Background: Understanding complex psychological treatment mechanisms is important in order to refine and improve treatment. Mechanistic theories can be evaluated using mediation analysis methods. The Pacing, Graded Activity, and Cognitive Behaviour Therapy: A Randomised Evaluation (PACE) trial studied complex therapies for the treatment of chronic fatigue syndrome. The aim of the project was to study different mediation analysis methods using PACE trial data, and to make trial design recommendations based upon the findings. Methods: PACE trial data were described using summary statistics and correlation analyses. Mediation estimates were derived using: the product of coefficients approach, instrumental variable (IV) methods with randomisation by baseline variables interactions as IVs, and dual process longitudinal structural equation models (SEM). Monte Carlo simulation studies were done to further explore the behaviour of IV estimators and to examine aspects of the SEM. Results: Cognitive and behavioural measures were mediators of the cognitive behavioural and graded exercise therapies in PACE. Results were robust when accounting for correlated measurement error and different SEM structures. Randomisation by baseline IVs were weak, giving imprecise and sometimes extreme estimates, leaving their utility unclear. A flexible version of a latent change SEM with contemporaneous mediation effects and contemporaneous correlated measurement errors was the most appropriate longitudinal model. Conclusions: IV methods using interaction IVs are unlikely to be useful; designs with randomised IV might be more suitable. Longitudinal SEM for mediation in clinical trials seems a promising approach. Mediation estimates from SEM were generally robust when allowing for correlated measurement error and for different model classes. Mediation analysis in trials should be longitudinal and should consider the number and timing of measures at the design stage. Using appropriate methods for studying mediation in trials will help clarify treatment mechanisms of action and allow for their refinement, which would maximize the information gained from trials and benefit patients.

Endometrios är en kronisk sjukdom som drabbar en av tio kvinnor världen över. Vanliga symptom är menstruationssmärta, samlagssmärta och en nedsatt fertilitet. Diagnosen endometrios ställs oftast i samband med en titthålsoperation och kan i många fall dröja upp till flera år. Tidigare forskning på området har funnit att individer som lever med endometrios kan uppleva en minskad livskvalité, komplikationer med sociala relationer samt emotionella besvär. Syftet med föreliggande studie var att studera kvinnors upplevelse av endometrios. Åtta kvinnor intervjuades, samtliga bosatta i Stockholmsområdet. Resultatet visar på flera olika psykologiska aspekter som sjukdomen för med sig. En minskad livskvalité, komplikationer med sociala relationer och en nedsatt arbetsförmåga är aspekter som påverkas av de upplevda symptomen. En nedsatt fertilitet kan vidare skapa en reducering av individens självkänsla. Slutsatsen är att en tidigare diagnos och ökad forskning skulle kunna bidra till underlättande av endometriosdrabbades vardag och därmed förbättra deras livskvalité.

Vascular, especially cerebrovascular, dysfunction may be a critical factor in ageing and dementia. Cerebrovascular impairment due to risk factors such as ageing, stroke, smoking, diabetes and cerebral hypoperfusion has a deterious impact on the normal supply of basic nutrients such as oxygen and glucose to the brain; their absence leads inevitably to neuronal death. The cerebral white matter lesions found in most forms of dementia are reportedly the result of chronic cerebral hypoperfusion. However the temporal and spatial evolution of damage remains unclear. Furthermore, any decrease in the integrity of the blood-brain barrier (BBB) has been hypothesised to be a precocious attack on white matter. The “milieu interieure” the most protected in the body, namely the extracellular fluid of the brain, is no longer maintained homeostatically. The cumulation of these various pathophysiological processes alters cerebral function and it has been postulated that, in the most extreme instances, the outcome of this cascade of nefarious events leads to dementia. This thesis examines the supposition that chronic cerebral hypoperfusion could be responsible for the time-related development of white and grey matter pathology and investigates the relationships between the disturbances in the integrity of the BBB and white matter pathology. Three studies addressed these aims. In the first, chronic cerebral hypoperfusion, induced in male Wistar rats by bilateral common carotid artery occlusion (BCCAo), was chosen as the model to study changes in axons, myelin, perikarya as well as microglial activation. The groups of rats that underwent BCCAo were examined at three hours as well as three, seven, 14 and 28 days after the induction of chronic cerebral hypoperfusion. The microscopic examination revealed that, after three hours post BCCAo, damage was detected only in axons and myelin. In contrast, no visible pathology to the neuronal perikarya or enhancement of activated microglia (compared to the sham group) was observable. Injury in both white and grey matter and enhancement of activated microglia was observed from three days post BCCAo and increased with time post BCCAo. The most severe damage to the white and grey matter and enhancement of microglial activation was detected at seven days post BCCAo. These results would indicate that white matter damage precedes grey matter pathology and the enhancement of activated microglia. In the second study, the integrity of the BBB at three hours (when only white matter pathology was found according to the results of the first study) and seven days post BCCAo (when more severe damage to the white and grey matter was shown) was assessed by the use of MRI on T1-weighted image acquisitions with gadolinium as a tracer for BBB permeability. White matter integrity was measured by MTR maps from MTI acquisitions in four brain structures (corpus callosum, caudatoputamen, the external and internal capsules). No differences in white matter integrity were detected between the BCCAo and sham group at three hours and seven days. No differences in signal enhancement of gadolinium were detected three hours post BCCAo. However, a significant signal enhancement of gadolinium was detected at seven days post BCCAo in the caudatoputamen and in the external capsule. Furthermore, immunohistochemistry revealed a significant enhancement of activated microglia seven days post BCCAo compared to the sham group. This functional and immunohistochemical finding, when taken together, might indicate that chronic cerebral hypoperfusion is not in itself responsible for BBB permeability. Rather, the damage to the white matter caused by cerebral hypoperfusion may be responsible for the dysfunction of the BBB over time. Another point of interest was the evidence that the enhancement of activated microglia may play a critical role in the increased permeability of the BBB. The final study in this thesis aimed to investigate the possible pathway and proteins potentially implicated in white matter damage and BBB permeability. To address this question, protein levels and the expression of genes involved in the apoptotic and nonapoptotic hypoxic pathways were compared to the sham groups (at three hours and seven days after BCCAo), in three brain structures (cortex, corpus callosum and caudatoputamen). The levels of HIF-1α, MMP-2, Caspase-3 and VEGF were unchanged compared to the sham group after BCCAo. However, VEGF mRNA expression was found to be significantly different to the sham group seven days post BCCAo in all the three structures examined. An overexpression of HIF-1α and a significant level of Caspase-3 would indicate the activation of the apoptotic pathway. However, neither of these criteria were met and these negative results suggest that the apoptotic pathway is not implicated in the mechanisms that lead to white matter pathology after cerebral hypoperfusion. Finally, the significant expression of VEGF mRNA, compared to the sham group seven days post BCCAo, may contribute to the time-relate increased permeability of the BBB. The results presented within this thesis provide a body of evidence to support the hypothesis that chronic cerebral hypoperfusion is - at least – causal to the damage to different components of the white matter which precedes either early ischaemic changes to the perikarya or enhancement of activated microglia following BCCAo. The increased permeability of the BBB, which can be related to the significant over-expression of VEGF mRNA (compared to the sham group seven days post BCCAo), does not appear to be primarily responsible for white matter pathology, because the MRI investigations indicated that BBB integrity was not affected after three hours of BCCAo. The increased permeability of the BBB, observed seven days post BCCAo with MRI, seems to be the consequence of increased brain damage; thereafter, there is a time-dependent relationship between increasing BBB permeability and increasing brain pathology. Overall, the studies reported herein, strengthen the initial working hypothesis. The conclusion – and direction for future studies – would be that minimising white matter pathology and protecting components of the BBB represent potential targets to decrease then incidence of neuropsychological function or to obtund the cerebral dysfunction in patients who suffer from chronic cerebral hypoperfusion.

Cardiovascular disease is common in Chronic Obstructive Pulmonary Disease (COPD), and forced expiratory volume in one second (FEV1) independently predicts cardiovascular morbidity and mortality. Pathological changes in the systemic vasculature have been proposed as potential mechanisms linking COPD to cardiovascular disease, and patients with COPD may be at increased risk of acute myocardial infarction during acute exacerbations. Notwithstanding causation, FEV1 may be a useful prognostic marker in patients undergoing cardiac surgery. This thesis examined these three aspects of cardiovascular co-morbidity in relation to COPD and FEV1. In 2,241 consecutive cardiac surgery patients, FEV1 was associated with length of hospital stay (p<0.001) and mortality (p<0.001) adjusting for age, sex, height, body mass index, socioeconomic status, smoking, cardiovascular risk factors, chronic pulmonary disease, and type/urgency of surgery. In a survey of Scottish Respiratory Consultants there was no consensus regarding the investigation and management of acute coronary syndrome in exacerbation of COPD. In a case-series of 242 patients with exacerbations 2.5% (95% CI 1.0 to 5.6%) had chest pain, raised serum troponin and serial electrocardiogram changes suggestive of acute coronary syndrome. However, over half reported chest pain, while raised troponin was not associated with chest pain or serial ECG changes. Carotid-radial pulse wave velocity (PWV), aortic distensibility, and aortic calcification were measured to assess the relationship of the systemic vasculature to FEV1 and emphysema severity on CT. In adjusted analyses, emphysema was associated with PWV in patients with COPD (p = 0.006) and, in population based samples, with extent of distal aortic calcification (p=0.02) but not with aortic distensibility (p=0.60). This thesis found that FEV1 was associated with mortality and length of hospital stay in patients undergoing cardiac surgery, and that chest pain and raised troponin were common but unrelated in exacerbation of COPD. In the vascular studies distal but not proximal vascular pathology was associated with FEV1, and if COPD is truly related to systemic arterial disease, the distal arterial tree is implicated.

Recent clinical studies suggest that white matter pathology rather than grey matter abnormality is the major neurobiological substrate of age- related cognitive decline during “healthy” aging. According to this hypothesis, cerebrovascular (e.g. chronic cerebral hypoperfusion) and molecular (e.g. APOE, epigenetics) factors might contribute to age-related white matter pathology and cognitive decline. To test this, I used a new mouse model of chronic cerebral hypoperfusion and examined the following predictions: 1) hypoperfusion- induced white matter pathology might be associated with cognitive deficits, 2) APOE deficiency might be associated with white matter anomalies under normal physiological conditions and more severe hypoperfusion- induced white matter pathology, 3) chronic cerebral hypoperfusion might impact on hydroxymethylation (a newly discovered epigenetic marker) in white matter, via perturbations in associated epigenetic pathways, namely methylation and/ or TETs. I. Effects of chronic cerebral hypoperfusion on white matter integrity and cognitive abilities in mice To test the hypothesis suggesting that hypoperfusion- induced white matter pathology is associated with working memory and executive function impairment in mice, behavioural performance and neuropathology were systematically examined in two separate cohorts of sham and hypoperfused C57Bl6J mice. Spatial working memory, memory flexibility, learning capacity, short and long term memory recall were taxed using radial arm maze and water maze paradigms one month after surgery. At the completion of the behavioural testing white and grey matter integrity, inflammation were evaluated using standard immunohistochemistry with antibodies recognizing neuronal axons (APP), myelin sheath (MAG) and microglia (Iba1) as well as H&E histological staining to examine neuronal morphology and ischemic injury. In agreement with previous reports, the behavioral data indicated spatial working memory impairment in the absence of spatial memory flexibility, learning, short- and long- term memory recall deficits in hypoperfused mice However, in contrast to previous reports, a spectrum of white and grey matter abnormalities accompanied by an increased inflammation were observed in hypoperfused mice Although there was a significant association between hypoperfusion- induced inflammation in white matter and performance on a working memory radial arm maze task (p<0.05), the present pathological findings suggest that white matter abnormalities, neuronal ischemia and increased inflammation might be at the basis of hypoperfusioninduced cognitive impairment in mice. Further, chronic cerebral hypoperfusion might have affected alternative, non- examined brain processes (e.g. cerebral metabolism, neurotransmission) which might have contributed to the observed cognitive deficits in hypoperfused mice. II. Effects of APOE on white matter integrity under normal physiological and chronically hypoperfused conditions in mice To test the hypothesis suggesting that mouse APOE deficiency might be associated with white matter anomalies under normal physiological conditions and the development of more severe white matter pathology following chronic cerebral hypoperfusion, white and grey matter integrity, inflammation were examined in APOE deficient mice on a C57Bl6J background (APOEKO) and C57Bl6J wild- type (WT) counterparts one month after chronic cerebral hypoperfusion or sham surgery. A combined neuroimaging (MRI- DTI)/ immunochemical approach was attempted in these mice as an additional step towards translation of this research to human subjects. The ex vivo MRI- DTI findings demonstrated APOE genotype effects on the development of white matter abnormalities following chronic cerebral hypoperfusion in mice. Significant reductions in MRI metrics (FA and MTR) of white matter integrity were observed in examined white matter areas of APOEKO hypoperfused mice compared with WT hypoperfused counterparts (p<0.05). However, the neuroimaigng findings were not supported by the pathological analysis where no significant APOE differences were observed in hypoperfusion- induced axonal (APP), myelin (MAG, dMBP) pathology and inflammation (Iba1) (p>0.05). No significant differences in MRI parameters and pathological grades of white matter integrity were evidenced between APOEKO and WT sham mice (p>0.05). An absence of grey matter abnormalities was evidenced on T2- weighted scans and corresponding H&E stained brain sections in all experimental animals. However, significant reductions in MTR values and dMBP immunoreactivity (myelin pathology) (p<0.05) were observed in grey matter (the hippocampus) following chronic cerebral hypoperfusion in the absence of significant APOE genotype effect (p>0.05) suggesting the existence of both white and grey matter abnormalities in this animal model. Overall, the present neuroimaging data, but not pathological analysis, partially validated the main study hypothesis suggesting that APOE deficiency might be associated with the development of more severe white matter abnormalities in hypoperfused mice. III. Characterization of methylation and hydroxymethylation in white matter under normal physiological and chronically hypoperfused conditions in mice Lastly, I sought to test the hypothesis that chronic cerebral hypoperfusion might alter oxygen dependent DNA hydroxymethylation (5hmC) in white matter regions via perturbations in methylation (5mC) and/ or Ten- eleven translocation proteins (e.g. TET2) in mice. DNA methylation (5mC), hydroxymethylation (5hmC) and TET2 were immunochemically studied in white and grey matter of sham and chronically hypoperfused C57Bl6J mice a month after surgery. The immunochemical results demonstrated significant increases (p<0.05) in 5hmC in the hypoperfused corpus callosum (CC) in the absence of significant hypoperfusion- induced alterations in the distribution of 5mC and TET2 (p>0.05) in white matter. Significant hypoperfusion- induced increases were evident for TET2 in the cerebral cortex (Cx) (p<0.05). These data partially validated the main study hypothesis suggesting hypoperfusion- induced alterations in 5hmC in white matter. However, in contrast to the study hypothesis, the observed hypoperfusion- induced alterations in 5hmC occurred in the absence of changes in 5mC and TET2 in white matter. A subsequent correlation analysis between hydroxymethylation and 5mC, TET2 in the CC failed to show significant associations (p>0.05). In search of the cellular determinants of 5hmC in the CC, hydroxymethylation was examined in relation to some of the cell types in white matter- mature oligodendrocytes, oligodendrolial progenitors (OPC) and microglia both in vivo and in vitro. Specifically, a separate parametric correlation analysis between the proportion of 5hmC positive cells and the respective proportions of mature oligodendrocytes, OPC and microglia in the CC demonstrated that hydroxymethylation correlated significantly only with microglia in vivo (p<0.05). Following this, 5hmC immunochemical distribution was studied in vitro in oligodendroglia cells at different stages of maturation, and interferon γ/ lypopolisaccharide activated and nonactivated microglia. The in vitro analysis demonstrated that 5hmC is high in OPC, activated and nonactivated microglia, but it is low in mature oligodendrocytes. Taken together the in vivo and in vitro cellular analyses suggest that the processes of hydroxymethylation in white matter might be immunoregulated. However, it is possible that in vivo in addition to microglia, other cell types (e.g. astrocytes, OPC) contributed to the presently observed 5hmC upregulation in the hypoperfused CC. Conclusion The experimental work presented in this thesis further developed and characterized a new mouse model of chronic cerebral hypoperfusion by confirming previous behavioural findings (e.g. working memory deficits) and revealing previously undetected spectrum of white and grey matter pathology in this animal model. The thesis demonstrated for the first time by using a newly developed ex vivo MRI procedure that APOE might modulate hypoperfusion- induced white matter pathology in mice. Additional immunochemical analysis revealed important hypoperfusion- induced epigenetic alterations in white (5hmC) and grey (TET2) matter in this animal model. Future experiments on chronically hypoperfused mice would allow to get a better insight into the neurobiological determinants (e.g. white vs. grey matter) underlying the observed cognitive deficits in this animal model, the involved cellular and molecular pathways as well as the functional significance of genetic (APOE) and epigenetic (5hmC, TETs) alterations in the hypoperfused brain. Future experimental work on this animal model would potentially reveal new biological targets for the pre- clinical development of therapies for age- related cognitive decline. Further development and optimization of the newly developed ex vivo MRI procedure would allow its broader application in preclinical settings and would facilitate the translation of experimental findings to clinics.

Background: Chronic kidney disease (CKD) affects approximately 26 million individuals in the United States and is a top priority in the objectives for Healthy People 2020. Despite efforts to improve awareness, discussion of CKD is often minimal or ineffective in the primary care setting. This leads to a lack of patient awareness and knowledge of self-care skills to prevent or slow progression of the disease. A lack of communication of has been attributed to the provider's lack of confidence and knowledge to discuss CKD and to avoid unnecessary stress. Purpose: The purpose of the DNP project is to provide a systematic review of patient-provider communication processes used to influence self-management or behavioral change in primary care and propose a tool to enhance communication and slow progression of CKD. Methods: A systematic review was conducted following the method guidelines of the Cochrane Collaboration. Six electronic databases were searched. Inclusion criteria were adult humans, primary research studies, systematic and literature reviews, focus on communication of self-management or behavioral change strategies, primary outcomes of improving self-management and/or patient outcomes and availability of full-text online or by request. Outcomes: Of the 5765 articles initially identified, 28 studies met inclusion criteria. The studies revealed a lack of evidence directed towards CKD and communication was not directly addressed in a majority of the studies. Interventions most successful in improving patient outcomes were individualized, elicited collaboration or interaction with the patient and provider, were motivational or encouraging and aided in barrier identification and problem solving. A communication tool was developed from the evidence in order to stimulate more meaningful conversation between the patient and provider.

Chronic kidney disease (CKD) is associated with a complex state of immune dysfunction characterised by immune depression, which predisposes CKD patients to infections, and by immune activation resulting in inflammation, which is associated with cardiovascular disease among these patients. It has been suggested that regular moderate exercise may enhance immune function and exert anti-inflammatory effects. However, such effects are still unclear in CKD. Therefore, we investigated the effects of acute and regular (1-month and 6-months) moderate intensity aerobic exercise (walking) on measures of immunity and inflammation in pre-dialysis CKD patients. A single bout of walking exercise induced an overall immune and inflammatory response that was comparable to that observed in healthy individuals, with no indication of harmful effects to patients underlying state of immune dysfunction. Acute exercise induced a normal pattern of mobilisation of immune cells. Concerning immune cell function, acute exercise had no effect on T lymphocyte and monocyte activation, while it actually improved neutrophil responsiveness to a bacterial challenge in the recovery period. In addition, acute exercise induced a systemic anti-inflammatory environment, evidenced by the marked elevation in plasma IL-10 levels after exercise, which was most likely mediated by the observed increase in plasma IL-6 levels. Regular walking exercise exerted anti-inflammatory effects, with no apparent detrimental effects to patients immune and inflammatory status. Regular exercise led to improvements in the systemic inflammatory status (ratio of pro-inflammatory IL-6 to anti-inflammatory IL-10 cytokine levels) that were accompanied, and most likely mediated, by the observed down-regulation of T lymphocyte (only evident at 6-months) and monocyte activation. In addition, a reduction in IL-6 production in PBMC and whole blood cultures was also observed (only assessed at 1-month). Regular exercise had no effect on circulating immune cell numbers and neutrophil degranulation responses. These findings provide compelling evidence that walking exercise is safe from an immune and inflammatory perspective and has the potential to be an effective anti- inflammatory therapy in pre-dialysis CKD patients.

Résumé : Le muscle squelettique étant d’une grande plasticité, il peut être la cible lors de thérapies en réhabilitation motrice. Toutefois, les structures neurales impliquées dans cette plasticité sont encore peu connues. Afin de déterminer si un mécanisme spinal est suffisant pour induire une plasticité musculaire, le nerf innervant le gastrocnémien latéral et le soleus a été sectionné unilatéralement chez 4 chats ayant retrouvé une locomotion au niveau des pattes arrières suite à une spinalisation complète. Des enregistrements électromyographiques et cinématiques ont été enregistrés avant et jusque 8 semaines après dénervation chez ces chats. Des analyses histologiques ont été réalisées pour les deux gastrocnémiens médial et latéral chez les 4 chats spinalisés et chez 4 chats intacts servant de contrôle. Chez les chats spinaux, la durée de cycle pour la patte ispilatérale et controlatérale à la dénervation pouvait être diminuée ou augmentée par rapport aux valeurs de pré-dénervation. Pour la durée de la phase d’appui, elle était généralement augmentée pour la patte controlatérale et diminuée pour la patte ipsilatérale. L’amplitude EMG du MG était augmentée bilatéralement après la dénervation et est restée élevée 8 semaines post dénervation. Concernant le poids des muscles, chez les chats spinaux, le LG ipsilatéral était significativement plus petit que le LG controlatéral alors que le MG ipsilatéral était plus gros que le MG controlatéral. Les analyses histologiques ont montré une plus grande aire pour les fibres de type IIa pour le MG ipsilatéral pour 3 des 4 chats. La densité de capillaires sanguins dans le MG ipsilatéral était aussi plus élevée que dans le MG controlatéral. Pour les chats intacts, aucune différence n’a été observée pour le poids, l’aire des fibres ou la densité capillaire entre les 2 MG. Ces résultats montrent que le muscle squelettique peut s’adapter même après une lésion de la moelle épinière, ce qui souligne l’importance de son utilisation en réhabilitation motrice. / Abstract : Skeletal muscle is highly plastic and can be targeted for motor rehabilitation. Although neural activity potently regulates muscle phenotype, the neural structures required are poorly defined. To determine if a spinal mechanism is sufficient for adaptive muscle plasticity, the nerve supplying the lateral gastrocnemius and soleus muscles was sectioned unilaterally in four cats that had recovered hindlimb locomotion following spinal transection. In these spinal cats, kinematics and electromyography (EMG) were collected before and for 8 weeks after denervation. Muscle histology was performed on the lateral (LG) and medial (MG) gastrocnemii bilaterally in four spinal and four intact cats. In spinal cats, cycle duration for the hindlimb ipsilateral or contralateral to the denervation could be increased or decreased compared to pre-denervation values. Stance duration was generally increased and decreased for the contralateral and ipsilateral hindlimbs, respectively. The EMG amplitude of MG was increased bilaterally following denervation and remained elevated 8 weeks post-denervation. In spinal cats, the ipsilateral LG was significantly smaller than the contralateral LG whereas the ipsilateral MG weighed significantly more than the contralateral MG. Histological characterizations revealed significantly larger fiber areas for Type IIa fibers of the ipsilateral MG in three of four spinal cats. Microvascular density in the ipsilateral MG was significantly higher than the contralateral MG. In intact cats, no differences were found for muscle weight, fiber area or microvascular density between homologous muscles. Results show that skeletal muscle remains remarkably adaptable after complete spinal cord injury, highlighting its importance to maximize force production in motor rehabilitation.

Objectives: Managed care organizations reduce healthcare costs and may improve patient health outcomes by encouraging better control of prevalent chronic diseases. The purpose of this study was to determine whether changing from a fee-for-service program to a capitated managed care program improved medication adherence for Medicaid patients in Kentucky with hypertension, hypercholesterolemia, or type 2 diabetes. Methods: We conducted a quasi-experimental study of patients enrolled in Kentucky Medicaid to evaluate the impact of transitioning to capitated managed care in November 2011. Medication adherence was measured using the proportion of days covered (PDC) method. Multivariable analyses measured the adjusted differences in adherence as a result of the implementation of capitated managed care. Results: Adjusted analyses indicate an average decrease in PDC by about 17-22 days of therapy coverage in the post-policy time period. However, no significant difference in adherence rate changes between the treatment and control populations were observed. Conclusions: Results indicate clinically inconclusive evidence regarding the immediate effect of the implementation of Medicaid managed care in Kentucky on medication adherence rates in patients with prevalent chronic diseases. There is a need to address the decline in average adherence rates, and the efficacy of Medicaid managed care based on medication adherence.

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.