Relative changes are detectable in the blood of end-stage renal disease (ESRD) patients during hemodialysis (HD) treatment using optical spectroscopy. However, the potential impacts of several confounding factors that could affect the detection of these changes have not been evaluated. The objectives of this thesis were to: 1) investigate how the variations and/or changes in acid-base and oxygen parameters during HD treatment can affect the optical signature of whole blood of ESRD patients, 2) to investigate the effect of heparin on the optical properties of whole blood and its impact on our method. Blood samples were drawn from 23 ESRD patients at 5 time points during a 4 hour HD treatment and sent for blood gas and blood spectroscopy analyses. No significant correlations were found between the changes in the blood transmittance spectra and acid-base and oxygen parameters. This indicates that the perturbations in these parameters due to HD procedures do not confound the detection of changes in the blood transmittance spectra of ESRD patients during HD treatment. Additionally, the effect of heparin in modifying the optical properties of whole blood does not confound the detection of changes in the blood of ESRD patients due to HD treatment using whole blood-based optical spectroscopy. ANOVA revealed significant (P<0.05) measurable changes in the blood transmittance spectra of ESRD patients during HD treatment. Significant spectral differences (P<0.05) were found between ESRD patients. The lack of uniform spectral characteristics across patients is

Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide component of the renin angiotensin system and the endogenous ligand for the Mas receptor. Ang-(1-7) is generated mainly via angiotensin converting enzyme 2 (ACE2)-dependent cleavage of Angiotensin (Ang) II. Studies suggest Ang-(1-7) may protect against progression of renal injury in experimental models of chronic kidney disease, although the responses may be dose dependent. The role of Ang-(1-7) in the progression of renal fibrosis in unilateral ureteral obstruction (UUO) remains unclear. We tested the hypothesis that endogenous Ang-(1-7) and low dose exogenous Ang-(1-7) would protect against renal injury in the UUO model, while high dose Ang-(1-7) would exacerbate renal injury. Male C57Bl/6 mice underwent UUO and received vehicle, the Ang-(1-7) antagonist A779, or one of three doses of Ang-(1-7) for 10 days. Treatment with A779 exacerbated renal injury as seen by increased fibronectin, transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) expression, increased tubulointerstitial fibrosis scores, macrophage infiltration, apoptosis, and NADPH oxidase activity in obstructed kidneys. Paradoxically, delivery of exogenous Ang-(1-7) was associated with increased renal injury regardless of dose. Taken together, these data indicate the Mas receptor may be sensitive to concentrations of Ang-(1-7) within the obstructed kidney and that exogenous Ang-(1-7) stimulates pro-fibrotic and pro-inflammatory signalling through unclear pathways.

Cyclooxygenases (COXs) and their main renal product, prostaglandin E2 (PGE2), regulate many physiological renal functions and are involved in the pathogenesis of diabetic kidney disease. The PGE2 receptor EP3 has been repeatedly shown to be upregulated during diabetes. Physiologically, EP3 is best recognized to act as a diuretic by antagonizing arginine-vasopressin (AVP)-mediated water reabsorption. Incidentally, the first renal manifestation of diabetes is polyuria, which may trigger a cascade of events leading to DN. We hypothesize that EP3 contributes to polyuria and kidney dysfunction during diabetes. We injected EP3-/- mice with streptozotocin (STZ) and evaluated their renal function 12-weeks post injection. EP3-/- STZ mice exhibit attenuated polyuria while exhibiting increased urine osmolality suggesting enhanced water reabsorption. Western blots reveal that EP3-/- STZ mice have increased expression of aquaporin-1 and aquaporin-2 as well as reduced urinary AVP excretion compared to STZ mice. However, salt transporters were equivalently increased in STZ and EP3-/- STZ mice. In vitro microperfusion shows that EP3 completely abrogates AVP-mediated water reabsorption in STZ cortical collecting ducts. Furthermore, EP3-/- STZ mice showed blunted renal COX-2 expression as well as reduced renal hypertrophy, glomerular hyperfiltration, and albuminuria. Taken together, the data suggests that EP3 contributes to polyuria during diabetes by inhibiting expression of aquaporins. Additionally, EP3 seems to contribute to renal COX-2 induction during diabetes. The lack of an increase in renal COX-2 protein levels in EP3-/- STZ mice may be protective by preventing further renal damage.

Atherosclerotic renovascular disease (ARVD) is a significant cause of chronic kidney disease (CKD) and is associated with an increased risk for cardiovascular morbidity and mortality. Randomised controlled trials, representing over 2100 patients, have failed to demonstrate any prognostic benefit of percutaneous renal revascularisation when utilised in addition to standard medical therapy. This negative finding has been interpreted in three ways. Firstly, that ARVD may be an association of CKD and not a specific disease process. Secondly, that published studies have recruited low-risk patients who are least likely to benefit from revascularisation. Thirdly, that the focus of treatment for patients with ARVD should be optimal medical therapy, not renal revascularisation. This research project had a series of linked aims. These were investigated in two large patient cohorts that had been accumulated at this centre over the last decade. These cohorts comprised > 900 patients with ARVD, the Salford Renovascular Database (SRVD), and > 2500 patients with all-cause CKD, the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). The first aim was to consider whether ARVD should be considered as a specific cause of CKD. Here risks for death and progression to renal replacement therapy were compared between patients having ARVD as their primary cause of renal failure and patients with other coded causes of CKD. In this analysis, patients with ARVD had a greater risk for death and a lesser risk for RRT than patients with other forms of CKD.The second aim of this thesis was to consider if specific patient sub-groups of ARVD could be identified. Patients in the SRVD with currently accepted high- risk clinical presentations were selected and outcomes compared to patients without a high-risk presentation. In this analysis, presentation with flash pulmonary oedema (but with not refractory hypertension or rapidly declining renal function) was associated with an increased risk for death and cardiovascular event. When the effects of revascularisation were considered in patients with high-risk presentations, a mortality benefit was observed in patients with flash pulmonary oedema and in patients presenting with rapidly declining renal function and refractory hypertension in combination. A separate analysis was performed in the SRVD to consider if a high-risk sub-group of ARVD patients could be identified using laboratory measurements. Here, a classification tree methodology was employed to identify ARVD patients with the greatest risk for progression to end stage kidney disease. The results of this analysis were converted into a practically applicable clinical scoring system incorporating renal function, proteinuria, medications, smoking history and renal artery occlusion. The final aim of this thesis was to describe how the majority of ARVD patients should be treated. In this analysis of the SRVD effects of treatment with anti- platelet and beta-blocker therapy were considered, and shown to be associated with reduced risks for cardiovascular events and death.

Chronic kidney disease (CKD), a reduction in kidney function, has reached pandemic proportions and imposes a major healthcare burden worldwide. A hallmark of CKD is the accumulation of several chemical compounds, called uremic toxins, which inflict systemic and renal-specific damage. Of the known uremic toxins, kynurenine (Kyn) is known to be particularly vasculotoxic and is implicated in several complications of CKD. Indoleamine 2,3-dioxygenase 1 (IDO), which catalyzes the first step in the metabolism of Tryptophan (Trp), regulates immune response to inflammatory cytokines in tissues. IDO plays a role in apoptosis and damage during acute kidney injury (AKI), a transient decrease in kidney function. During metabolism of Trp, IDO generates Kyn, a uremic solute, and therefore IDO may play a role in the brain and kidney damage due to accumulation of Kyn. The objective of the current study was to investigate the role and regulation of IDO in CKD pathology. Studies were performed to determine whether IDO is protective or pathologic and to find how IDO is regulated in the kidney during CKD. IDO in renopathology was examined using murine models of CKD. CKD was induced via a 0.2% adenine-supplemented diet (AD) model for 21 days. IDO regulation was examined using an Indoxyl Sulfate (IS)-specific solute model. Renal function in the IDO+/+ and IDO-/- AD mice was assessed through weekly measurement of blood urea nitrogen (BUN). H&E and Masson’s trichrome stains were used to assess percentages of glomerulosclerosis (GS) and immune infiltration (II), and combined interstitial fibrosis and tubular atrophy (IFTA) score in IDO+/+ and IDO-/- mice with and without CKD. IDO protein concentration in the kidneys of all mice with and without CKD and IDO+/+ IS mice was determined via immunoblotting. Patients with kidney disease suffer from neuropsychological disorders and neurocognitive decline. The effects of uremic solutes on the CNS was examined using immortalized human umbilical endothelial vein cells (HUVEC-TERT), in vitro. Cell proliferation and viability, in the presence of IS, were measured by BrdU and Alamar blue assays, respectively. In both IDO+/+ and IDO-/-, 21 days of AD results in significant deterioration of renal function. The average IFTA score and percentage of II in IDO-/- mice increased with AD compared to ND (p<0.05, p<0.001). IDO expression was seen sporadically in the glomeruli and walls of major vessels in the kidneys of 4d AD IDO+/+ mice, and in the tubules and vessel walls in the kidneys of 14d AD IDO+/+ mice. In IDO+/+ ND mice, endogenous IDO protein expression was undetectable at a signal intensity of 119.86 ± 268.01, whereas IDO+/+ AD mice showed a 370-fold higher level of IDO protein expression compared to IDO+/+ ND (p<0.001). IDO-/- AD IDO protein expression was 9.5-fold higher than in IDO-/- AD (p<0.05). IDO expression was found to be 58-fold higher in IDO+/+ mice with IS treatment (p<0.05). In the IS mice, non-significant trends toward decrease in cellular proliferation and viability with time were also observed (p=ns). IDO is upregulated at the protein level both in a CKD model and directly by the uremic solute, IS. IDO appears to be protective in the kidney during CKD, given the trend toward increased percentage of GS and II in IDO-/- compared to IDO+/+ mice with CKD, though there is little difference seen in total kidney IFTA. IDO upregulation is linked to increased apoptosis. Blocking uremic solute production would therefore prevent IDO protein upregulation and reduce apoptosis, alleviating renal damage during CKD.

A doença renal crônica (DRC) tem sido considerada um problema de saúde pública mundial. Estima-se que cerca de 17% da população adulta dos EUA apresente algum grau de comprometimento da função renal. No Brasil, um estudo realizado na cidade de Bambuí - Minas Gerais detectou-se alteração da função renal variando de 0,48% a 8,19%, sendo mais frequente nos pacientes idosos. Os pacientes que evoluem para DRC terminal necessitam de algum tipo de terapia renal substitutiva (TRS), sendo as opções disponíveis: a hemodiálise (HD), a diálise peritoneal (DP) e o transplante renal (TX renal). No caso da DP, a membrana peritoneal realiza a função de filtrar o sangue do paciente, e esta é utilizada através da implantação de um cateter na cavidade abdominal. No Brasil, segundo dados do Censo Brasileiro de Diálise (2016) existem aproximadamente 122.825 pacientes em diálise, sendo 8,6% em DP. O objetivo do estudo foi analisar a evolução dos pacientes que foram admitidos na Unidade de Diálise do HCFMRP para submeterem-se à DP nos últimos 22 anos. Os dados foram coletados dos prontuários dos pacientes atendidos no período de 1993 a 2015, de onde foram extraídas variáveis demográficas, clínicas e laboratoriais. É um estudo de coorte retrospectiva de 199 prontuários de pacientes atendidos na Unidade de Diálise do HCFMRP-USP. Os resultados demonstram que a população do estudo é em sua maioria do sexo feminino, com média de idade 57 anos. Foi encontrada a mudança de TRS para a hemodiálise como desfecho clínico mais frequente, seguida por óbito. A etiologia da DRC mais frequente foi a hipertensão arterial sistêmica (HAS), seguida por Diabetes mellitus (DM) tipo 2. Houve associação com menor média de idade de entrada em programa (48 anos), desfecho clínico óbito e maior tempo de seguimento (10 anos) com o grupo de pacientes que entraram em programa de diálise em 1993 (p<0,05). Encontramos associação do uso de medicamentos (Cloridrato de Sevelamer e Análogos da vitamina D3 com níveis categorizados de paratormônio, cálcio total e fósforo (p<0,05). CONCLUSÃO: Os pacientes que entraram em programa no período de 1993-2000 apresentaram menor média de idade e maior tempo de acompanhamento quando comparados aos demais grupos. O desfecho clínico mais frequente foi a transferência para HD, tendo como causa principal a ocorrência de peritonites. / INTRODUCTION: Chronic kidney disease (CKD) has been considered a worldwide public health problem, as well as the progressive increase of the population in renal replacement therapy (TRS). With the technological advances accumulated, the survival of patients on dialysis has increased greatly. Peritoneal dialysis (PD) is considered a safe and effective method of SRT, a challenge for the binomial patienthealth team. OBJECTIVES: To analyze the main characteristics and outcomes of patients in a PD program. METHODS: This was a retrospective cohort study of 199 patients submitted to PD in the Dialysis Unit of the HCFMRP-USP from 1993 to 2015. The primary source of data was the individual medical records. The variables were classified as: demographic, clinical and laboratorial. Statistical analyzes were performed using the Chi-square test, ANOVA and Kruskal Wallis. RESULTS: The mean age of the patients was 57 years, with a predominance of females (51.5%); the most frequent clinical outcome was the change in HRT for hemodialysis (37.2%). Type 2 diabetes mellitus (DM) was the most common cause of CKD (31,7). There was an association between lower mean age of program entry, clinical outcome and longer follow-up (10 years) in the group of patients who entered the dialysis program in the period from 1993 to 2000 (p <0.05). There was an association between the use of medications (Sevelamer\'s Hydrochloride and vitamin D3 analogues) with categorized values of parathormone, total calcium and phosphorus (p <0.05). CONCLUSION: Patients who entered the program in 1993-2000 had a lower mean age and longer follow - up when compared to the other groups. The most frequent clinical outcome was the transfer to HD, the main cause being the occurrence of peritonitis.

ABSTRACT: Hepatitis C virus (HCV) is associated with various glomerulopathies and nephrotic syndrome. However nephrotic syndrome following treatment is rare. Ledipasvir/sofosbuvir (L/S) has recently come into favor in treating HCV due to its relatively mild side effects compared to the more traditional interferon therapy. To the best of our knowledge, there are no reported cases of nephrotic syndrome following treatment with L/S. We present a case of nephrotic syndrome suspected secondary to L/S in a patient with chronic kidney disease. Increased vigilance when assessing therapeutic options in HCV patients with renal comorbidities can improve patient outcomes. A 63 year-old male patient presented to the hospital with shortness of breath, and a two-week history of bilateral lower extremity edema. Past medical history was significant for liver cirrhosis secondary to Hepatitis C genotype Ia, hepatocellular carcinoma status post liver transplantation 6 months prior to admission and Stage 3b chronic kidney disease with baseline creatinine (Cr) approximately 1.5 mg/dl. Medications included L/S for HCV and tacrolimus and prednisone for post-transplant treatment. Patient’s vitals were stable and physical exam was remarkable for facial swelling, mainly on the eyelids, decreased breath sounds bilaterally, distended abdomen with a fluid wave, and 2-3+ pitting edema up to the knees on lower extremities bilaterally. Laboratory work-up was remarkable for low albumin of 3.0 g/dl, and total protein of 5.6 g/ dl. Creatinine of 1.8 mg/dl was elevated from patient’s baseline. HCV viral load was undetectable and electrolytes, transaminases and the complete blood count were within normal limits. Subsequently, urine protein to creatinine ratio was measured because of generalized swelling and hypoproteinemia, which was found to be significantly high at 8.80, compared to 0.04 one year prior. 24-hour total urine protein was found to be 2065 mg/day. Renal ultrasonography showed no hydronephrosis and was otherwise unremarkable. Renal biopsy however, revealed changes suggestive of membranoproliferative glomerulonephritis (MPGN] most likely secondary to HCV. No immune complexes, lambda/kappa light chains, or cryogloblin were appreciated. Nephrotoxic agents such as diuretics and corticosteroids were held. Tacrolimus trough was appropriate to dose level and was continued along with L/S. As admission progressed the patient’s creatinine continued to get worse and rose up to 4.3 mg/dl with persistent proteinuria. With tacrolimus trough levels within normal limits and given L/S was the most recently initiated drug, L/S was thought to be the culprit and was thus held. The renal function began to improve gradually, and the patient was discharged in stable condition with close follow up. Follow up one month later found creatinine and renal function return to baseline and proteinuria resolved. Our case shows that Ledipasvir/sofosbuvir may possibly be related to nephrotic syndrome in HCV patients. Although further studies are needed to prove the causality our case seeks to raise clinical suspicion and increase vigilance when assessing therapeutic options in HCV patients with renal comorbidities such as chronic kidney disease.

BACKGROUND Vascular calcification is a major risk factor for cardiovascular morbidity and mortality in patients with end stage renal disease (ESRD). In Western countries, Blacks with ESRD appear to have lesser degrees of vascular calcification compared to non-Blacks. However, there is no published data on the association of ethnic differences in vascular calcification and survival in ESRD from Sub-Saharan Africa. METHODS This study assessed the 5-year change in vascular calcification and mortality in a previously published cohort of patients with ESRD. Vascular calcification was assessed by abdominal aortic calcification score (lateral abdominal radiograph) and vascular stiffness by pulse wave velocity. RESULTS Sixty-six of the original 74 participants, studied a baseline, were identified. The median age was 46.6 years (37.6-59.2) and 57.6% were women. Abdominal aortic calcification showed no progression among Blacks [baseline range 0-5, follow up range 0-8 (p=1.00)], but a nonsignificant trend to progression among non-Blacks [baseline range 0-19, follow up range 0-22 (p=0.066)]. Black participants did not display a survival advantage (p=0.870). Overall, sepsis was the most common cause of mortality (64% of those with an identifiable cause of death). Non-Blacks had higher parathyroidectomy rates than Blacks with 9/30 cases compared to 2/36 (p=0.036). After adjustment for parathyroidectomy at follow up, the odds ratio of having abdominal vascular calcification score of ≥1 amongst non-Blacks was 8.6-fold greater compared to Blacks (p= 0.03). Central aortic systolic pressures (CASP) and pulse wave velocities (PWV) were higher in the study population than age matched normative values. At follow up, a positive correlation (r=0.3) was observed between PWV and abdominal aortic calcification (p=0.04). Elevated baseline coronary artery calcification score and FGF-23 level at baseline were not associated with a difference in mortality. CONCLUSION There was no significant progression in vascular calcification among Blacks. After adjusting for increased parathyroidectomy rates, there was a greater progression of vascular calcification amongst non-Blacks compared to Blacks highlighting possible ethnic differences in calcium phosphate metabolism in patients with ESRD. The lack of vascular calcification progression in Blacks was not however associated with improved survival, but the sample size was small.

There is an epidemic of chronic kidney disease of unknown origin (CKDu) primarily affecting younger men in Central America, especially El Salvador and Nicaragua. The primary hypothesis has included heat stress and dehydration. Although medication usage is widely viewed as a likely contributor to kidney damage, the association with chronic kidney disease in Central America has not been fully explored. This study investigated medication usage, symptom presentation, and kidney function among 524 outdoor workers in agricultural and non-agricultural industries enrolled in the Mesoamerican Nephropathy Occupational Study (MANOS) led by Boston University researchers. An overview of the literature on the adverse effects of medication on renal function and thermoregulation, with a focus on medications considered in MANOS, was conducted. Medication usage and symptom presentation on both a short- and long-term timeframe were explored in relation to kidney function measured by estimated glomerular filtration rate. Long-term usage of NSAIDS and potassium supplements was significantly associated with kidney function. Neither short- or long-term uses of acetaminophen, the most commonly used medication, were associated with kidney function. While several self-reported health symptoms were significantly associated with lower kidney function in crude models, the associations’ significance levels lessened after adjusting for age, country, and industry. In contrast, symptoms of chistata (a local term for painful urination) and lower abdominal pain three months prior to data collection each significantly predicted higher kidney function. The results of this exploratory, cross-sectional study present an opportunity for further study on how medications and symptoms, related to both nephrotoxicity and heat stress, could be associated with kidney function.

Orientador: Amanda Martins Baviera / Resumo: No Brasil, o número de indivíduos com doença renal crônica (DRC) em terapia dialítica no ano de 2017 foi de aproximadamente 127 mil indivíduos; dentre estes, 92% realizavam hemodiálise (HD). A HD tem como principal objetivo a remoção dos solutos urêmicos e assim a redução dos sintomas relacionados à síndrome urêmica, melhorando a qualidade de vida do indivíduo com DRC. No entanto, aumentam as evidências de que a HD seja um fator exacerbante do estresse oxidativo, via aumento na produção de espécies reativas de oxigênio devido à ativação de leucócitos estimulada pela diálise ou pelo tipo de membrana utilizada, bem como via remoção dialítica de compostos antioxidantes solúveis em água e de baixo peso molecular. No entanto, a literatura reporta resultados contraditórios em relação às alterações em biomarcadores de lesão oxidativa e atividade antioxidante em indivíduos submetidos à HD. O objetivo deste trabalho foi avaliar as alterações na capacidade antioxidante total, nas atividades de enzimas antioxidantes e nos níveis de biomarcadores de danos oxidativos no soro de indivíduos saudáveis e de indivíduos com DRC, antes (pré-HD) e após (pós-HD) uma sessão de HD. Foram selecionados 40 indivíduos saudáveis, sem DRC ou qualquer outra patologia, doadores de sangue do Hemonúcleo Regional de Araraquara para compor o grupo controle, e 40 indivíduos com DRC que realizam HD no Centro Regional de Hemodiálise de Araraquara. Amostras de soro foram utilizadas para determinação dos marcadores ... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre