Orientador: Maria Jaqueline Mamprim / Resumo: O diagnóstico da Leishmaniose visceral é complexo, devido à infinidade de sinais clínicos inespecíficos e por vezes os cães apresentam-se assintomáticos por longos períodos de incubação, contribuindo para a disseminação da doença. Com a finalidade de auxiliar o diagnóstico, o presente estudo tem por objetivo descrever alterações ultrassonográficas ao modo B, Doppler e elastográficos em rim e baço de cães soropositivos para LV. Foram avaliados ao exame ultrassonográfico rins de 33 animais naturalmente infectados por LV, sendo as alterações mais relevantes observadas: o aumento da ecogenicidade cortical (75,75%) e a perda da definição corticomedular (27,27%). O índice de resistividade apresentou-se elevado 0,70 e 0,71, para o rim esquerdo e direito, respectivamente. A dimetilarginina simétrica se mostrou elevada em apenas 12 animais. O escore elastográfico observado com maior frequência foi o dois, referente a tecidos de elasticidade intermediária, tendendo a macio. Também foram avaliados 36 baços de animais soropositivos, o sinal mais frequente foi a heterogeneidade do parênquima (77,77%) com áreas micronodulares hipoecogênicas (60,7%) e esplenomegalia (55,5%). O escore elastográfico esplênico mais observado foi o três, referente a tecidos de elasticidade intermediária tendendo a rígido. As alterações renais e esplênicas descritas no estudo devem ser inclusas como diagnóstico diferencial em cães provenientes de áreas endêmicas. / Abstract: The diagnosis of visceral Leishmaniasis is complex, due to the infinity of nonspecific clinical signs and dogs are often asymptomatic for long incubation periods, which may contribute to the spread of the disease. In order to help early diagnosis, the present study aims to describe sonographic mode B, Doppler and elastographic changes in kidney and spleen of VL seropositive dogs. Kidneys of 33 animals naturally infected with VL were evaluated by ultrasound examination. The most relevant changes were the increase in cortical echogenicity (75.75%) and the loss of corticomedullary definition (27.27%). The resistivity index remained high 0.70 and 0.71 for the left and right kidney respectively. Symmetric dimethylarginine was elevated in only 12 animals. The most frequently observed elastographic score was two, referring to tissues of intermediate elasticity. Thirty-six spleens from seropositive animals were also evaluated, the most frequent sign being parenchymal heterogeneity (77.77%) with hypoechogenic micronodular areas (60.7%), followed by splenomegaly (55.5%), and these changes could appear concomitant or not. The most observed splenic elastographic score was three (47.22%), referring to intermediate elasticity tissues tending to rigid. The renal and splenic changes described in the study should be included as differential diagnosis in dogs from endemic areas. / Doutor

Bakgrund: Kronisk njursjukdom drabbar mer än var 10:e människa världen över. Sjukdomen är komplex och kan ses i samband med andra sjukdomar. Individer behöver utföra en livslång och krävande egenvård av denna progressiva sjukdom. I dagens hälso- och sjukvård vårdas vanligtvis en sjukdom i taget vilket kan få vården att brista i individanpassat egenvårdsstöd. Syfte: Syftet med litteraturstudien är att beskriva erfarenheter av egenvård för individer med kronisk njursjukdom. Metod: En kvalitativ litteraturstudie baserad på åtta empiriska studier. Artiklarna hämtades från databaserna PubMed och Cinahl. Innehållsanalysen gjordes utifrån Fribergs femstegsmodell. Resultat: Två kategorier och sju underkategorier skapades utifrån resultatet. Kategorierna; 1) Hälsorelaterade värderingar och upplevelser påverkar egenvården 2) Behov av stöd för att utföra egenvård. Konklusion: Litteraturstudien visar att individer kan uppleva ångest och oro över sitt hälsotillstånd vilket försvårar utförandet av egenvård. Hälso- och sjukvården behöver ha ett personcentrerat bemötande och beakta individens beteenden och värderingar för att kunna ge en individanpassad information och ett kontinuerligt egenvårdsstöd. Därefter kan individen få en god förutsättning att ta till sig kunskap om sin hälsa. Sjuksköterskan har ett ansvar i att möta det egenvårdsbehov individen har genom att ge egenvårdsstöd för att leva ett mer hälsosamt liv. / Background: Chronic kidney disease affects more than every 10th person worldwide. The disease is complex and can be seen with other diseases. Individs need to perform a lifelong and demanding self-management of this progressive disease. In today's health care, one illness is usually cared for at a time, which can cause the care to fail in individualized self-management support. Aim: The aim of this study was to describe experiences of self-management for individs with chronic kidney disease. Methods: A qualitative literature study based on eight empirical articles. The articles were retrieved from the databases PubMed and Cinahl. The content analysis was based on Friberg's five-step model. Results: Two categories and seven subcategories were created based on the result. The two categories were: 1) Health-related values and experiences affect self-management 2) Need for support to perform self-management. Conclusion: The study shows that participants may experience anxiety about their state of health, which makes it difficult to perform self-management. Healthcare needs to have a person-centered approach and take into account the individ's behaviors and values in order to be able to provide individualized information and continuous self-management support. After that, individs can have a good chance of absorbing knowledge about their health. The nurse has a responsibility to meet the individs self-management needs by providing support to live a healthier life.

The kidneys are a paired organ that has many functions in the body. They are responsible for the regulation of the internal surroundings, the excretion of metabolic products (nitrogen metabolites and foreign substances) and the secretion of certain hormones. In the theoretical part of the diploma thesis I give a brief description of the anatomy and physiology of the kidneys and a description of some renal diseases, with emphasis on acute kidney injury and chronic kidney disease. I also discuss the possibilities of kidney function replacement and the adjustment of eating habits if a patient develops any of the kidney diseases. The practical part of the diploma thesis deals with the issue of nutritional status of hospitalized patients who are indicated for dialysis therapy. The research took place at the Faculty Hospital in Královské Vinohrady, mainly at the 1st internal clinic. The research group consisted of 17 patients who completed a questionnaire and kept a prospective record of the food portions eaten. Based on the calculation of the meals list, it was found that most of the patients do not receive enough energy or basic components of nutrition. The intake of minerals, with the exception of calcium, averaged the recommended values. Blood levels of serum albumin and minerals correspond on...

El documento ¨Formulación técnica, económica, financiera y social en la implementación de Clínicas de Hemodiálisis” definirá la viabilidad del funcionamiento de una clínica privada que presta servicio de tercerización de la hemodiálisis a Essalud – Seguro Social de Salud y cuyo servicio de hemodiálisis es diferente del resto de las clínicas privadas del país por su calidad de productos y tecnología de equipos que propenden a mejorar la calidad de vida del paciente renal crónico. Para determinar esta viabilidad, este documento nos mostrará las características y planes económico financiero y estratégicos que generen respuesta a la siguiente pregunta: ¿El proyecto de clínicas de hemodiálisis para tercerización con Essalud genera valor al inversionista y es económicamente rentable? La Enfermedad Renal Crónica Terminal (ERCT) es una enfermedad progresiva que evoluciona en las personas en diferentes estadios y que da inicio a un tratamiento sustitutivo de la función mediante diálisis o trasplante de riñón con unas tasas de incidencia y prevalencia crecientes en las dos últimas décadas. Nuestro enfoque va direccionado al servicio de hemodiálisis que se ofrecerá en tercerización al Seguro Social de Salud que actualmente cobertura al 66.66% de pacientes asegurados a nivel nacional en Perú. Las tercerizaciones se realizan mediante un Concurso Público para la Contratación del Servicio. / The document "Technical, economic, financial and social formulation in the implementation of Hemodialysis Clinics" will define the feasibility of operating a network of private clinic that provide outsourcing of hemodialysis to Essalud - Social Health Insurance and whose hemodialysis service It is different from the rest of the private clinics in the country because of its quality of products and equipment technology that tend to improve the quality of life of the chronic renal patient. To determine this viability, this document will show us the economic and strategic economic characteristics and plans that generate an answer to the following question: Does the hemodialysis clinic project for outsourcing with Essalud generate value for the investor and is it economically profitable? Terminal Chronic Kidney Disease (ERCT) is a progressive disease that evolves in people at different stages and that begins a substitute treatment of function by dialysis or kidney transplant with increasing incidence and prevalence rates in the last two decades. Our approach is directed to the hemodialysis service that will be offered in outsourcing to the Social Health Insurance that currently covers 66.66% of insured patients nationwide in Peru. Outsourcing is carried out through a Public Tender for the Service Hiring. / Trabajo de investigación

Das Ziel dieser Arbeit war die Identifikation und Assoziation nierenpathogener Gen-Varianten mit dem klinischen Phänotyp einer chronischen Niereninsuffizienz (CKD) durch chronisch tubulo-interstitielle Nephritis (CIN) unbekannter Ursache bei Erwachsenen. Die Auswahl der Studienkohorte erfolgte anhand festgelegter histologischer und klinischer Kriterien (prädominante CIN unklarer Ursache), die sich in 52 von 785 Biopsie-Befunden aus den Jahren 1983 bis 2013 finden ließen. Insbesondere aufgrund fehlender Kontaktierbarkeit infolge des langen Beobachtungszeitraums konnten letztlich 10 der 52 Probanden rekrutiert und in die genetische Analyse inkludiert werden. Nach der Durchführung einer Exom-Sequenzierung wurden die Rohdatensätze jedes einzelnen Probanden auf ausschließlich seltene Varianten gefiltert. Der verbliebene Datensatz wurde dann auf seltene Varianten in 199 bekannten mit hereditären Nephropathien assoziierten Gene hin untersucht (virtuelles CKD-Genpanel). Zunächst konzentrierten wir uns auf Gene die mit tubulo-interstitiellen Nephropathien assoziiert sind (NPHP-RC, ARPKD, ADTKD). Im weiteren Verlauf inkludierten wir Gene für glomeruläre Nephropathien (FSGS und COL4-Nephropathie/Alport-Syndrom) und kongenitale Nierenanomalien (CAKUT). Die dabei detektierten genetischen Varianten wurden auf mögliche Pathogenität anhand der ACMG-Klassifizierung final bewertet. Daraus resultierten bei vier Probanden insgesamt fünf wahrscheinlich pathogene Varianten der ACMG-Klasse 4 und 5 (pathogenic, likely pathogenic) in den Genen NPHS2, COL4A4, COL4A3 und DSTYK. Die diagnostisch bedeutsamen Varianten wurden in der Literatur bereits im Zusammenhang mit hereditäre FSGS, Kollagen-IV-Nephropathie und CAKUT beschrieben. Bei einem Probanden (A5204) mit pathogenen Varianten im NPHS2-Gen konnten wir mittels Segregationsanalyse der Eltern den klinischen Phänotyp eindeutig zuordnen. Des Weiteren konnten wir 12 Varianten unklarer Signifikanz (VUS) bei insgesamt sechs Probanden ausfindig machen, welche sich teilweise in funktionell bedeutsamen Genregionen befinden. Hier zu nennen sind insbesondere die gefundenen VUS-Varianten in den Genen TNXB und FN1, die eine Pathogenität nahelegen, deren Bedeutung aber für die Entwicklung einer chronischen Niereninsuffizienz in der vorliegenden Studie nicht abschließend beurteilt werden konnte. Zusammenfassend demonstriert diese Arbeit die häufig fehlende Übereinstimmung von histologischen Diagnosen (vordergründig tubulo-interstitielle Nephropathie) und genetischen Diagnosen (vordergründig glomeruläre Nephropathie) in der Abklärung einer chronischen Niereninsuffizienz. Insbesondere zeigt sich in der vorliegenden Arbeit der Wert einer breiten genetischen Analyse zur genaueren ätiologischen Abklärung von CKD-Patienten mit unspezifischen nephropathologischen Veränderungen, wie der der chronisch-interstitiellen Nephritis.:1 Inhaltsverzeichnis ........................................................................................................................... 1 2 Abkürzungsverzeichnis ................................................................................................................... 3 3 Einführung ....................................................................................................................................... 6 3.1 Chronische Niereninsuffizienz (CKD) ...................................................................................... 6 3.1.1 Bedeutung der Nierenbiospie ......................................................................................... 8 3.1.2 CIN – chronische interstitielle Nephritis .......................................................................... 9 3.2 Hereditäre chronische Nephropathien .................................................................................. 9 3.2.1 Hereditäre tubulo-interstitielle Nephropathien ............................................................ 11 3.2.1.1 Nephronophthise (NPHP) / Nephronophthise-assoziierte Ziliopathien .................... 11 3.2.1.2 ADPKD – autosomal dominante polyzystische Nierenerkrankung ........................... 14 3.2.1.3 ARPKD – autosomal rezessive polyzystische Nierenerkrankung ............................... 15 3.2.1.4 ADTKD – autosomal dominante tubulo-interstitielle Nierenerkrankung .................. 15 3.2.2 Hereditäre Glomerulopathien ....................................................................................... 16 3.2.2.1 Alport-Syndrom / Syndrom der dünnen Basalmembran (TBMD, TBMN) ................. 16 3.2.2.2 FSGS – fokal segmentale Glomerulosklerose ............................................................ 17 3.2.3 CAKUT ............................................................................................................................ 17 4 Aufgabenstellung .......................................................................................................................... 18 5 Material und Methoden ............................................................................................................... 19 5.1 Studienaufbau ....................................................................................................................... 19 5.1.1 Nierenbiopsien und histologischer Befund ................................................................... 19 5.1.2 Auswahl und Rekrutierung der Probanden ................................................................... 19 5.2 Exom-Sequenzierung ............................................................................................................ 20 5.2.1 Definition und Bedeutung ............................................................................................. 20 5.2.2 Durchführung des WES .................................................................................................. 21 5.2.3 Zu untersuchende Gene ................................................................................................ 21 5.3 Filterung und Analyse genetischer Varianten...................................................................... 24 5.3.1 Filterkriterien für Rohdatensätze .................................................................................. 24 5.3.2 Prädiktionstools für genetische Varianten .................................................................... 27 5.3.3 Mutationsdatenbank (HGMD) ....................................................................................... 28 5.3.4 ACMG-Klassifizierungssystem ....................................................................................... 28 6 Ergebnisse ..................................................................................................................................... 29 6.1 WES-Datenqualität ............................................................................................................... 29 6.2 Ergebnisse anhand der ACMG-Klassifizierung ..................................................................... 31 6.2.1 Genetische Varianten der Klasse 4 und 5 (pathogen und wahrscheinlich pathogen) .. 31 6.2.2 Genetische Varianten der Klasse 3 (VUS) ...................................................................... 36 7 Diskussion ..................................................................................................................................... 43 8 Zusammenfassung ........................................................................................................................ 49 9 Literaturverzeichnis ...................................................................................................................... 51 10 Anlagen ......................................................................................................................................... 57 10.1 Abbildungsverzeichnis ........................................................................................................... 57 10.2 Tabellenverzeichnis ............................................................................................................... 57 11 Selbstständigkeitserklärung ......................................................................................................... 58 12 Lebenslauf 13 Danksagung

Background: Chronic Kidney Disease (CKD) can be described as the loss of the kidney function over time. Symptoms usually develop slowly and it may not appear in early stages. Lab tests can confirm a CKD diagnosis. The approximate number of incidents per year is more than 200,000 cases and approximately 30 million people are living with CKD today in the United States. This long-standing disease ultimately leads to renal failure at the end. At this present time, there are no known cures for CKD and the only treatment available is dialysis. Objectives: The purpose of this study is to determine the association between CKD and further with Hemodialysis (HD) and medical condition such as cardiac complications, cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications, and death. Methods: The study employed secondary data in a cross-sectional design. A sample of 106,969 was drawn from the population. The outcome variables were a diagnosis of CKD and/or CKD with HD. The predictor variables were cardiac complications, cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications and death. Logistic regression was conducted to analyze the relationship between outcome variable and each independent variable. Variables with a p-value <0.05 were considered significant. Odds Ratio (OR) and 95% Confidence Intervals (CI) were reported and discussed. The statistical analysis was performed using SAS version 9.4. Results: Analysis shows that subjects with cardiac complications were 17% less likely to have CKD as compared to those who did not have cardiac complications (OR: 0.83, 95% CI: 0.78-0.88). CKD patients who had cardiac complications were 18% more likely to have HD than the subjects who did not have cardiac complications (OR: 1.18, 95% CI: 1.01-1.39). Patients with cardiogenic shock were 86% more likely to have CKD than the subjects who did not have cardiogenic shock (OR: 1.86, 95% CI: 1.82-1.91). CKD patients who had cardiogenic shock were also 18% more likely to have HD than the subjects who did not have cardiogenic shock (OR: 1.18, 95% CI: 1.11-1.25). Similar results have been reported if a patient had other conditions. Conclusion: Chronic kidney disease with hemodialysis is significantly associated by the other medical conditions such as cardiac complications cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications and death in the United States. Further studies are needed to confirm the results and to understand the prognosis.

The prevalence of pregnancies complicated by chronic kidney disease (CKD) is increasing. Yet, CKD in pregnancy tends to be under-diagnosed, as women of childbearing age are not regularly screened for renal dysfunction, nor is screening incorporated into routine pregnancy follow up. Further, renal dysfunction has significant implications for maternal and fetal outcomes, with degree of renal dysfunction at conception being the most important prognostic factor. It is established that the risk for poorer renal, maternal and fetal outcomes, increases incrementally with severity of CKD, with intrauterine death and progression to end-stage renal disease (ESDR) associated with severe CKD. However, it is difficult to predict which CKD pregnancies will lead to poor outcomes as the definition of CKD in pregnancy is not uniform between studies, nor are measurement parameters. This paucity of data prevents the establishment of a standard of care protocol and leaves clinicians ill-equipped to care for and manage this complex patient cohort. This review discusses renal, maternal and fetal outcomes in CKD pregnancies as presented by the literature, in order to demonstrate the contradictions in data and gaps in knowledge surrounding this topic, as well as the need for a general management algorithm.

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.

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