Pulmonary embolisms and infections after renal trauma.

INTRODUCTION: The objective of this study was to describe and evaluate the management of patients with renal trauma and their complications at the Department of Urology at Aarhus University Hospital (AUH), Denmark. METHODS: All patients diagnosed with renal injury due to trauma and with contact to the Department of Urology at the AUH, Denmark, between March 2016 and March 2021 were included. Patients were identified by the International Classification of Diseases, Tenth version, code and data obtained from electronic patient records. RESULTS: A total of 58 patients were identified. The median age was 33 years (7-95 years) and the median length of hospitalisation was five days (range: 0-52 days). All patients were evaluated with a multiphase computed tomography upon admission. Injuries to the kidney were graded using the American Association for the Surgery of Trauma kidney injury scale. Twelve percent had grade I injury, 26% had grade II injury, 26% had grade III injury, 36% had grade IV injury and 3% had grade V injury. In the acute phase, all patients were managed non-operatively. Early complications were found in 24% of patients. Pulmonary embolism was diagnosed in 7%. Furthermore, 7% had an infection as a late complication and all of these patients had also had an early infection. A total of 60% were followed up with a renal-scintigraphy three months after their renal trauma. This examination had no consequence for any of the patients. CONCLUSIONS: No patients died due to the renal trauma. However, many experienced complications in terms of infections and pulmonary embolisms. These data support earlier findings and suggest that a renal scintigraphy after renal traumas may be obsolete. FUNDING: None. TRIAL REGISTRATION: Not relevant.

An animal-free preclinical drug screening platform based on human precision-cut kidney slices.

OBJECTIVE: Renal fibrosis is one of the main pathophysiological processes underlying the progression of chronic kidney disease and kidney allograft failure. In the past decades, overwhelming efforts have been undertaken to find druggable targets for the treatment of renal fibrosis, mainly using cell- and animal models. However, the latter often do not adequately reflect human pathogenesis, obtained results differ per strain within a given species, and the models are associated with considerable discomfort for the animals. Therefore, the objective of this study is to implement the 3Rs in renal fibrosis research by establishing an animal-free drug screening platform for renal fibrosis based on human precision-cut kidney slices (PCKS) and by limiting the use of reagents that are associated with significant animal welfare concerns. RESULTS: Using Western blotting and gene expression arrays, we show that transforming growth factor-ß (TGF-ß) induced fibrosis in human PCKS. In addition, our results demonstrated that butaprost, SC-19220 and tamoxifen - all putative anti-fibrotic compounds - altered TGF-ß-induced pro-fibrotic gene expression in human PCKS. Moreover, we observed that all compounds modulated fairly distinct sets of genes, however they all impacted TGF-ß/SMAD signaling. In conclusion, this study revealed that it is feasible to use an animal-free approach to test drug efficacy and elucidate mechanisms of action.

Urinary NGAL, cystatin C, ß2-microglobulin, and osteopontin significance in hydronephrotic children.

BACKGROUND: Ureteropelvic junction obstruction (UPJO) accounts for 35 % of all congenital hydronephrosis cases. The challenge in managing childhood hydronephrosis is to distinguish obstructive from nonobstructive cases and, thereby, identify patients requiring surgical intervention. This study aimed to examine four urinary proteins as potential biomarkers of obstruction in hydronephrosis. METHODS: Urine samples from 24 children with UPJO were collected pre-, peri-, and postoperatively, together with urine samples from healthy children. Neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CyC), ß2-microglobulin (ß2-M), and osteopontin (OPN) in the samples were measured simultaneously using multiplex sandwich immunoassay technology. RESULTS: Compared with controls, NGAL and ß2-M were significantly increased in urine from patients with obstructed kidneys at the time of surgery. This increase was followed by a decrease and stabilization to the same level as that of the controls. Furthermore, age was negatively correlated with preoperative urinary concentrations of CyC, ß2-M, and OPN. CONCLUSIONS: This study confirms increased concentrations of NGAL and ß2-M in urine from obstructed kidneys and should be tested in larger studies to ascertain their ability to identify obstruction and to determine the importance of age-adjusted reference values.

Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis.

OBJECTIVE: In search of potential urinary biomarkers of obstructive nephropathy, this study examined whether a potential change in the concentration of urinary cytokines [interferon-γ(IFN-γ), interleukin-1ß (IL-1ß), IL-2, IL-6, IL-10 and tumour necrosis factor-α (TNF-α)] reliably reflects changes in renal parenchymal levels of the same cytokines following the release of acute and chronic unilateral ureteral obstruction, respectively. MATERIAL AND METHODS: Acute obstruction was performed in 12 adult rats. After 48 h, six rats were used for selective urine collection and six rats had their kidneys removed and dissected into inner medulla and cortex. Chronic obstruction was performed in newborn rats. After 10 weeks, a similar set-up to that of the acute study was implemented. Sham-operated rats were prepared in parallel. Urine and tissue cytokines were measured with a bead-based multiplex sandwich immunoassay and analysed on a Luminex 100 IS instrument. RESULTS: In the acute study, there were significantly increased concentrations of IL-1ß and IL-6 in inner medulla and in urine from the obstructed kidney, significantly increased concentrations of TNF-α in urine from the obstructed kidney and, importantly, significantly increased levels of IL-10 in cortex and in urine from the non-obstructed kidney. In the chronic study, there were similar changes in IL-1ß and IL-6 (not significant) but no changes in TNF-α and IL-10. CONCLUSIONS: This study showed that inflammatory cytokines can be detected both in renal parenchyma and in urine from rats with experimental unilateral ureteral obstruction. Further studies are needed to confirm the diagnostic accuracy of IL-1ß, IL-6, IL-10 and TNF-α in urine.

Immunohistochemical Screening of Upper Tract Urothelial Carcinomas for Lynch Syndrome Diagnostics: A Systematic Review.

OBJECTIVE: To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome diagnostics. MATERIALS AND METHODS: Studies were identified through PubMed on December 1, 2021. Eligibility criteria were universal immunohistochemical analyses for at least 2 MMR proteins in unselected, consecutively collected UTUC cohorts. Exclusion criteria included reviews, case-reports, non-English language, and non-humans. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Meta-analyses were performed to compare the association between clinical criteria and Lynch syndrome diagnoses. RESULTS: From 12 included studies, 1628 surgically removed UTUC from 1626 patients were screened for MMR protein loss. In 11 studies, 140 of the 1559 patients had tumors with loss (9.0%) with 80.7% showing loss of MSH2, MSH6, or both. In 7 studies, genetic testing confirmed Lynch syndrome diagnosis for 20 of 970 patients (2.1%). In 8 studies, 31 patients were given a clinical Lynch syndrome diagnosis (2.6%). In total, 51 assumed or verified Lynch syndrome patients were identified among 1087 patients (4.7%). Meta-analyses of 3 studies showed significant association between previous cancer diagnosis and Lynch syndrome-associated UTUC (P = .038). CONCLUSION: Despite the few studies conducted and lack of genetic testing, current data suggests that universal screening for MMR protein loss in UTUC may result in Lynch syndrome diagnoses in 4.7%. However, for the screening to be effective for Lynch syndrome diagnostics, follow-up investigations, such as genetic testing for MMR variants, are needed.

EP1 receptor antagonism mitigates early and late stage renal fibrosis.

AIM: Renal fibrosis is a major driver of chronic kidney disease, yet current treatment strategies are ineffective in attenuating fibrogenesis. The cyclooxygenase/prostaglandin system plays a key role in renal injury and holds great promise as a therapeutic target. Here, we used a translational approach to evaluate the role of the PGE2 -EP1 receptor in the pathogenesis of renal fibrosis in several models of kidney injury, including human (fibrotic) kidney slices. METHODS: The anti-fibrotic efficacy of a selective EP1 receptor antagonist (SC-19220) was studied in mice subjected to unilateral ureteral obstruction (UUO), healthy and fibrotic human precision-cut kidney slices (PCKS), Madin-Darby Canine Kidney (MDCK) cells and primary human renal fibroblasts (HRFs). Fibrosis was evaluated on gene and protein level using qPCR, western blot and immunostaining. RESULTS: EP1 receptor inhibition diminished fibrosis in UUO mice, illustrated by a decreased protein expression of fibronectin (FN) and α-smooth muscle actin (αSMA) and a reduction in collagen deposition. Moreover, treatment of healthy human PCKS with SC-19220 reduced TGF-ß-induced fibrosis as shown by decreased expression of collagen 1A1, FN and αSMA as well as reduced collagen deposition. Similar observations were made using fibrotic human PCKS. In addition, SC-19220 reduced TGF-ß-induced FN expression in MDCK cells and HRFs. CONCLUSION: This study highlights the EP1 receptor as a promising target for preventing both the onset and late stage of renal fibrosis. Moreover, we provide strong evidence that the effect of SC-19220 may translate to clinical care since its effects were observed in UUO mice, cells and human kidney slices.

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Activation of the prostaglandin E2 EP2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices.

AIM: Renal fibrosis plays a pivotal role in the development and progression of chronic kidney disease, which affects 10% of the adult population. Previously, it has been demonstrated that the cyclooxygenase-2 (COX-2)/prostaglandin (PG) system influences the progression of renal injury. Here, we evaluated the impact of butaprost, a selective EP2 receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices. METHODS: We studied the anti-fibrotic efficacy of butaprost using Madin-Darby Canine Kidney (MDCK) cells, mice that underwent unilateral ureteral obstruction and human precision-cut kidney slices. Fibrogenesis was evaluated on a gene and protein level by qPCR and Western blotting. RESULTS: Butaprost (50 µM) reduced TGF-ß-induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial-mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg/day butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α-smooth muscle actin, FN and collagen 1A1. More importantly, a similar anti-fibrotic effect of butaprost was observed in human precision-cut kidney slices exposed to TGF-ß. The mechanism of action of butaprost appeared to be a direct effect on TGF-ß/Smad signalling, which was independent of the cAMP/PKA pathway. CONCLUSION: In conclusion, this study demonstrates that stimulation of the EP2 receptor effectively mitigates renal fibrogenesis in various fibrosis models. These findings warrant further research into the clinical application of butaprost, or other EP2 agonists, for the inhibition of renal fibrosis.

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.

Childhood pneumothorax in Birt-Hogg-Dubé syndrome: A cohort study and review of the literature.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported. METHODS: To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed. RESULTS: In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified. CONCLUSION: Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance.

Cryoablation of Renal Angiomyolipoma: An Evaluation of Safety and Efficacy.

BACKGROUND: Small series have reported that cryoablation (CA) is a safe and feasible minimally invasive nephron-sparing alternative for the treatment of renal angiomyolipomas (renal AMLs). The aim of the present study was to investigate the safety and efficacy of CA in patients with renal AML. MATERIALS AND METHODS: A retrospective review of 19 renal AML lesions treated with CA at Aarhus University Hospital, Denmark, over a 5-year period. RESULTS: The treatment was performed as laparoscopy-assisted CA on 7 lesions, and in the remaining 12 lesions CA was performed as a percutaneous ultrasound-guided CA. The mean patient age was 46 years [interquartile range (IQR) 30] and the mean tumor volume was 50.1 cm3 (IQR 53.3). In all cases, the procedure was effectively conducted with no conversion to open surgery, and no major complications were experienced. The mean follow-up time was 25 months (IQR 13). Mean maximum tumor volume was reduced from 50.1 cm3 (IQR 53.3) to 12.2 cm3 (IQR 14.1), p = 0.05. No patients presented with retroperitoneal hemorrhage or recurrence during follow-up. CONCLUSION: Treating renal AMLs with CA appears to be a safe and effective nephron-sparing approach and could be a valuable alternative to other treatment modalities. The low complication rate, absence of retreatment and a good preservation of renal function might allow treatment of even subclinical renal AMLs to minimize the risk of potentially life-threatening hemorrhage.

Birt-Hogg-Dubé syndrome: a case report and a review of the literature.

Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited syndrome caused by mutations in the folliculin coding gene (FLCN). The clinical manifestations of the syndrome involve the skin, lungs, and kidneys. Because of the rarity of the syndrome, guidelines for diagnosis and management of the patients with BHDS are lacking. Objective: To present a case story and a review of the literature on BHDS in order to give an update on genetics, clinical manifestations, diagnosis, treatment, prognosis and follow-up strategies. Design: Literature review and case story. Results: A PubMed and Embase search identified 330 papers. BHDS is characterized by small benign tumors in the skin, spontaneous pneumothoraces caused by cysts in the lungs and a seven-fold increased risk of renal cancer. A case story of a young female patient presenting with pneumothorax and a family history of recurrent pneumothoraces in many relatives illustrates how the history and the diagnostic work up resulted in a diagnosis of BHDS. Conclusion: BHDS is a rare inherited disorder. In patients with spontaneous pneumothorax or cystic lung disease without any obvious explanation, BHDS should be considered. Concomitant skin manifestations, a family history of familiar pneumothorax, renal cancers and skin manifestations supports the suspicion of BHDS. Early diagnosis is important in order to subject patients to systematic screening for renal cancers. A radiological surveillance strategy for renal cancer is proposed.

[Foreign objects in the urethra].

Foreign objects in the urethra are rare. Most cases are often caused by self-mutilating behaviour, in which the patient inserts an object into the urethra. Usually this is performed in a sexual context, and many different objects have been used. This case report presents a patient who used a 4 cm bullet-looking metal object for sexual pleasure. Cystoscopy revealed an object deep in the urethra, penetrating through the urethral mucosa. The object was removed endoscopically. At follow-up the patient experienced no sequelae, although infections, urethral stricture or fistula may occur in these cases.

Urinary biomarkers in hydronephrosis.

UNLABELLED: Hydronephrosis is diagnosed in 0.5-1% of all newborns, and ureteropelvic junction obstruction (UPJO) accounts for 35% of those cases. A urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation, and growth, and in the most severe cases, this will ultimately lead to progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The clinical management of these patients remains a controversial topic. The aim is to preserve renal function by identifying the 15-20% of children who require early surgical intervention from those for whom watchful waiting may be appropriate because of spontaneous resolving/stabilization without significant loss of renal function. Although the patients attend regular follow-ups, including repetitive blood tests, ultrasonographies, and the more invasive diuretic renograms, the surgeons still miss reliably biomarkers that could be used as predictors for renal parenchymal damage and decreased renal function, and thereby provide more clear indications for surgical intervention. The aim of this PhD thesis was to further elucidate the pathophysiology of obstructive nephropathy (study I) and to search for potential candidate biomarkers that may have a predictive and/or diagnostic value in the management of hydronephrosis (study II). Study I: Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis. AIM: To study the dynamics of the urinary secretion of cytokines after the release of unilateral ureteral obstruction, and to study whether the urinary concentrations of these compounds reliably reflects changes in the renal parenchyma. This was tested in 2 experimental rat models: an acute obstruction model and a chronic obstruction model. RESULTS: The acute obstruction model demonstrated significant differences in the renal levels of IL-1ß, IL-6, TNF-α, and IL-10 in comparison with controls, and these differences were associated with similar differences in their urinary excretion. Such results were not obtained in the chronic obstruction model in which significant differences were only demonstrated in the urinary concentrations of IL-6. Study II: Candidate urinary biomarkers in hydronephrosis - a clinical study. AIM: To study the dynamics of the urinary excretion of selected potential biomarkers in children after the relief of UPJO, and to compare their findings with healthy controls. RESULTS: Twenty-eight children with UPJO were included in the study from 2007-2011 together with 13 healthy children. Pre-, peri- and post-operatively (1 year) urine samples were collected. The median age of the patients was 8.1 (3.5-14.5) years. Five proteins (EGF, IP-10, MCP-1, RANTES, and MIP-1α) were examined in study IIa, and 4 proteins (NGAL, CyC, ßM-2, and OPN) were examined in study IIb. In brief, significantly increased urinary concentrations of EGF and MCP-1 were demonstrated in children with UPJO compared to controls, which was followed by a decline in the post-operative period to levels similar to the controls. This indicates that the urinary concentrations of EGF and MCP-1 are regulated as a response to the obstruction, suggesting that they may have a potential as urinary biomarkers in hydronephrosis. In general, urine from the obstructed kidney exhibited higher concentrations of the proteins compared to urine from the nonobstructed kidney. Furthermore, CyC, ß-2M, and OPN were negatively correlated with age, and IP-10 and MCP-1 were negatively correlated with DRF. In conclusion, this PhD study confirmed increased concentrations of selected proteins in urine from kidneys suffering from obstruction. Interestingly, it was observed that some urinary proteins had an age-dependent excretion. Further investigations are required to test the ability of the examined proteins to identify an obstruction and reveal disease progression and, thereby, be useful clinical tools.

Epidermal growth factor and monocyte chemotactic peptide-1: potential biomarkers of urinary tract obstruction in children with hydronephrosis.

OBJECTIVE: Hydronephrosis is diagnosed in 0.5% of all newborns, and ureteropelvic junction obstruction (UPJO) is a common cause. The aim of this study was to test whether specific urinary cytokines can be used as UPJO biomarkers in children with hydronephrosis. MATERIALS AND METHODS: Twenty-eight children referred for pyeloplasty due to UPJO and 13 controls were included in this prospective study. Kidney function was assessed and urine samples collected pre-, peri-, and post-operatively. Urine levels of epidermal growth factor (EGF), monocyte chemotactic peptide-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), interferon-γ-inducible protein-10 (IP-10), and RANTES were measured simultaneously by using a bead-based multiplex sandwich immunoassay. RESULTS: In hydronephrotic children, preoperative urine levels were significantly increased for EGF (median 7.4 [1.2-60.2] vs. median 4.0 [1.2-13.8] ng/mg creatinine) and MCP-1 (median 136.9 [47.7-545.5] vs. median 80.1 [28.8-149.9] pg/mg creatinine) compared to those of controls. Urine levels of EGF and MCP-1 were identical to controls at the postoperative 1-year follow-up exam. CONCLUSION: Urine levels of EGF and MCP-1 were preoperatively increased and postoperatively normalized. This study demonstrates that urine-excreted kidney cytokines may be potential biomarkers of obstruction in children with hydronephrosis.

Urinary proteome analysis in congenital bilateral hydronephrosis.

OBJECTIVE: A proteomics strategy was applied to map protein changes in urine after relief of congenital bilateral hydronephrosis to identify proteins correlated with the pathophysiological processes in congenital obstructive nephropathy as potential urinary biomarkers. MATERIAL AND METHODS: Urine samples from 10 infants with bilateral abnormal drainage from the kidneys were collected at the time of relief from obstruction, and after 2 and 4 weeks. Proteomics techniques were used on samples from three patients for identification of protein changes between the three time-points, and enzyme-linked immunosorbent assay (ELISA) was used on samples from all 10 patients for validation of five selected proteins. RESULTS: Mass spectrometry quantified 315 protein hits, out of which 33 proteins showed significantly changed urinary excretion between the time-points. Validation by ELISA showed high urinary excretion of fibrinogen, plasminogen, transthyretin and transferrin at the time of relief from obstruction, followed by a significant reduction. In contrast, Tamm-Horsfall protein exhibited the reverse pattern. CONCLUSION: Using a mass spectrometry-based proteomics approach, this study identified 33 proteins related to congenital bilateral hydronephrosis, and pinpointed a panel of five proteins consistently linked to this congenital kidney disorder as potential urinary biomarkers.

Urinary biomarkers in prenatally diagnosed unilateral hydronephrosis.

The introduction of prenatal ultrasonography as a screening method entails an increasing number of infants diagnosed with prenatal hydronephrosis. Ureteropelvic junction obstruction accounts for 35% of prenatal hydronephrotic cases. Urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation and growth, and in the most severe cases this will ultimately cause renal insufficiency. A major challenge in the clinical management of these patients is to preserve renal function by selection of the 15%-20% who require early surgical intervention, leaving those for whom watchful waiting may be appropriate because of spontaneous resolution/stabilization without significant loss of renal function. Today, this requires medical surveillance, including repetitive invasive diuretic renograms relying on arbitrary threshold values, and therefore there is a need for non-arbitrary, non-invasive urinary biomarkers that may be used as predictors for renal structural changes and/or decreasing renal function, and thereby provide the surgeon with more clear indications for surgical intervention. In this review, we summarize the currently well-known facts about urinary biomarkers in ureteropelvic junction obstruction concerning renal function, and we also suggest potential novel urinary biomarkers.