The incidence of chronic kidney disease (CKD) is increasing. CKD is characterized by a gradual decrease in renal function leading to end stage renal disease (ESRD). Damage to the glomerular podocytes, is one of the first hallmarks of CKD. We hypothesized that podocyte prostaglandin E2 (PGE2) receptors contribute to the progression of glomerular injury in models of CKD. To test this hypothesis, transgenic mice were generated with either podocyte-specific overexpression or deletion of the PGE2 EP4 receptor (EP4pod+and EP4pod-/- respectively). Mice were next tested in the 5/6 nephrectomy (5/6 Nx) or angiotensin II (Ang II) models of CKD. These studies revealed increased proteinuria and decreased survival for EP4pod+ mice while EP4pod-/- mice were protected against the development of glomerular injury. Furthermore, our findings were supported by in vitro studies using cultured mouse podocytes where an adhesion defect was uncovered for cells overexpressing the EP4 receptor. Additionally, our investigations have demonstrated a novel synergy between angiotensin II AT1 receptors and prostaglandin E2 EP4 receptors. This was revealed by in vitro studies using isolated mouse glomeruli. There we were able to show that Ang II stimulation leads to increased expression of cyclooxygenase 2 (COX-2), the enzyme responsible for synthesis of PGE2, in a p38 mitogen activated protein kinase (MAPK) dependent fashion. Moreover increased PGE2 synthesis was measured in response to Ang II stimulation. We confirmed the presence of this synergy in our cultured mouse podocytes and showed an adhesion defect in response to Ang II stimulation which was COX-2 and EP4 dependent. These findings suggest that Ang II AT1 receptors and PGE2 EP4 receptors act in concert to exacerbate glomerulopathies. Studies using mice with either podocyte-specific overexpression of a dominant negative p38 MAPK or mice with global deletion of the EP1 receptor did not provide conclusive results as to their respective signaling involvement in podocyte injury. Altogether our findings provide novel insight for podocyte PGE2 EP4 and Ang II AT1 receptor signaling in models of CKD. These studies provide novel avenues for pursuing therapeutic interventions for individuals with progressive kidney disease.

Acute kidney injury (AKI) is a major complication in hospitalized patients and is associated with elevated mortality rates. Numerous recent studies indicate that AKI also significantly increases the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), hypertension, cardiovascular disease, and mortality in those patients who survive AKI. Moreover, the risk of ESRD and mortality after AKI is substantially higher in patients with preexisting CKD. However, the underlying mechanisms by which AKI and CKD interact to promote ESRD remain poorly understood. The recently developed models that superimpose AKI on rodents with preexisting CKD have provided new insights into the pathogenic mechanisms mediating the deleterious interactions between AKI and CKD. These studies show that preexisting CKD impairs recovery from AKI and promotes the development of mechanisms of CKD progression. Specifically, preexisting CKD exacerbates microvascular rarefaction, failed tubular redifferentiation, disruption of cell cycle regulation, hypertension, and proteinuria after AKI. The purpose of this review is to discuss the potential mechanisms by which microvascular rarefaction and hypertension contribute to impaired recovery from AKI and the subsequent progression of renal disease in preexisting CKD states.

Introduction Severe hypercalcemia from chronic gout is a rare phenomenon seen after the advent of newer drugs for its treatment. The hypercalcemia is secondary to either granuloma formation around the tophi or chronic immobilization from severe gouty arthritis. We present a patient with chronic tophaceous gout presenting with severe hypercalcemia and acute kidney injury. Case presentation A 63-year-old male patient with a past medical history of hypertension and chronic gout presented to the office with chronic, severe left knee pain. Initial evaluation of the knee with X-rays revealed destruction of the knee joint with cystic changes, and subsequent MRI with contrast showed soft tissue mass in the suprapatellar pouch with intraosseous extension and involvement of medial and lateral collateral ligament involvement. After interdisciplinary evaluation between radiology, orthopedic surgery, and oncology, this was concerning for highly aggressive pigmented villonodular synovitis of the knee, and a decision was made for the patient to undergo complete knee replacement. Perioperative workup was significant for severe hypercalcemia with a total calcium level of 13.2 mg/dl with ionized calcium of 7.2 mg/dl. Further evaluation into the cause of hypercalcemia revealed a low normal intact parathyroid hormone (PTH) level with normal phosphorus, calcidiol, and calcitriol levels. Other etiologies of hypercalcemia such as multiple myeloma, malignancies, metastatic disease, autoimmune, granulomatous, and infectious processes are excluded with extensive workup. The hypercalcemia is treated with fluids, diuretics, and bisphosphonates, eventually normalizing the calcium levels. The patient underwent total left knee replacement, and the mass identified was sent for biopsy. Biopsy revealed a prominent granulomatous reaction to amorphous crystals containing birefringent crystals under polarised light. Uniquely during our evaluation, vitamin D metabolites, uric acid, and PTH levels were normal despite the biopsy findings. The patient's calcium continued to be normal (8.4 to 10.4 mg/dl) over six months after the surgery. Thus, the scenario is supportive of hypercalcemia secondary to granulomatous inflammation around the large tophi. Conclusion Although rare, the knee joint is a site of severe tophaceous gout, and deposition of uric acid crystals can invoke a granulomatous reaction presenting with severe hypercalcemia as in our patient. Unique to our case, the patient can have benign lab findings on evaluation of hypercalcemia. Only a few case reports are illustrated in the literature, making our case and patient presentation unique.

There is an epidemic of chronic kidney disease of unknown etiology, also referred to as Mesoamerican Nephropathy (MeN), in Central America. Researchers studying this epidemic believe the disease etiology likely has an occupational component, with a growing body of evidence to support the hypothesis that heat stress and dehydration play an important role. Previous research has focused extensively on sugarcane workers, but there are limited data describing the heat strain experienced at work for these and other workers. There are no established early indicators of disease onset and the role of other exposures in the disease’s etiology are still uncertain. This dissertation aims to address some of these gaps using data from two occupational cohort studies in Central America. The first is a cohort of Nicaraguan sugarcane workers who were monitored across the 2010-2011 harvest season. The second is the MesoAmerican Nephropathy Occupational Study (MANOS)—a cohort of 569 workers in El Salvador and Nicaragua from the sugarcane, corn, plantain, brick manufacturing, and construction industries. We found that dipstick leukocyte esterase at the end of the harvest, which was relatively common among cane cutters (33%), seed cutters (22%), and seeders/reseeders (21%), was associated with a 12.9 ml/min per 1.73 m2 (95% CI: −18.7 to −7.0) lower mean eGFR and 2.8 times (95% CI: 1.8 to 4.3) higher mean neutrophil gelatinase-associated lipocalin (NGAL). We also found that workers who reported symptoms (e.g., flank pain, fever/chills, and dysuria) had higher mean kidney injury biomarker levels. Among MANOS participants, we found that sugarcane workers, especially cane cutters and Nicaraguan agrichemical applicators, had the highest estimated work rates, core temperatures (Tc), and heart rates (HR), but workers in other industries occasionally reached high Tc (> 39°C) as well. We found that workers with low eGFR had higher average Tc and HR values and that spending more time on break was associated with lower average HR. We report a higher incidence of cross-shift, serum creatinine-defined kidney injury among sugarcane workers, particularly at one Nicaraguan company, and found evidence that core body temperature and work rate were risk factors for this outcome. / 2023-03-21T00:00:00Z

Bakgrund: Det är mer fördelaktigt att en organdonation sker med levande donator istället för avliden donator, då det är lägre risk för avstötning. Det är många som väntar på att få en njure vilket gör att levande donation blir allt vanligare. I Sverige genomfördes 147 levande njurdonationer år 2019. Njurdonation ökar vilket leder till ökat behov av kunskap och förståelse hos sjuksköterskan. Syfte: Syftet var att belysa donatorns upplevelser i samband med njurdonation. Metod: Studien genomfördes via en litteraturstudie, där 12 vetenskapliga artiklar granskades och analyserades från två databaser. Resultat: Resultatet består av tre teman och sju subkategorier. Temat Kommunikation med subkategorierna upplevelsen av kommunikation med vårdpersonal och anknytning till mottagaren, temat upplevda känslor med subkategorierna oro, glädje och hopp, temat upplevelsen av stöd med subkategorierna socialt stöd och ekonomiskt stöd. Slutsatser: Upplevelserna hos donatorerna var individuella, genomgående var upplevelsen av bristande kommunikation och oro. Bristen på kommunikation indikerar till ett ökat kunskapsbehov hos sjuksköterskor för att göra donationsupplevelsen bra. / Background: It is more advantageous that a organdonation to take place with a living donor instead of a deceased donor, as there is a lower risk of rejection. There are many waiting for a new kidney, thus living donations are becoming more frequent. In 2019 there were 147 living kidney donations in Sweden. Because of the increase in kidney donations, the nurses are in need of more knowledge and understanding of the whole procedure. Aim: The aim was to give an account of the donor’s experience throughout the process of donating a kidney. Method: The study was conducted through literary research, where 12 scientific articles from two databases were reviewed and analyzed. Result: The result consists of three themes and seven sub categories; Communication - Communication experience between patients and medical staff andConnection to the recipient, Emotions - Worry, Joy and Hope, Support - Social support and Economical support. Conclusion: The donor’s feelings were varied, but overall they felt a lack of communication and therefore worry. This indicates that the nurses are in need of improved communication skills in order to make the donation experience as good as possible.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21008号 / 医博第4354号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 小川 修, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Renal phase-contrast magnetic resonance imaging (PC-MRI) is an MRI modality where the phase component of the MR signal is made sensitive to the velocity of water molecules in the kidneys. PC-MRI is able to assess the Renal Blood Flow (RBF), which is an important biomarker in the development of kidney disease. RBF is analyzed with the manual or semi-automatic delineation by experts of the renal arteries in PC-MRI. This is a time-consuming and operator-dependent process. We have therefore trained, validated and tested a fully-automated deep learning model for faster and more objective renal artery segmentation. The PC-MRI data used in model training, validation and testing come from four studies (N=131 subjects). Images were acquired from three manufacturers with different imaging parameters. The best deep learning model found consists of a deeply-supervised 2D attention U-Net with residual skip connections. The output of this model was re-introduced as an extra channel in a second iteration to refine the segmentation result. The flow values in the segmented regions were integrated to provide a quantification of the mean arterial flow in the segmented renal arteries. The automated segmentation was evaluated in all the images that had manual segmentation ground-truths that come from a single operator. The evaluation was completed in terms of a segmentation accuracy metric called Dice Coefficient. The mean arterial flow values that were quantified from the auto-mated segmentation were also evaluated against ground-truth flow values from semi-automatic software. The deep learning model was trained and validated on images with segmentation ground-truths with 4-fold cross-validation. A Dice segmentation accuracy of 0.71±0.21 was achieved (N=73 subjects). Although segmentation results were accurate for most arteries, the algorithm failed in ten out of 144arteries. The flow quantification from the segmentation was highly correlated without significant bias in comparison to the ground-truth flow measurements. This method shows promise for supporting RBF measurements from PC-MRI and can likely be used to save analysis time in future studies. More training data has to be used for further improvement, both in terms of accuracy and generalizability.

Syftet med denna studie var att undersöka hur personer med egenadministrerad peritonealdialys (PD) upplever sitt dagliga liv. Metoden var en intervjustudie där sju personer som behandlades med PD intervjuades med hjälp av en semistrukturerad intervjuguide. Materialet som analyserades med en manifest kvalitativ innehållsanalys resulterade i tre huvudkategorier: kroppsliga förändringar, upplevelser av PD-behandling samt egenvård. Resultatet visade att PD hade inverkan på olika plan i informanternas dagliga liv. Ett viktigt fynd var hur informanterna uppfattade att PD hade lett till vissa kroppsliga förändringar, exempelvis vad gäller vikt och aptit. Det mest framträdande fyndet var emellertid att PD ledde till en bundenhet, vilket orsakade en oönskad passivitet hos informanterna. Det framkom dessutom att de informanter som väntade på njurtransplantation upplevde att denna väntan ledde till mer inskränkning i det dagliga livet än vad PD gjorde. Informanterna beskrev även de positiva aspekterna av PD-behandlingen och betonade fördelen med att PD möjliggjorde en självständighet och en flexibilitet. Denna studie gav ett brett perspektiv av hur personer med PD upplever sitt dagliga liv och visade att det inte bara är de kroppsliga förändringarna som påverkar personerna utan att PD även leder till känslor av bundenhet och passivitet. / The purpose of this study was to explore how people with self-administered peritoneal dialysis (PD) experience their daily life. The method was an interview study in which seven people who were treated with PD were interviewed using a semistructured interview guide. The material was analyzed with a manifest content analysis and resulted in three main categories: bodily changes, sensations of PD treatment and self-care. The results showed that PD had an effect in different levels in the informants’ daily lives. One important finding was how the informants perceived that the PD had led to certain bodily changes for example in terms of weight and appetite. The most striking finding, however, was that the PD led to a lack of freedom causing an undesirable passivity of the informants. It also showed that respondents who were waiting for kidney transplantation felt that this anticipation led to more restriction in daily life than PD did. The informants also described the positive aspects of PD treatment and stressed advantages such as that PD allowed autonomy and flexibility. This study gave a broad perspective of how people with PD experience their daily life and showed that not only the physical changes affected them but also led to feelings of restraint and passivity.

The kidney is one of the most important and complex organs in the human body, filtering hundreds of litres of blood daily. Kidney disease is one of the fastest growing causes of death in the modern world, and this motivates extensive research for better understanding the function of the kidney in health and disease. Some of the most important cellular structures for blood filtration in the kidney are of very small dimensions (on the sub-200 nm scale), and thus electron microscopy has been the only method of choice to visualize these minute structures. In one study, we show for the first time that by combining optical clearing with STED microscopy, protein localizations in the slit diaphragm of the kidney, a structure around 75 nanometers in width, can now be resolved using light microscopy. In a second study, a novel sample preparation method, expansion microscopy, is utilized to physically expand kidney tissue samples. Expansion improves the effective resolution by a factor of 5, making it possible to resolve podocyte foot processes and the slit diaphragm using confocal microscopy. We also show that by combining expansion microscopy and STED microscopy, the effective resolution can be improved further. In a third study, influences on the development of the kidney were studied. There is substantial knowledge regarding what genes (growth factors, receptors etc.) are important for the normal morphogenesis of the kidney. Less is known regarding the physiology behind how paracrine factors are secreted and delivered in the developing kidney. By depleting calcium transients in explanted rat kidneys, we show that calcium is important for the branching morphogenesis of the ureteric tree. Further, the study shows that the calcium-dependent initiator of exocytosis, synaptotagmin, is expressed in the metanephric mesenchyme of the developing kidney, indicating that it could have a role in the secretion of paracrine growth factors, such as GDNF, to drive the branching. / <p>QC 20170523</p>

Chronic kidney disease (CKD) is a complex and progressive condition with limited curative therapies and is associated with both physical comorbidity, impaired health-related quality of life, and financial strain on the healthcare system. Currently, CKD is defined by a fixed threshold of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, which coincides with approximately 60% of healthy kidney function, for ≥3 months regardless of age. However, this definition does not account for natural declines in kidney function with advanced age, leaving older individuals (ages >65 years) with naturally lower eGFR and without significant kidney damage being over-diagnosed with CKD. Conversely, there is also concern of underdiagnosis of CKD in younger adults (ages <40 years) with “modest” eGFR reductions (eGFR levels well above 60, but below age-expected values). Indeed, severe impairment is not detected in younger adults until they lose close to 50% of their healthy kidney function, precluding timely prevention of CKD progression and its associated complications (premature mortality, cardiovascular events, etc.). However, whether these “modest” eGFR reductions are associated with elevated clinical risk in younger adults is unknown. This thesis is based on a retrospective cohort study using linked healthcare administrative databases to examine the association of index eGFR categories with time to adverse outcomes, relative to age-specific referents. In the first manuscript, we compared associations with key adverse outcomes (all-cause mortality, cardiovascular events, and kidney failure) and patterns of healthcare utilization between younger (ages 18-39), middle-aged (40-49), and older adults (50-65 years). In the second manuscript, we examined associations with major cardiovascular events (cardiovascular mortality, acute coronary syndrome, ischemic stroke, heart failure) by age group. In both manuscripts, we noted significant elevations in risk of adverse outcomes at higher eGFR levels relative to age-specific referents in younger, compared to middle-aged and older adults. Despite this age-related vii disparity in clinical risk with modestly reduced eGFR, younger adults were least likely to obtain a repeated eGFR measure or be referred to a specialist during follow-up. Notably, these findings persisted for individual adverse events and in clinically important subgroups, as well as after various sensitivity analyses (adjusting for additional comorbidities, defining index eGFR using repeated measures, using common referents, and excluding individuals with different underlying mechanisms for reduced eGFR (pregnancy, acute kidney injury, etc.)). The current thesis presents evidence of elevated clinical risk with modest reductions in kidney function in younger adults, emphasizing the importance of risk-based eGFR thresholds that vary with age and considering modestly reduced eGFR as important cardiovascular risk factors worth monitoring in routine clinical practice.