Microalbuminuria and hypertension in long-term renal donors

In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.     

Urinary albumin excretion after donor nephrectomy

Surgical ablation of renal tissue in animals leads to compensatory hyperfiltration, hypertension, and focal glomerular sclerosis in remnant nephrons, in association with albuminuria; the detection of slightly elevated urinary albumin (microalbuminuria) has been shown to predict later, more severe renal disease in diabetics. To determine whether unilateral nephrectomy in humans initiates a similar pathogenetic sequence, we measured urinary albumin excretion (UalbV), total protein excretion (UprotV), creatinine clearance (Ccreat) and blood pressure in 22 transplant donors before and at intervals up to 3 years after donor nephrectomy. Urinary albumin was determined using a sensitive enzyme immunoassay (ELISA). Mean Ccreat fell on average to 68% of prenephrectomy values at all times after nephrectomy, indicating a rise of 33% in average single nephron filtration rate. Mean absolute and fractional albumin excretion rates and UprotV values were transiently elevated one week postnephrectomy, but returned thereafter to values not significantly different from prenephrectomy values. Blood pressure rose slightly, but significantly, with time after nephrectomy. Average increases of 10 mm and 5 mm in systolic and diastolic pressures, respectively, were noted by 2 years after surgery. In this study, there was no evidence of glomerular injury from hyperfiltration in the 3 years following donor nephrectomy.     

Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion.

Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA1, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women.     

Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria?

This perspective deals with prediction of overt diabetic nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). The role of elevated urinary albumin excretion rate (microalbuminuria) in predicting diabetic nephropathy has been emphasized by new follow-up studies. Development of severe kidney impairment was seen in a large percentage of patients with microalbuminuria, but with more intensive care for diabetic patients, this percentage may be falling. Herein, I analyzed alternatives to microalbuminuria in predicting kidney disease in diabetes. 1) Parental predisposition to hypertension is not seen in all studies and therefore may not be a decisive factor, and it cannot be used in prediction of nephropathy. 2) Prediabetic blood pressure may predict nephropathy in certain non-insulin-dependent diabetic patients, but elevated blood pressure seems to develop after early microalbuminuria and is likely to be an aggravating factor in established microalbuminuria in IDDM patients. 3) At the clinical diagnosis of IDDM, diabetic nephropathy cannot be predicted. 4) Glycemic control is poor in normoalbuminuric patients with later development of microalbuminuria, and multiple glycosylated hemoglobin measurements are therefore important. 5) In diabetes, glomerular hyperfiltration is associated with late nephropathy, but it alone cannot be the decisive factor, because hyperfiltration in nondiabetic individuals does not produce kidney disease, according to new long-term follow-up studies. 6) Studies of glomerular structure and ultrastructure have not yet documented predictive values for overt nephropathy, but further studies are in progress. 7) Isolated blood pressure elevation without microabuminuria (probably representing essential hypertension in diabetes) has not been predictive. 8) It is clear that elevation of serum creatinine is a very late and insensitive parameter, occurring only with pronounced proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulse pressure and isolated systolic hypertension: association with microalbuminuria. The GUBBIO Study Collaborative Research Group

BACKGROUND: The long-term risk of end-stage renal disease is high in persons with isolated systolic hypertension, that is, those with an elevation of pulse pressure and not of diastolic pressure. Other data suggest that pulse pressure is a predictor of the hypertension-induced organ damage. Microalbuminuria is considered an early sign of glomerular damage caused by hypertension. The study shows the relationship of pulse pressure and isolated systolic hypertension to microalbuminuria in nondiabetic subjects. METHODS: This is a cross sectional analysis for a population sample of 677 men and 890 women, aged 45 to 64 years, who were without diabetes mellitus and macroalbuminuria. Data collection included: overnight urinary albumin and creatinine excretion; fasting plasma glucose, cholesterol, and creatinine; creatinine clearance; and blood pressure, weight, height, medical history, and smoking habit. Pulse pressure was calculated as systolic minus diastolic pressure. Isolated systolic hypertension was defined as systolic pressure > or =140 mm Hg in persons not on antihypertensive drugs and with diastolic pressure <90 mm Hg. Microalbuminuria was defined as urinary albumin excretion > or =20 microg/min. RESULTS: Pulse pressure and isolated systolic hypertension were significantly related to urinary albumin excretion and the prevalence of microalbuminuria in univariate and multivariate analyses. Controlling for gender and other variables, the risk of microalbuminuria was 1.71 with a 15 mm Hg higher pulse pressure (95% CI, 1.31 to 2.22) and 4.95 in the presence of isolated systolic hypertension (95% CI, 3.15 to 7.76). CONCLUSIONS: In nondiabetic, middle-aged adults, pulse pressure and isolated systolic hypertension are directly related to microalbuminuria, independent of diastolic pressure and other correlates.     

Five-year follow-up of patients with epidemic glomerulonephritis due to Streptococcus zooepidemicus.

BACKGROUND: In 1998 there was a large outbreak of acute glomerulonephritis in Nova Serrana, Brazil, caused by group C Streptococcus zooepidemicus. This study describes the follow-up of these patients, after a mean time of 5.4 years of the acute episode. METHODS: Of 135 cases identified in 1998, 56 were re-examined in a prospective study and had measurements of blood pressure, creatinine clearance (estimated by the Cockcroft and Gault formula), microalbuminuria (radioimmunoassay), urine sediment analysis and a protein dipstick test. RESULTS: Of the original group of 135 subjects, 3 died in the acute phase and 5 (3.7%) required chronic dialysis. Of the 56 cases re-evaluated, 54 (96%) were adults (mean+/-SD age, 43+/-17 years) and 36 (64%) females. At the follow-up examination, we found arterial hypertension in 30% (n = 17/56) of the subjects, reduced creatinine clearance (<80 ml/min) in 49% (n = 26/53) and increased microalbuminuria (>20 microg/min) in 22% (n = 11/51). Compared to the evaluation carried out 3 years before, the number of cases with creatinine clearance lower than 80 ml/min increased from 20 to 26 (of 53 cases). Increased microalbuminuria and/or reduced creatinine clearance were detected in 57% (n = 32/56) of the subjects. Patients with reduced creatinine clearance were older than those without reduced renal function (54+/-15 vs 34+/-12 years, P<0.001). CONCLUSIONS: After a mean time of 5.4 years, a relatively high proportion of patients with epidemic poststreptococcal glomerulonephritis due to S.zooepidemicus present hypertension, reduced renal function and increased microalbuminuria.     

Prevalence of albuminuria in Australia: the AusDiab Kidney Study

BACKGROUND: Albuminuria is an important predictor of risk of progressive renal disease, cardiovascular disease, and mortality; however, the prevalence in the general population is not well defined. We determined estimates of the population prevalence and associations of microalbuminuria and macroalbuminuria in Australian adults; 11,247 Australians aged > or = 25 years living in 42 randomly selected population clusters were tested for albuminuria (spot urine albumin:creatinine (mg/mmol): normal < 3.4, microalbuminuria 3.4 to 34, macroalbuminuria > 34). METHODS: Prevalence of micro- and macroalbuminuria were assessed with age, sex, obesity, smoking, hypertension (> or = 140/90 mm Hg or known diagnosis on treatment), glucose metabolism status (WHO criteria according to fasting glucose and oral glucose tolerance test), ischemic heart and cerebrovascular disease, and low glomerular filtration rate (calculated glomerular filtration rate < 60 mL/min/1.73m2). RESULTS: Microalbuminuria and macroalbuminuria proteinuria were present in 6.0% and 0.6% of the population, respectively. The majority of subjects with microalbuminuria (64%) and macroalbuminuria (76%) had hypertension, and approximately half of those with albuminuria had abnormal glucose metabolism. Of all participants with microalbuminuria, 25.9% had normal blood pressure and glucose metabolism, and in this group, alternative associations of microalbuminuria included obesity (13.5%), smoking (20.7%), and low glomerular filtration rate (12.3%). CONCLUSION: Albuminuria is present in a small percentage of the general adult population, but is highly prevalent in subjects with hypertension and/or abnormal glucose metabolism. The majority of cases of microalbuminuria and macroalbuminuria in the general population are among those with hypertension.     

Glomerular hyperfiltration after unilateral nephrectomy in living kidney donors

Glomerular hyperfiltration, which is expected to occur after uninephrectomy, could potentially damage the non-transplanted donor kidney in living donor transplantation. We therefore prospectively measured renal function (inulin and PAH clearance), albumin excretion and blood pressure in the donors of 30 consecutive living donor kidney transplants before uninephrectomy (n = 29) and 1 week (n = 27) and 1 year (n = 16) after. Hyperfiltration was defined as: (post-nephrectomy inulin clearance)/(0.5 x pre-nephrectomy inulin clearance); hyper-perfusion was defined in an analogous way for PAH clearance. Hyperfiltration averaged 128 ± 5% [SEM] and hyperperfusion 133 ± 6% 1 week after uninephrectomy. Hyperfiltration was nearly unchanged (126 ± 7%) 1 year after nephrectomy, whereas hyperperfusion had significantly decreased to 118 ± 8% (P < 0.02). There was no significant change in blood pressure after nephrectomy, and no new cases of hypertension were observed during the 1-year follow-up. The degree of hyperfiltration did not correlate with donor age. Microalbuminuria > 30 mg/24 h was found in two donors 1 week after nephrectomy (one of which normalized at 1 year) and in one additional donor 1 year after nephrectomy. The degree of hyperfiltration did not correlate with albumin excretion rate. In conclusion, no adverse consequences of hyperfiltration were demonstrable during the 1-year observation period, but the prognostic role of occasional microalbuminuria should be further investigated.     

Glomerular filtration surface in type I diabetes mellitus

Previously we have shown that relative glomerular mesangial expansion was an important correlate of renal dysfunction in diabetes. To extend the understanding of structural functional relationships, 37 patients with type I diabetes mellitus for 5 to 33 years were studied with multiple creatinine clearance (Ccr), urinary albumin excretion, and blood pressure measurements, and percutaneous renal biopsies. Glomerular volume and percent sclerosed glomeruli were determined; quantitative stereology was performed to determine relative glomerular structural parameters. Per glomerulus we calculated mesangial volume and capillary filtration surface and per patient we estimated capillary filtration surface. Capillary filtration surface per glomerulus or per patient were highly predictive of Ccr (r = +0.78, r = +0.79, P less than 0.001). There was a significant but weak relationship between Ccr and mesangial volume. However, mesangial volume and glomerular volume together were highly predictive of both Ccr and filtration surface. Mesangial volume was increased and filtration surface decreased in the hypertensive patients and the patients with urinary albumin excretion less than 250 mg/24 hr. Thus, it appears that mesangial expansion within a relatively large glomerulus has less influence on filtration than does a similar increase in mesangial volume within a smaller glomerulus. There is a striking relationship between glomerular filtration rate and filtration surface in diabetes throughout the range from hyperfiltration to significant hypofiltration.     

Urinary albumin excretion in normal pregnancy and pregnancy-induced hypertension.

We measured the urinary excretion of albumin in 67 healthy primigravidae, at monthly intervals, from 16 to 36 weeks of gestation and 12 weeks postpartum. Of the 67 primigravidae, 55 completed a normal pregnancy and 12 developed pregnancy-induced hypertension. In the latter group, an additional measurement of urinary albumin excretion was performed at 24 weeks postpartum. The aims of the study were: to look for changes of urinary albumin excretion during the progression of normal pregnancy; to assess if microalbuminuria could be an early feature of pregnancy-induced hypertension; to evaluate the effects of physical activity on the excretion of albumin in normal pregnancy and pregnancy-induced hypertension. In contrast with glomerular hyperfiltration and increased urinary total protein, two recognized characteristics of the pregnant state, we found that normal primigravidae, during the day, excrete significantly less albumin (p between less than 0.01 and less than 0.001) in comparison with the postpartum period and nonpregnant women. Normal primigravidae, as a group, showed parallel changes of urinary albumin excretion and diastolic blood pressure throughout pregnancy and postpartum, suggesting an important physiologic role of hemodynamic factors in regulating glomerular permeability to albumin. The daytime urinary albumin excretion in patients developing pregnancy-induced hypertension was significantly higher (p between less than 0.005 and less than 0.001) than in normal pregnancy from the 28th gestational week onwards. The increased urinary albumin excretion preceded the onset of hypertension and tended to persist long after blood pressure had returned to normal levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular hyperfiltration and albuminuria in children with sickle cell anemia

Early manifestations of sickle nephropathy include glomerular hyperfiltration and proteinuria, typically microalbuminuria. Over time, a subset of patients develops histologic changes, decreased glomerular filtration, and ultimately renal failure. This study was designed to determine the rate of glomerular hyperfiltration and prevalence of albuminuria in a cross-sectional analysis of untreated children with sickle cell anemia (SCA), and to identify correlates of both complications. Measured glomerular filtration rate (GFR) by plasma clearance of 99-technetium diethylenetriaminepentaacetate was compared to GFR estimates calculated from published formulas. Eighty-five children (mean age 9.4 ± 4.8 years) were studied; 76% had glomerular hyperfiltration with mean GFR = 154 ± 37 ml/min/1.73 m². GFR declined in teenage years and was significantly correlated with increased serum cystatin C levels and higher systolic blood pressure. Measured GFR had only modest correlations with GFR estimates (Pearson correlation coefficients ≤0.5). Albuminuria, usually microalbuminuria, occurred in 15.9% and was associated with higher diastolic blood pressure and lower white blood cell and absolute neutrophil counts. Cystatin C levels inversely reflect GFR changes and are associated with albuminuria; serial monitoring may provide a sensitive and accurate marker of nephropathy in children with SCA.     

C-reactive protein is associated with renal function abnormalities in a non-diabetic population

BACKGROUND: C-reactive protein (CRP) has recently been introduced in cardiovascular medicine as a predictor of myocardial infarction, stroke and peripheral artery disease in different populations. We hypothesized that elevated CRP levels are associated with renal function abnormalities. METHODS: To test this hypothesis, we studied the relationship between CRP levels and renal function loss measured as diminished creatinine clearance in a large non-diabetic population (7317 subjects). In addition, the associations and confounding effects of established renal risk factors that could explain the association between CRP and diminished renal filtration were studied. Also, the association of CRP with early alterations in renal function, such as those evidenced by a relatively high glomerular filtration ("hyperfiltration"), was examined. CRP levels were divided in quartiles. Subjects with CRP levels within the first quartile were defined as the reference group. Diminished renal filtration and hyperfiltration were defined as a creatinine clearance below or exceeding two times the prediction interval of the age- and sex-related reference group. RESULTS: Elevated CRP levels were positively associated with cardiovascular and renal risk factors: age, body mass index, blood pressure, serum cholesterol level, smoking, plasma glucose level and elevated urinary albumin excretion. Elevated CRP was positively associated with diminished filtration (OR 1.8; 95% CI 1.2 to 2.6). In multivariate analyses, CRP was independently associated with a diminished filtration (OR 1.9; 95% CI 1.3 to 2.9). Interestingly, CRP also was associated with hyperfiltration (highest quartile, OR 1.7; 95% CI 1.2 to 2.5). However, body mass index accounted for most of the relationship between CRP and hyperfiltration. CONCLUSIONS: As in cardiovascular disease, CRP appears to be a risk marker for renal function loss. The mechanism of this relationship remains to be clarified. However, the association between CRP, body weight, and a relatively elevated creatinine clearance is a hypothesis-generating finding, suggesting that early inflammatory processes related to high body fat may predispose the kidney to glomerular hyperfiltration-related renal function loss.     

Glomerular hyperfiltration increases the risk of developing microalbuminuria in diabetic children

An elevated glomerular filtration rate (GFR) is frequently detectable in type 1 diabetic children and adolescents and in those without any other evidence of incipient diabetic nephropathy. In 1982 we detected 23 patients with hyperfiltration (GFR>140 ml/min per 1.73 m²), aged 9–15 years, with diabetes for longer than 4 years; 23 age- and sex-matched patients with diabetes of a similar duration and without hyperfiltration served as controls. Both groups were followed until March 1992, by assessing GFR every 12 months, albumin excretion rate every 6 months, blood pressure and glycated haemoglobin (HbA1) every 3 months. Dietary protein intake was similar in patients with hyperfiltration and in controls. No other drug except insulin was used throughout the study. The insulin regimen was similar in the two groups. There was no significant difference between the two groups regarding albumin excretion, blood pressure and HbA1 at the beginning of the study. Of the 23 patients with hyperfiltration, 7 developed persistent microalbuminuria (defined as an overnight albumin excretion rate >30 g/min per 1.73 m² on at least 5 consecutive measurements); 2 of these patients had overt proteinuria. Only 1 of the diabetics with normal GFR developed persistent microalbuminuria. The positive predictive value for microalbuminuria of an initial GFR>140 ml/min per 1.73 m² was 63%; the negative predictive value of an initial GFR<140 ml/min per 1.73 m² was 94%. The increase of albumin excretion rate into the microalbuminuric range precedes the elevation of both systolic and diastolic blood pressure. Persistent glomerular hyperfiltration is a risk factor for the development of microalbuminuria and incipient nephropathy in type 1 diabetic children, adolescents and young adults.     

Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 +/- 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 +/- 1.7 vs. 20.5 +/- 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 +/- 8.6 ml/min, filtration fraction 20.4 +/- 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 +/- 31 to 40.4 +/- 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.     

RENAL OUTCOME 25 YEARS AFTER DONOR NEPHRECTOMY

PURPOSE: The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS: From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS: Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS: Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.     

Central obesity, incident microalbuminuria, and change in creatinine clearance in the epidemiology of diabetes interventions and complications study

Weight gain and central obesity are associated with insulin resistance, hypertension, and dyslipidemia in type 1 diabetes. These metabolic abnormalities are risk factors for kidney disease in the general population, but data addressing the relationship of central obesity with kidney disease in type 1 diabetes are limited. Whether waist circumference is associated with incident microalbuminuria and change in creatinine clearance was examined among 1279 participants who had type 1 diabetes and were enrolled in the Epidemiology of Diabetes Interventions and Complications Study, the observational extension of the Diabetes Control and Complications Trial (DCCT). Ninety-three of 1105 participants with normal albumin excretion rate (AER) at DCCT closeout developed incident microalbuminuria over 5.8 yr of follow-up. The hazard ratio for incident microalbuminuria that was associated with each 10-cm greater waist circumference at DCCT closeout was 1.34 (95% confidence interval 1.07 to 1.68), after adjustment for DCCT closeout age, gender, duration of diabetes, treatment group, smoking status, glycosylated hemoglobin, and AER. This increased risk was modestly attenuated when additional adjustment was made for levels of BP and serum lipids. Creatinine clearance declined by an average of 0.34 ml/min per 1.73 m2 each yr over 8 yr of follow-up. Greater rate of decline in creatinine clearance was associated with greater age, conventional insulin therapy during the DCCT, smoking, and greater glycosylated hemoglobin and AER at DCCT closeout but not with waist circumference. In conclusion, waist circumference predicts the subsequent development of microalbuminuria in type 1 diabetes. In contrast, no association of waist circumference with decline in creatinine clearance was observed.     

Prevalence of microalbuminuria and relationship to the risk of cardiovascular disease in the Japanese population

The prevalence of microalbuminuria and its relationship to cardiovascular disease risk factors were examined in subjects participating in an annual physical and laboratory examination program. The urinary albumin concentration and the urinary albumin/creatinine ratio were determined in morning urine specimens. A turbidimetric immunoassay was used for the measurement of urinary albumin. Of the 731 subjects, 41 (5.6%) who were weakly positive or positive on a routine dipstick test for protein were excluded from the final analysis of data. Microalbuminuria was present in 14.5% of the men, in 12.4% of the women, and in 13.2% of the entire subject population when defined as a urinary albumin concentration of 30-299 microgram/ml. The prevalence of microalbuminuria was significantly higher in subjects with a high normal blood pressure (15.0%) or hypertension (26.2%) as compared with normotensive subjects (6.5%). Subjects with impaired glucose tolerance (24.3%) or hyperglycemic subjects (50.0%) had a significantly higher prevalence of microalbuminuria than normoglycemic subjects (11.3%). The prevalence of microalbuminuria was significantly higher in subjects with left ventricular hypertrophy (47.1%) as compared with those with normal electrocardiograms (11.3%). A good correlation was observed between urinary albumin concentration and albumin/creatinine ratio, and both showed a significant positive correlation with age, systolic and diastolic blood pressures, and fasting plasma glucose, total serum protein, albumin, and triglyceride levels, but not with angiotensin-converting enzyme activity. Multiple regression analysis demonstrated that both the urinary albumin concentration and the albumin/creatinine ratio show a significant positive correlation with systolic blood pressure and fasting plasma glucose. The prevalence of microalbuminuria was about 13% in this Japanese cohort, and the systolic blood pressure and the fasting plasma glucose level were demonstrated as independent risk indicators for both urinary microalbumin level and urinary microalbumin/creatinine ratio.     

Glomerular hyperfiltration: a new marker of metabolic risk

Chronic kidney disease coexists with metabolic syndrome and this relationship may be apparent before overt manifestations of cardiovascular disease. To investigate early stages of the natural history of associations between renal function and metabolic syndrome, we phenotyped 1572 young (mean age=18.4 years), apparently healthy men for metabolic risk factors and estimated their creatinine clearance based on the Cockcroft-Gault equation. High metabolic risk (clustering of at least three metabolic risk factors) was revealed in 8.7% (137) of the subjects and was associated with a 6.9-fold increase in the odds of glomerular hyperfiltration (95% confidence interval (CI): 3.9-11.5) when compared to reference (from none to two metabolic risk factors). Overweight, elevated blood pressure, and low high-density lipoprotein (HDL) cholesterol increased the multivariate-adjusted odds ratio of glomerular hyperfiltration to 6.6 (95% CI: 3.8-11.6), 1.8 (95% CI: 1.0-3.0), and 2.5 (95% CI: 1.5-4.3), respectively. Systolic and diastolic blood pressures clustered together with leptin in the factor analysis and this blood pressure-adiposity component correlated with estimated creatinine clearance (r=0.329, P<0.0001) and explained on its own 10.2% of the variance in the estimated renal function. Our data reveal the silent epidemics of metabolic risk among young, apparently healthy men. Furthermore, the results indicate that high metabolic risk is associated with glomerular hyperfiltration before overt manifestations of cardiovascular disease.     

Decreasing glomerular filtration rate - an indicator of more advanced diabetic glomerulopathy in the early course of microalbuminuria in IDDM adolescents?

Background. Overt diabetic nephropathy is accompanied by a progressive decline in glomerular filtration rate (GFR). In this study we have investigated if a reduction of GFR already during the transition from normo- to microalbuminuria is associated with glomerular structural changes. Methods. Seventeen adolescents (11 girls/6 boys) with 10.5 (3.4) (mean, SD) years of IDDM were studied. GFR was previously measured in the normoalbuminuric stage 2-5 years prior to the renal biopsy, and measured again at the time for the biopsy, after in mean 1.8 years of microalbuminuria (15-200 &mgr;g/min). HbAlc and albumin excretion rate were measured 3 or 4 times yearly and blood pressure 1-4 times yearly between the GFR examinations. The associations between the yearly rate of fall in GFR and basement membrane (BM) thickness, mesangial and matrix volume fractions, matrix star volume, mean capillary diameter (CAPD), area of filtration surface (peripheral BM) per glomerulus, total capillary length per glomerulus, the ratio of peripheral BM to capillary surface, glomerular volume, and interstitial volume fraction were analysed. Results. BM thickness and matrix star volume were increased in patients with, as compared to those without, a decline in GFR⩾6 ml/min per year (P<0.005 respectively). Patients with previous glomerular hyperfiltration (⩾135 ml/min per 1.73 m²) showed the steepest decline in GFR; 11 ml/min per year versus -0.8 ml/min per year in previously normofiltering patients, P<0.001. The rate of fall in GFR was positively correlated to BM thickness (P<0.001), interstitial volume fraction (P=0.02) and CAPD (P=0.04), mean HbAlc (P=0.01), but not to the change in HbAlc between GFR examinations. Conclusion. A decreasing glomerular filtration rate in the early stage of microalbuminuria may be due to more advanced diabetic glomerulopathy than in IDDM patients with stable GFR.