DISSERTATION (PH.D.)--THE UNIVERSITY OF MICHIGAN / CO-CHAIRMEN: ARNOLD MONTO; GENE HIGASHI

DISSERTATION (PH.D.)--THE UNIVERSITY OF MICHIGAN / CO-CHAIRMEN: ARNOLD MONTO; GENE HIGASHI

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: OBJECTIVES The aim of this study was to determine long-term renal function in boys presenting with posterior urethral valves at Tygerberg Children’s Hospital and to determine the prognostic value of certain clinical, biochemical and radiological variables DESIGN Retrospective, descriptive study of boys diagnosed and treated with posterior urethral valves at Tygerberg Children’s Hospital between 2001 and 2011. RESULTS Between 2001 and 2011, 47 cases of posterior urethral valves were diagnosed and treated at our institution. Thirteen patients were excluded from this study. Seven (20,6%) were diagnosed antenatally and 27 (79,4%) presented postnatally. Mean age at presentation was 13,9 months (median 2; range 0-74). The most common postnatal presentation was urinary tract infection (51,9%). Mean follow-up was 54,2 months (median 47,5; range 12-133). A total of 13 boys (38,2%) progressed to chronic renal failure or end-stage renal disease. Initial and nadir serum creatinine, poor corticomedullary differentiation and moderate-severe hydronephrosis were significant predictors of final renal function (p<0,050). Patient age at presentation, type of primary surgical intervention, increased renal echogenicity, bladder wall thickness, the presence of vesicoureteric reflux (no matter what the laterality or severity), severe bladder dysfunction and initial or breakthrough urinary tract infection had no significant impact on future renal function. Receiver operating characteristic curve analysis confirmed that boys with an initial serum creatinine ≥145μmol/L and a nadir serum creatinine ≥62μmol/L were at highest risk to develop chronic renal insufficiency (area under the curve 0,8 and 0,9, respectively). CONCLUSION More than a third of boys (38,2%) developed chronic renal failure or end-stage renal disease at the end of follow-up. Our data confirmed the high prognostic value of initial and nadir serum creatinine. Optimal threshold levels for initial and nadir serum creatinine to predict final renal function were 145μmol/L and 62μmol/L, respectively. Similarly, poor corticomedullary differentiation and moderate-severe hydronephrosis on initial kidney ultrasound were significant indicators of poor renal prognosis. Although all patients with posterior urethral valves should be counselled on potential renal morbidity, children with risk factors warrant closer monitoring. / AFRIKAANSE OPSOMMING: DOELWITTE Die doel van hierdie studie was om langtermyn nierfunksie te bepaal in seuns wat gediagnoseer is met posterior uretrale kleppe by Tygerberg-kinderhospitaal. Die prognostiese waarde van sekere kliniese, biochemiese en radiologiese veranderlikes is ook ondersoek. STUDIE ONTWERP Retrospektiewe, beskrywende studie van seuns wat tussen 2001 en 2011 by Tygerberg-kinderhospitaal gepresenteer het met posterior uretrale kleppe. RESULTATE Tussen 2001 en 2011 is 47 gevalle van posterior uretrale kleppe gediagnoseer en behandel by ons instelling. Dertien pasiënte is uitgesluit van hierdie studie. Sewe (20,6%) is met voorgeboorte sonar gediagnoseer en 27 (79,4%) het ná geboorte gepresenteer. Die gemiddelde ouderdom by diagnose was 13,9 maande (mediaan 2; reeks 0-74 ). Urienweginfeksie was die mees algemene metode waarmee postnatale pasiënte gepresenteer het (51,9%). Die gemiddelde opvolgperiode was 54,2 maande (mediaan 47,5; reeks 12-133). Dertien seuns (38,2%) het chroniese nierversaking of eind-stadium nierversaking ontwikkel. Aanvanklike en nadir serumkreatinien, swak kortiko-medullêre differensiasie en matig-erge hidronefrose was beduidende voorspellers van finale nierfunksie (p<0,050). Pasiënt ouderdom met diagnose, tipe chirurgiese ingryping, verhoogde niereggogenisiteit, blaaswanddikte, vesikoureteriese refluks, blaasdisfunksie en aanvanklike of deurbraak urienweginfeksies het geen beduidende impak op toekomstige nierfunksie gehad nie. Seuns met 'n aanvanklike serumkreatinien ≥145μmol/L en 'n nadir serumkreatinien ≥62μmol/L het die grootste risiko om chroniese nierversaking te ontwikkel, soos bevestig met ‘n ROC-ontleding (AUC 0,8 en 0,9, onderskeidelik). GEVOLGTREKKING Meer as 'n derde van die pasiënte (38,2%) het chroniese nierversaking of eindstadium nierversaking ontwikkel. Ons data bevestig die prognostiese waarde van aanvanklike en nadir serumkreatinienvlakke. Die optimale drempelwaardes vir die aanvanklike en nadir serumkreatinien om finale nierfunksie te voorspel was 145μmol/L en 62μmol/L, onderskeidelik. Swak kortiko-medullêre differensiasie en matig-erge hidronefrose op die aanvanklike niersonar was ook beduidende aanwysers van toekomstige nierfunksie. Alhoewel alle pasiënte met posterior uretrale kleppe berading moet ontvang oor potensiële niermorbiditeit, regverdig seuns met risikofaktore noukeurige monitering.

published_or_final_version / abstract / Community Medicine / Master / Master of Public Health

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

This descriptive, correlational designed study was concerned with noncompliance with therapeutic regimens, a pervasive clinical problem which is confounded with the lack of a strong link among theory, research and practice. The focus was on one of the constructs included the Reciprocal Interaction Model of Compliance Behaviors, which was derived using a modified grounded theory methodology and following various theory building prescriptions. The overall purpose was to begin to evaluate the goodness-of-fit of this empirically, qualitatively and retroductively generated explanation of compliance behaviors. The specific aims were to develop, refine and test a 6-point response, 64-item Likert-type instrument, Olivas' Health Motivation Scale - OHMS, that adequately measures the construct, Health Motivation: the force within the patient which is developed as he/she gains experience with his/her illness as a function of time. It has two major dimensions: expectations and values. Health Motivation as indexed by an expectations/values interaction was predicted to impact compliance as measured by dietary and medication measures, both objective and subjective estimates. Using trait and nomological construct perspectives, the OHMS was systematically evaluated by internal and external association criteria and therefore validity and reliability estimates, with a purposive sample of 84 heterogeneous hemodialysis patients who represented two cultures (Anglo and Hispanic), varying in gender, age and length in hemodialysis. Internal consistency reliability and trait construct validity were derived through Cronbach's alpha and principal components factor analysis. Refined OHMS Scales had alphas and thetas ranging from .58 to .89. Explained scale variance ranged from .54 to .84. Epistemic coefficients, the validity links between concept and operational measures, ranged from .76 to .94. Internal validity of the design, estimated through multiple regression, was concluded to be satisfactory. External association assessment via multiple regression produced mixed findings. Select expectations, in linear combination with select values, explained varying degrees of the variance, in select compliance measures, R² = .11 to .44. Through empirical modeling via path analysis, select subject characteristics (ethnicity, length on dialysis, age) were found to have direct or indirect relationships with compliance. Theory, research, and practice based limitations and recommendations were made from the results of the study. (Abstract shortened with permission of author.)

Title: Muscle metabolism and its effect on physical condition in patients with chronic renal failure receiving hemodialysis Objective: Assess the status of muscle metabolism in patients starting hemodialysis and patients receiving hemodialysis long time, to determine some changes in muscle metabolism in both groups in the time period and ultimately assess its impact on physical condition and quality of life of hemodialysis patients. Method: Fill anamnestic questionnaire and examination of body composition using bioimpedence device (BCM) in the group of patients with chronic renal failure who are beginning to be treated with hemodialysis and a group of patients treated with hemodialysis for several years. Compare the results of both groups. To obtain additional information from medical records. Results: It was found that hemodialysis therapy affects the status of muscle metabolism in terms of reducing muscle mass (LTM). The dependence of LTM, however, the duration of hemodialysis treatment assays. The study showed that if patients are nutritionally stable and regularly engaged in some physical activity, loss of muscle mass is lower than in individuals who have a passive way of life. Keywords: chronic renal failure, hemodilysis, muscle metabolism, physical condition

A doença renal crônica (DRC) atinge cada vez mais uma parcela significativa da população, e entre os pacientes adultos as doenças metabólicas são as principais causas, respondendo por aproximadamente 70% dos pacientes em tratamento dialítico. Porém, há poucas publicações sobre levantamento epidemiológico de DRC em crianças disponíveis na literatura. O objetivo deste trabalho foi descrever o perfil clínico-epidemiológico das crianças e adolescentes com DRC atendidos pelo Serviço de Nefrologia Pediátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), contemplando 22 anos de experiência. Para tanto, foram revisados 121 prontuários e coletadas 21 variáveis de cada um deles. Do total, 58,7% eram do sexo masculino, e 41,3% do sexo feminino. A média de idade de entrada foi 59,1 meses. Os pacientes menores que 5 anos somaram 62,5% do total. Os pacientes procedentes de Ribeirão Preto ou de cidades com até 300km de distância somaram 63% dos casos. As causas básicas de DRC foram: uropatias (48,8%), glomerulopatias (20,7%), displasias renais congênitas ou policísticas (7,4%), vasculopatias (6,6%), tubulopatias (2,5%), outras causas (7,4%) e causa indeterminada (6,6%). Das glomerulopatias, os tipos histológicos encontrados foram a glomeruloesclerose segmentar e focal (GESF) (25,0%), a proliferação mesangial difusa (PMD) (20,8%), a glomerulonefrite (GN) avançada (12,5%), a glomerulonefrite crescêntica (GNC) (8,3%) e a Síndrome de Alport (8,3%), sendo que 4,2% dos casos foram considerados indeterminados e 20,8% dos pacientes não foram submetidos a biópsia. A grande maioria dos pacientes (59,8%) tinha estatura abaixo do 5º percentil para idade e sexo no momento do diagnóstico. O tempo de seguimento clínico variou de 2 a 263 meses, com média de 67,5 meses. A creatinina sérica no momento do diagnóstico variou de 0,5 a 12,1 mg/dL, com média igual a 3,0 mg/dL. A média de RFG calculado pela Fórmula de Schwartz no momento do diagnóstico foi 27,4 mL/min/1,73m2. A maioria dos casos (62,3%) chegou ao serviço em DRC estágios 4, 5 ou em diálise. Hipertensão arterial (HA) foi detectada em 56,2% dos pacientes em algum momento do curso clínico. Acidose metabólica foi detectada em 53,7% dos pacientes no momento do diagnóstico. Do total de pacientes, 38,0% foram submetidos a tratamento dialítico, sendo as modalidades peritoneais preferidas em 80,4% dos casos. Transplante renal foi realizado em 24,8% dos pacientes, sendo as proporções de doador vivo relacionado (DVR) e doador cadáver (DC) semelhantes. A proporção de óbitos no período do estudo foi 22,3%. Dos demais pacientes, 17,4% foram transferidos para seguimento pela Clínica Médica do HCFMRP-USP, e 38,8% dos casos ainda estavam em seguimento pela Nefrologia Pediátrica em dezembro de 2005. Concluímos que a população estudada mostrou características clínico-epidemiológicas semelhantes às publicações nacionais e internacionais consultadas. / The prevalence of chronic renal failure (CRF) increases every day, and among adult patients, the principal causes are metabolic diseases, responsible to almost 70% of patients who are under dialysis. However, there are few studies regarding epidemiologic data of CRF in children. The objective of this study was to describe clinical and epidemiological profiles of children and adolescents with CRF who have been followed up by the Pediatric Nephrology Team of the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), along 22 years of experience. Data of 121 medical records have been reviewed, and 21 variables have been collected from each of them. From the total of the patients, 58.7% were male and 41.3% were female. The average of age of registration was 59.1 months. Patients who were younger than 5 years summed 62.5% of all. From the total of patients, 63% lived in Ribeirão Preto or in cities until 300km far. The primary renal diseases described were: uropathies (48.8%), glomerulopathies (20.7%), congenital or polycystic renal dysplasia (7.4%), vasculopathies (6.6%), tubular diseases (2.5%), miscellaneous (7.4%) and unknown causes (6.6%). Among the glomerulopathies group, the histological patterns described were: Focal Segmental Glomerulosclerosis (25.0%), Diffuse Mesangial Proliferation (20.8%), Advanced Glomerulonephritis (12.5%), Crescentic Glomerulonephritis (8.3%) and the Alport Syndrome (8.3%). From total of biopsies, 4.2% were not able to define a diagnosis, and 20.8% of the glomerulopathies\' patients were not undergone renal biopsy. From the total, 59.8% of the patients were under the 5o percentile of the NCHS curve in their registration, related to their height. The follow up showed a variation of 2 to 263 months, which average was 67.5 months. The blood creatinine level showed a variation of 0.5 to 12.1 mg/dL, which average was 3.0 mg/dL. The average Glomerular Filtration Rate, estimated by the Schwartz\'s formula, was 27.4 mL/min/1,73m2. At the onset, 62.3% of the patients were classified at the stages 4, 5 or under dialysis. Hypertension was described in 56.2% of the patients at any time of the follow up. Metabolic acidosis was described in 53.7% of the patients at the onset. Patients who underwent dialysis summed 38.0%, and the peritoneal modalities performed 80.4% of all cases. Renal transplantation was performed in 24.8% of the patients, with similar proportions of live-related and cadaveric donors. The proportion of deaths during the 22 years of study was 22.3% of all. The rest of them were delivered to the Clinical Team of the HCFMRP-USP (17.4%) or still had been followed up by the Pediatric Nephrology Team by December 2005 (38.8%). We concluded that the population described had similar clinical and epidemiological characteristics to the other Brazilian and international data available.

A doença renal crônica (DRC) está associada com inibição da atividade de sistemas enzimáticos e de transportadores de fármacos. O carvedilol, um ?-bloqueador não seletivo é substrato e inibidor da P-gp intestinal. A lercanidipina, antagonista de canais de cálcio é metabolizada pelo CYP3A4, sendo descrita como provável inibidora da P-gp. O presente estudo avalia a interação carvedilol-lercanidipina em pacientes hipertensos portadores ou não de DRC. Foram investigados 8 pacientes hipertensos portadores de DRC estágios 3 e 4 e 8 pacientes hipertensos com função renal normal, fenotipados para o CYP2D6 e CYP3A, e genotipados para o CYP2C9 e P-gp. Os pacientes receberam dose única oral de 25 mg de carvedilol racêmico (Fase 1) ou 20 mg de lercanidipina racêmica (Fase 2) ou dose única oral de 25 mg de carvedilol racêmico associada com 20mg de lercanidipina racêmica (Fase 3). As amostras seriadas de sangue foram coletadas até 32h. A freqüência cardíaca foi avaliada na situação de exercício isométrico durante 2 min com o handgrip, a 30% da contratilidade voluntária máxima, em cada tempo de colheita de sangue. As concentrações plasmáticas dos enantiômeros do carvedilol e da lercanidipina foram realizadas por LC-MS/MS. A farmacocinética do carvedilol, como monoterapia ou em associação com a lercanidipina, é enantiosseletiva no GRUPO DRC com acúmulo plasmático do enantiômero (+)-(R)- carvedilol. A administração de dose única oral de 20 mg de lercanidipina racêmica ao GRUPO DRC reduziu o clearance total aparente e aumentou a AUC somente para o enantiômero (+)-(R)-carvedilol. O GRUPO CONTROLE também apresentou acúmulo plasmático do enantiômero (+)-(R)-carvedilol. No entanto, a administração de dose única oral de 20 mg de lercanidipina racêmica não alterou a farmacocinética de ambos os enantiômeros do carvedilol no GRUPO CONTROLE. A comparação do GRUPO DRC com o GRUPO CONTROLE, na monoterapia ou em associação com lercanidipina, mostra que a DRC não altera a farmacocinética de ambos os enantiômeros do carvedilol. A relação PK-PD não mostra diferenças com significância estatística entre as Fases 1 e 3, tanto para o grupo DRC quanto para o grupo CONTROLE. No entanto, a comparação do GRUPO DRC com o GRUPO CONTROLE permite observar maiores valores de ECe50 nos pacientes do GRUPO DRC na Fase 3. A administração de dose única oral de 20 mg de lercanidipina, sob monoterapia ou em associação ao carvedilol, aos GRUPOS DRC e CONTROLE não mostra enantiosseletividade no parâmetro AUC. A administração de dose única oral de 25 mg de carvedilol racêmico reduziu de maneira enantiosseletiva o clearance total da (S)-lercanidipina no GRUPO DRC, mas não no CONTROLE. A comparação do GRUPO DRC com o CONTROLE não mostra diferenças com significância estatística nos parâmetros farmacocinéticos de ambos os enantiômeros da lercanidipina nas Fases 2 e 3. Concluindo, o carvedilol reduziu o clearance total aparente do eutômero (S)-lercanidipina e a lercanidipina reduziu o clearance total aparente do enantiômero (+)-(R)-carvedilol nos pacientes do Gupo DRC, mas não nos pacientes do GRUPO CONTROLE. Os dados permitem sugerir enantiosseletividade na atividade da P-gp e sugerir que a DRC estágios 3 e 4 não altera a farmacocinética do carvedilol e da lercanidipina em pacientes hipertensos fenotipados como metabolizadores rápidos do CYP2D6 e com atividade normal do CYP3A. No entanto, os maiores valores de ECe50 nos pacientes do GRUPO DRC na Fase 3 sugerem uma menor potência do (-)-(S)- carvedilol na inibição da atividade simpática. / Chronic kidney disease (CKD) is associated with inhibition of enzyme systems and drug transporters. Carvedilol, a nonselective ?-blocker, is a substrate and inhibitor of intestinal Pgp. Lercanidipine, a calcium channel antagonist, is metabolized by CYP3A4, which is described as a probable inhibitor of P-gp. The present study evaluates the carvedilollercanidipine interaction in hypertensive patients, with or without CKD. We investigated 8 hypertensive patients with CKD stages 3 and 4 and 8 hypertensive patients with normal renal function, phenotyped for CYP2D6 and CYP3A, and genotyped for CYP2C9 and P-gp. Patients received a single oral dose of 25 mg of racemic carvedilol (Phase 1), or 20 mg of racemic lercanidipine (Phase 2), or a single oral dose of 25 mg of racemic carvedilol associated with 20 mg of racemic lercanidipine (Phase 3). Serial blood samples were collected up to 32h. Heart rate was assessed in the situation of isometric exercise for 2 min with handgrip at 30% of maximal voluntary contractility, in each blood collection time. Plasma concentrations of the enantiomers of carvedilol and lercanidipine were performed by LCMS/ MS. The pharmacokinetics of carvedilol, alone or in combination with lercanidipine in the CKD group, is enantioselective with plasma accumulation of the enantiomer (+)-(R)- carvedilol. The administration of a single oral dose of 20 mg of racemic lercanidipine reduced the total apparent clearance and increased the AUC for the enantiomer (+)-(R)-carvedilol on CKD group. The CONTROL group also presented plasma accumulation of the enantiomer (+)-(R)-carvedilol. However, the administration of single oral dose of 20 mg of racemic lercanidipine does not alter the pharmacokinetics of the enantiomers of carvedilol in CONTROL group. The comparison between the CONTROL group with the CKD group, in monotherapy or in combination with lercanidipine, shows that CKD does not alter the pharmacokinetics of both enantiomers of carvedilol. The PK-PD modeling shows no statistically significant differences between Phases 1 and 3 in any group. However, comparing the CKD group with the CONTROL group, higher values of ECe50 were observed in the patients of CKD group in Phase 3. The administration of a single oral dose of 20 mg of racemic lercanidipine, in monotherapy or in combination with carvedilol to the CONTROL and CKD group does not show enantioselectivity in the parameter AUC. Administration of a single oral dose of 25 mg of racemic carvedilol reduced the total apparent clearance and increased de AUC for the enantiomer (S)-lercanidipine on CKD group, but not in CONTROL group. The comparison between the CKD group with the CONTROL group does not show statistically significant differences in pharmacokinetic parameters of both enantiomers of lercanidipine in Phases 2 and 3. In conclusion, carvedilol reduced the apparent total clearance of the eutomer (S)-lercanidipine and lercanidipine reduced the apparent total clearance of the enantiomer (+)-(R)-carvedilol in the patients of CKD group, but not in the patients of CONTROL group. The findings suggest enantioselectivity in the activity of P-gp, and that CKD stages 3 and 4 does not alter the pharmacokinetics of carvedilol and lercanidipine in hypertensive patients phenotyped as extensive metabolizers of CYP2D6 and with normal CYP3A activity. However, the highest values of ECe50 in patients of CKD group in the Phase 3 suggest a lower potency of (-)-(S)-carvedilol in the inhibition of sympathetic activity in these patients.

Introdução: Em pacientes com insuficiência renal crônica em tratamento de hemodiálise (HD), existe necessidade de ferramenta simples, segura e eficaz para avaliar a composição corporal (CC) e permitir diagnóstico de suas alterações, com finalidade de planejamento e monitoramento de tratamento nutricional. Objetivo: Em 60 pacientes em insuficiência renal dialítica determinou-se a eficiência da análise de bioimpedância elétrica (BIA) e a somatória das pregas cutâneas (SPC) na estimativa da gordura corporal total. Métodos: Estudo prospectivo, observacional de comparação de gordura corpórea total (GC) e massa magra total (MM) estimadas, antes e após hemodiálise,por BIA multifrequencial e pela SPC com os valores estimados pelo método de referência, pletismografia a ar de deslocamento (PDA). Resultados: A média estimada GC (kg,%) observado por PDA antes da hemodiálise (HD) foi 17,95 kg ± 0,99 (IC 95% 16,00-19,90) e 30,11% ± 1,30 (IC 95% 27,56-32,66); após hemodiálise (HD), foi 17,92 kg ± 1,11 (IC 95% 15,74-20 10) e 30,04% ± 1,40 (IC 95% 27,28-32,79). Em nenhum período do estudo encontrou-se diferença de GC e de MM (para kg e %) estimadas pelo método SPC em comparação com PDA, no entanto, o BIA subestimou a GC e superestimou a MM (para kg e %) quando comparado com PDA. Conclusão: O método SPC mostrou resultados semelhantes aos PDA e pode ser considerado adequado para avaliação GC em pacientes HD. A BIA não foi considerada método para ser utilizado nessas condições / Introduction: In patients with chronic renal failure on hemodialysis (HD), there is need for simple tool, safe and effective for assessing body composition (BC) diagnosis and allow your changes, with the purpose of planning and monitoring of nutrition therapy. Objective: In 60 patients in renal dialysis efficiency was determined from the analysis of bioelectrical impedance analysis (BIA) and sum of skin folds (SPC) in the estimation of total body fat. Methods: Prospective, observational comparison of total body fat (BF) and total lean mass (LM) estimated before and after hemodialysis by multifrequency BIA and the SPC with the values estimated by the reference method, air displacement plethysmography (PDA). Results: The estimated average GC (kg,%) observed by PDA prior to hemodialysis (AHD) was 17.95 kg ± 0.99 (95% CI 16.00 to 19.90) and 30.11 ± 1.30% (95% CI 27.56 to 32.66), after hemodialysis (DHD) was 17.92 kg ± 1.11 (95% CI 15.74 to 20 10) and 30.04% ± 1.40 (IC 95% from 27.28 to 32.79). At no period of the study there was a difference of GC and MM (for kg and%) estimated by the SPC method compared with PDA, however, the BIA underestimated FFM and overestimated GC (for kg and%) compared to PDA. Conclusion: The SPC method showed similar results to PDA and can be considered adequate for evaluating GC in HD patients. The BIA was not considered to be the method used in these conditions