Lovro Lamot

Complement dysregulation may occur secondary to systemic immune activation, but its relationship with inflammatory bowel disease (IBD) remains poorly defined. We report a 10-year-old boy presenting with severe anemia and newly diagnosed IBD who developed acute kidney injury with microscopic hematuria and proteinuria. Complement studies showed markedly reduced C3 and CH50 with normal C4. Kidney biopsy demonstrated diffuse proliferative glomerulonephritis with dominant C3 deposition and subendothelial immune complexes, consistent with C3 glomerulopathy. Additional complement testing revealed factor H depletion, high titers of anti-factor H autoantibodies, and elevated soluble C5b-9, while C3 nephritic factor and genetic testing of complement genes were negative. Multiple systemic autoantibodies were simultaneously present. Treatment with glucocorticoids resulted in rapid clinical improvement with normalization of kidney function, complement parameters, and disappearance of anti-factor H antibodies during follow-up. This case illustrates how transient systemic immune activation associated with intestinal inflammation may induce acquired complement dysregulation and trigger C3 glomerulopathy.

Despite being one of the most common infectious diseases, urinary tract infections (UTIs) still represent a challenge for clinicians to diagnose and treat, especially in the era of growing antibiotic resistance among uropathogenic bacteria. Recent studies investigating the pathophysiology of UTIs have discovered the prominent role of antimicrobial peptides in the urinary tract defense system. Cathelicidin is an evolutionary conserved antimicrobial peptide encoded by one single gene in humans. Except for being stored in neutrophil cytoplasmic granules, cathelicidin is produced by uroepithelial cells rapidly upon contact with a uropathogen, even before leukocytes invade the urinary tract. In addition to its bactericidal effect, cathelicidin acts as a chemoattractant for multiple immune cells and a potent inductor of numerous cytokine synthesis. Such a crucial role in the initial pathogenesis of a UTI makes cathelicidin a potential biomarker for an early UTI diagnosis. Indeed, multiple studies over the last two decades have proved the potential clinical utility of cathelicidin as a UTI diagnostic biomarker. Furthermore, since patients after the resolution of a UTI have been found to express a lower urinary cathelicidin level than healthy controls, decreased cathelicidin levels have been suggested as a risk factor for developing UTI recurrence. Therefore, measuring cathelicidin levels in urine might help in distinguishing patients with a higher risk for a recurrent UTI. Interestingly, except in UTIs, cathelicidin has also been evaluated in other urinary tract diseases and proposed as a biomarker for diagnosing severe vesicoureteral reflux (VUR) and for recognizing renal scar development in patients with VUR. Finally, a prominent role in UTI pathogenesis also makes cathelicidin an attractive therapeutic target for treating UTIs and, lately, different therapeutic agents up-regulating cathelicidin expression have been investigated in this matter. Therefore, the present review aims to summarize the current body of knowledge on the diagnostic, prognostic and therapeutic potential of cathelicidin in urinary tract diseases. For this purpose, three databases (Scopus, Medline and Web of Science) were extensively searched to cover all the published articles. This exhaustive review will update clinicians on the contemporary state of knowledge about the potential clinical utility of cathelicidin in urinary tract diseases and hopefully encourage further research, resulting in improvement in the current management of urinary tract diseases.

Editorial: Cystic kidney diseases in children and adults: from diagnosis to etiology and back

Introduction: Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes. Aim: A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period. Methods and Materials: Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes. Results: During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet–Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0–31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0–141.0) months. The median follow-up duration in the cohort was 3.0 (1.0–7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation. Conclusion: This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

Recurrent urinary tract infections (rUTI) represent a major healthcare and economic burden along with a significant impact on patient’s morbidity and quality of life, even in the absence of well-known risk factors, such as vesicoureteral reflux. Despite numerous attempts to find a suitable therapeutic option, there is no clear benefit of any currently available intervention for prevention of UTI recurrence and its long-term consequences such as hypertension, renal scarring and/or insufficiency. The common treatment practice in many centers around the globe involves the use of continuous low-dose antibiotic prophylaxis, irrespective of various studies indicating increased microbial resistance against the prophylactic drug, leading to prolonged duration and escalating the cost of UTI treatment. Moreover, the rapid appearance of multi-drug resistant uropathogens is threatening to transform UTI to untreatable disease, while impaired host-microbiota homeostasis induced by a long-term use of antibiotics predisposes patients for various autoimmune and infectious diseases. New biomarkers of the increased risk of UTI recurrence could therefore assist in avoiding such outcomes by revealing more specific patient population which could benefit from additional interventions. In this light, the recent findings suggesting a crucial role of urothelial innate immunity mechanisms in protection of urinary tract from invading uropathogens might offer new diagnostic, prognostic and even therapeutic opportunities. Uroepithelial cells detect uropathogens via pattern recognition receptors, resulting in activation of intracellular signaling cascade and transcription factors, which ultimately leads to an increased production and secretion of chemokines, cytokines and antimicrobial peptides into the urinary stream. Emerging evidence suggest that the disturbance of a single component of the urinary tract innate immunity system might increase susceptibility for rUTI. The aim of the current review is to update clinicians and researchers on potential biomarkers of host immune response alterations predisposing for rUTI and propose those well worth exploring further. For this purpose, over a hundred original papers were identified through an extensive PubMed and Scopus databases search. This comprehensive review might enrich the current clinical practice and fill the unmet clinical needs, but also encourage the development of therapeutic agents that would facilitate urinary bacterial clearance by enhancing the host immune response.

Background Biosimilars have been adopted by clinicians more slowly than anticipated in the post-marketing phase. Objectives We aimed to reveal the perceptions and attitudes of pediatric rheumatologists towards biosimilars and the obstacles to biosimilar therapy. Methods A web-based survey designed to determine the knowledge, experience, and perceptions of pediatric rheumatologists about biosimilars was electronically mailed to the participants between April and August 2021. Responses were collected anonymously and subsequently analyzed. Results A total of 114 pediatric rheumatologists including fellows (32.4%), specialists (29.8%), and seniors (37.7%) responded to the questionnaire. According to the data, 75 (65.8%) physicians had already prescribed at least one biosimilar. The vast majority of participants were aware of the potential cost savings of biosimilars (84, 73.3%). Participants who felt insufficiently informed were 41.8%, 67.6%, and 83.7% among seniors, specialists, and fellows, respectively. In pediatric rheumatology, the scarcity of clinical trials and real-life data (64%) and inadequate information about tolerance to the biosimilars and related side effects in children (49.1%) were the most common barriers expressed by prescribers. Nearly half (45%) of the pediatric rheumatologists preferred to prescribe biosimilars in the treatment of biologic-naive cases. However, most (93%) were reluctant to switch a reference molecule to a biosimilar while the patient was doing well under the originator medicine. Conclusions This survey provided insights into the concerns about prescribing biosimilars among pediatric rheumatologists. In the field of pediatric rheumatology, further education about biosimilars and real-life experiences is required to better inform about treatment options in children.

Juvenile spondyloarthritis (jSpA) represents a spectrum of inflammatory arthritis with strong HLA-B27 association and involvement of enthesis and/or axial skeleton that appears in children and young adults. ILAR classification criteria for enthesitis related arthritis subtype of juvenile idiopathic arthritis, which is undifferentiated form of jSpA, includes arthritis, enthesitis, presence of sacroiliac joint tenderness, inflammatory lumbosacral pain, HLA-B27 positivity, positive family history and acute anterior uveitis. We present a case of 16 years old girl diagnosed with juvenile spondyloarthritis that first presented with recurrent monthly swelling of index finger at the age of 14. Symptoms progressed to low back pain in the morning which partly declined with activity. Additionally, her right knee was swollen and painful. She was examined on multiple occasions by pediatric orthopedic surgeon and in pediatric emergency department before seeing a pediatric rheumatologist. The first examination revealed sacroiliac joint tenderness with positive FABER test and abnormal modified Schober test. Family history was negative for rheumatic diseases and there were no signs of uveitis nor enthesitis, with ANA, RF and extensive laboratory workup being either negative or within reference range. However, HLA-B27 turned positive and MRI showed right sacroiliitis. NSAID was prescribed but symptoms nevertheless persisted. Thus, after the exclusion of TBC with quantiferon test, intraarticular corticosteroid injection was applied to the right knee and oral corticosteroid was introduced as bridging therapy. Subsequently, according to ACR guidelines, a therapy with TNF-alpha inhibitor, adalimumab, was initiated. Within a month, a substantial reduction of the low back pain was noted, with a decrease in juvenile spondyloarthritis disease activity score (jSpADA). Low back pain often begins in childhood, with the prevalence in adolescence being similar to that in adulthood. Among many possible causes, inflammatory etiology should be thoroughly considered due to irreversible damage if not treated adequately. Therefore, children and adolescents complaining of a back pain, especially in the presence of other signs of arthritis, should be referred to pediatric rheumatologist for a further work-up and treatment.

Background Intermittent fever along with increased inflammatory markers (CRP and ESR) most commonly is the sign of an infectious disease. Nevertheless, without an adequate response to antibiotic treatment, it should raise concern of other conditions, including several rheumatic, like Kawasaki disease, periodic fever syndromes and systemic form of juvenile idiopathic arthritis (JIA), even when no clear arthritis is present. Case Presentation We present a case of a 7-year-old girl with a 14-month history of intermittent fever with increased inflammatory markers, along with unspecific symptoms such as hepatomegaly, polymorphous rash and migratory arthralgia. An extensive diagnostic workup excluded infectious aetiology, genetic testing did not detect pathogenic mutations. Despite the treatment with intravenous imunoglobulines and low dose glucocorticoids (GCs), the fever did not subside. Finally, extensive laboratory workup revealed increased proinflammatory cytokines IL-6 and TNF-alpha along with chronic anaemia and thrombocytosis. The systemic subtype of JIA was considered, and treatment with pulse (30mg/kg), continued with high (2mg/kg) doses of GCs was initiated with an instant resolution of symptoms. Nevertheless, after the weaning of GCs, the new exacerbation was observed and therefore tocilizumab, humanized monoclonal antibody against IL-6 receptor, was initiated. Conclusion Systemic form of juvenile idiopathic arthritis is a heterogeneous disease dominated musculoskeletal and systemic symptoms. While the former ones are a result of similar pathophysiologiocal mechanisms as other forms of JIA, activation of the nonspecific immune response is responsible for the sytemic ones, similar to other autoinflammatory diseases. Therefore, it is possible that in some cases of systemic form of JIA, systemic inflammation is present without the musculoskeletal symptoms. With the existing classification criteria of the International League against rheumatism (ILAR) it can be difficult to diagnose and initiate appropriate therapy. Consequently it can mislead to recognize a serious complication – macrophage activation the syndrome. The recognition of the unique nature of systemic JIA in comparison to other types of JIA as well as an increased understanding of its pathogenesis, provides a better outcome and prognosis for children who often go undiagnosed with a debilitating chronic condition.