Introdução: A nefropatia crônica do enxerto permanece sendo a principal causa de perda tardia de enxertos renais. No momento, não existe uma estratégia terapêutica definida para minimizar ou reverter a perda da função renal. Diversas tentativas terapêuticas foram empregadas sem resultados definitivos. As estratégias de minimização de inibidores da calcineurina (CNI) com conversão para Micofenolato mofetil (MMF) e conversão para Sirolimo (SRL) são as mais promissoras. Este estudo avaliou a segurança e a eficácia dessas duas estratégias terapêuticas na progressão da nefropatia crônica do enxerto em pacientes transplantados renais. Métodos: Foram selecionados pacientes com filtração glomerular (RFG) medida por depuração de 51Cr-EDTA entre 25 e 60 ml/min/1,73 m2 que apresentaram alterações histológicas compatíveis com nefropatia crônica do enxerto e que não apresentaram proteinúria 24 h superior a 800 mg/24 h. Os pacientes foram randomizados para serem convertidos ao SRL ou manterem-se sob níveis baixos de CNI associados ao MMF e prednisona. O objetivo primário foi avaliar um objetivo composto pelos seguintes eventos: morte, perda do enxerto, rejeição aguda ou perda de RFG inicial superior a 20%. Os pacientes foram acompanhados por 12 meses e a uma análise por intenção de tratar foi realizada ao fim desse período. Resultados: Vinte e nove pacientes foram randomizados para os grupos SRL (n=14) e CNI (n=15). Não houve diferença entre os grupos quanto a os dados demográficos e imunológicos. Os valores de creatinina sérica e a TFG foram semelhantes no momento da randomização. A sobrevida dos pacientes e dos enxertos foi de 100%. Não foram observados episódios de rejeição aguda. Após 12 meses, não houve diferença significativa entre os grupos com relação à TFG. Houve maior número de eventos adversos não-graves no grupo SRL, destacandose, acne, edema, piora de dislipidemia e anemia. Entretanto, o número de eventos adversos graves não foi estatisticamente diferente entre os grupos. SRL foi descontinuado temporariamente em 1 paciente, mas não ocorreu descontinuação definitiva no estudo. Conclusão: Os dois esquemas terapêuticos apresentaram desempenhos rigorosamente semelhantes com relação à evolução da função renal e quanto à evolução histológica, mas houve um número maior de eventos adversos não-graves com o uso de sirolimo / Chronic allograft nephropathy is the main cause of late kidney graft loss. Several treatments have been proposed for this condition without conclusive results. Calcineurin inhibitors minimization and conversion to Sirolimus are the most promising alternatives. This study evaluated the safety and the efficacy of these therapeutic strategies on one-year progression of chronic allograft nephropathy in kidney transplant recipients. Patients with measured glomerular filtration rate (51Cr-EDTA plasmatic clearance) between 25 e 60 ml/min/1,73 m2 and histological findings of CAN, with proteinuria less than 800 mg/24 h were included. They were randomized either to Sirolimus or to low-level of CNI (both groups received MMF and prednisone). The primary end-point was a composite of first occurrence of death, graft loss, acute rejection or a 20% decrease of initial GFR. Patients were followed for 12 months and evaluated as intention-to-treat analysis. Twenty-nine patients were included in this study. Fourteen patients were randomized to SRL group and fifteen to CNI group. At baseline, no differences were detected in any of the demographic and immunologic group characteristics. Also, serum creatinine and GFR were not different at randomization. One year after conversion, patient and graft survival was 100%. At 12 months, there were no differences in GFR between two groups, in SRL group was 41,99 ± 13,48 ml/min/1,73 m2and in CNI group was 41,21 ± 9,10 ml/min/1,73 m2 (p=0,96). Non-serious adverse events, like anemia (p=0,006), acne (p=0,006), edema (p=0,005) and mouth ulcers (p=0,017) were more frequently found in the SRL group. No significant difference in serious adverse events was observed. SRL was temporarily interrupted in one patient. None of the patients dropped-out from the study and none required study drug discontinuation. In conclusion both regimens conferred equal beneficial in GFR preservation in CAN patients. However, SRL was associated with more adverse events

Os efeitos da suplementação de creatina sobre a função renal são debatidos intensamente na literatura científica. Os poucos trabalhos sobre o tema envolvendo humanos têm sido severamente criticados por apresentarem ausência de randomização, dosagens não uniformes de creatina, baixo poder estatístico e, sobretudo, ausência de marcadores padrão-ouro de função renal. Além disso, embora tenhamos mostrado recentemente que a suplementação de creatina não prejudica a função renal em sujeitos submetidos a treinamento aeróbio, a natureza desse tipo de atividade, bem como o habitual consumo de proteína dessa amostra, não permite que generalizemos nossos achados à população que mais utiliza creatina: praticantes de treinamento de força sob dietas ricas em proteína. Desta forma, foi conduzido um ensaio randomizado, duplo-cego, controlado por placebo, com o objetivo de investigar os efeitos da suplementação de creatina e sua possível interação com o alto consumo de proteínas sobre a função renal, em praticantes de treinamento de força. Os sujeitos foram divididos aleatoriamente em 2 grupos: a) suplementação de creatina (20g/dia durante cinco dias e 5g/dia até o término do estudo) e b) placebo (dextrose). No período basal e após 12 e 24 semanas, os sujeitos tiveram acompanhamento do consumo alimentar, e foram analisados o clearance de 51Cr-EDTA, creatinina sérica, sódio e potássio séricos e urinários e microalbuminúria. Não foram encontradas diferenças significativas nas variáveis analisadas após 12 e 24 semanas. Demonstrando assim, a ausência de alteração da função renal decorrente da suplementação de creatina, em praticantes de treinamento de força recreacionais com consumo proteico >=1,2g/kg peso/dia / The effects of creatine supplementation on renal function are discussed extensively in the literature. Few studies on the topic involving humans have been severely criticized because of the absence of randomization, non-uniform doses of creatine, low statistical power and, above all, the absence of a gold standard markers of renal function. Furthermore, although we have recently shown that creatine supplementation does not impair renal function in subjects undergoing aerobic training, the nature of this type of activity, as well as the usual protein intake in this sample does not allow generalization of our findings to the population who consume creatine: practitioners of strength training with a high protein intake. Thus, we conducted a randomized, double-blind, placebo-controlled study, in order to investigate the effects of creatine supplementation and its possible interaction with high protein intake on renal function in practicioners of strength training. The subjects were randomly assigned to 2 groups: a) creatine supplementation (20g/day during five days and 5g/day until the end of the study) and b) placebo (dextrose). At baseline and after 12 and 24 weeks, food intake, 51Cr-EDTA clearance, serum creatinine, sodium and potassium serum and urinary microalbuminuria was assessed. No significant differences were observed throughout the trial. Demonstrating that creatine supplementation on practitioners of strength training with high protein intake does not harm renal function

Wong Wai Lun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 119-125). / Abstract also in Chinese. / Acknowledgments --- p.i / Legend for Figures --- p.ii / Legend for Tables --- p.iv / Abstract --- p.v / Abstract in Chinese --- p.ix / Chapter Chapter I --- Introduction --- p.1 / Objective --- p.5 / Chapter Chapter II --- Literature Review / Chapter II.1. --- Anatomy of the urinary system --- p.6 / Chapter II.2. --- Physiology of the urinary system --- p.10 / Chapter II.3. --- Methods for investigating the urinary system --- p.12 / Chapter II.3.1. --- Plain film radiography --- p.12 / Chapter II.3.2. --- Excretory Urogram --- p.12 / Chapter II.3.3. --- Ultrasound --- p.13 / Chapter II.3.4. --- Computed Tomography --- p.15 / Chapter II.3.5. --- Renal Angiography --- p.16 / Chapter II.3.6. --- Magnetic Resonance Imaging (MRI) --- p.16 / Chapter II.3.7. --- Radionuclide Imaging --- p.17 / Chapter II.4. --- Radiopharmaceuticals for renal parenchyma imaging --- p.17 / Chapter II.4.1. --- Tc-99m GHA --- p.18 / Chapter II.4.1.1. --- Chemistry of Tc-99m GHA --- p.18 / Chapter II.4.1.2. --- Preparation --- p.18 / Chapter II.4.1.3. --- Doses --- p.18 / Chapter II.4.1.4. --- Biological behavior --- p.19 / Chapter II.4.2. --- Tc-99m DMSA / Chapter II.4.2.1. --- Chemistry of Technetium-99m Dimercaptosuccinic Acid (Tc-99m DMSA) --- p.20 / Chapter II.4.2.2. --- Chemical property of Tc-99m DMSA --- p.21 / Chapter II.4.2.3. --- Preparation --- p.22 / Chapter II.4.2.4. --- Radiochemical purity measurement --- p.22 / Chapter II.4.2.5. --- Doses --- p.23 / Chapter II.4.2.6. --- Pharmacokinetic of Tc-99m DMSA --- p.23 / Chapter II.4.2.7. --- Renal handling of injected Tc-99m DMSA --- p.25 / Chapter II.5. --- General consideration for quantitative uptake measurement in organs --- p.26 / Chapter II.5.1. --- Clinical significance of renal Tc-99m DMSA uptake --- p.28 / Chapter II.5.2. --- Special consideration and problems for quantitative renal Tc-99m uptake measurement --- p.29 / Chapter II.5.3. --- Suggestions and solutions for quantitative renal Tc-99m uptake measurement --- p.29 / Chapter II.5.3.1. --- Planar images Vs SPECT images for quantification --- p.29 / Chapter II.5.3.2. --- Background subtraction --- p.31 / Chapter II.5.3.3. --- Choice of location for background ROI --- p.32 / Chapter II.5.3.4. --- Attenuation --- p.35 / Chapter II.5.3.5. --- Principle of the conjugate view method --- p.36 / Chapter II.5.3.6. --- Body thickness and kidney depth measurement --- p.37 / Chapter II.6. --- Glomerular Filtration / Chapter II.6.1. --- Introduction --- p.39 / Chapter II.6.2. --- Gold standard for GFR measurement --- p.40 / Chapter II.6.3. --- Laboratory studies for the measurement of glomerular filtration : Serum Creatinine and Blood Urea Nitrogen (BUN) levels --- p.41 / Chapter II.6.3.1. --- Calculation of Creatinine Clearance Rate --- p.43 / Chapter II.6.3.2. --- Critique for using creatinine clearance as a measurement of renal function --- p.44 / Chapter II.6.3.3. --- Limitation of the serum creatinine concentration used alone as a measurement of renal function --- p.46 / Chapter II.6.4. --- Radionuclide technique for the assessment of the glomerular function --- p.48 / Chapter II.6.4.1. --- Diethylene Triamine Penta Acetic acid (DTPA) --- p.49 / Chapter II.6.4.2. --- Methods / Chapter II.6.4.2.1. --- Measurement of Glomerular Filtration Rate using Tc-99m DTPA with single injection techniques --- p.51 / Chapter II.6.4.2.2. --- Compartment model --- p.52 / Chapter II.6.4.2.2a. --- Two-compartment model --- p.52 / Chapter II.6.4.2.2b. --- Single-compartment model --- p.54 / Chapter II.6.4.2.3. --- Single blood sample technique: a modification of Tauxe's OIH method in which counts in a single plasma sample correlated with a GFR nomogram --- p.56 / Chapter II.6.4.2.4. --- Gamma camera based method --- p.58 / Chapter II.6.4.2.4a. --- Gates-modification of Schlegel's OIH technique --- p.58 / Chapter II.6.4.2.4b. --- Critique for the Gamma camera technique for measuring GFR --- p.62 / Chapter II.7. --- The relationship between the Tc-99m DMSA uptake and GFR --- p.67 / Chapter Chapter III --- Material and Methods --- p.69 / Chapter III.1. --- Subjects and Sampling Methods --- p.69 / Chapter III.2. --- Quantitation of Absolute DMSA uptake --- p.70 / Chapter III.2.1. --- Parameters for Tc-99m DMSA uptake study --- p.70 / Chapter III.2.1.1. --- Materials and methods --- p.70 / Chapter III.2.1.1.1. --- Instrumentation --- p.70 / Chapter III.2.1.1.2. --- Dosage --- p.70 / Chapter III.2.1.1.3. --- Optimum acquisition start time --- p.70 / Chapter III.2.1.1.4. --- Length of acquisition time --- p.71 / Chapter III.2.1.1.5. --- Acquisition parameter --- p.71 / Chapter III.3. --- Calculation of absolute renal DMSA uptake --- p.72 / Chapter III.3.1. --- Attenuation Coefficient factor(μ) --- p.73 / Chapter III.3.2. --- Table attenuation --- p.75 / Chapter III.3.3. --- Body thickness measurement --- p.77 / Chapter III.3.4. --- Decay correction --- p.78 / Chapter III.3.5. --- Calculation of DMSA uptake --- p.78 / Chapter III.3.6. --- Counting dose injected --- p.80 / Chapter III.3.7. --- Calculation of absolute quantitation of Tc-99m DMSA uptake --- p.80 / Chapter III.3.8. --- Dose infiltration --- p.81 / Chapter III.4. --- GFR measurement --- p.82 / Chapter III.4.1. --- Instrumentation --- p.82 / Chapter III.4.2. --- Methods --- p.82 / Chapter III.5. --- Statistical and analytical methods --- p.84 / Chapter Chapter IV --- Results --- p.87 / Chapter IV. 1. --- Characteristics of experimental subjects and their serum creatinine profile --- p.88 / Chapter IV.2. --- Absolute Tc-99m DMSA uptake / Chapter IV.2.1. --- The change of absolute Tc-99m uptake with time --- p.89 / Chapter IV.2.2. --- Absolute Tc-99m DMSA uptake measurement at 6 and 24 hours --- p.90 / Chapter IV.2.3. --- Gender difference in absolute Tc-99m uptake measurement at 6 hour --- p.92 / Chapter IV.3. --- GFR measurement --- p.93 / Chapter IV.3.1. --- GFR measurement by single (3hr) and double (1&3 hrs) plasma sampling --- p.93 / Chapter IV.3.2. --- Gender difference in GFR measurement using single plasma sampling --- p.96 / Chapter IV.4. --- Univariate Correlation --- p.97 / Chapter IV.4.1. --- Correlation between GFR using single plasma sampling and absolute Tc-99m uptake --- p.97 / Chapter IV.4.2. --- Correlation between GFR using single plasma sampling and plasma creatinine levels --- p.98 / Chapter IV.4.3. --- Correlation between anthropometric variables on GFR(3 hr) --- p.99 / Chapter IV.4.4. --- Correlation between anthropometric variables and serum creatinine plasma level on absolute Tc-99m DMSA uptake measurement at 6 hour --- p.101 / Chapter IV.4.5. --- Multiple linear stepwise regression --- p.103 / Chapter Chapter V. --- Discussion / Chapter V. 1 --- . Review of the study --- p.104 / Chapter V.1.1. --- Experimental subjects and their absolute Tc-99m DMSA uptake (%) at 6 hr --- p.104 / Chapter V.1.2. --- Experimental subjects and their GFR(3 hr) --- p.105 / Chapter V.2. --- Discussion on subject --- p.105 / Chapter V.2.1. --- Subject preparation --- p.106 / Chapter V.3. --- Discussion of method --- p.106 / Chapter V.3.1. --- Equipment --- p.106 / Chapter (a) --- Dose calibrator --- p.106 / Chapter (b) --- The sensitivity of the head 1 and 2 of the gamma camera --- p.106 / Chapter (c) --- Validation of quantification of injected activity by gamma camera method--------constancy of performance for gamma camera --- p.110 / Chapter (d) --- LEHR Collimator --- p.112 / Chapter (f) --- Dead time loss --- p.112 / Chapter V.4. --- Discussion on measurement --- p.113 / Chapter (a) --- Length of acquisition time --- p.113 / Chapter (b) --- Attenuation Coefficient factor (\x) --- p.113 / Chapter (c) --- "Body thickness, L, measurement" --- p.113 / Chapter (d) --- Optimum acquisition time for data collection --- p.115 / Chapter v.5. --- Discussion on overall error estimation --- p.115 / Chapter (a) --- Tc-99m DMSA uptake measurement at 6 hr --- p.115 / Chapter (b) --- GFR measurement by single (3 hr) sample --- p.116 / Chapter Chapter VI --- Conclusion --- p.117 / Reference --- p.119 / Appendix I --- p.126 / Appendix II --- p.128 / Appendix III --- p.134

Objetivo: O objetivo do presente estudo foi avaliar o impacto da doença periodontal sobre a função renal em pacientes pré–dialíticos nos estágios 3, 4 e 5 da doença renal crônica (DRC). Metodologia: Dados demográficos, socioeconômicos e de história médica de 139 pacientes do Serviço Nefrologia do Hospital de Clínicas de Porto Alegre (HCPA) foram obtidos por meio de entrevista e análise de prontuário. Exames clínicos periodontais completos foram realizados por examinadores treinados e calibrados. Foram realizadas associações entre a condição periodontal e os diferentes estágios da DRC e com a taxa de filtração glomerular (TFG). Resultados: Ter periodontite grave aumentou em, aproximadamente, 2,8 e 3,4 vezes a chance de estar nos estágios 4 e 5 da DRC quando comparado a estar no estágio 3 (referência), respectivamente (p<0,05). Além disso, ter dois ou mais dentes com perda de inserção maior ou igual a 6mm aumentou em 3,9 vezes a chance de estar no estágio 5 da DRC (p<0,05). Com relação à TFG, tanto o fato de ter periodontite grave quanto o de apresentar dois ou mais dentes com perda de inserção maior ou igual a 6mm estiveram significativamente associados a uma menor taxa de filtração glomerular (p=0,02 e p=0,01, respectivamente). Conclusão: A doença periodontal aumenta a chance de piores desfechos renais em pacientes com DRC pré-dialiticos, mesmo quando ajustado para importantes confundidores. / Aims: The aim of the present study was to evaluate the impact of periodontal disease on renal function in pre-dialytic patients in stages 3, 4 and 5 of chronic kidney disease (CKD). Materials and Methods: Demographic, socioeconomic and medical history data of 139 patients from the Nephrology Service at the Hospital de Clínicas de Porto Alegre (HCPA) were obtained through interview and clinical records. Complete periodontal clinical examinations were performed by trained and calibrated examiners. Associations between the periodontal condition and different stages of CKD, as well as with the glomerular filtration rate (GFR) were evaluated. Results: Severe periodontitis increased by 2.8 and 3.4 times the chance of being in stages 4 and 5 of CKD when compared to the reference (stage 3), respectively (p <0.05). In addition, having two or more teeth with clinical attachment loss ≥6mm increased by 3.9 times the probability of being in stage 5 of the CKD (p <0.05). Regarding GFR, severe periodontitis and having two or more teeth with clinical attachment loss ≥6mm were significantly associated with a lower glomerular filtration rate (p = 0.02 and p = 0.01, respectively). Conclusion: Periodontal disease increases the chance of worse renal outcomes in patients with pre-dialytic CKD, even when adjusted for major confounders.

INTRODUÇÃO: A cistatina C é uma proteína não glicosilada de baixo peso molecular que é produzida por todas as células nucleadas. A medida da concentração sérica (CS) de cistatina C tem sido aclamada como um marcador de função renal superior à medida da CS de creatinina. No presente estudo, avaliou-se a acurácia diagnóstica da proteína cistatina C em estimar mudanças no Ritmo de Filtração Glomerular (RFG) medido por 51Cr-EDTA, em análise longitudinal prospectiva de pacientes transplantados renais com tempo de transplante recente e tardio. Em uma fase inicial (Fase A), definimos a melhor estratégia metodológica para a realização do RFG por depuração plasmática de 51Cr-EDTA em receptores de enxerto renal utilizando a depuração renal de inulina como método padrão-ouro. MÉTODOS: Medidas simultâneas de depuração renal de inulina e de depuração plasmática de 51Cr-EDTA foram feitas em pacientes transplantados renais. A precisão do método de medida do RFG por 51Cr-EDTA foi avaliada em doadores após um ano de doação de rim. A análise de Bland&Altman foi empregada para avaliar a concordância entre os métodos. Em uma segunda fase, foram realizadas medidas das CS de cistatina C e de creatinina e do RFG por 51Cr-EDTA nos meses 1, 3, 6 e 12 de seguimento clínico do estudo em pacientes transplantados renais. A cistatina C foi dosada em amostras de soro, por técnica de imunonefelometria (N Latex Cystatin C kit - Dade Behring). A tendência da função renal foi obtida por Regressão Linear Simples. RESULTADOS: Na fase A, foram incluídos 44 pacientes transplantados renais e 22 doadores de rim com tempo de doação de 12,4 a 53,5 meses. A depuração de 51Cr-EDTA com amostras de sangue coletadas nos tempos 2, 4, 6 e 8 horas após injeção do radiofármaco apresentou forte correlação e alto grau de concordância com a depuração de inulina; uma estratégia única para todos os níveis de função foi estabelecida com amostras de sangue nos tempos 4 e 6 horas. Em uma segunda fase do estudo, oitenta e dois pacientes foram incluídos, com idade média de 43,4 ± 11,9 anos. A maioria era da raça branca (56%) e do sexo masculino (68%). No mês 1, a média do RFG por 51Cr-EDTA foi de 50,6 ± 17,3 ml/min/1,73m², e foi de 1,62 ± 0,65 mg/L para a CS de cistatina C e de 1,40 ± 0,62 mg/dL para a CS de creatinina. Na análise transversal, foi encontrada uma forte correlação entre o RFG e a medida de CS de cistatina C. Entretanto, na análise longitudinal do seguimento clínico a CS de cistatina C não estimou a tendência de mudança no RFG. CONCLUSÕES: A depuração plasmática de 51Cr-EDTA é uma medida precisa e acurada de RFG que pode ser utilizada em substituição à depuração renal de inulina, em pacientes transplantados renais. Medidas seriadas da CS de cistatina C não foram capazes de detectar mudanças no RFG em pacientes transplantados renais. / INTRODUCTION: Cystatin C is a nonglycosylated protein that is synthesized by all nucleated cells. The present study aimed to analyze the accuracy of serum concentration of cystatin C for detecting longitudinal change in glomerular filtration rate in transplanted recipients, as well to define a better methodological strategy to perform the plasma clearance of 51Cr-EDTA in renal transplant patients using inulin clearance as the gold standard method. METHODS: in the first phase of the study, simultaneous measurements of plasma clearance of 51Cr-EDTA and renal clearance of inulin in stable renal transplanted patients were performed. The within-subject repeatability of the 51Cr-EDTA was evaluated in live kidney donors at least 12 months after donation. Bland&Altman statistical approach was used to quantify the degree of agreement between clearance of inulin and plasma clearance of 51Cr-EDTA. In a second phase, serial measures of plasma clearance of 51Cr-EDTA, serum cystatin C and serum creatinine were examined in folowing at 1, 3, 6 and 12 months in kidney transplanted patients. Serum cystatin C was measured by a nephelometric immunoassay (N latex cystatin C kit - Dade Behring). The trend in renal function over time was obtained by linear regression. RESULTS: In the first phase, 44 transplanted patients and 22 kidney donors at least 12 months after donation (range 12,4 to 53,5 months) were enrolled. Plasma clearance of 51Cr-EDTA with four samples taken at 2, 4, 6 and 8 hours presented a strong association and closely agreement with inulin clearance. An abbreviated strategy was recommended with two blood sampling collected at 4 and 6 hours. In the second phase, 82 kidney transplanted patients were enrolled. Mean age was 43.4 ± 11.9 years. The majority were white (56%) and male (68%). The mean of the plasma clearance of 51Cr-EDTA was 50.6 ± 17.3, and it was 1.62 ± 0.65 mg/L and 1.40 ± 0.62 mg/dL for serum cystatin C and creatinine, respectively, at baseline. In cross-section analysis, serum cystatin C was strongly correlated with plasma clearance of 51Cr-EDTA. However, in longitudinal analysis serum cystatin C was not able for estimate GFR. CONCLUSIONS: Plasma clearance of 51Cr-EDTA is a precise method to measure GFR in renal transplanted recipients. The results showed that serial measurements of serum cystatin C are not able to detect trends in renal function in transplanted patients.

<p><strong>Objective</strong><em>:</em> Estimation of glomerular filtration rate (GFR) is an important tool in the diagnosis and management of chronic kidney disease. Today creatinine is the most frequently used marker for kidney function though several studies indicate that cystatin C is a superior marker. The purpose of this study was to validate Abbott Diagnostics turbidimetric cystatin C assay and enzymatic creatinine assay.</p><p><strong>Methods</strong><em>:</em> The validation was performed by studies of CV for the two methods and correlations between the two and other available methods for assessing GFR. The stability of cystatin C at room temperature was also evaluated.</p><p><strong>Results</strong><em>: </em>Both methods showed good precision. The Abbott cystatin C assay generally gave lower values and thereby higher estimated GFRs than the correlated Gentian method. The Abbott enzymatic creatinine assay gave higher values than the correlated Jaffe method. Those results are generally unexpected, but in this study the cause is an automatically applied negative intercept used together with the Jaffe method. Cystatin C showed high stability when stored at room temperature.</p><p><strong>Conclusions</strong><em>:</em> Estimated GFRs tend to differ depending on the choice of method for analyzing cystatin C or creatinine and this study gives an overview of the range of variation. The study also enlightens the need for an international calibrator for the cystatin C methods presented by different manufacturers.</p>

Objective: Estimation of glomerular filtration rate (GFR) is an important tool in the diagnosis and management of chronic kidney disease. Today creatinine is the most frequently used marker for kidney function though several studies indicate that cystatin C is a superior marker. The purpose of this study was to validate Abbott Diagnostics turbidimetric cystatin C assay and enzymatic creatinine assay. Methods: The validation was performed by studies of CV for the two methods and correlations between the two and other available methods for assessing GFR. The stability of cystatin C at room temperature was also evaluated. Results: Both methods showed good precision. The Abbott cystatin C assay generally gave lower values and thereby higher estimated GFRs than the correlated Gentian method. The Abbott enzymatic creatinine assay gave higher values than the correlated Jaffe method. Those results are generally unexpected, but in this study the cause is an automatically applied negative intercept used together with the Jaffe method. Cystatin C showed high stability when stored at room temperature. Conclusions: Estimated GFRs tend to differ depending on the choice of method for analyzing cystatin C or creatinine and this study gives an overview of the range of variation. The study also enlightens the need for an international calibrator for the cystatin C methods presented by different manufacturers.

Podocytes are specialized epithelial cells which wrap glomerular capillaries with numerous interdigitating foot processes (FP). Between adjacent FPs a unique junction, the slit diaphragm (SD), functions as the final blood filtration barrier. Actin organization is critical for maintaining FP structure and SD function, and the adaptor protein Nck can bind an intracellular SD component to couple it with actin regulators. Podocyte-specific deletion of Nck in mice results in proteinuria and FP effacement. To better understand FP remodelling, we have pursued a transgenic mouse model utilizing an inducible and reversible dominant negative Nck (DN-Nck) to prevent signalling to actin regulators, exclusively in podocytes. Effects of DN-Nck were first confirmed in vitro, and transgenic mice were then generated and induced to express DN-Nck. Despite obtaining several mice which exhibited a mild renal phenotype, transgene expression appeared to be lost in successive generations. Full in vivo analysis awaits generation of additional transgenic founders.

Since its discovery in 1988 the powerful vasoconstrictor endothelin-1 (ET-1) has been widely implicated in the pathophysiology of chronic kidney disease (CKD) as well as the cardiovascular disease with which it is associated. ET receptor antagonists have favourable effects in experimental models of these conditions and orally acting antagonists are now licensed for the treatment of pulmonary arterial hypertension. However, there is a paucity of human data regarding the role of ET-1 in CKD. In this thesis, I have therefore explored the utility of ET-1 as a biomarker in CKD, and, using selective ET receptor antagonists, the beneficial renal and cardiovascular effects of ET receptor antagonism in CKD. I have shown that as glomerular filtration rate (GFR) declines plasma ET-1 increases linearly whereas urinary ET-1 shows an exponential increase. Furthermore, urinary ET-1 may be a useful marker of disease activity in patients with lupus nephritis. Its levels are high in those with biopsy-proven active renal inflammation and these fall with treatment. I have shown that in subjects with stable non-diabetic proteinuric CKD, acute selective ETA receptor antagonism reduces blood pressure and arterial stiffness and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. Importantly, these effects are seen on top of those achieved with maximal therapy with angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers. Following a study confirming unchanged pharmacokinetics in CKD, I have used an oral selective ETA receptor antagonist to show that the reductions in BP, arterial stiffness and proteinuria seen in my acute studies are maintained longer term. This results of this study also suggest that the mechanism for the reduction in proteinuria is haemodynamic and relates to a reduction in GFR and filtration fraction. In summary, these studies suggest that ET-1 may act as a potential biomarker of renal inflammation, and confirm its role in the pathophysiology of the systemic and renal vasoconstriction seen in CKD. They also suggest that selective ETA receptor antagonism may provide a novel therapeutic approach in proteinuric CKD on top of standard therapies. Larger and longer term studies are now warranted to confirm this potential.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.