An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder.

Laminin alpha 5 (LAMA5) is a member of a large family of proteins that trimerise and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung and limb, and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerisation domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development, and by a range of other congenital defects. Using CRISPR-generated mouse models and biochemical assays, we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/ß/γ laminin trimers. Comparing these in vivo phenotypes with those apparent upon gene deletion in mice provides insights into the specific functional importance of laminin polymerisation during development and tissue homeostasis.

A connectomics approach to understanding a retinal disease.

Macular telangiectasia type 2 (MacTel), a late-onset macular degeneration, has been linked to a loss in the retina of Müller glial cells and the amino acid serine, synthesized by the Müller cells. The disease is confined mainly to a central retinal region called the MacTel zone. We have used electron microscopic connectomics techniques, optimized for disease analysis, to study the retina from a 48-y-old woman suffering from MacTel. The major observations made were specific changes in mitochondrial structure within and outside the MacTel zone that were present in all retinal cell types. We also identified an abrupt boundary of the MacTel zone that coincides with the loss of Müller cells and macular pigment. Since Müller cells synthesize retinal serine, we propose that a deficiency of serine, required for mitochondrial maintenance, causes mitochondrial changes that underlie MacTel development.

Podocyte endowment and the impact of adult body size on kidney health.

Low birth weight is a risk factor for chronic kidney disease, whereas adult podocyte depletion is a key event in the pathogenesis of glomerulosclerosis. However, whether low birth weight due to poor maternal nutrition is associated with low podocyte endowment and glomerulosclerosis in later life is not known. Female Sprague-Dawley rats were fed a normal-protein diet (NPD; 20%) or low-protein diet (LPD; 8%), to induce low birth weight, from 3 wk before mating until postnatal day 21 (PN21), when kidneys from some male offspring were taken for quantitation of podocyte number and density in whole glomeruli using immunolabeling, tissue clearing, and confocal microscopy. The remaining offspring were fed a normal- or high-fat diet until 6 mo to induce catch-up growth and excessive weight gain, respectively. At PN21, podocyte number per glomerulus was 15% lower in low birth weight (LPD) than normal birth weight (NPD) offspring, with this deficit greater in outer glomeruli. Surprisingly, podocyte number in LPD offspring increased in outer glomeruli between PN21 and 6 mo, although an overall 9% podocyte deficit persisted. Postnatal fat feeding to LPD offspring did not alter podometric indexes or result in glomerular pathology at 6 mo, whereas fat feeding in NPD offspring was associated with far greater body and fat mass as well as podocyte loss, reduced podocyte density, albuminuria, and glomerulosclerosis. This is the first report that maternal diet can influence podocyte endowment. Our findings provide new insights into the impact of low birth weight, podocyte endowment, and postnatal weight on podometrics and kidney health in adulthood.NEW & NOTEWORTHY The present study shows, for the first time, that low birth weight as a result of maternal nutrition is associated with low podocyte endowment. However, a mild podocyte deficit at birth did not result in glomerular pathology in adulthood. In contrast, postnatal podocyte loss in combination with excessive body weight led to albuminuria and glomerulosclerosis. Taken together, these findings provide new insights into the associations between birth weight, podocyte indexes, postnatal weight, and glomerular pathology.

Vitamin A: its many roles-from vision and synaptic plasticity to infant mortality.

The recognition that a dietary factor is essential to maintain good and sensitive vision as well as overall health goes back over 3,000 years to the ancient Egyptians. With the discovery of the vitamins at the turn of the twentieth century, fat-soluble vitamin A was soon shown to be the essential factor. In the first half of the twentieth century, the role vitamin A plays in vision, as precursor to the light-sensitive visual pigment molecules in the photoreceptors was elegantly worked out, especially by George Wald and his colleagues. Beginning in the 1960s, with the recognition of the active metabolite of vitamin A, its acid form now called retinoic acid, the roles of vitamin A in maintaining overall health of an organism began to be explored, and this research continues to this day. Receptors activated by retinoic acid, the RARs and RXRs have been shown to regulate gene transcription in a surprisingly wide variety of biological processes from early growth and development to the maintenance of epithelial tissues in many organs, the regulation of the immune system, and even the modulation of synaptic function in the brain involved in mechanisms underlying memory and learning. Therapeutic uses for retinoic acid have been developed, including one for a specific form of leukemia. The story is by no means complete and it is likely more surprises await with regard to this remarkable molecule.

A Case of Cutaneous Inflammatory Myofibroblastic Tumor.

Inflammatory myofibroblastic tumor (IMT) rarely occurs as a primary cutaneous lesion. We report a case of cutaneous IMT in an 8-year-old girl presenting with an ulcerated nodule on the cheek. Although cutaneous IMT poses a diagnostic challenge because of its rarity, excision of the lesion is likely to be curative.

Acute kidney injury due to glomerular haematuria and obstructive erythrocyte casts associated with thrombocytopaenia and thin basement membrane disease: a case report.

BACKGROUND: Acute kidney injury due to glomerular bleeding has been described with IgA nephropathy and supratherapeutic warfarin anticoagulation. There is usually demonstrable tubular obstruction by erythrocyte casts associated with acute tubular injury. Although severe thrombocytopaenia increases the risk of bleeding, most cases of haematuria have been ascribed to non-glomerular or urological bleeding without a direct link to acute kidney injury. We describe a patient with acute kidney injury due to glomerular bleeding and tubular injury related to severe thrombocytopaenia, who was subsequently found to have thin basement membrane disease. CASE PRESENTATION: A 56 year old man presented with macroscopic haematuria, acute kidney injury and a platelet count of 35 × 10(9)/L, in the absence of anticoagulation. Urinalysis demonstrated an active urinary sediment. His kidney biopsy demonstrated extensive intraluminal erythrocyte casts associated with acute tubular injury, along with haemosiderin deposition suggestive of recurrent glomerular bleeding. There was no histological evidence of glomerular pathology but electron microscopy analysis demonstrated thin basement membrane disease and effacement of podocyte foot processes. During long term follow-up, thrombocytopaenia and intermittent haematuria persisted. At 9 months, the patient progressed to Stage 5 chronic kidney disease with the development of gross renal atrophy. CONCLUSION: Recurrent macroscopic haematuria may be a risk factor for progressive renal injury in patients with thin basement membrane. The mechanism may be due to recurrent acute kidney injury from glomerular bleeding leading to repeated tubular damage. In the absence of anticoagulation, severe thrombocytopaenia may be a risk factor for heavy glomerular bleeding and acute kidney injury in these patients.

MRI-based glomerular morphology and pathology in whole human kidneys.

Nephron number (N(glom)) and size (V(glom)) are correlated with risk for chronic cardiovascular and kidney disease and may be predictive of renal allograft viability. Unfortunately, there are no techniques to assess N(glom) and V(glom) in intact kidneys. This work demonstrates the use of cationized ferritin (CF) as a magnetic resonance imaging (MRI) contrast agent to measure N(glom) and V(glom) in viable human kidneys donated to science. The kidneys were obtained from patients with varying levels of cardiovascular and renal disease. CF was intravenously injected into three viable human kidneys. A fourth control kidney was perfused with saline. After fixation, immunofluorescence and electron microscopy confirmed binding of CF to the glomerulus. The intact kidneys were imaged with three-dimensional MRI and CF-labeled glomeruli appeared as punctate spots. Custom software identified, counted, and measured the apparent volumes of CF-labeled glomeruli, with an ~6% false positive rate. These measurements were comparable to stereological estimates. The MRI-based technique yielded a novel whole kidney distribution of glomerular volumes. Histopathology demonstrated that the distribution of CF-labeled glomeruli may be predictive of glomerular and vascular disease. Variations in CF distribution were quantified using image texture analyses, which be a useful marker of glomerular sclerosis. This is the first report of direct measurement of glomerular number and volume in intact human kidneys.

Histopathologic and clinical predictors of kidney outcomes in ANCA-associated vasculitis.

BACKGROUND: A predictive histologic classification recently was proposed to determine the prognostic value of kidney biopsy in patients with antineutrophil cytoplasmic antibody-associated renal vasculitis (AAV). STUDY DESIGN: A dual-purpose retrospective observational cohort study to assess the reproducibility of the new classification and clinical variables that predict outcomes. SETTING & PARTICIPANTS: 169 consecutive patients with AAV were identified; 145 were included in the reproducibility study, and 120, in the outcomes study. PREDICTOR: Kidney biopsy specimens were classified according to the predominant glomerular lesion: focal, mixed, crescentic, and sclerotic. An assessment of tubular atrophy also was performed. OUTCOMES: The primary outcome was time to end-stage kidney disease or all-cause mortality, modeled using Cox regression analysis. MEASUREMENTS: Estimated glomerular filtration rate, requirement for renal replacement therapy. RESULTS: For the reproducibility study, the overall inter-rater reliability of the classification demonstrated variability among 3 histopathologists (intraclass correlation coefficient, 0.48; 95% CI, 0.38-0.57; κ statistic=0.46). Although agreement was high in the sclerotic group (κ=0.70), it was less consistent in other groups (κ=0.51, κ=0.47, and κ=0.23 for crescentic, focal, and mixed, respectively). For the clinical outcomes study, patients with sclerotic patterns of glomerular injury displayed the worst outcomes. Patients with focal (HR, 0.26; 95% CI, 0.12-0.58; P=0.001), crescentic (HR, 0.33; 95% CI, 0.16-0.69; P=0.003), and mixed (HR, 0.39; 95% CI, 0.18-0.81; P=0.01) patterns of injury had lower risk of the primary outcome. Tubular atrophy correlated with outcome, and advanced injury was associated with worse outcomes (HR, 5.9; 95% CI, 2.25-15.47; P<0.001). Level of kidney function at presentation strongly predicted outcome (HR per 10-mL/min/1.73m(2) increase in estimated glomerular filtration rate, 0.63; 95% CI, 0.46-0.81; P<0.001). LIMITATIONS: Data availability, given the retrospective nature of the study. CONCLUSIONS: Reproducibility of the classification was seen only in patients with sclerotic patterns of glomerular injury. Sclerotic pattern of glomerular injury, advanced chronic interstitial injury, and decreased kidney function all predicted poor outcomes.

myosin 7aa(-/-) mutant zebrafish show mild photoreceptor degeneration and reduced electroretinographic responses.

Mutations in myosin VIIa (MYO7A) cause Usher Syndrome 1B (USH1B), a disease characterized by the combination of sensorineural hearing loss and visual impairment termed retinitis pigmentosa (RP). Although the shaker-1 mouse model of USH1B exists, only minor defects in the retina have been observed during its lifespan. Previous studies of the zebrafish mariner mutant, which also carries a mutation in myo7aa, revealed balance and hearing defects in the mutants but the retinal phenotype has not been described. We found elevated cell death in the outer nuclear layer (ONL) of myo7aa(-/-) mutants. While myo7aa(-/-) mutants retained visual behaviors in the optokinetic reflex (OKR) assay, electroretinogram (ERG) recordings revealed a significant decrease in both a- and b-wave amplitudes in mutant animals, but not a change in ERG threshold sensitivity. Immunohistochemistry showed mislocalization of rod and blue cone opsins and reduced expression of rod-specific markers in the myo7aa(-/-) ONL, providing further evidence that the photoreceptor degeneration observed represents the initial stages of the RP. Further, constant light exposure resulted in widespread photoreceptor degeneration and the appearance of large holes in the retinal pigment epithelium (RPE). No differences were observed in the retinomotor movements of the photoreceptors or in melanosome migration within the RPE, suggesting that myo7aa(-/-) does not function in these processes in teleosts. These results indicate that the zebrafish myo7aa(-/-) mutant is a useful animal model for the RP seen in humans with USH1B.

The effects of nicotine on cone and rod b-wave responses in larval zebrafish.

Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON-bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant ( n o optokinetic response f ) fi sh that has no cone function. We fi nd that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity.

Using chief complaints for syndromic surveillance: a review of chief complaint based classifiers in North America.

A major goal of Natural Language Processing in the public health informatics domain is the automatic extraction and encoding of data stored in free text patient records. This extracted data can then be utilized by computerized systems to perform syndromic surveillance. In particular, the chief complaint--a short string that describes a patient's symptoms--has come to be a vital resource for syndromic surveillance in the North American context due to its near ubiquity. This paper reviews fifteen systems in North America--at the city, county, state and federal level--that use chief complaints for syndromic surveillance.

Zebrafish larvae lose vision at night.

Darkness serves as a stimulus for vertebrate photoreceptors; they are actively depolarized in the dark and hyperpolarize in the light. Here, we show that larval zebrafish essentially turn off their visual system at night when they are not active. Electroretinograms recorded from larval zebrafish show large differences between day and night; the responses are normal in amplitude throughout the day but are almost absent after several hours of darkness at night. Behavioral testing also shows that larval zebrafish become unresponsive to visual stimuli at night. This phenomenon is largely circadian driven as fish show similar dramatic changes in visual responsiveness when maintained in continuous darkness, although light exposure at night partially restores the responses. Visual responsiveness is decreased at night by at least two mechanisms: photoreceptor outer segment activity decreases and synaptic ribbons in cone pedicles disassemble.

Neuromodulation: Actions of Dopamine, Retinoic Acid, Nitric Oxide, and Other Substances on Retinal Horizontal Cells.

Whereas excitation and inhibition of neurons are well understood, it is clear that neuromodulatory influences on neurons and their synapses play a major role in shaping neural activity in the brain. Memory and learning, emotional and other complex behaviors, as well as cognitive disorders have all been related to neuromodulatory mechanisms. A number of neuroactive substances including monoamines such as dopamine and neuropeptides have been shown to act as neuromodulators, but other substances thought to play very different roles in the body and brain act as neuromodulators, such as retinoic acid. We still understand little about how neuromodulatory substances exert their effects, and the present review focuses on how two such substances, dopamine and retinoic acid, exert their effects. The emphasis is on the underlying neuromodulatory mechanisms down to the molecular level that allow the second order bipolar cells and the output neurons of the retina, the ganglion cells, to respond to different environmental (ie lighting) conditions. The modulation described affects a simple circuit in the outer retina, involves several neuroactive substances and is surprisingly complex and not fully understood.

Sexual and urinary function in prostate cancer clinical studies and the Europa Uomo Patient Reported Outcome Study: does it match?

BACKGROUND: We aimed to quantify the difference in patient reported outcome (PRO) data between clinical studies and the (patient initiated) EUPROMS study for sexual functioning and urinary incontinence after radical prostatectomy (RP) and external beam radiotherapy (RT). METHODS: Europa Uomo, the patient organization of men with prostate cancer (PCa) in Europe, initiated the EUPROMS study. Data involved 1101 men with PCa treated with RP and 304 patients treated with RT. In a literature search we identified investigator-initiated studies which matched EUPROMS characteristics. The observed scores in the literature were compared to the scores calculated using the EUPROMS-models. Data from EUPROMS was used to develop four regression models for men treated with RP and RT. RESULTS: The time between diagnosis and questionnaire completion was estimated to be 3/4 years for men after RP, and 5 for RT. Eight studies were identified which reported PRO data using the EPIC with comparable follow-up. Large heterogeneity was observed in reported literature. For sexual function, the difference in calculated and observed scores is at most 24 points (range 3-24 points) and differences between studies were less evident; for urinary incontinence, the difference between calculated and observed scores is at most 15 points (range 1.5-15) (4 scores above the MID) and previous studies underreported the actual effect compared to the current study. CONCLUSIONS: Previous clinical investigator studies underreported the actual effect for urinary incontinence compared to the EUPROMS study. Clinicians should be aware of a potential underestimation of the reported PRO in the patient-physician communication.

The Europa Uomo Patient Reported Outcome Study 2.0-Prostate Cancer Patient-reported Outcomes to Support Treatment Decision-making.

BACKGROUND: To further strengthen the voice of patients, Europa Uomo initiated the Europa Uomo Patient Reported Outcome Study 2.0 (EUPROMS 2.0) in October 2021. OBJECTIVE: To collect the self-reported perspective of prostate cancer (PCa) patients on physical and mental well-being after PCa treatment outside a clinical trial setting to inform future fellow patients about the impact of PCa treatment. DESIGN, SETTING, AND PARTICIPANTS: Europa Uomo invited PCa patients to complete a cross-sectional survey including the validated EQ-5D-5L, EORTC-QLQ-C30, and the EPIC-26 questionnaires. Furthermore, the nine-item Shared Decision Making Questionnaire (SDM-Q-9) and diagnostic clinical scenarios were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics was used to assess the demographic and clinical characteristics and to analyze the patient-reported outcome data. RESULTS AND LIMITATIONS: Between October 25, 2021 and January 17, 2022, 3571 men from 30 countries completed the EUPROMS 2.0 survey. The median age of respondents was 70 yr (interquartile range 65-75 yr). Half of the respondents underwent one treatment, most often radical prostatectomy. Men who are treated actively experience lower health-related quality of life than men on active surveillance, mainly regarding sexual function, fatigue, and insomnia. Lower urinary incontinence levels were seen for men who underwent radical prostatectomy (single treatment or in combination with other treatments). Of the respondents, 42% indicated that the determination of the prostate-specific antigen (PSA) value was part of a routine blood test; 25% wanted to undergo screening/early detection for PCa, and 20% indicated that the determination of the PSA value had a clinical reason. CONCLUSIONS: A large sample of 3571 international patients has contributed patient experience after PCa treatment in the EUPROMS 2.0 study, confirming that treatment for PCa mainly affects urinary incontinence, sexual function, fatigue, and insomnia. Such information can be used to direct toward a better patient-doctor relationship, to offer patients ready access to responsible information and a better understanding of their disease and treatment. PATIENT SUMMARY: Through the EUPROMS 2.0 survey, Europa Uomo has strengthened the voice of the patient. Such information can be used to inform future prostate cancer (PCa) patients about the impact of PCa treatment and to engage them in informed and shared decision-making.

IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation.

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.

Renal biopsy findings among Indigenous Australians: a nationwide review.

Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS.