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.

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.

[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.

[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.

[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.

[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.

C4d Is an Independent Predictor of the Kidney Failure in Primary IgA Nephropathy.

Background: C4d deposits are present in a substantial proportion of patients with IgA nephropathy (IgAN), indicating the activation of the lectin pathway (LP) of the complement system. It seems that patients with activated LP have worse renal prognosis. The aim of this study was to investigate the prevalence and prognostic significance of C4d in our cohort of patients with primary IgA nephropathy (pIgAN). Methods: Patients with pIgAN were recruited from a hospital register of kidney biopsies of the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb. Additional immunohistochemistry staining for C4d was performed on paraffin-embedded kidney tissue, and patients were stratified into being C4d positive or C4d negative. The clinical and histologic features of patients were analyzed and compared regarding C4d positivity. The primary outcome was defined as kidney failure (KF), and predictor variables of KF and renal survival were analyzed. Results: Of a total of 95 patients with pIgAN included in the study, C4d was present in 43 (45.3%). C4d-positive patients had a higher value of systolic (p = 0.039) and diastolic (p = 0.006) blood pressure at diagnosis as well as higher 24 h proteinuria (p = 0.018), serum urate (p = 0.033), and lower eGFR (p < 0.001). C4d-positive patients had worse renal survival (p < 0.001), higher rates of disease progression to KF (p < 0.001), and higher proteinuria (p < 0.001) and lower eGFR (p < 0.001) at the last follow-up. Glomerular C4d was an independent predictor of disease progression to KF (HR = 5.87 [0.95 CI 1.06-32.44], p = 0.032). Conclusions: C4d is an independent predictor of disease progression in patients with pIgAN. C4d may be used as an additional marker of progressive disease course in IgAN. The therapeutic implications of C4d status in IgAN, particularly in terms of complement inhibitors application, are not yet known.

[Membranous glomerulonephritis--recent advances in pathogenesis and treatment]. / Membranski glomerulonefritis--novosti u patogenezi i lijecenju.

Membranous glomerulonephritis is one of the leading causes of nephrotic syndrome in adults. It may have very variable course, with some patients slowly progressing to renal failure and some entering spontaneous remission. The aim of this article is to review recent advances in the pathogenesis and treatment of the disease in recent years. In recent years, first human podocyte autoantigens, responsible for autoantibodies and in situ immune complexes formation, were discovered: neutral endopeptidase, m-type phospholipase A2 receptor, superoxide-dismutase 2, aldose-reductase, alpha-enolase. It is postulated that these discoveries will help in differentiation between primary and secondary membranous glomerulonephritis, in predicting remission and/or relapse and also in determining more specific therapy. There have been also some pilot studies recently, in which new drugs have been introduced in the treatment of membranous glomerulonephritis: ACTH, rituximab and tacrolimus.

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.

Effects of ramipril and valsartan on proteinuria and renal function in patients with nondiabetic proteinuria.

The renin-angiotensin system is involved in the progression of chronic renal disease of both diabetic and nondiabetic origin. The angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have been demonstrated to reduce urinary protein excretion and attenuate the development of renal injury. This prospective, randomized, 12-month study assessed the effects of ramipril (N = 23) vs. valsartan (N = 22) vs. combination of ramipril and valsartan (N = 26) on proteinuria, renal function and metabolic profile in 71 patients with nondiabetic proteinuria with normal or slightly impaired renal function. Monotherapy with ramipril or valsartan and combination of these two drugs significantly reduced proteinuria, serum creatinine, cholesterol and triglycerides as well as systolic and diastolic arterial blood pressure. There was no significant difference among three study groups according to reduction of arterial blood pressure, serum cholesterol and triglycerides. At one year, a significant reduction in serum creatinine was recorded in all three study groups, whereas at 3 and 6 months a statistically significant reduction in serum creatinine was only observed in patients on combination therapy. In addition, at 3 months the reduction of proteinuria was significantly greater in patients on combination therapy than in those on either monotherapy. These results indicated the combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to be more efficacious than either monotherapy in reducing proteinuria and serum creatinine level in the first 3 (proteinuria and serum creatinine) or 6 (serum creatinine) months of treatment.

[Drug induced allergic interstitial nephritis]. / Alergijski intersticijski nefritis uzrokovan lijekovima.

The allergic interstitial nephritis (AIN) is a rare renal disorder which is commonly clinically presented with an acute renal failure. AIN is the most frequent result of the hypersensitivity related to drugs (most often antibiotics). In the patients with clinical suspicion to a drug related AIN, kidney biopsy is the most important diagnostic procedure. Except of causative drug discontinuation, AIN therapy is based on high dose glucocorticoids 1 mg/kg/day with dose tapering during consecutive 3 months. In the present work, we have shown 10 patients with drug induced AIN. We identified 4 causative drug groups among which most frequent were antibiotics. In clinical presentation of our patients acute renal failure was dominant and median of baseline serum creatinine was 497.5 micromol/L. In all patients the kidney biopsy was performed and nine patients (90%) have been treated with recommended glucocorticoid regimen, additionally, in 3 patients hemodialysis was introduced. In all patients, reduction in serum creatinine value was achieved with serum creatinine median of 152 micromol/L after a three-month glucocorticoid treatment (p=0.018).

[Fibrillary glomerulonephritis and immunotactoid glomerulopathy: case reports]. / Fibrilarni glomerulonefritis i imunotaktoidna glomerulopatija: prikaz bolesnika.

Fibrillary glomerulonephritis and immunotactoid glomerulopathy belong to the rare renal disorders characterized by formation of the organized glomerular deposits. Pathogenesis of these disorders is still not fully clarified but they could appear as a primary condition or be regarded as a part of the various systemic mainly lymphoproliferative disorders. Clinical presentation includes proteinuria, hematuria, arterial hypertension and progressive renal insufficiency during several years. In this work we presented a male patient with fibrillary glomerulonephritis and a female patient with immunotactoid glomerulopathy as a part of a non-Hodgkin lymphoma. The aim of this presentation is to show the features of the fibrillary glomerulonephritis and immunotactoid glomerulopathy as well as emphasize the significance of the electron microscopy in the identification of these uncommon entities.

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.

[Value of ultrasound-guided percutaneous renal biopsy in diagnosis of the renal diseases]. / Znacenje perkutane biopsije u dijagnostici bubreznih bolesti.

Percutaneous renal biopsy (PRB) is an integral part of the clinical practice of nephrology. It is a safe and effective tool in the diagnosis of glomerular, vascular and tubulointerstitial diseases of the kidney, providing information that is invaluable in prognosis and patient management. PRB of native kidneys was performed by nephrologists in 249 patients consecutively from May 1997 through May 2005 at the Department of Nephrology, Dubrava University Hospital, Zagreb, Croatia. The biopsy was done using continuous ultrasound guidance and a 16-gauge biopsy needle (Tru-Cut) in an automated gun (Biopty Bard). All biopsies were processed for light, immunofluorescence and electron microscopy. We analyzed yield of diagnostically useful material and frequency of postbiopsy complication. Adequate tissue for histologic diagnosis was obtained in 95% of the procedures. The mean glomerular yield was 11.9 glomeruli. The main indications for renal biopsy were nephrotic syndrome (33%) hematuria and/or non-nephrotic proteinuria (13%) and renal failure (12%). The dominant types of primary glomerulonephritis (GN) were focal segmental glomerulosclerosis (FSGS) in 27%, mesangioproliferative in 13%, IgA nephropathy in 11%, membranous GN in 11%, membranoproliferative GN in 5%, crescentic GN--5%, and minimal change disease (MCD) in 3% of cases. The most frequent complications were perirenal hematoma (clinically asymptomatic) in 3.6%, macrohematuria in 1.2%; bleeding complications requiring blood transfusion and/or therapeutic radiologic intervention were not seen, and surgical procedure was indicated in one (0.4%) patient. We conclude that real-time ultrasound is a safe, accurate method in localizing the kidney for percutaneous renal biopsy and a very effective approach for early detection of perirenal hematoma and other potential postbiopsy complications. The present data are an important contribution to the epidemiology of renal disease, highlighting significant epidemiological differences in European countries, particularly a higher incidence of FSGS as a proportion of primary GN in our population. This report represents a basis for the future Croatian Registry of Renal Biopsies and is intended to serve as a source of information for further studies.

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.

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.