Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review.

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.

Two sides of the same coin: a complex presentation of autosomal dominant tubulointerstitial kidney diseases: a literature review and case reports.

Introduction: Genetic kidney diseases are underdiagnosed; namely, from 7% to 40% of patients suffering from chronic kidney disease (CKD) can carry a pathogenic variant, depending on population characteristics. Hereditary tubulointerstitial kidney diseases, including autosomal dominant tubulointerstitial kidney diseases (ADTKD), are even more challenging to diagnose. ADTKD is a rare form of genetic kidney disease resulting from pathogenic variants in the MUC1, UMOD, HNF1B, REN, SEC61A1, and DNAJB11 genes. There is no typical clinical or histopathological sign of ADTKD, it is characterized by progressive CKD, an autosomal dominant inheritance pattern, and tubular atrophy with interstitial fibrosis on kidney biopsy. There is no significant proteinuria, and the urinary sediment is bland. The patients usually do not have severe arterial hypertension. There can be a history of early gout, especially when compared to the UMOD gene variants. Children can have enuresis due to a loss of renal concentration. On ultrasound, the kidneys can appear normal or small in size. Renal cysts are not pathognomonic for any of the named diseases. End-stage renal disease (ESRD) develops at the average age of 45, but this can be very variable. Family history that suggests autosomal dominant inheritance and CKD fulfilling the aforementioned characteristics of tubulointerstitial kidney disease should raise suspicion of ADTKD. In the setting of a negative family history for CKD, clinical suspicion should be raised based on clinical characteristics, including early onset of hyperuricemia or gout and compatible histology on the kidney biopsy. Contrary to the aforementioned characteristics of ADTKD, in the case of HNF1B-related disease, there is a more complex clinical presentation with extrarenal manifestations of the disease (diabetes mellitus, hypomagnesemia, neurologic and psychiatric disturbances, etc.). The diagnosis of ADTKD is based on a positive family history and a detection of the pathogenic variant in one of the genes in an affected individual. Aim: The aim of our study is to present two case reports of ADTKD with different characteristics (slowly progressive CKD vs. complex clinical presentation with an extrarenal manifestation of the disease) with a literature review. Methods: A 34-year-old patient with CKD and a positive family history of CKD in whom kidney biopsy showed nonspecific chronic changes, with only genetic analysis confirming the diagnosis of MUC1-related ADTKD. Our second case is of a 17-year-old patient with an unremarkable family history who was initially referred to genetic counseling due to cognitive and motor impairment with long-lasting epilepsy. Extensive workup revealed increased serum creatinine levels with no proteinuria and bland urinary sediment, along with hypomagnesemia. His genetic analysis revealed 17q12 deletion syndrome, causing the loss of one copy of the HNF1B gene, the AATF, and the LHX1 gene. Conclusion: Autosomal dominant tubulointerstitial kidney diseases are challenging to diagnose due to a lack of typical clinical or histopathological signs as well as an uncharacteristic and versatile clinical presentation. Increased clinical awareness is crucial for the detection of these diseases.

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers.

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.

Case report: Sevelamer-associated colitis-a cause of pseudotumor formation with colon perforation and life-threatening bleeding.

Chronic kidney disease (CKD) is a very common chronic non-communicable disease. Phosphate and calcium metabolism disorders are one of the most common features of CKD. Sevelamer carbonate is the most widely used non-calcium phosphate binder. Gastrointestinal (GI) injury associated with sevelamer use is a documented adverse effect but is underrecognized as a cause of gastrointestinal symptoms in patients with CKD. We report a case of a 74-year-old woman taking low-dose sevelamer with serious gastrointestinal adverse effects causing colon rupture and severe gastrointestinal bleeding.

Typical course of cystinuria leading to untypical complications in pregnancy: A case report and review of literature.

Cystinuria is a rare genetic disorder inherited by an autosomal recessive pattern which affects the transmembrane transporter for the base amino acid cystine. It has a general prevalence of 1 in 7000 with demographic variations. Patients with cystinuria have excessive urinary excretion of cystine, which can lead to the formation of stones. Up to 70% of patients will develop chronic kidney disease that can progress even to end-stage renal disease. Symptoms usually start in the first two decades of life with a typical presentation consisting of flank pain and renal colic, usually accompanied by urinary tract infection and deterioration of kidney function. Men are typically affected twice as often as women and have a more severe clinical course. Diagnosis is made by spectrophotometric analysis of the stones that are collected after spontaneous expulsion or medical intervention. Genetic testing is not mandatory but is recommended in uncertain cases or as a part of genetic counseling. Treatment consists of diet modification, alkalization of urine, and thiol-based therapies if other measures fail to prevent stone formation. In pregnancy, cystinuria with the formation of cystine stones represents a therapeutic challenge and requires a multidisciplinary approach consisting of an uro-nephrology team and a gynecologist. We present the case of a 34-year-old woman with cystinuria on whom the diagnosis was made by analysis of the expulsed stone. While her previous pregnancies were without complications, her third pregnancy was accompanied by frequent urinary tract infections, acute worsening of kidney function, and urological interventions during pregnancy due to the formation of new stones. Despite the complicated course, the pregnancy was successfully carried to term with the delivery of a healthy female child.

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature.

Introduction: As the global pandemic continues, new complications of COVID-19 in pediatric population have turned up, one of them being hemolytic uremic syndrome (HUS), a complement-mediated thrombotic microangiopathy (CM-TMA) characterized by triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI). With both multisystem inflammatory syndrome in children (MIS-C) and HUS sharing complement dysregulation as one of the key factors, the aim of this case report is to highlight differences between these two conditions and also emphasize the importance of complement blockade as a treatment modality. Case report: We describe a 21-month-old toddler who initially presented with fever and confirmed COVID-19. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement. Conclusion: Although reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure.

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.

Two novel variants in the lecithin:cholesterol acyltransferase gene resulted in classic LCAT deficiency.

Background and aims: We report the first two cases of familial lecithin:cholesterol acyltransferase (LCAT) deficiency in Croatia with classical clinical and biochemical features. Patients and methods: A 30-year-old man with nephrotic syndrome, corneal opacities, hepatosplenomegaly, anemia, low high-density lipoprotein (HDL)-cholesterol levels and arterial hypertension (blood pressure >200/100 mmHg) was admitted to our department. At admission, he had an elevated creatinine serum level (233 µmol/L), proteinuria of 12 g in 24-h urine (g/24 h), 3-7 erythrocytes in urine sediment and notable anemia (hemoglobin level 90 g/l). His HDL-cholesterol was significantly low (0.42 mmol/L). Besides chronic kidney disease (CKD), other secondary causes of hypertension were ruled out. The patient was previously diagnosed with membranous nephropathy and treated unsuccessfully with immunosuppressive agents (steroids, cyclosporine, cyclophosphamide). Re-evaluation of histopathological findings of kidney biopsy revealed massive deposition of lipid material in the glomerular basal membrane and in the mesangial region. His 4-year younger brother was also evaluated due to corneal opacities and new-onset arterial hypertension. Nephrotic range proteinuria with preserved global renal function was determined. He also had very low HDL-cholesterol levels. Results: Kidney biopsies from both patients were consistent with LCAT deficiency. The disease was confirmed by measurement of LCAT enzyme activity, plasma cholesterol esterification rate, and genetic testing. Two novel missense variants in the LCAT gene (c.496G > A and c.1138T  >  C) were found. Conclusions: To our knowledge, the presented cases are the first reported cases of genetic LCAT deficiency in Croatia. Given the clinical presentation, the complete lack of LCAT activity and cholesterol esterification rate, diagnosis of familial LCAT deficiency was made.

Arterial Stiffness in Balkan Endemic Nephropathy, an Environmental Form of Aristolochic Acid Nephropathy.

Balkan endemic nephropathy (BEN), an environmental form of aristolochic acid nephropathy is characterized with later onset and milder forms of hypertension (HT). Thus, we hypothesized that arterial stiffness progresses slower in BEN patients resulting in lower CV mortality. A total of 186 hemodialysed (HD) patients (90 BEN, 96 non-BEN; 67.3 + 13.0 years) were enrolled and followed-up for 25 months. Brachial blood pressure (BP) and pulse wave velocity (PWV) were determined before mid-week dialysis. BEN patients were older (72.1 ± 37.1 vs. 62.8 ± 15.1; p < 0.001), had shorter duration of HT prior commencement of HD than non-BEN patients (36 vs. 84 months; p < 0.001). There were no differences in BP, but BEN patients were treated with less antihypertensive drugs (p < 0.01). BEN patients had lower PWV values at baseline and at the end of follow-up period despite being chronologically older (p < 0.001). Baseline PWV > 10 m/s was associated with higher risk for CV mortality (aHR 1.8 [1.4, 2.4]). In multivariate analyses BEN was predictor of lower PWV. During the follow-up period significantly less CV deaths were observed in BEN vs. on-BEN patients (12 vs. 31; p = 0.001). CV mortality adjusted for other risk factors was significantly lower in BEN group (aHR 0.2 [0.1, 0.5]). Overall BEN patients had longer mean survival time on HD (22.3 vs. 18.2 months; p < 0.001). Observed slower vascular aging (i.e., lower PWV) in BEN patients compared to other ESRD patients is related to the later onset of HT and milder stages of HT during predialytic clinical course and better control of BP and phosphate during HD.

Reliability of CKD-EPI predictive equation in estimating chronic kidney disease prevalence in the Croatian endemic nephropathy area.

INTRODUCTION: Chronic kidney disease (CKD) is a significant public health problem and it is not possible to precisely predict its progression to terminal renal failure. According to current guidelines, CKD stages are classified based on the estimated glomerular filtration rate (eGFR) and albuminuria. Aims of this study were to determine the reliability of predictive equation in estimation of CKD prevalence in Croatian areas with endemic nephropathy (EN), compare the results with non-endemic areas, and to determine if the prevalence of CKD stages 3-5 was increased in subjects with EN. MATERIALS AND METHODS: A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). RESULTS: The results showed a very high CKD prevalence in the Croatian rural area (19%). CKD prevalence was significantly higher in EN then in non EN villages with the lowest eGFR value in diseased subgroup. CONCLUSIONS: eGFR correlated significantly with the diagnosis of EN. Kidney function assessment using CKD-EPI predictive equation proved to be a good marker in differentiating the study subgroups, remained as one of the diagnostic criteria for EN.