Objective - To correlate blood pressure and inflammatory markers with urine albumin analysed with a point-of-care testing (POCT) instrument, nephelometric determination of albumin and creatinine related urine albumin in elderly males. Methods and Results - The study population consisted of 103 diabetic and 603 nondiabetic males (age 77 years) in a cross-sectional study in central Sweden. We analyzed urine albumin with a HemoCue® Urine Albumin POCT instrument and a ProSpec® nephelometer and creatinine related urine albumin. There were strong correlation between both systolic and diastolic blood pressure and all three urine albumin methods (p<0.0001). There were also significant correlations between the different urine albumin measurements and SAA, hsCRP and IL-6. Conclusions - Hypertension has a strong impact on hyperfiltration in diabetic and nondiabetic elderly males.

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Background: We aimed to assess the point prevalence of microalbuminuria (MAU) in a sample of unselected consecutive primary-care attendees, with particular focus on patients with diabetes mellitus (with and without additional concomitant diseases) and those with hypertension. Design: Cross-sectional observational study in a nationwide representative sample of 1912 primary-care practices and a patient population consisting of 39 125 primary-care attendees. Diagnoses for diabetes, hypertension and co-morbidities were provided by the treating physician and complemented by blood pressure (BP) measurements and selected lab tests. Screening for microalbuminuria (>20 and <200 μg/ml) was done with a spot urine dipstick test. Results: The clinical diagnosis of nephropathy was assigned to 7.6% of patients. The point prevalence of MAU was 19.0% in the total sample; the proportion was 33.6% in diabetics whereas the diagnosis was assigned to only 7.1% in the total sample. Amongst diabetic patients with MAU, 92.6% had BP above the target value of < 130/80 mmHg. Frequency rates rose with increasing BP (e.g. 20.6% in diabetic patients with BP< 120/70 mmHg, and 36.3% in diabetic patients with BP > 140/90 mmHg). Of note, patients with MAU had a higher burden of co-morbidity compared to those without MAU. Conclusions: We found a high prevalence of MAU in primary care, particularly in diabetic patients. The frequency of MAU was closely related to the BP level and the degree of co-morbidity. The present study underlines the magnitude of the problem of MAU in primary care, and should serve as a starting point to initiate measures to address this important public health issue.

Notre équipe a identifié le thé Labrador [Rhododendron groenlandicum L. (Ericaceae)] comme une plante potentiellement antidiabétique de la pharmacopée traditionnelle des Cris de la Baie James orientale. Dans la présente étude, nous avons évalué les effets néphroprotecteurs potentiels de la plante. De la microalbuminurie et de la fibrose rénale ont été développées chez des souris alimentées avec une diète grasse (DG). Le R. groenlandicum améliore d’une façon non-significative la microalbuminurie, avec des valeurs de l’aire sous la courbe (ACR) diminuant de 0.69 à 0.53. La valeur de la fibrose rénale qui était, à l’origine, de 4.85 unités arbitraires (UA) dans des souris alimentées à la DG, a chuté à 3.27 UA après avoir reçu un traitement de R. groenlandicum. Le R. groenlandicum a réduit la stéatose rénale de presque la moitié alors que l’expression du facteur de modification Bcl-2 (Bmf) a chuté de 13.96 UA à 9.43 UA. Dans leur ensemble les résultats suggèrent que le traitement avec R. groenlandicum peut améliorer la fonction rénale altérée par DG. Dans l’étude subséquente, notre équipe a identifié 17 espèces de la forêt boréale, de la pharmacopée traditionnelle des Cris de la Baie James orientale, qui ont présenté des activités biologiques prometteuses in vitro et in vivo dans le contexte du DT2. Nous avons maintenant examiné ces 17 extraits afin d’identifier lesquels possèdent un potentiel cytoprotecteur rénale en utilisant des cellules Madin Darby Canine Kidney (MDCK) mises à l’épreuve dans un médium hypertonique. Nous concluons que plusieurs plantes antidiabétiques Cris exercent une activité de protection rénale qui pourrait être pertinente dans le contexte de la néphropathie diabétique (ND) qui affecte une proportion importante des Cris. La G. hispidula et la A. balsamea sont parmi les plantes les plus puissantes dans ce contexte et elles semblent protectrices principalement en inhibant la caspase 9 dans la voie de signalisation apoptotique mitochondriale. Finalement, nous avons utilisé une approche de fractionnement guidée par un test biologique pour identifier les fractions actives et les composés de A. balsamea avec un potentiel de protection rénale in vitro dans des cellules MDCK mises au défi avec un médium hypertonique. La fraction d’hexane (Hex) possède le potentiel le plus élevé parmi toutes les fractions de solvant contre les dommages cellulaires induits par le stress hypertonique. Dans des études précédentes, trois composés purs ont été identifiés à partir de la fraction Hex, à savoir, l’acide abiétique, l’acide déhydroabiétique et le squalène. L’acide abiétique se distinguait par son effet puissant dans le maintien de la viabilité des cellules MDCK (AnnV-/PI-) à un niveau relativement élevé (augmentation de 25.48% relative au stress hypertonique, P<0.0001), ainsi qu’une réduction significative (diminution de 20.20% par rapport au stress hypertonique, P<0.0001) de l’apoptose de stade précoce (AnnV+/PI-). L’acide abiétique peut donc servir à normaliser les préparations traditionnelles d’A. balsamea et à trouver des applications potentielles dans le traitement de la néphropathie diabétique. Les trois études ont été intrinsèquement liées les unes aux autres, par conséquent, nous avons réussi à identifier R. groenlandicum ainsi que A. balsamea comme nouvelles plantes prometteuses contre la néphropathie diabétique. Nous croyons que ces résultats profiteront à la communauté crie pour la gestion des complications diabétiques, en particulier la néphropathie diabétique. En parallèle, nos données pourraient faire avancer l'essai clinique de certaines plantes médicinales de la pharmacopée traditionnelle des Cris de la Baie James orientale du Canada. / Our team has identified Labrador tea [Rhododendron groenlandicum L. (Ericaceae)] as a potential antidiabetic plant from the traditional pharmacopeia of the Eastern James Bay Cree. In the present study, we assessed the plant’s potential renoprotective effects. Microalbuminuria and renal fibrosis was developed in high fat diet (HFD)-fed mice. Meanwhile, there was a tendency for R. groenlandicum to improve microalbuminuria, with the values of area under the curve (ACR) reducing from 0.69 to 0.53. Renal fibrosis value was originally 4.85 arbitrary units (AU) in HFD-fed mice, dropped to 3.27 AU after receiving R. groenlandicum treatment. R. groenlandicum reduced renal steatosis by nearly one half whereas the expression of Bcl-2-modifying factor (Bmf) diminished from 13.96 AU to 9.43 AU. Taken altogether, the results suggest that R. groenlandicum treatment can improve renal function impaired by HFD. In the following study, our team has identified 17 Boreal forest species from the traditional pharmacopeia of the Eastern James Bay Cree that presented promising in vitro and in vivo biological activities in the context of type 2 diabetes (T2D). We now screened the 17 plants extracts for potential renal protective activity using Madin Darby Canine Kidney (MDCK) cells challenged with hypertonic medium. Cytoprotective potential as well as underlying mechanisms were investigated. We conclude that several Cree antidiabetic plants exert renal protective activity that may be relevant in the context of diabetic nephropathy that affects a significant proportion of Cree diabetics. G. hispidula and A. balsamea are amongst the most powerful plants in this context and they appear to exert their modulatory effect primarily by inhibiting caspase 9 in the mitochondrial apoptotic signaling pathway. We used a bioassay-guided fractionation approach to identify active fractions and compounds of A. balsamea with renal protective potential in vitro in MDCK cells challenged with hypertonic medium. The hexane (Hex) fraction possessed the highest potential among all solvent fractions against cell damage induced by hypertonic stress. In previous studies, three pure compounds were identified from the Hex fraction, namely, abietic acid, dehydroabietic acid and squalene. Abietic acid stood out by its strongest effect in maintaining MDCK cell viability (AnnV-/PI-) at a relatively high level (25.48% increase relative to hypertonic stress, P<0.0001) as well as a significant reduction (20.20% decrease relative to hypertonic stress, P<0.0001) of early stage apoptosis (AnnV+/PI-). Abietic acid may thus serve to standardize A. balsamea traditional preparations and find potential applications in the treatment of diabetic nephropathy. The three studies were inherently associated with each other, as a result we had successfully identified R. groenlandicum as well as A. balsamea as novel medicinal plants against diabetic nephropathy. We believe such findings will benefit the Cree community for the management of diabetic related complications, especially diabetic nephropathy. Meanwhile, our data might advance the clinical trial of certain medicinal plants from the traditional pharmacopeia of the Canadian Eastern James Bay Cree.

Diabetic vasculopathy (DV) is the most important consequence of chronic hyperglycemia in patients with diabetes mellitus (DM). This thesis explores the interaction of blood, bone and kidney in the pathogenesis of DV by i) reviewing the current understanding of pathogenesis of macrovascular and microvascular diseases in DM to identify gaps in literature and generate hypotheses relating to various facets of DV ii) undertaking a series of prospective studies to examine these hypotheses iii) analysing the findings and integrating any new information obtained from the clinical studies into the current knowledge base and iv) generating hypotheses upon which future work might be based. The literature search was carried out with the aim of understanding current concepts of pathogenesis of DV and its potential modulators. The original reviews resulting from this process are presented in chapters 2 to 4. A series of pilot studies reported in chapters 7 to 11, were then carried out to interrogate hypotheses originating from this process. The first study was carried out in healthy individuals to define the biological variation of potential modulators of DV, namely erythropoietin (EPO), parathyroid hormone, 25 hydroxyvitamin D and 1, 25-dihydroxyvitamin D to facilitate the design and interpretation of subsequent studies. It revealed a wide biological variation of these modulators in the healthy population thus,emphasizing the need to have a control group in the subsequent study population. To examine whether tubulointerstitial dysfunction occurs before the onset of microalbuminuria, a measurement of the above mentioned parameters was carried out along with markers of tubulointerstitial injury in patients with type 1 and type 2 DM without microalbuminuria and in non-diabetic controls. It was found that tubulointerstitial dysfunction with low levels of EPO and 1, 25-dihydroxyvitamin D and higher excretion of tubular injury markers, occurs before the onset of microalbuminuria. Subsequently, diabetic and nondiabetic chronic kidney disease (CKD) patients with EPO deficiency anaemia were examined to study the effects of EPO therapy on the excretion of tubular injury markers. However, in these patient groups, we were unable to demonstrate an effect of EPO therapy on the markers of tubular injury in spite of a beneficial haematological response. To examine whether vascular calcification (VC) and bone mineral density (BMD) were linked in patients with diabetes mellitus and to explore their relationship to modulators of DV, an assessment of VC and BMD was undertaken in patients with type 2 DM with different degrees of proteinuria and normoalbuminuria. VC was assessed by CT scan and BMD by a DEXA scan. Modulators of DV were measured including serum Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-b-ligand (RANKL). The findings were i) a high prevalence of VC and osteopenia in normoalbuminuric type 2 DM patients with normal serum creatinine ii) a weak inverse relationship between VC and osteopenia iii) proteinuric patients had worse VC but not osteopenia iv) weak relationships between OPG levels and both VC and osteopenia, masked by age in multivariate analysis. The final study examined the relationship between modulators of DV, including OPG and RANKL, and the degree of CKD. It was found that abnormalities of OPG and RANKL occur before the onset of microalbuminuria and progress with deterioration of renal function. Compared to nondiabetics, DM patients have higher OPG levels in the predialysis phase and lower levels in haemodialysis phase, a phenomenon that might indicate endothelial exhaustion in dialysis patients with DM. The derangements associated with DV seem to occur earlier than previously thought. Further work is required to untangle these complexities and to define the contribution of factors such as the adverse blood milieu, the vasculature, abnormal bone and mineral metabolism, and early tubulointerstitial damage. The findings from the studies reported here may help in the formulation of new hypotheses, which might contribute to future work in this area.