AKI-D) have been developed. Only a few direct comparisons of these models have been done. Recently, a new, more uniform and objective definition of AKI has been proposed [Kidney Disease: Improve Global Outcomes (KDIGO)-AKI]. The performance of these prediction models has not yet been tested. METHODS: Preoperative demographic and clinical characteristics of 1056 consecutive adult patients undergoing cardiac surgery were collected retrospectively for the period 2012-2014. Multivariable logistic regression analysis was used to determine the independent predictors of AKI-D and the KDIGO-AKI stages. Risk scores of five prediction models were calculated using corresponding subgroups of patients. The discrimination of these models was calculated by the c-statistics (area under curve, AUC) and the calibration was evaluated for the model with the highest AUC by calibration plots. RESULTS: The incidence of AKI-D was 3.5% and for KDIGO-AKI 23% (17.3% for Stage 1, 2.1% for Stage 2 and 3.6% for Stage 3). Older age, atrial fibrillation, NYHA class III or IV heart failure, previous cardiac surgery, higher preoperative serum creatinine and endocarditis were independently associated with the development of AKI-D. For KDIGO-AKI, higher body mass index, older age, female gender, chronic obstructive pulmonary disease, previous cardiac surgery, atrial fibrillation, NYHA class III or IV heart failure, higher preoperative serum creatinine and the use of cardiopulmonary bypass were independent predictors. The model by Thakar et al. showed the best performance in the prediction of AKI-D (AUC 0.837; 95% CI = 0.810-0.862) and also in the prediction of KDIGO-AKI stage 1 and higher (AUC = 0.731; 95% CI = 0.639-0.761), KDIGO-AKI stage 2 and higher (AUC = 0.811; 95% CI = 0.783-0.838) and for KDIGO-AKI stage 3 (AUC = 0.842; 95% CI = 0.816-0.867). CONCLUSIONS: The performance of known prediction models for AKI-D was found reasonably well in the prediction of KDIGO-AKI, with the model by Thakar having the highest predictive value in the discrimination of patients with risk for all KDIGO-AKI stages.

[C1Q NEPHROPATHY: CASE REPORTS AND LITERATURE REVIEW]. / C1Q-NEFROPATIJA: PRIKAZI BOLESNIKA I PREGLED LITERATURE.

C1q nephropathy is considered a form of glomerulonephritis, defined by histological findings of dominant Clq immune deposits in renal biopsy. It is a rare disease, most often manifested in children and young adults. The most common clinical manifestation of the disease is nephrotic syndrome, but other renal syndromes could also be found. The cause of the disease is not known, but the immune pathogenesis could be assumed. Often, resistance to glucocorticoid or other immunosuppressive therapy is present, potentially leading to chronic renal insufficiency. We present ten patients with renal biopsy and clinical findings of Clq nephropathy. None of the patients had clinical or serological manifestations of systemic lupus. All patients had normal findings of C3 and C4 components of complement, as well as normal ANF, anti-dsD-NA and ANCA antibodies.

[Henoch-Schönlein purpura with late-onset necrotising glomerulonephritis--a case report]. / Prikaz bolesnice s Henoch-Schönleinovom purpurom i kasnom pojavom nekrotizirajuceg glomerulonefritisa.

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, while it is rare in adults. Typical clinical manifestations include palpable purpura without thrombocytopenia and/or coagulopathy, arthritis/arthralgia, abdominal pain, and/or renal involvement. In adulthood the disease tends to be more serious than in children, with renal manifestations developing over a period of several days to one month after initial symptoms. In this article we present a 22-year-old female patient with cutaneous vasculitis and arthralgia, in whom renal disease developed 8 weeks after disease onset with microscopic hematuria and proteinuria in urinalysis. Renal biopsy subsequently performed revealed focal necrotising glomerulonephritis with IgA deposits. The patient was treated with high dose methylprednisolone followed by gradual tapering, which induced complete remission of the disease. In conclusion, patients with HSP should be carefully monitored for systemic involvement, since serious renal disease can develop even as late as two months after disease onset.

[Treatment of anti-neutrophil cytoplasmic antibody related vasculitis]. / Lijecenje vaskulitisa povezanih s antineutrofilnim citoplazmatskim protutijelima.

ANCA-associated vasculitides are a well-known clinico-pathological group of systemic diseases comprising microscopic poliangiitis, granulomatosis with poliangiitis and eosinophilic granulomatosis with poliangiitis. This article shows contemporary treatment of this diseases with extensive literature review. Stepwise treatment of ANCA-associated vasculitides is divided into induction therapy and remission maintenance therapy. Standard induction therapy is a combination of glucocorticoids and cyclophosphamide, and in maintenance therapy, combination of low-dose glucocorticoids and azathioprine or methotrexate is used. Leading rheumatology and nephrology associations developed treatment guidelines. Since ANCA-associated vasculitides are relatively rare diseases, there are only few randomized controlled studies to provide high level of evidence and treatment recommendations. Most patients achieve remission, but relapses often occur. The main treatment considerations, apart from frequently relapsing disease, are disease refractory to treatment and potentially harmful effects of immunosuppressants, especially cyclophosphamide. Future studies are needed to determine the effects of less toxic immunosuppressants, mainly biological agents.

Non-diabetic renal disease in Croatian patients with type 2 diabetes mellitus.

AIM: Our study aimed to examine the prevalence of non-diabetic renal disease in selected patients with type 2 diabetes mellitus and to determine important risk factors for non-diabetic renal disease. METHODS: We conducted retrospective analysis of clinical, laboratory and pathohistological data of type 2 diabetes mellitus patients in whom renal biopsies were performed from January 2004 to February 2013 at Dubrava University Hospital Zagreb Croatia (n=80). RESULTS: According to renal biopsy findings, isolated diabetic nephropathy was found in 46.25%, non-diabetic renal disease superimposed on diabetic nephropathy in 17.5% and isolated non-diabetic renal disease in 36.25% of the patients. The most common non-diabetic renal diseases found were: membranous nephropathy, followed by IgA nephropathy and focal segmental glomerulosclerosis. In univariate analysis shorter duration of diabetes, independence of insulin therapy, lower levels of HbA1c and absence of diabetic retinopathy were found to be significant clinical predictors of non-diabetic renal disease. In multivariate analysis only independence of insulin therapy (OR 4.418, 95%CI=1.477-13.216) and absence of diabetic retinopathy (OR 5.579, 95%CI=1.788-17.404) were independent predictors of non-diabetic renal disease. CONCLUSIONS: This study confirmed usefulness of renal biopsy in patients with type 2 diabetes mellitus, due to the high prevalence of non-diabetic renal disease found. Since non-diabetic renal disease are potentially curable, we should consider renal biopsy in selected type 2 diabetes mellitus patients with renal involvement, especially in those with absence of diabetic retinopathy and independence of insulin therapy.

Epidemiologic data of adult native biopsy-proven renal diseases in Croatia.

PURPOSE: There is a paucity of epidemiological data on biopsy-proven renal disease in Croatia. The purpose of this report is a review of clinical and histological data, over a period of 15 years, from the single biggest adult native renal biopsy center in Croatia. METHODS: This report includes data from 922 adult native renal biopsies in patients referred from the whole country and performed in our center from 1996 till February 2012. Data on age, gender, serum creatinine, urine sediment, 24-h proteinuria, clinical syndrome and histological diagnosis were collected and analyzed retrospectively. In all patients, light, immunofluorescence and electron microscopic analysis was performed. RESULTS: The median age of the patients was 48 years (interquartile range 36-59 years), and the majority of patients were men (57.8 %). The most common indication for renal biopsy was nephrotic syndrome (40.3 %) followed by asymptomatic urinary abnormalities (31.7 %). The most common biopsy-proven renal disease in total was IgA glomerulonephritis (19.3 %), followed by focal segmental glomerulosclerosis (FSGS) (15.8 %) and membranous glomerulonephritis (9.2 %). In men, similar results were found, while in women, the most common were hereditary nephritis (13.4 %), FSGS (12.9 %) and connective tissue disease-related glomerular disorders (11.6 %). CONCLUSION: The presented data are an important contribution to the better understanding of the epidemiology of biopsy-proven renal disease in Croatia and Europe throughout comparison with other registry data. This data should be the basis for the formation of Croatian Registry of Renal Biopsies.

Treatment of renal manifestations of ANCA-associated vasculitis.

CONTEXT: Vasculitis is a clinicopathological entity characterized by inflammation and necrosis of blood vessels. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Two major autoantigens for ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3), which are proteins in the primary granules of neutrophils and in the lysosomes of monocytes. They are expressed in mature neutrophils of patients with ANCA, while absent in healthy subjects. CONCLUSIONS: The kidney is the most commonly affected vital organ in ANCA-associated vasculitis, and patient outcomes are largely determined by the severity of renal disease at diagnosis and by its response to treatment.

Atorvastatin-related rhabdomyolysis and acute renal failure in a genetically predisposed patient with potential drug-drug interaction.

CASE DESCRIPTION: A 75-year-old man developed rhabdomyolysis and acute renal failure during atorvastatin therapy. All medications were discontinued and the patient was treated with intermittent hemodialysis throughout the course of hospitalization. After four weeks, patient's kidney function tests and serum myoglobin levels decreased to normal values and muscle weakness gradually disappeared. Genotyping results showed that the patient had a single-nucleotide polymorphism within genes encoding the organic anion-transporting polypeptide 1B1 and ATP binding cassette sub-family B member 1, which predisposed him for statin-induced myopathy. He was also a poor metabolizer of cytochrome P450 2C19. Concomitant therapy with pantoprazole could have resulted in the inhibition of cytochrome P450 3A4-mediated metabolism of atorvastatin and contributed to the development of rhabdomyolysis. CONCLUSION: The case illustrates the clinical relevance and relationship between pharmacogenetic and pharmacokinetic factors in the development of statin-induced myopathy.

Prognostic significance of glomerular and tubulointerstitial morphometry in idiopathic membranous nephropathy.

The purpose of our study was to investigate the prognostic value of clinical and pathological, in particular glomerular and tubulointerstitial morphometric variables in idiopathic membranous nephropathy (IMN). We prospectively followed 60 Caucasian patients diagnosed with idiopathic membranous nephropathy for at least 2 years or until primary outcome (≥50% permanent decrease in estimated glomerular filtration rate or death). Glomerular and tubulointerstitial morphometric variables at the time of renal biopsy were analyzed with respect to this outcome. Univariate analysis revealed that significant negative prognostic factors for this outcome were higher cholesterol and smaller albumin concentrations, higher creatinine and maximal 24-h proteinuria, higher grade of nephroangiosclerosis, higher glomerular basement membrane thickness and glomerulopathy index, higher interstitial fibrosis and tubular atrophy percentage and higher injury score. In multivariate analysis, only the maximal 24-h proteinuria and interstitial fibrosis and tubular atrophy percentage were independent predictors of this outcome. The results suggest that morphometric analysis, mainly quantitative measurement of interstitial fibrosis and tubular atrophy percentage, injury score, glomerular basement membrane thickness and glomerulopathy index could be used as an additional method for risk stratification of patients with idiopathic membranous nephropathy.