Microalbuminuric Patients Research Articles

尿中グリコサミノグリカン濃度の臨床的意義―インスリン非依存型糖尿病,膠原病,IgA腎症患者における検討―

Urinary levels of glycosaminoglycans (U-GAG) were measured in 72 patients with non-insulin-dependent diabetes mellitus, 12 patients with collagen diseases, 14 patients with IgA nephropathy and 35 healthy subjects as controls to investigate the clinical significance of urinary GAG. The mean urinary GAG levels in diabetics and patients with collagen diseases were 72.4 +/- 36.2 and 147.8 +/- 59.2 mg/g.cr, respectively. These were significantly higher than the level in healthy subjects (46.7 +/- 11.3 mg/g.cr, p < 0.01). The mean urinary GAG level in patients with IgA nephropathy was 56.4 +/- 21.0 mg/g.cr and did not differ from that in healthy subjects. The mean urinary GAG level in 35 normoalbuminuric diabetic patients (U-A1b < 30 mg/g.cr) was 64.4 +/- 25.6 mg/g.cr and was significantly higher than that in healthy subjects (p < 0.01). The mean urinary GAG levels in 24 microalbuminuric patients (30 < U-A1b < or = 300 mg/g.cr) and 13 patients with overt albuminuria (U-Alb > or = 300 mg/g.cr) were 71.4 +/- 30.1 and 95.8 +/- 58.4 mg/g.cr, respectively and were also higher than the level in healthy subjects (both p < 0.01). Urinary GAG levels correlated positively with urinary albumin levels (r = 0.251, p < 0.05) and urinary N-acetyl-beta-D-glucosaminidase activities in diabetics (r = 0.491, p < 0.01). The prevalence of diabetic macroangiopathies in diabetic patients with elevated levels of urinary GAG was significantly higher than that in those with normal levels of urinary GAG (p < 0.05).

Microalbuminuria in relation to metabolic control and blood pressure in adolescents with type 1 diabetes.

IntroductionThe objective of this study was to assess the frequency of microalbuminuria and the relationship with other risk factors for the development of diabetic nephropathy.Material and methodsOur cross-section study involved a group of 60 adolescence of both sexes, mean age 15.3 ±2.43 years with mean duration of diabetes 7.74 ±3.44 years. Albumin excretion rate was measured on 2-3 samples of the first morning urine in the period below 6 months and persistent microalbuminuria was defined if its increased in two out of three urine specimens. Ambulatory blood pressure was monitored (ABPM, SpaceLabs 90207).ResultsMicroalbuminuria developed in 13.3% of adolescents with mostly completed sexual development, statistically significantly poorer metabolic control (9.79% vs. 8.7%) and higher BMI (23.59 kg/m2 vs. 20.85 kg/m2) than in the patients with normoalbuminuria. The mean night-time systolic blood pressure (SBP) was statistically significantly higher in microalbuminuric patients than in normoalbuminurics. The nocturnal dip was reduced in 41.7% of our patients; 38.5% of nondippers were in normoalbuminuric and 62.5% in microalbuminuric patients.ConclusionsDiabetic adolescents require particular attention in order to minimize the factors such as high HbA1c, elevated body mass index and night-time SBP in the development of incipient nephropathy.

MULTIPLEX BEAD ANALYSIS OF URINARY CYTOKINES OF TYPE 2 DIABETIC PATIENTS WITH NORMO- AND MICROALBUMINURIA

Renal damage of diabetic patients is linked to chronic low-grade inflammation. The aim of this study was to analyze urinary concentrations of 27 cytokines in type 2 diabetic patients with normo- and microalbuminuria by multiplex bead immunoassay. Urinary levels of IL-8, IP-10, MCP-1, G-CSF, EOTAXIN, RANTES, and TNF-α in microalbuminuric patients were significantly increased compared to those in normoalbuminuric patients (p < 0.05) or controls (p < 0.05). GM-CSF, MIP-1α, and MIP-1β levels were more elevated in microalbuminuric patients than in controls (both p < 0.05). IP-10 and MCP-1 levels were correlated with urinary albumin excretion rate (r = 0.668 and 0.544, both p < 0.01), and estimated glomerular filtration rate (r = −0.454 and −0.418, both p < 0.05). EOTAXIN, GM-CSF, IP-10, MCP-1, and RANTES levels were correlated with HbA1c (r = 0.457, 0.466, 0.678, 0.567, 0.542, respectively, p ≤ 0.01). These results indicate that urinary cytokine determination might be useful for the early diagnosis and management of patients with diabetic nephropathy.

The frequency of factor V Leiden mutation, ACE gene polymorphism, serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria

The aim of present study was to determine if factor V Leiden (FVL) mutation and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism are associated with diabetic nephropathy (DN) among Kurdish population from Western Iran. This case-control study comprised 144 unrelated adult type 2 diabetic mellitus patients (T2DM) including 72 patients with microalbuminuria and 72 age and sex matched patients without nephropathy. The ACE I/D polymorphism and FVL mutation were detected by polymerase chain reaction (PCR) and PCR-RFLP, respectively. The frequency of FVL G1691A and ACE D allele in T2DM patients with microalbuminuria were 1.6 and 57%, respectively and in normoalbuminuric T2DM patients were 4.9 and 58.3%, respectively (P > 0.05). ACE genotypes affected on serum ACE activity and a better response to ACE inhibitor therapy (captopril) compared to angiotensin II receptor antagonist (losartan) was obtained with significant reduction of ACE activity in diabetic patients without nephropathy carrying DD genotype. However, the beneficial effect of losartan therapy was observed in microalbuminuric patients with II genotype compared to ID and DD genotypes.

Urine Proteome Analysis May Allow Noninvasive Differential Diagnosis of Diabetic Nephropathy

OBJECTIVEChronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy in more than one-third of patients. We interrogated urine proteomic profiles generated by surface-enhanced laser desorption/ionization-time of flight/mass spectrometry with the aim of isolating a set of biomarkers able to reliably identify biopsy-proven diabetic nephropathy and to establish a stringent correlation with the different patterns of renal injury.RESEARCH DESIGN AND METHODSTen micrograms of urine proteins from 190 subjects (20 healthy subjects, 20 normoalbuminuric, and 18 microalbuminuric diabetic patients and 132 patients with biopsy-proven nephropathy: 65 diabetic nephropathy, 10 diabetic with nondiabetic CKD [nd-CKD], and 57 nondiabetic with CKD) were run using a CM10 ProteinChip array and analyzed by supervised learning methods (Classification and Regression Tree analysis).RESULTSThe classification model correctly identified 75% of patients with normoalbuminuria, 87.5% of those with microalbuminuria, and 87.5% of those with diabetic nephropathy when applied to a blinded testing set. Most importantly, it was able to reliably differentiate diabetic nephropathy from nd-CKD in both diabetic and nondiabetic patients. Among the best predictors of the classification model, we identified and validated two proteins, ubiquitin and β2-microglobulin.CONCLUSIONSOur data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis.

Silent cerebral infarction is associated with the development and progression of nephropathy in patients with type 2 diabetes

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease in patients with diabetes. The relationship between renal manifestations of CKD (albuminuria and decreased glomerular filtration rate) and silent cerebral infarction (SCI) has attracted attention; however, most studies examined the effects of components of CKD on prevalence of SCI. We sought to assess the relationship between SCI and the development and progression of nephropathy in type 2 diabetic patients. We studied 366 type 2 diabetic patients with normoalbuminuria (urinary albumin-to-creatinine ratio [ACR] <30 mg g(-1), N=246) or microalbuminuria (ACR=30-299 mg g(-1), N=120). SCI was defined by cranial MRI. The primary end point was progression from normo- to microalbuminuria or from micro- to macroalbuminuria. The cumulative incidence of the primary end point was estimated using the Kaplan-Meier method. Risk estimates for reaching the end point were calculated using Cox proportional hazard model analyses. During a median follow-up period of 3.9 years, 23 normoalbuminuric and 24 microalbuminuric patients reached the primary end point. Patients with SCI (N=171) had a greater incidence of reaching the end point than those without SCI (N=195, P=0.020 by the log-rank test), with a hazard ratio of 2.02 (95% confidence interval=1.09-3.72, P=0.025) in the multivariate Cox regression model. Although the common pathogenesis of SCI and albuminuria in diabetic patients is still unclear, SCI may be a predictor of progression of nephropathy in type 2 diabetic patients.

Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients

The aim of this study was to identify possible risk factors for albuminuria, an early marker of sickle cell anemia (SCA) glomerulopathy, in a cohort of 189 SCA adult patients followed at the Sickle Cell Center of Guadeloupe, a French Caribbean island. Biological parameters obtained at baseline, α-globin gene status, and β S haplotypes were compared in patients stratified accordingly to graded albuminuria. Abnormal albumin excretion rate was detected in half of the studied adult patients and macroalbuminuria occurred in 21.6%. Graded albuminuria was associated with advanced age ( p = 0.006), systolic blood pressure ( p = 0.031), and worsened anemia, i.e. low hemoglobin rate ( p < 0.0001) and red blood cell count ( p < 0.0001). Alpha-thalassemia frequency was lower in microalbuminuric and macroalbuminuric patients than in normoalbuminuric patients, 12.5%, 13.75% and 26%, respectively ( p = 0.0057). Comparison of albuminuria-free survival curves in SCA patients without and with α-thalassemia showed that the median time of albuminuria onset was delayed in the later ones ( p = 0.021). In contrast, no association of albuminuria was detected with the Bantou β S haplotype. Our results strongly suggest a protective effect of α-thalassemia against glomerulopathy in SCA adult patients which could be related to a decreased hemolytic rate.

Microalbuminuria is not associated with endothelial dysfunction and coronary atherosclerosis in patients with acute coronary syndromes

Background: Microalbuminuria is associated with atherosclerosis and it is a strong and independent predictor of increased risk for cardiovascular morbidity and mortality. However, the underlying mechanisms of the association of albuminuria and cardiovascular disease are not well understood. We examined the association of endothelial dysfunction with microalbuminuria in non-diabetic and non-hypertensive patients with acute coronary syndromes (ACS). Methods: We compared endothelial function by flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated dilatation (GTN) and angiographic properties among 27 microalbuminuric and 106 normoalbuminuric patients. Severity of coronary arteriosclerosis was evaluated using the Gensini score and number of diseased vessels. Results: We evaluated 133 patients (106 males; mean age 59 ± 11 years). Microalbuminuria was present in 27 (20.3%) subjects. Patients with microalbuminuria and normoalbuminuria had similar baseline characteristics. FMD and GTN responses were not different in microalbuminuric patients compared with normoalbuminuric patients (FMD 8.2 ± 5.3 vs. 7.9 ± 6.5%, p = 0.54 and GTN 9.3 ± 5.4 vs. 10.2 ± 6.9%, p = 0.82). Microalbuminuria was not associated with endothelial dysfunction (p = 0.49). Morphological properties of coronary lesion were not different. Conclusion: The presence of microalbuminuria is not associated with endothelial dysfunction and severity of angiographic coronary atherosclerosis in non-diabetic and non-hypertensive patients with ACS.

β-Adrenoceptor and GRK3 expression in human lymphocytes is related to blood pressure and urinary albumin excretion

The objective of our work was to analyze if changes in the expression of beta-adrenoceptors (beta-ARs) and G-protein-coupled receptor kinases (GRKs) in human lymphocytes - a practical surrogate for myocardial or vascular cells - are related to the hypertensive state and its clinical consequences. Real-time quantitative RT-PCR was employed to evaluate the expression of the three beta-ARs (beta1, beta2, beta3) and three GRKs (GRK2, GRK3, GRK5) in human lymphocytes obtained from both normotensive and hypertensive patients, some of whom had been treated with blockers of the renin-angiotensin system. Office blood pressure, 24-h ambulatory blood pressure, urinary albumin excretion and serum biochemical profile were also recorded. beta1-AR expression levels were higher in circulating lymphocytes from hypertensive patients (2-DeltaDeltaCt = 2.135 +/- 0.4252*, vs. control group), but this difference was not observed when these patients were treated with blockers of the renin-angiotensin system. beta1-AR levels directly correlated (r2 = 0.5711, P = 0.0185) with urinary albumin excretion in microalbuminuric patients, which relates alterations of this receptor to cardiovascular risk. An inverse correlation was observed between the expression levels of beta2-AR and diastolic blood pressure (r2 = 0.2078, P = 0.0031), suggesting that beta2-AR levels in lymphocytes mirror their expression in vascular cells, in which beta2-AR-mediated relaxation regulates vascular resistance. mRNA levels for GRK3 were inversely correlated with systolic and diastolic blood pressure (day, night and 24 h), which suggests a protective role for GRK3 in the regulation of human blood pressure, as supported by previous findings in transgenic mice.

Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes

BackgroundThe evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene...

Proteomic approaches for discovering biomarkers of diabetic nephropathy

More and more patients worldwide suffer from end-stagerenal disease which often is secondary to diabetes (e.g.36.9% of all US patients with end-stage renal disease havea diabetic nephropathy [1]). Indeed, both types of diabetesare burdened by long-term complications, including retin-opathy and nephropathy. Nephropathy occurs in 25–40%of type 1 and type 2 diabetic patients [2], and is character-izedbythepresenceofabnormalamountsofproteinsintheurine, a sign of alteration in the renal filtration capabilitiesof the nephron. In many patients, diabetic nephropathy(DN) progresses to end-stage renal disease. However, it iscurrently impossible to reliably predict which and whendiabetic patients will develop nephropathy and progressto kidney failure. The persistent presence of albumin inthe urine is considered predictive of the subsequent devel-opment and clinical progression of DN [3,4]. Currently,microalbuminuria (MA) is considered the first clinicalevidence of incipient diabetic nephropathy. It is definedas an urinary albumin excretion of 30–300 mg/day andcharacterizes the stage III of diabetic nephropathy accord-ing to Mogensen’s classification [5]. However, despite itscapacity to highlight nephron damage, MA is a non-spe-cific marker of DN especially in subjects with type 2 dia-betes. Indeed, only 30–45% of microalbuminuric type 2diabetic patients will develop overt proteinuria over morethan 10 years [6], and MA is also proposed as a markerof high cardiovascular risk in diabetic and non-diabeticpatients [7], as recently highlighted [8]. Thus, MA shouldnot be considered an early and specific marker of DN.Urineandplasmaproteomicshavegainedmuchattentionas tools for the identification of diagnostic and prognosticbiomarkers of renal diseases. For many years now, it hasbeen hoped that proteomic methods would unveil earlierandmorespecificbiomarkersthanMA[9].Someprevious-ly published reviews have focused on the methodologicalaspects of proteomics [10,11] or on the approaches for dis-coveringandvalidatingdiagnosticmarkers[12,13].Aspro-teomics studies devoted to DN biomarker discovery begantobepublishedin2004[14],inthisarticle,wewillcompre-hensively review the available information published sincethen.Targeting DN biomarkers: an overview of the experimentalmethodsTable 1 summarizes the key information available from theanalysis of the literature. Urine is the biological fluid thatattracted most of the interest in the proteomic quest of DNbiomarkers. This makes sense because the protein compos-ition of urine might correctly reflect the renal functionalabnormalities associated with DN [15]. Moreover, urinehas some unique advantages such as its availability in largequantities as well as the solubility and stability of its pro-tein content [16]. Nevertheless, serum from type 2 diabeticpatients (four studies) [17–20] and pooled haemofiltratesfrom patients suffering from chronic renal insufficiency(most of them were also diabetics) (one work) [21] werealso analysed.Concerning the choice of separation and identificationtechniques (Table 1), two-dimensional gel electrophoresis(2D-GE) was frequently employed (however in differentexperimental set-ups). This is likely due to the fact that2D-GE easily provides a semi-quantitative estimation ofthe amount of each separated protein (spot intensity) andsome qualitative information about the size and the post-translational modifications of such proteins. These positivefeatures compensate for the limitations of 2D-GE such aslow throughput and a possible lack of sensitivity. Profilingmethods were chosen for several studies (indicated inTable 1). They generate a list of mass peaks which needthen to be assigned to a specific peptidic/protein se-quence. Surface-enhanced laser desorption/ionizationtime-of-flight (SELDI-TOF) mass spectrometry (a prote-omic method that enables mass fingerprinting of proteinsretained onto an affinity chip) was used in four differentstudies [18,22–24]. Interestingly, in each work, a differentseparationsurface(ProteinChip)wasconsideredasthemost

Microalbuminuria is associated with impaired arterial and venous endothelium-dependent vasodilation in patients with Type 2 diabetes

Microalbuminuria in Type 2 diabetes is associated with arterial endothelial dysfunction, but the venous bed was never evaluated. To study the endothelial function in the venous and arterial bed in patients with Type 2 diabetes with normoalbuminuria or microalbuminuria. We evaluated 28 patients with Type 2 diabetes, glycated hemoglobin (HbA(₁c)) <7.5%, who were classified as normo- (albuminuria <30 mg/24 h; no.=16) or microalbuminuric (albuminuria 30-300 mg/24 h; no.=12). Venous and arterial endothelial function were assessed by the dorsal hand vein technique (venodilation by acetylcholine) and brachial artery flow-mediated vasodilation, respectively. Patients were normotensive (systolic arterial pressure: 131.1±10.6 mmHg) and on good metabolic control (HbA(₁c): 6.6±0.6%). Microalbuminuric patients presented impaired venous (32.9±17.4 vs 59.3±26.5%; p=0.004) and arterial vasodilation (1.8±0.9 vs 5.1±2.4; p<0.001), as compared to normoalbuminuric patients. There was a negative correlation between acetylcholine-induced venodilation and albuminuria (r=-0.62; p<0.001) and HbA(₁c) (r=-0.41; p=0.032). The same was observed between flow mediated arterial vasodilation and albuminuria (r=-0.49; p=0.007) and HbA(₁c) (r=-0.44; p=0.019). Venous and arterial vasodilation was positively correlated (r=0.50; p=0.007). Both venous and arterial endothelial function are impaired in Type 2 microalbuminuric diabetics, in spite of good metabolic control, suggesting that other factors are involved in its pathogenesis.

Microalbuminuria and its relations with serum lipid abnormalities in adult Nigerians with newly diagnosed hypertension

Microalbuminuria (MA) has been associated with increased risk of adverse cardiovascular events in nondiabetic hypertensive patients. This may be partly due to increased serum lipid abnormalities in these patients. The objective was to evaluate the association between MA and serum lipid abnormalities in nondiabetic adult Nigerians with hypertension. A prospective study which recruited 96 consecutive newly diagnosed adult Nigerian hypertensive met the study criteria. These patients were compared with the same number of age- and sex-matched healthy normotensive individuals. 52 (54.2%) and 44 (45.8%) of patients were males and females, respectively. Mean +/- SD ages were 51.2 +/- 10.1 and 48.2 +/- 8.8 years for male and female patients, respectively. Microalbuminuria was more than five times more prevalent in the patients than in the controls. The means +/- SD serum total cholesterol (5.0 +/- 0.56 vs. 4.05 +/- 0.50 mmol/L, P = 0.04) and low-density lipoprotein cholesterol (3.99 +/- 0.49 vs. 2.84 +/- 0.58 mmol/L, P = 0.001) were significantly higher, while the mean +/- SD for high-density lipoprotein cholesterol was (0.91 +/- 0.16 vs. 1.04 +/- 0.13 mmol/L, P = 0.03) significantly lower in microalbuminuric patients than in non-microalbuminuric patients. This study has shown that adult nondiabetic Nigerians with MA are significantly more likely to have dyslipidemia than patients without MA. Hence, this subset of hypertensive patients constitutes a high risk group. Screening for MA, and early recognition and prompt treatment of serum lipid abnormalities in these patients may reduce the risk of adverse cardiovascular events.

Transient Elevations of Microalbuminuria May Represent a Marker of Systemic Vascular Injury in Sickle Cell Disease Patients.

Abstract 4611Sickle cell disease (SCD) is a genetic blood disorder of hemoglobin function resulting in severe morbidity and early mortality. Hemolysis and vascular obstruction, endothelial activation and dysfunction, and inflammation, are hallmarks of this disease contributing to a chronic and progressive pathophysiology. Renal complications include hematuria, proteinuria, chronic renal insufficiency, and end stage renal disease. Several studies in SCD patients have shown that microalbuminuria may be a potential marker of progression to chronic renal disease. Also, microalbuminuria has been proposed as a marker of worsening outcome in diabetes, cardiovascular disease, cancer, lymphoma, and clotting. The Steno hypothesis (Diabetologia 1989; 32: 219) proposed that albuminuria is a biomarker of systemic vascular damage in diabetics, not just a marker of localized renal disease but also of retinopathy and macroangiopathy. We propose that the Steno hypothesis may also apply to SCD patients in that albuminuria may reflect systemic vascular disease injury besides potential renal impairment. From a cohort of 33 SCD patients in a county hospital hematology clinic, 11 patients were admitted through the emergency department with acute vaso-occlusive pain crisis over a one month period, and all were evaluated for microalbuminuria. [7 males, 4 females; 7 HbSS, 3 HbSC, 1 HbS beta-thalassemia; median age 41.7 years (range, 20 - 59 years), median hospital stay of 3.5 days (range, 2 – 8 days)]. None of the patients had renal insufficiency. Hospitalized patients were treated with intravenous fluids and intravenous narcotics. The median albuminuria value at admission was 21 mg/g creatinine. During hospitalization, 6 patients remained normoalbuminuric (<30 mg/g creatinine) during their entire hospital stay, 5 patients (3 HbSS, 2 HbSC) were microalbuminuric (30 – 299 mg/g creatinine), and none were macroalbuminuric (> 300 mg/g creatinine). Three of the microalbuminuric patients were followed with daily early morning albuminuria determinations. Two of those patients displayed a peak microalbuminuria level followed by a progressive drop at the time of hospital discharge. For instance, one HbSS patient was hospitalized for 8 days and at admission his albuminuria level was 69 mg/g creatinine. His daily microalbuminuria level progressively rose and peaked at 100 mg/g creatinine on hospital day 4, and then decreased daily to 86 mg/g creatinine at discharge on hospital day 8. Another microalbuminuric HbSC patient presented on admission with a microalbuminuria level of 67 mg/g creatinine. His microalbuminuria level peaked at 98 mg/g creatinine on hospital day 2 and then dropped to 3 mg/g creatinine at discharge on hospital day 4. These patients had elevations of their daily albuminuria values from initial baseline values during a pain crisis which peaked and then decreased as their crisis resolved and were discharged from the hospital. Only a subset of SCD patients hospitalized in pain crisis showed evanescent increases in albuminuria levels during a pain crisis. This incremental elevation of albuminuria represents an extension of the Steno hypothesis, in that it may serve as a sensitive biomarker for vaso-occlusive pain crisis, a unique form of systemic vascular endothelial injury. Furthermore, a decrease in microalbuminuria, or even a drop to normoalbuminuria, in SCD patients may be a useful marker to assess response to therapy. A prospective study on SCD patients with normoalbuminuria and microalbuminuria is needed to confirm this hypothesis. Disclosures:No relevant conflicts of interest to declare.

Relationships among microalbuminuria, insulin resistance and renal-cardiac complications in insulin dependent and non insulin dependent diabetes.

A rate of albumin excretion rate above 20 micrograms/min is a predicting factor of overt nephropathy in Type I diabetes. It has not yet been established whether this is the case also for Type II diabetes, where microalbuminuria is antecedent to general and cardiovascular mortality but not to end-stage renal disease. The reasons accounting for this discrepancy between Type I and Type II diabetes have not been fully elucidated. In principle two different hypotheses can be postulated to explain these findings. Firstly it can be suggested that overt proteinuria is not detected with similar incidence rates in microalbuminuric patients with the two types of diseases because Type II diabetics are older and more prone to develop cardiovascular events. Therefore these patients would die frequently before developing overt proteinuria not because microalbuminuria is not a predicting factor of End-stage Renal Disease, but rather because the follow-up period is not long enough to monitor the patients till the very moment they develop renal complications. Alternatively it is possible that microalbuminuria reflect a systemic, endothelial and vascular disorder rather than glomerular structural abnormalities in these patients. We have recently described a clustering of clinical features encompassing microalbuminuria, hypertension, peripheral extrahepatic insulin resistance, renal and cardiac hypertrophy and altered cation membrane transport systems, not in the overall Type II diabetic population, but only in a cohort of these patients. Evidences in keeping with a strict association between insulin resistance, hypertension and microalbuminuria in a subgroup of Type II diabetic patients have been recently reported by several authors both in cross-sectional and longitudinal studies. However the hypothesis that microalbuminuria reflects a systemic endothelial and vascular disorder in Type II diabetic patients, does not rule out the possibility that these systemic disturbances are also associated with histologic abnormalities of the kidney. With regard to the characteristics of renal histology in Type II diabetic patients with and without microalbuminuria, preliminary data from our laboratory demonstrate that there is no evidence of any renal disorder other than diabetes in microalbuminuric Type II diabetic patients. More particularly in this subset of patients we observed typical features of diabetic nephropathology (glomerular, tubulo-interstitial and arteriolar changes), while a substantial number of patients with increased albumin excretion rate exhibited either marked tubulo-interstitial lesions or arteriolar hyalinosis or both, in absence of significant glomerular changes. These findings suggest that it is not true that Type II diabetic patients with microalbuminuria show quite often normal renal histology, but rather than hyperglycemia may cause different patterns of renal injury as compared to Type I Diabetes. Furthermore always with regard to renal histology, it has been pointed out that in Type I diabetes glomerulopathy (especially mesangial) is the crucial change, whereas recent studies found considerable structural heterogeneity amongst proteinuric Type II diabetic patients with relatively high incidence of renal diseases other than diabetes. However parallel studies in a small group of micromacroalbuminuric Type II diabetic patients reported the typical glomerular changes, usually shown by Type I diabetic patients with similar patterns of renal damage. The issue of the relationships between microalbuminuria, hypertension and the development of overt nephropathy in Type II diabetes has been also examined in Pima Indians. The clinical scenario found in these patients does closely resemble that of Caucasian Type I diabetic patients.

Higher brachial-ankle pulse wave velocity as an independent risk factor for future microalbuminuria in patients with essential hypertension: the J-TOPP study

Brachial-ankle pulse wave velocity (baPWV) is a new measure of arterial stiffness. We have shown that a higher baPWV is associated with more severe albuminuria in patients with essential hypertension. However, it is still unclear as to whether baPWV predicts the future albuminuria status in patients under standard care. A total of 321 nondiabetic patients with essential hypertension who had normoalbuminuria or microalbuminuria and were receiving treatment under the current hypertension guidelines were followed up for 2 years. Resting BP, fasting blood glucose, urinary albumin excretion and baPWV were measured before treatment, and periodically thereafter for 2 years. A 2-year treatment regimen lowered BP from 156/93 to 135/81 mmHg (P < 0.0001) and reduced the incidence of microalbuminuria from 25.8 to 14.0%. To determine the predictors for future microalbuminuria status, we compared the baseline data between patients with normoalbuminuria (n = 276) and those with microalbuminuria (n = 45) 2 years after the treatment. The microalbuminuric patients had a significantly higher baPWV and urinary albumin excretion and a significantly lower high-density lipoprotein concentration than the normoalbuminuric patients. Furthermore, the frequency of the use of renin-angiotensin system inhibitors was significantly lower in the microalbuminuric patients than in the normoalbuminuric patients. A multiple logistic regression analysis showed that higher baPWV was an independent risk factor for microalbuminuria 2 years after treatment of hypertension. When we restricted our analysis to a cohort of patients without microalbuminuria at the baseline, we found that higher baPWV was an independent predictor of the development of microalbuminuria after 2 years. Higher baPWV could be an independent risk factor for future microalbuminuria in patients with essential hypertension.

Continuous subcutaneous insulin infusion is more effective than multiple daily insulin injections in preventing albumin excretion rate increase in Type 1 diabetic patients

To compare the effect of continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) on albumin excretion rate (AER) in Type 1 diabetic patients. In a 3-year multicentre retrospective observational study, 110 Type 1 diabetic patients treated with CSII were compared with 110 patients treated with MDI matched at baseline for age, sex, diabetes duration and HbA(1c). At entry, 90 patients in each group had normal AER and 20 persistent microalbuminuria. AER, estimated glomerular filtration rate (eGFR), HbA(1c,) lipids and blood pressure were assessed. HbA(1c) was lower in the CSII than in the MDI group (8.1 +/- 0.9 vs. 8.4 +/- 1.3%; P < 0.005 after 3 years). Blood pressure and eGFR were similar during the study. AER [median (95% confidence interval)], similar at baseline [6.0 microg/min (9, 21) in the CSII group vs. 4.4 (8, 16) in the MDI group, NS] was significantly lower in the patients treated with CSII both at year 2 and at year 3 of follow-up [4.7 microg/min (6, 12) vs. 6.4 (13, 29), P < 0.002]. This difference was observed even when normo- and microalbuminuric patients were analysed separately. Nine patients progressed to microalbuminuria in the MDI group and only one in the CSII group. Nine patients regressed to normoalbuminuria in the CSII group, whereas only two regressed to normoalbuminuria in the MDI group. Despite a small benefit in terms of improved glycaemic control, CSII therapy may be useful in decreasing the progressive increase in AER in Type 1 diabetic patients.

Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy

Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6 years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher ( p < 0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p < 0.01 and p < 0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria ( R = 0.49, p < 0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients ( R = 0.61, p < 0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease.

Cardiorenal Risk Prevalence in Sickle Cell Hemoglobinopathy

Introduction: The spectrum of kidney functional and structural alterations in sickle cell hemoglobinopathy (SCH) is broad. Also, morbidity and mortality from end organ dysfunction, especially cardiorenal dysfunction, are substantial. Consequently, screening an SCH population prospectively for surrogate markers of cardiorenal risk such as albuminuria and intima-media thickness (IMT) was the aim of this cross-sectional study. Patients and Methods: We screened 165 patients with SCH over 4 months at the Primary Care Department, King Abdulaziz Armed Forces Hospital, Saudi Arabia. The 133 who fulfilled the inclusion criteria have been referred for further investigations. Anthropometric evaluation of body mass index (BMI) and blood pressure (BP), determination of 24-hour urine albuminuria, fasting lipids, computed atherogenic risk ratio (ARR), estimated glomerular filtration rate (eGFR), common carotid artery (CCA) IMT measurements, and hemoglobin (Hb) electrophoresis were done. Results: Increased urinary albumin excretion (UAE) rate [380 (272.2–489.6) mg/day; mean and 95% confidence interval (95% CI) of mean] was detected in 24% of SCH patients (6 males and 26 females). Microalbuminuria (168.8 ± 59.7 mg/day) was noted in the majority (63.6%) while macroalbuminuria (752.7 ± 205.4 mg/day) was detected in a smaller percentage (36.4%). Patients with sickle cell disease (SCD) contributed about 66.6% of subjects with microalbuminuria and 100% of those with macroalbuminuria, while most individuals with sickle cell trait (89%) were normoalbuminuric (p < 0.0001). Preclinical atherosclerosis (increased CCA IMT and/or atheromatous plaques) was noticed in 68.8% of SCH individuals with increased UAE (ANOVA p = 0.003). The microalbuminuric and macroalbuminuric patients had comparable BMI, BP values and lipid profiles. However, the microalbuminuric sicklers were significantly younger (28.4 ± 6.7 vs. 34.0 ± 7.2 years, p = 0.04), less anemic (Hb: 9.13 ± 2 vs. 7.47 ± 0.8 g/dl, p = 0.015), with lesser atherosclerosis (IMT; 0.68 ± 0.1 vs. 0.78 ± 0.1 mm, p = 0.004) and higher eGFR (83.3 ± 17.2 vs. 61 ± 10.7 ml/min/1.73 m², p = 0.0004) compared to those with macroalbuminuria. UAE correlated positively with age (r = 0.591, p = 0.0001), systolic BP (r = 0.483, p = 0.005), IMT (r = 0.399, p = 0.024) and negatively with Hb (r = –0.409, p = 0.02), and eGFR (r = –0.620, p = 0.0001). By univariate analysis, the significant indicators of UAE in SCH patients were age (p = 0.05), BMI (p = 0.041), IMT (p = 0.018) and eGFR (p = 0.016). Also, increased risk (odds ratio) of albuminuria was noted with SCD, age, anemia, abnormal eGFR, obesity, and ARR. Conclusions: Markers of cardiorenal risk such as albuminuria and IMT are common findings in SCH patients of Arabic descent and could be useful screening tools to identify sicklers at risk for cardiovascular and renal events.

Increased Ambulatory Arterial Stiffness Index and Pulse Pressure in Microalbuminuric Patients With Type 1 Diabetes

Ambulatory arterial stiffness index (AASI) has been proposed as an indirect measure of arterial stiffness. The aims of this study were (i) to analyze AASI and pulse pressure (PP) in micro- and normoalbuminuric type 1 diabetes mellitus (T1DM) patients and healthy controls and (ii) to explore the relation between nocturnal blood pressure (BP) reduction, BP variability, and AASI. Ambulatory BP monitoring was performed in 34 micro- and 34 normoalbuminuric T1DM patients matched for gender, age, and diabetes duration and in 34 nondiabetic controls matched for gender and age. AASI and PP were calculated based on 24-h, day, and night BP recordings. AASI increased from the control group (0.30 +/- 0.14) to the normo- (0.35 +/- 0.15) and microalbuminuric group (0.41 +/- 0.19; P < 0.05). After adjustment for nightly systolic BP reduction and systolic daytime BP variability (s.d.) in multivariate analysis, the association weakened and became nonsignificant (P = 0.078). No significant intergroup differences were found when AASI was calculated separately from day and night BP data. There was no significant difference between day and night AASI. The 24-h PP increased from the control group (48 +/- 7 mm Hg) to the normo- (50 +/- 6 mm Hg) and microalbuminuric group (54 +/- 9 mm Hg; P < 0.01). The association remained in the multivariate analysis. Day and night PPs were higher in microalbuminuric patients compared to healthy controls. AASI and PP are higher in microalbuminuric T1DM patients compared to healthy controls. The nocturnal BP reduction and systolic daytime BP variability are determinants of AASI. We propose these associations to reflect biological characteristics of arterial stiffness.