Abstract Background Nephrotic syndrome (NS) is a rare complication that can occur after haematopoietic stem cell transplantation (HSCT). In patients with membranous nephropathy (MN) who have ...undergone allogeneic HSCT, a new antigen called protocadherin FAT1 has been identified. Our objective is to present a case series of MN patients after HSCT with a novel antigen-based stratification. Case presentations Patients who developed full-blown NS due to MN after an HSCT were enrolled in the University Hospital Centre Zagreb study. The first two patients were treated with an HSCT for acute myeloid leukaemia, and both developed NS after cessation of graft versus host disease (GVHD) prophylaxis. The first patient had reduced kidney function, while the second had completely preserved function. Kidney biopsy showed MN with only subepithelial deposits. A thorough examination revealed that there was no secondary cause of the disease. The patients achieved complete remission after undergoing immunosuppression treatment. The third patient underwent HSCT for acute lymphoblastic leukaemia. He developed both acute and chronic GVHD and also experienced avascular hip necrosis. After sixteen years, the patient developed NS with preserved kidney function. The kidney specimen showed membranous nephropathy (MN) with mesangial and subepithelial deposits. Extensive research was conducted, but no secondary cause for the MN was detected. All three cases tested negative for anti-PLA2R antibodies. Biopsy tissue samples were analysed using laser microdissection and tandem mass spectrometry of glomeruli for the detection of different specific antigens. Patients one and two tested positive for FAT1, whereas patient three tested positive for PCSK6. Conclusions MN can develop at various time intervals after HSCT. Specific antigen testing can help establish the relationship between MN and HSCT. In the future, serum testing for anti-FAT1 antibodies in HSCT patients could be significant in diagnosing FAT1-associated MN, similar to how anti-PLA2R antibodies are significant in diagnosing PLA2R-associated MN.
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.
What's new?
Ingestion of aristolochic acid (AA) via contaminated wheat‐containing food products is a major cause of endemic neuropathy and urologic carcinogenesis in southeastern Europe. Here, using integrated multi‐omics analysis, the authors identified molecular programs underlying upper tract urothelial tumors (UTUC) in patients in Southern Europe with past carcinogenic AA exposure. Analyses reveal associations between 89 miRNAs and 1,862 target mRNAs, with confirmation of UTUC‐specific transcripts at protein level. AA‐specific mutations in UTUC and deleterious mutations were uncovered at both gene and transcript levels. The findings suggest that tumors in the urinary tract can be monitored by urine miRNA signature.
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.
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.
Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes.
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.
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.
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.
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.
We report the first two cases of familial lecithin:cholesterol acyltransferase (LCAT) deficiency in Croatia with classical clinical and biochemical features.
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.
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.
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.
•A 30-year-old man presents with nephrotic syndrome and corneal opacities.•Dyslipidemia with very low high-density lipoprotein cholesterol level is determined.•Analysis confirms absent lechitin:cholesterol acyltransferase activity.•Genetic analysis confirms the diagnosis with the two novel gene variants.
Introduction: Intrauterine growth restriction (IUGR) is linked to a higher incidence of cardiovascular and renal diseases. Methods: A total of 91 healthy individuals were included, 40 women and 51 ...men, born below the 10th percentile of birth weight for gestational age. Anthropometric parameters, arterial pressure (AP), blood glucose, estimated glomerular filtration rate (eGFR), albumin/creatinine ratio, lipid profile, uric acid, renal volume by ultrasound, pulse wave velocity, central arterial pressure (cAP), and augmentation index (Aix) were measured. Results: Men have higher body mass index (BMI), waist circumference, ambulatory and continuous AP, lower eGFR, pulse, higher uric acid and LDL cholesterol, lower HDL cholesterol, higher cAP and Aix, higher corrected renal volume, and birth weight than females. Overweight men had hypertension, lower eGFR, and dyslipidemia more often. Systolic pressure correlated positively with BMI in men. In women, systolic pressure correlated positively with heart rate and negatively with gestational age. BMI affected the systolic pressure in men and eGFR in women. Conclusion: Results indicate the more unfavourable effect of IUGR on men. Higher AP, vascular dysfunction, poorer renal function, and dyslipidemia predispose men to earlier chronic disease development. Key words: intrauterine growth restriction, arterial pressure, renal function
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.
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.
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.
The most common cause of rapidly progressive glomerulonephritis in elderly, antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), demands immunosuppressive therapy (IS) regimen ...in a multi-morbid disease burdened population. Our aim was to assess outcome differences in two age groups. The study included a total of 38 ANCA-GN renal limited patients (18 men) treated from 1990 to 2018, of which 11 were 65 years of age and older (median 70, min. - max. 66 - 79 years), and 27 younger than 65 (median 55, min. - max. 23 - 64 years). All patients were treated with mono/combination of IS. Most commonly applied IS in elderly was combination of IV cyclophosphamide and corticosteroids (CS) (in 9 81.8%), while in younger it was a combination of CS and cyclophosphamide or rituximab (59.2%). Older patients had comparable mortality (3, 14.8% vs. 4, 27.3%; P = 0.369), malignancies (1, 3.7% vs. 1, 9.1%; P = 0.5) and infectious complications (10, 46.7% vs. 7, 63.6%; P = 0.388). Ten patients at the end of the follow up were at renal replacement therapy (RRT), with no difference between age groups (6, 22.2% vs. 4, 36.4%; P = 0.369). Interestingly, from initial need for RRT, half of the younger and older patients recovered with IS. Our findings give more credit to the current paradigm to treat elderly ANCA-GN patients with IS therapy due to the similar outcome of elderly as younger ones. Key words: Antineutrophil Cytoplasmic antibodies, Glomerulonephritis, elderly, Immunosuppression, Mortality, Kidney failure
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