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Outre les facteurs métaboliques et hémodynamiques, l’inflammation est actuellement considérée comme un facteur pathogénique potentiel de la néphropathie diabétique (ND), pouvant contribuer à l’initiation et à la progression de la maladie. Les mécanismes menant au développement de l’inflammation rénale dans la ND sont encore peu connus, bien qu’une augmentation d’activité des systèmes rénine angiotensine (RAS) et de l’endothéline (ET) semble y contribuer. L’objectif général de cette étude mono-centre, à double aveugle, randomisée et incluant un groupe placebo était de démontrer que l’inhibition simultanée du RAS et du système de l’ET chez des patients avec ND induisait des effets rénoprotecteurs et anti-inflammatoires supérieurs à ceux observés par blocage du RAS seul. L’objectif spécifique de notre étude était d’évaluer la possibilité que l’administration d’un bloqueur des récepteurs de l’ET-1, le bosentan, à des patients atteints de ND et traités par bloqueurs des récepteurs de l’angiotensine II (BRA), réduisait, chez ces derniers, la protéinurie et les marqueurs inflammatoires systémiques et rénaux. Ce travail constitue un rapport d’un cas clinique et illustre les résultats obtenus suite à l’administration pendant 16 semaines du bosentan chez un patient diabétique de type 2 avec néphropathie clinique traité au long cours par BRA. Le protocole de recherche comprenait 6 visites médicales à 4 semaines d’intervalle, la première visite (V1) correspondant au recrutement du patient, la deuxième visite (V2) constituant le temps 0 de l’étude et la dernière visite (V6) représentant la fin de l’étude. Des échantillons de sang et d’urine étaient prélevés à 3 reprises soit à V2, V4 c’est-à-dire 8 semaines après le début du traitement et à V6 soit 16 semaines après le début du traitement pour mesure des taux sériques et urinaires de divers facteurs pro-inflammatoires incluant l’ET-1, le facteur de nécrose tumorale alpha (TNF-α), l’interleukine-6 (IL-6), le facteur chémoattractant des monocytes-1 (MCP-1), la molécule d’adhésion intracellulaire-1 (ICAM-1), la molécule d’adhésion vasculaire-1 (VCAM-1) et la protéine C-réactive (CRP). Un profil lipidique était aussi déterminé au début et à la fin de l’étude. La fonction rénale était mesurée aux visites V1, V2, V4 et V6 par détermination du taux de filtration glomérulaire (TFG) et de l’excrétion urinaire d’albumine (UAE). Des tests biochimiques de routine étaient aussi faits à chaque visite. La corrélation entre les paramètres inflammatoires et rénaux sous étude et la filtration glomérulaire était enfin déterminée. Nos résultats chez ce sujet ont démontré que le bosentan réduisait l’UAE de 32 % et 35% aux semaines 8 et 16, et ce, sans affecter la pression artérielle ou la filtration glomérulaire. L'effet anti-protéinurique du bosentan était associé à une réduction des concentrations urinaires de VCAM-1, ICAM-1, IL-6, TNF-α et d’ET-1 ainsi qu’à une diminution des concentrations sériques de TNF-α. Le changement dans la protéinurie était corrélé de manière positive avec les changements des niveaux urinaires de VCAM-1 (r=0.86), ICAM-1 (r=0.88), ET-1 (r=0.94), et du TNF-α (r=0.96) ainsi qu’avec les changements des niveaux sériques de TNF-α (r=0.98). Ces données suggèrent que l’inhibition du système de l’ET induit dans la ND des effets rénoprotecteurs additifs à ceux observés par blocage du RAS seul. Ils supportent le concept que l’activation du système de l’ET au niveau rénal, par ses effets inflammatoires, puisse jouer un rôle important dans la pathogenèse de la ND. L’effet anti-inflammatoire et anti-protéinurique du bosentan constitue une découverte intéressante susceptible d’engendrer dans le futur une alternative thérapeutique et préventive dans la prise en charge de la ND. / Apart from metabolic and hemodynamic factors, inflammation has recently been introduced as a potential key pathogenic mechanism involved in the development and progression of diabetic nephropathy (DN). The mechanisms by which renal inflammation occurs in DN are still poorly understood, yet increased renal activity of the renin-angiotensin system (RAS) and endothelin (ET) system may play a key role. The main objective of this mono-centre, double blind, randomized, placebo-controlled study was to demonstrate that concomitant blockade of the RAS and ET system in patients with DN produces greater renal protective effects and exerts greater anti-inflammatory changes than those seen with blockade of the RAS system alone. The specific aim of the study was to evaluate whether administration of bosentan to patients with DN on angiotensin II receptor blockers (ARB) reduces systemic and renal inflammation and improves glomerular filtration. The work presented herein illustrates the results obtained in one type 2 diabetic patient with clinical DN and treated with ARB following the administration of bosentan for 16 weeks. The study protocol included 6 medical visits at 4 weeks interval, with the first visit (V1) being the screening visit and the second visit (V2) being the baseline and randomization visit. Blood and urine samples were taken at V2, after 8 weeks of treatment (V4), and at the end of the study (V6) for determination of serum and urinary inflammatory markers including ET-1, tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and C-reactive protein (CRP). Lipid profile was done at the beginning and end of the study. Renal function was assessed at V1, V2, V4 and V6 by determination of glomerular filtration rate and urinary albumin excretion (UAE). Routine biochemical analyses were done at each visit. Correlation between serum and urinary inflammatory markers and UAE was determined. Our results demonstrated that bosentan administration to this patient reduced UAE by 32% and 35% at weeks 8 and 16, respectively, without affecting blood pressure and glomerular filtration. The anti-proteinuric effect of bosentan was associated with a reduction in urinary levels of VCAM-1, ICAM-1, IL-6, TNF- and ET-1 and a reduction in serum TNF- levels. Change in UAE was positively correlated with changes in urinary levels of VCAM-1 (r=0.86), ICAM-1 (r=0.88), ET-1 (r=0.94), and TNF- (r=0.96) and with change in serum TNF- levels (r=0.98). Our data suggest that blockade of the ET system in top of RAS inhibition exerts additive renoprotective effects in DN. They support the notion that activation of the ET system, by promoting renal inflammation, may play a role in the pathogenesis of DN. The anti-inflammatory and anti-proteinuric effect of bosentan represents an interesting finding which may leads in the future to an alternate therapeutic and preventive for the treatment of DN.

The main focus of our research was to compare changes in ion excretion in urine, osmolality, indicators of exercise-induced proteinuria and tubular markers before and after dynamic exercise on a bicycle ergometer. The test sample consisted of 7 healthy, physically active women aged 27.4 years ( σ = 3.82 ). For dynamic exercise we uniformly set parameters 65 % VO2max and duration of load in 50 minutes. We compared the laboratory results of urine samples taken just before the exercise with urinary samples that we have collected immediately after exercise. The results of our measurements showed a significant changes in exercise-induced urinary sodium ions, creatinine and phosphorus. Statistically insignificant changes excretion was found between markers: chlorine, urine, osmolality, and N-acetyl-beta- d-glucosaminidase. These markers, however, show a trend the significance. Statistically insignificant changes after exercise have shown excretion of urinary markers: potassium, gelatinase-associated lipocalin, neutrophil microalbuminuria and alpha-1-microglobulin. Tubular markers of kidney damage after exercise is not at the reference values, that would indicate the tubular kidney damage.

Síndrome nefrótica é definida pela presença simultânea de edema sistêmico, hipoalbuminemia e proteinúria intensa. Vários componentes da composição corporal, principalmente relacionados à água corporal, sofrem rápidas e frequentes alterações nessa síndrome. A espectroscopia por bioimpedância (BIS) é um método de fácil execução, baixo custo, que pode ser repetido e praticamente isento de riscos que permite avaliar água corporal, massa magra e gordura corporal e tem sido pouco utilizado na síndrome nefrótica. Objetivo. Avaliar as alterações da água e de outros componentes da composição corporal através da BIS em pacientes com síndrome nefrótica. Métodos. Pacientes foram avaliados na ocasião da biópsia renal e no desfecho com ou sem remissão do edema. Foram medidos o peso corporal, albumina sérica e proteinúria de 24 h e, pela BIS, variáveis relacionadas à água corporal e a outros parâmetros de composição corporal. Resultados. Foram estudados 17 pacientes (idade: 51,1 + 17,4 anos) com síndrome nefrótica. Dez pacientes obtiveram remissão do edema (grupo R), sendo que em nove ocorreu também remissão da síndrome nefrótica. Em sete pacientes o edema permaneceu presente, sem remissão (grupo SR). A variação entre a primeira e a segunda medida para a sobrecarga hídrica foi de -5,4 L (-8,5 L; -1,8 L) no grupo R e de 0,0 L (-1,1 L; 1,2 L) no grupo SR (p < 0,05). A água corporal total variou de -4,75 L (- 10,20 L; -2,50 L) e de 4,80 L (-1,30 L; 6,10 L) nos grupos R e SR, respectivamente (p < 0,05), e a água extracelular variou de -5,90 L (-10,10 L; -0,42 L) e de 1,20 L (-0,80 L; 2,70 L) nos mesmos grupos (p < 0,05). Não houve diferença estatisticamente significante na variação entre as duas avaliações nos grupos R e SR para a água intracelular, massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. A variação do ângulo de fase entre as avaliações foi de 1,55° (0,41°; 2,24°) no grupo R e 0,10° (-0,28°; 0,46°) no grupo SR (p < 0,05). Houve correlação estatisticamente significante entre cada variável definidora da síndrome nefrótica (peso corporal, proteinúria e albumina sérica) versus sobrecarga hídrica, água corporal total, água extracelular e ângulo de fase, mas não versus as demais medidas de composição corporal obtidas pela BIS. Conclusão. A espectroscopia por bioimpedância mostrou-se eficiente em detectar mudanças da água corporal e do ângulo de fase em pacientes com síndrome nefrótica, mas não para identificar variações relacionadas à massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. . / Nephrotic syndrome is established by the simultaneous presence of systemic edema, hypoalbuminemia, and severe proteinuria. Several components of the body composition, mainly related to the body fluid, undergo to rapid and frequent changes in this syndrome. Spectroscopy by bioimpedance (BIS) is a reliable, cost-effective and easy-to-perform method to evaluate body water, adipose tissue mass, and body cell mass. Despite these advantages, BIS has barely been used to evaluate patients with nephrotic syndrome. Aims. To evaluate body fluid variable changes and other components of the body composition in patients with nephrotic syndrome by bioimpedance spectroscopy. Methods. Patients were studied in two moments: at the occasion of the renal biopsy (1st evaluation), and at the end-point (2nd evaluation). Patients were grouped according to they reached remission (Group R) or remained without remission (Group WR) of the edema at the 2nd evaluation. Body weight, serum albumin and 24 hours proteinuria were measured at the two time-points, as well as other variables associated with body fluid and other components of the body composition obtained by the BIS. Results. Seventeen patients (age: 51,1 + 17,4 years-old) with nephrotic syndrome were studied. Ten patients reached remission of the edema while nine of them were also in remission of the nephrotic syndrome. Seven patients remained with edema at the end-point. The variation between the 1st and the 2nd measurement for the overhydration was of -5,4 L (-8,5L; -1,8L) at the group R and of 0,0 (-1,1 L; 1,2 L) at the group NR (p < 0,05). Total body water changes were of -4,75 L (-10,20 L; -2,50 L) and of 4,80 L (-1,30 L; 6,10 L) at the groups R and WR, respectively (p < 0,05), and the extracellular water changed of the -5,90 L (-10,10 L; -0,42 L) and of 1,20 L (-0,80 L; 2,70 L) at the same groups, respectively (p < 0,05). There was no statistically significant difference in the variation between the two evaluations for the groups R and NR for intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass. The variation of the phase angle between the two evaluations was of the 1,55° (0,41°; 2,24°) at the group R and 0,10° (-0,28°; 0,46°) at the group WR (p < 0,05). There was a statistically significant correlation between each related nephrotic syndrome variable compared with overhydration, total body water, extracellular water, and phase angle, but no difference when compared with the other variables related to the body composition measured by the BIS. Conclusion. The spectroscopy by bioimpedance was efficient to measure body water changes and the phase angle in patients with nephrotic syndrome. However, the BIS could not detect changes related to the intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass.

A sobrecarga de proteínas nas células tubulares proximais pode levar a lesão intersticial por mecanismos não claros que podem envolver a ativação da imunidade inata. Nós investigamos a hipótese de que a exposição prolongada de células tubulares a altas concentrações de proteínas estimula a imunidade inata, desencadeando inflamação intersticial progressiva e lesão renal. Além disso, investigamos se a inibição específica da imunidade inata ou adaptativa proporcionaria renoproteção em um modelo estabelecido de proteinúria maciça, nefropatia por adriamicina (ADR). Os ratos adultos Munich-Wistar receberam uma dose única de ADR (5 mg / kg iv), sendo acompanhados por 2, 4 e 20 semanas. A albuminúria maciça foi associada à ativação precoce das vias da imunidade inata NF-?B e NLRP3, cuja intensidade correlacionou-se fortemente com a densidade da infiltração de linfócitos. Além disso, os ratos ADR exibiram sinais claros de estresse oxidativo renal. Vinte semanas após a administração de ADR, observaram-se fibrose intersticial intensa, glomerulosclerose e perda da função renal. A administração de micofenolato de mofetil (MMF), 10 mg / Kg / dia, impediu a ativação da imunidade inata e adaptativa, bem como do estresse oxidativo renal e fibrose renal. Além disso, o tratamento MMF foi associado com a mudança de MØ do tipo M1 para o fenótipo M2. Nas células cultivadas de NRK52-E, o excesso de albumina aumentou o teor de proteína de TLR4, NLRP3, Caspase-1, IL6, IL1-beta, MCP-1, alfa-SMA e COLL-1. O silenciamento do TLR4 e / ou NLRP3 mRNA atenuou esse comportamento proinflamatório / profibrótico. A ativação simultânea de imunidade inata e adaptativa podem ser fundamentais para o desenvolvimento de lesão renal em doenças altamente proteinúricas. A inibição da imunidade inata e/ou adaptativa podem constituir uma estratégia para prevenir a DRC nesse contexto / Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated the hypothesis that prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury. In addition, we investigated whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin (ADR) nephropathy. Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg iv), being followed for 2, 4 or 20 weeks. Massive albuminuria was associated with early activation of both the NF-kB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/Kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M0 from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of TLR4, NLRP3, Caspase-1, IL6, IL- 1beta, MCP-1, alpha-actin and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavily proteinuric disease. Inhibition of innate and/or adaptive immunity may constitute a strategy to prevent CKD in this setting

Síndrome nefrótica é definida pela presença simultânea de edema sistêmico, hipoalbuminemia e proteinúria intensa. Vários componentes da composição corporal, principalmente relacionados à água corporal, sofrem rápidas e frequentes alterações nessa síndrome. A espectroscopia por bioimpedância (BIS) é um método de fácil execução, baixo custo, que pode ser repetido e praticamente isento de riscos que permite avaliar água corporal, massa magra e gordura corporal e tem sido pouco utilizado na síndrome nefrótica. Objetivo. Avaliar as alterações da água e de outros componentes da composição corporal através da BIS em pacientes com síndrome nefrótica. Métodos. Pacientes foram avaliados na ocasião da biópsia renal e no desfecho com ou sem remissão do edema. Foram medidos o peso corporal, albumina sérica e proteinúria de 24 h e, pela BIS, variáveis relacionadas à água corporal e a outros parâmetros de composição corporal. Resultados. Foram estudados 17 pacientes (idade: 51,1 + 17,4 anos) com síndrome nefrótica. Dez pacientes obtiveram remissão do edema (grupo R), sendo que em nove ocorreu também remissão da síndrome nefrótica. Em sete pacientes o edema permaneceu presente, sem remissão (grupo SR). A variação entre a primeira e a segunda medida para a sobrecarga hídrica foi de -5,4 L (-8,5 L; -1,8 L) no grupo R e de 0,0 L (-1,1 L; 1,2 L) no grupo SR (p < 0,05). A água corporal total variou de -4,75 L (- 10,20 L; -2,50 L) e de 4,80 L (-1,30 L; 6,10 L) nos grupos R e SR, respectivamente (p < 0,05), e a água extracelular variou de -5,90 L (-10,10 L; -0,42 L) e de 1,20 L (-0,80 L; 2,70 L) nos mesmos grupos (p < 0,05). Não houve diferença estatisticamente significante na variação entre as duas avaliações nos grupos R e SR para a água intracelular, massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. A variação do ângulo de fase entre as avaliações foi de 1,55° (0,41°; 2,24°) no grupo R e 0,10° (-0,28°; 0,46°) no grupo SR (p < 0,05). Houve correlação estatisticamente significante entre cada variável definidora da síndrome nefrótica (peso corporal, proteinúria e albumina sérica) versus sobrecarga hídrica, água corporal total, água extracelular e ângulo de fase, mas não versus as demais medidas de composição corporal obtidas pela BIS. Conclusão. A espectroscopia por bioimpedância mostrou-se eficiente em detectar mudanças da água corporal e do ângulo de fase em pacientes com síndrome nefrótica, mas não para identificar variações relacionadas à massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. . / Nephrotic syndrome is established by the simultaneous presence of systemic edema, hypoalbuminemia, and severe proteinuria. Several components of the body composition, mainly related to the body fluid, undergo to rapid and frequent changes in this syndrome. Spectroscopy by bioimpedance (BIS) is a reliable, cost-effective and easy-to-perform method to evaluate body water, adipose tissue mass, and body cell mass. Despite these advantages, BIS has barely been used to evaluate patients with nephrotic syndrome. Aims. To evaluate body fluid variable changes and other components of the body composition in patients with nephrotic syndrome by bioimpedance spectroscopy. Methods. Patients were studied in two moments: at the occasion of the renal biopsy (1st evaluation), and at the end-point (2nd evaluation). Patients were grouped according to they reached remission (Group R) or remained without remission (Group WR) of the edema at the 2nd evaluation. Body weight, serum albumin and 24 hours proteinuria were measured at the two time-points, as well as other variables associated with body fluid and other components of the body composition obtained by the BIS. Results. Seventeen patients (age: 51,1 + 17,4 years-old) with nephrotic syndrome were studied. Ten patients reached remission of the edema while nine of them were also in remission of the nephrotic syndrome. Seven patients remained with edema at the end-point. The variation between the 1st and the 2nd measurement for the overhydration was of -5,4 L (-8,5L; -1,8L) at the group R and of 0,0 (-1,1 L; 1,2 L) at the group NR (p < 0,05). Total body water changes were of -4,75 L (-10,20 L; -2,50 L) and of 4,80 L (-1,30 L; 6,10 L) at the groups R and WR, respectively (p < 0,05), and the extracellular water changed of the -5,90 L (-10,10 L; -0,42 L) and of 1,20 L (-0,80 L; 2,70 L) at the same groups, respectively (p < 0,05). There was no statistically significant difference in the variation between the two evaluations for the groups R and NR for intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass. The variation of the phase angle between the two evaluations was of the 1,55° (0,41°; 2,24°) at the group R and 0,10° (-0,28°; 0,46°) at the group WR (p < 0,05). There was a statistically significant correlation between each related nephrotic syndrome variable compared with overhydration, total body water, extracellular water, and phase angle, but no difference when compared with the other variables related to the body composition measured by the BIS. Conclusion. The spectroscopy by bioimpedance was efficient to measure body water changes and the phase angle in patients with nephrotic syndrome. However, the BIS could not detect changes related to the intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass.

O tratamento combinado com IECA e BRA foi proposto como alternativa para o tratamento da ND. Nosso objetivo foi avaliar se o tratamento IECA+BRA era superior ao tratamento com IECA em termos de proteinúria e excreção urinária de marcadores inflamatórios. Cinqüenta e seis pacientes com ND iniciaram o uso de enalapril. Após 4 meses, os pacientes passaram a receber losartan (Grupo E+L) ou placebo (Grupo E). As incidências de hipercalemia (HK) e deterioração aguda da função renal (DAFR) foram avaliadas. A análise de ANOVA de medidas repetidas não revelou diferença entre os grupos, mas, após ajustes, a progressão da proteinúria foi pior no Grupo E+L. A proteinúria final mostrou-se significativamente maior no Grupo E+L (proteinúria final estimada de 1,2 vs 2,6 g/d/1.73m2, p= 0.03). Os resultados foram confirmados nos modelos de regressão logística. Ocorreram 7 eventos de HK (12,6%) e 9 de DAFR (16,1%). Nossos dados sugerem que, em ND avançada, o tratamento combinado IECA+BRA não seja superior ao tratamento com IECA isoladamente em relação à proteinúria e marcadores inflamatórios. / Combined treatment with an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for diabetic nephropathy (DN) treatment. In this study we compared the effect of association therapy versus ACEI on proteinuria progression and on urinary inflammatory biomarkers in DN. Fifty-six patients with DN were started on enalapril. After 4 months, losartan (Group E+L) or placebo (Group E) treatment was started. Incidences of hyperkalemia (HK) and acute kidney function deterioration (AKFD) were monitored. Unadjusted repeated measures ANOVA revealed no difference between groups. After adjustment, proteinuria progression was significantly higher in the E+L Group. In addition, final proteinuria was significantly higher in the E+L Group (predicted adjusted final proteinuria 1,2 vs 2,6 g/d/1,73m2, p=0,03). Finally, logistic regression models showed the same results. We observed 7 HK events (12,6%) and 9 AKFD events (16,1%). These results suggest that, at least in advanced DN, association therapy is not superior to ACEI monotherapy in terms of proteinuria and inflammatory biomarkers.

<p>Biochemical and epidemiological aspects of pre-eclampsia were investigated, with the main focus on possible pathophysiological differences between early-onset and late-onset disease.</p><p>In pre-eclamptic women poor correlation was found between albumin-creatinine ratio (ACR) in a random urine sample and total amount of albumin in a 24-hour urine collection. <i>(Paper I)</i><b> </b></p><p>In a cohort of women giving birth in Sweden in 1973-82 we estimated the adjusted incidence rate ratio (IRR) for ischaemic heart disease (IHD) during the years 1987–2001. The adjusted IRR for development of IHD was 1.6-2.8 in woman exposed to gestational hypertensive disease during her pregnancy compared with unexposed women. The higher risk represents more severe or recurrent hypertensive disease. <i>(Paper II)</i></p><p>Before delivery, in early-onset pre-eclampsia (24-32 weeks) there were pronounced alterations in plasma concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF), and also a higher placental 8-iso-PGF_2α concentration and an elevated serum ratio of plasminogen-activator inhibitor (PAI)-1 to PAI-2 compared with early controls. In late-onset pre-eclampsia (35-42 weeks) there were only moderate alterations in sFlt1 and PlGF concentrations, and the placental 8-iso-PGF_2α concentration and PAI-1/ PAI-2 ratio were similar to those in late controls. <i>(Papers III, V)</i> There was a rapid postpartum decrease in sFlt1 concentration in all groups. One week postpartum the sFlt1 concentration was persistently higher, however, in women with early-onset pre-eclampsia compared with early controls. <i>(Paper IV)</i></p><p>In conclusion: random ACR cannot replace 24-hour urine collections for quantification of albuminuria in pre-eclamptic women; gestational hypertensive disease, especially severe or recurrent, increases the risk for later IHD; early-onset, but not late-onset pre-eclampsia is associated with pronounced alterations of angiogenesis-related markers and only early-onset pre-eclampsia is associated with placental oxidative stress and an increased PAI-1/ PAI-2 ratio, all suggesting a stronger link between early-onset than late-onset pre-eclampsia and a dysfunctional placenta.</p>

RESUME Contexte La maladie rénale chronique (MRC) constitue un problème mondial majeur de Santé publique. Son ampleur réelle en Afrique demeure inconnue. Malgré, les progrès réalisés dans lidentification et la prévention de la MRC et le traitement de la phase terminale de la maladie, ces domaines restent un grand défi en Afrique Sub-saharienne à cause du manque cruel des ressources nécessaires. Objectif Ce travail a pour objectif de cerner lépidémiologie de la MRC à Kinshasa en vue délaborer des stratégies de dépistage précoce et de prévention adaptées. Le but ultime est de contribuer à la réduction de la morbidité et la mortalité rénales mais aussi cardiovasculaires. Méthodes : Le présent travail est une revue synthétique de 4 études menées à Kinshasa : Une étude documentaire des 412 cas réalisée aux Cliniques Universitaires de Kinshasa (CUK), durant la période allant de Janvier 2001 à Décembre 2004 pour identifier le profil épidémiologique et clinique des patients atteints de la MRC. Les résultats de cette étude ont motivé le besoin dévaluer lampleur de la maladie dans la population et dans les structures de santé existantes. Il en a résulté trois études. Une étude épidémiologique de type transversal effectuée à partir de 503 ménages sélectionnés de manière aléatoire selon un plan de sondage à plusieurs degrés dans 10 des 35 Zones de santé composant Kinshasa, capitale de la République Démocratique du Congo (RDC). Une seconde étude, aussi de type transversal, réalisée à partir de 527 patients à risque de MRC, fréquentant neuf Centres de santé (CS) de niveau primaire et quatre hôpitaux de référence de la ville de Kinshasa. Une campagne de dépistage de la protéinurie et des facteurs de risque de la MRC chez 3.018 sujets. Résultats : Lanalyse des données enregistrées en milieu hospitalier a montré : Une augmentation annuelle progressive et inquiétante des proportions (60,6%, 65,9%, 67,4% et 70,5%) de la MRC admises aux CUK quasi exclusivement au stade terminal de la maladie nécessitant une prise en charge rapide par la dialyse péritonéale. Malheureusement, 11% seulement pouvaient accéder à ce traitement onéreux. La majorité des malades à prédominance masculine (sexe ratio 2,2/1) décèdent prématurément à un âge moyen (45,8±14,5 ans), à un moment de leur vie où ils sont encore économiquement très productifs. Les causes probables de la MRC chez ces patients sont la glomérulonéphrite chronique (37%), lhypertension artérielle (27%) et le diabète sucré (26%). Les études transversales dans la population générale et les institutions de santé traditionnelles de la ville de Kinshasa ont mis en évidence les caractéristiques épidémiologiques suivantes: La prévalence globale (tous les stades confondus) de la MRC est de 12% dans la population générale, mais 3% seulement sont conscients de leur état de rein. Celle de linsuffisance rénale chronique (IRC) estimée par le débit de filtration glomérulaire (DFGe) < 60 ml/min/1,73 m² est de 8%. Cette MRC touche particulièrement les adultes (52±15 ans). Les facteurs de risque potentiels de la MRC, liés à des maladies non transmissibles (MNT) sont en progression comparativement aux études antérieures. Ces facteurs sont lhypertension (28%), le diabète sucré (12%) et lobésité (15%). Dans les Centres de santé de Kinshasa, la prévalence globale de la MRC méconnue parmi les sujets à risque est le triple de celle rapportée dans la population générale de la même ville. Parmi cette population malade, les proportions de la MRC atteignent 44% chez les hypertendus, 39% chez les diabétiques ; 16% chez les obèses et 12% chez les sujets infectés par le Virus de limmunodéficience humaine (VIH). 82% des diabétiques avaient une glycémie à jeun non contrôlée (> 126 mg/dl) et 78% dhypertendus navaient pas une pression artérielle sous la cible la moins stricte, cest à dire contrôlée à moins de 140/90 mmHg. Les déterminants identifiés de lIRC ont été lhypertension (OR ajusté 3,3), le diabète sucré (OR 2) et la protéinurie (OR 2,9). Les principaux déterminants de DFGe < 60 ml/min/1,73 m² chez les diabétiques étaient lâge et la durée du diabète sucré. Les résultats de la campagne de dépistage de la protéinurie et des facteurs de risque de la MRC ont révélé ce qui suit : La prévalence de la protéinurie a été de 17%. Les autres facteurs de risque de la MRC identifiés chez les sujets en bonne santé apparente ont été: lhypertension (37%), le diabète sucré (9%), lobésité (11%) et le syndrome métabolique (5%). Pour identifier un cas de protéinurie, il est nécessaire de dépister 4 diabétiques, 5 hypertendus, 4 sujets avec syndrome métabolique, 5 sujets âgés de plus de 50 ans et 9 personnes ne présentant aucune des conditions susmentionnées. Les déterminants majeurs de la protéinurie étaient lâge > 50 ans (OR ajusté 1,4), le diabète sucré (OR 1,3), le surpoids (OR 1,2) et le niveau socio-économique bas (OR 1,4). Conclusion : Ces études établissent pour la toute première fois dans une population africaine la forte prévalence de la MRC et ses facteurs de risque notamment lhypertension, le diabète sucré, lobésité, lâge > 50 ans et linfection à VIH. La maladie affecte ladulte encore jeune comparée aux Etats-Unis où elle prédomine à la vieillesse. Nos études ont montré aussi à la fois la forte prévalence de la protéinurie chez les sujets sans facteurs de risque traditionnels précités, le déficit du dépistage précoce de la MRC et de prise en charge des facteurs de risque dans le système de santé traditionnel favorisant la référence tardive et/ou les décès prématurés, ainsi que les limites malheureuses par manque de moyens de la prise en charge de la maladie au stade tardif. Ces études plaident pour la nécessité dun renforcement de la capacité du personnel soignant dans le domaine de détection précoce et de prise en charge des MNT dont la MRC. Elles montrent également quun dépistage annuel de masse de la population de la protéinurie et des facteurs de risque de la MRC est faisable et pourra, nous lespérons, constituer la base dune élaboration dune politique nationale de prévention. Mots-clé : diabète sucré, équation (Cockcroft & Gault, MDRD), hypertension artérielle, maladie rénale chronique, prévalence, protéinurie. SUMMARY Background Chronic kidney disease (CKD) is a worldwide public health problem. Little is known about its burden in Africa. Despite the advances in identification and prevention of CKD and management of end stage renal disease (ESRD), sub-Saharan Africa has been left far behind regarding these advances. This is because of the scarcity of necessary resources. Objective This work was designed to ascertain the epidemiologic knowledge of CKD in Kinshasa in order to define suitable baseline preventive strategies. It would aims ultimately, to reduce the morbidity and mortality from renal disease and related cardiovascular events. Methods: This current work summarises results of 4 studies undertaken in Kinshasa: A retrospective cross sectional study of 412 cases which was done in the Academic hospital of Kinshasa (AHK), from January 2001 to December 2004 to identify the epidemiologic and clinical profile of patients with CKD. The results of this study motivated us to investigate the extent of the burden of CKD in the population and the existing structures of healthcare. Thus, three further studies were carried out; In an epidemiologic cross sectional study, 503 adult residents in 10 of the 35 health zones of Kinshasa, the capital of the DRC were studied in a randomly selected sample; In a second study of higher risk subjects, 527 people in primary and secondary health care areas in the city of Kinshasa were studied from a random sample of at-risk out-patients with hypertension, diabetes, obesity, or who were infected by HIV; Finally, a mass screening for proteinuria and CKD risk factors was conducted in Kinshasa which involved 3,018 subjects. Results: The analysis of the data recorded in health care had showed: An overwhelmingly annual increasing proportion of CKD (60.6%, 65.9%, 67.4% and 70.5%) in AHK, unfortunately for the majority at stage 5, in other words at ESRD. Tragically enough, only 11% of them could be treated by peritoneal dialysis depending on their financial resources. The majority of the patients are young males (sex ratio 2.2/1) undergoing premature death (45.8±14.5). The probable causes of CKD in these subjects were chronic glomerulonephritis (37%), hypertension (27%) and diabetes mellitus (26%). The cross-sectional studies in the general population and the traditional structures of health care (HC) of the city of Kinshasa highlighted the following: The overall prevalence of CKD is 12% in the general population, but only 3% of those with CKD were aware of their condition. The prevalence of chronic renal failure (CRF) (eGFR < 60 ml/min/1.73 m ²) is 8%; CKD affects particularly young adults (52±15 years); Risk factors for CKD considered in this study, including hypertension (28%), diabetes (12%) and obesity (15%), are increasing compared to the former studies. In HC, the overall prevalence of undiagnosed CKD among at-the risk subjects is three times higher the prevalence of CKD in the general population of the same city. In those with the at-risk conditions, the % of CKD was: 44% in the hypertensive, 39% in the diabetics; 16% in the obese and 12% in those who were infected by the human immunodeficiency virus (HIV). 82% of those with history of diabetes had fasting serum glucose levels (> 126 mg/dl), and 78% of those with a history of hypertension did not have blood pressure controlled to less than 140/90 mmHg. The strongest determinants of CRF or CKD 3+ were: hypertension (adjusted OR 3.3), diabetes (OR 2) and proteinuria (OR 2.9). The principal determinants of eGFR < 60 ml/min/1.73 m² in the diabetic patients were age and the duration of diabetes. The results of the campaign of early detection for proteinuria and CKD risk factors revealed that: The prevalence of proteinuria was 17%. The other CKD risk factors identified were: hypertension (37%), diabetes (9%), obesity (11%) and metabolic syndrome (5%). To identify 1 case of proteinuria, one would need to screen 4 persons with diabetes, 5 persons with hypertension, 4 subjects having metabolic syndrome, 5 subjects aged ≥ 50 years and 9 people without any of the conditions mentioned above. The strongest determinants of proteinuria were age > 50 years (adjusted OR 1.4), diabetes (OR 1.3) and overweight (OR 1.2) and low socioeconomic status (OR 1.4). Conclusion: This work documents for the first time in Africa the high prevalence of CKD and its risk factors mainly hypertension, diabetes, obesity and HIV infection. CKD affects younger people in DRC, in contrast to the United States, where CKD is more prevalent in older. Our work also shows the high prevalence of proteinuria among subjects with neither diabetes nor hypertension, the deficit of the early detection and management of CKD risk factors in the traditional health care system leading to late referral or premature deaths, and the limits of renal replacement treatment. They also show that an annual mass screening of the population for proteinuria and CKD risk factors is feasible and will, it is hoped, provide the basis for building a nationwide prevention strategy. Key words: chronic kidney disease, diabetes mellitus, equation (Cockcroft &Gault, MDRD), arterial hypertension, prevalence, proteinuria.

Biochemical and epidemiological aspects of pre-eclampsia were investigated, with the main focus on possible pathophysiological differences between early-onset and late-onset disease. In pre-eclamptic women poor correlation was found between albumin-creatinine ratio (ACR) in a random urine sample and total amount of albumin in a 24-hour urine collection. (Paper I)<b> </b> In a cohort of women giving birth in Sweden in 1973-82 we estimated the adjusted incidence rate ratio (IRR) for ischaemic heart disease (IHD) during the years 1987–2001. The adjusted IRR for development of IHD was 1.6-2.8 in woman exposed to gestational hypertensive disease during her pregnancy compared with unexposed women. The higher risk represents more severe or recurrent hypertensive disease. (Paper II) Before delivery, in early-onset pre-eclampsia (24-32 weeks) there were pronounced alterations in plasma concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF), and also a higher placental 8-iso-PGF2α concentration and an elevated serum ratio of plasminogen-activator inhibitor (PAI)-1 to PAI-2 compared with early controls. In late-onset pre-eclampsia (35-42 weeks) there were only moderate alterations in sFlt1 and PlGF concentrations, and the placental 8-iso-PGF2α concentration and PAI-1/ PAI-2 ratio were similar to those in late controls. (Papers III, V) There was a rapid postpartum decrease in sFlt1 concentration in all groups. One week postpartum the sFlt1 concentration was persistently higher, however, in women with early-onset pre-eclampsia compared with early controls. (Paper IV) In conclusion: random ACR cannot replace 24-hour urine collections for quantification of albuminuria in pre-eclamptic women; gestational hypertensive disease, especially severe or recurrent, increases the risk for later IHD; early-onset, but not late-onset pre-eclampsia is associated with pronounced alterations of angiogenesis-related markers and only early-onset pre-eclampsia is associated with placental oxidative stress and an increased PAI-1/ PAI-2 ratio, all suggesting a stronger link between early-onset than late-onset pre-eclampsia and a dysfunctional placenta.