Baseline bone turnover marker levels can predict change in bone mineral density during antiresorptive treatment in osteoporotic patients: the Copenhagen bone turnover marker study.

Anti-resorptive osteoporosis treatment might be more effective in patients with high bone turnover. In this registry study including clinical data, high pre-treatment bone turnover measured with biochemical markers was correlated with higher bone mineral density increases. Bone turnover markers may be useful tools to identify patients benefitting most from anti-resorptive treatment. INTRODUCTION: In randomized, controlled trials of bisphosphonates, high pre-treatment levels of bone turnover markers (BTM) were associated with a larger increase in bone mineral density (BMD). The purpose of this study was to examine this correlation in a real-world setting. METHODS: In this registry-based cohort study of osteoporosis patients (n = 158) receiving antiresorptive therapy, the association between pre-treatment levels of plasma C-telopeptide of type I Collagen (CTX) and/or N-terminal propeptide of type I procollagen (PINP) and change in bone mineral density (BMD) at lumbar spine, total hip, and femoral neck upon treatment was examined. Patients were grouped according to their pre-treatment BTM levels, defined as values above and below the geometric mean for premenopausal women. RESULTS: Pre-treatment CTX correlated with annual increase in total hip BMD, where patients with CTX above the geometric mean experienced a larger annual increase in BMD (p = 0.008) than patients with CTX below the geometric mean. The numerical pre-treatment level of CTX showed a similar correlation at all three skeletal sites (total hip (p = 0.03), femoral neck (p = 0.04), and lumbar spine (p = 0.0003)). A similar association was found for PINP where pre-treatment levels of PINP above the geometric mean correlated with a larger annual increase in BMD for total hip (p = 0.02) and lumbar spine (p = 0.006). CONCLUSION: Measurement of pre-treatment BTM levels predicts osteoporosis patients' response to antiresorptive treatment. Patients with high pre-treatment levels of CTX and/or PINP benefit more from antiresorptive treatment with larger increases in BMD than patients with lower pre-treatment levels.

Irbesartan treatment does not influence plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone in participants with type 2 diabetes and microalbuminuria: An IRMA2 sub-study.

AIM: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. METHODS: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. RESULTS: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907-1509) nmol/l vs. irbesartan 300 mg 1053 (820-1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. CONCLUSION: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).

Prevalence of muscle dysfunction concomitant with osteoporosis in a home-dwelling Danish population aged 65-93 years - The Copenhagen Sarcopenia Study.

INTRODUCTION: As life expectancy increases, a growing percentage of older individuals with age-related diseases such as osteoporosis and sarcopenia are expected. Patients with both conditions, i.e. patient with osteosarcopenia, are suggested to have a higher risk of fall and fracture compared to individuals with either condition. AIM: To investigate the potential relationship between low bone mineral density (BMD) and muscle dysfunction in a Danish cohort of older home-dwelling individuals. Furthermore, to examine the prevalence of osteosarcopenia and alterations in prevalence depending on cut-off values chosen. METHOD: Measures of BMD, relative appendicular lean mass and hand grip strength were assessed in 529 individuals aged 65+ from the population-based cross-sectional Copenhagen Sarcopenia Study (CSS). Osteoporosis was diagnosed according to the World Health Organization guidelines. Sarcopenia was diagnosed in accordance with the guidelines from the European Working Group on Sarcopenia in Older People (EWGSOP2) with application of cut-off values from the EWGSOP2 paper compared to cut-off values derived from a local cohort (CSS). RESULTS: 19.2% had osteoporosis (66 women and 35 men), whereas 2.7% (6 women and 8 men) and 4.2% (7 women and 15 men) had sarcopenia with application of EWGSOP2 and CSS cut-off values, respectively. Using the EWGSOP2 cut-off values, 1.5% (4 women and 4 men) were diagnosed with osteosarcopenia compared to 1.4% (4 women and 3 men) using CSS cut-off values. In the osteoporosis sub-population, 8% (EWGSOP2) and 7% (CSS) had sarcopenia and within the sarcopenia sub-population, 61.5% (EWGSOP2) and 33.3% (CSS) had osteoporosis. At all sites, BMD was lower among individuals with sarcopenia and sarcopenia increased the risk of osteoporosis (odds ratios: EWGSOP2: 7.3 (p < 0.001) and CSS: 2.2 (ns)). CONCLUSION: Osteosarcopenia was present in 1.5% of a group of healthy home-dwelling older individuals. Notably, individuals with sarcopenia had lower BMD and a higher risk of osteoporosis, whereas the opposite (prevalence of sarcopenia in individuals with osteoporosis) was not as frequent. Our data indicate that screening for sarcopenia and osteoporosis should be performed simultaneously in older individuals at high risk of falls and fractures. However, further studies with outcome-related results are needed to identify optimal measures of osteosarcopenia and cut-off values for sarcopenia.

Incident microalbuminuria and complement factor mannan-binding lectin-associated protein 19 in people with newly diagnosed type 1 diabetes.

BACKGROUND: Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. METHODS: Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. RESULTS: Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. CONCLUSIONS: In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.

Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes.

BACKGROUND: In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control. METHODS: One hundred T1DM patients with haemoglobinA(1c) (HbA(1c)) > or =8.5% during the year before enrolment entered a 1-month run-in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year. RESULTS: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non-HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA(1c) (previously reported) was not significant different between treatments. CONCLUSION: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.

Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation.

We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis/bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2, 3 and 12 weeks postoperatively. Mean mGFR declined from 103 +/- 18 to 65 +/- 22, 53 +/- 16 and 57 +/- 18 mL/min/1.73m(2) at 1-, 3- and 12-weeks post-LTx (p < 0.0001), respectively. In a time-dependent repeated measures ANOVA, risk factors for a decline in mGFR posttransplant included: time (p < 0.0001), acute renal failure within 2 weeks post-LTx (p = 0.0003), use of heart and lung machine (p = 0.04), and the use of ephedrine (p = 0.048), as well as increasing age, older than 18 years at LTx (p = 0.006). These data demonstrate that renal function, measured with an isotope method, decreases dramatically during the first week after LTx.

Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes.

AIMS/HYPOTHESIS: Raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with a poor cardiac outcome in non-diabetic populations. Elevated NT-proBNP predicts excess morbidity and mortality in diabetic patients with an elevated urinary albumin excretion rate. This study investigated the prognostic value of NT-proBNP in a cohort of type 2 diabetic patients. SUBJECTS, MATERIALS AND METHODS: In a prospective observational follow-up study, 315 type 2 diabetic patients with normoalbuminuria (n=188), microalbuminuria (n=80) and macroalbuminuria (n=47) at baseline were followed for a median (range) of 15.5 (0.2-17.0) years. Plasma NT-proBNP concentrations were determined by immunoassay at baseline. Endpoints were overall and cardiovascular mortality. RESULTS: Of the patients, 162 died (51%), 119 of them (74%) due to cardiovascular causes. All-cause mortality was increased in patients with NT-proBNP in the second and third tertiles (hazard ratios [95% CI] compared with the first tertile, 1.70 [1.08-2.67] and 5.19 [3.43-7.88], p<0.001). These associations persisted after adjustment for urinary albumin excretion rate, glomerular filtration rate and conventional cardiovascular risk factors (covariate adjusted hazard ratios 1.46 [0.91-2.33] and 2.54 [1.56-4.14], p<0.001). This increased mortality was attributable to more cardiovascular deaths in the second and third NT-proBNP tertile (unadjusted hazard ratios 1.63 [0.96-2.77] and 4.88 [3.01-7.91], p<0.001; covariate adjusted 1.37 [0.79-2.37] and 2.26 [1.27-4.02], p=0.01). When patients with normo-, micro- and macroalbuminuria were analysed separately, NT-proBNP levels above the median (62 ng/l) were consistently associated with increased overall and cardiovascular mortality in all three groups (p<0.001). CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, elevated circulating NT-proBNP is a strong predictor of the excess overall and cardiovascular mortality, this predictor status being independent of urinary albumin excretion rate and conventional cardiovascular risk factors.

Remission of nephrotic-range albuminuria reduces risk of end-stage renal disease and improves survival in type 2 diabetic patients.

AIMS/HYPOTHESIS: We evaluated the impact of remission of nephrotic-range albuminuria (>2500 mg/24 h) (NRA) on end-stage renal disease (ESRD) and mortality in type 2 diabetic patients with nephropathy. METHODS: This was a follow-up observational study involving all 79 patients (35%; 62 men, 17 women) with NRA from a cohort of type 2 diabetic patients with nephropathy that was followed for at least 3 years at the Steno Diabetes Center (n=227). Patients were followed from the onset of NRA until death or January 2005. The mean age (+/-SD) was 60+/-8 years and known diabetes duration was 14+/-7 years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year. RESULTS: The duration of follow-up after onset of NRA was 6.5 years (range 2-20 years). Remission was induced in 20 (25%) of the patients, all treated with ACE inhibitors or angiotensin-II receptor blockers. Remission lasted 4.1 years (range 1-10 years) and only three patients relapsed. At the end of follow-up, only 30% (two ESRD and four deaths) of the 20 patients with remission had reached the composite endpoint of ESRD or death, in contrast to 66% (16 ESRD and 23 deaths) of the 59 patients without remission (p<0.01). Cox regression analysis revealed that remission was associated with a risk reduction of 67% (95% CI 10-87) for reaching the composite endpoint of ESRD or death and of 69% (95% CI 21-88%) for death alone. Male sex, greater age and systolic blood pressure at onset of NRA were also independently associated with an increased risk of ESRD and death. CONCLUSIONS/INTERPRETATION: Aggressive antihypertensive treatment can lead to long-term remission of NRA in a sizeable proportion of patients with type 2 diabetes. Such remission is associated with a slower progression of nephropathy and substantially improved survival.

Birth weight--a risk factor for progression in diabetic nephropathy?

OBJECTIVES: Intrauterine growth retardation, as seen in individuals with low weight at birth, may give rise to a reduction in nephron number. Oligonephropathy has been linked to hypertension and renal disease in adult life. We tested the concept that low weight at birth acts as a risk factor for progression of diabetic nephropathy. DESIGN AND SUBJECTS: We performed an observational follow-up study of 161 (97 men) type 1 diabetic patients with diabetic nephropathy [mean age (SD): 35 (11) years, mean duration of diabetes: 22 (8) years]. All patients had been followed for at least 3 years [median (range): 8 (3-20)] with at least three measurements [9 (3-31)] of glomerular filtration rate (GFR) (51Cr-EDTA). Information about birth size was obtained from midwife registrations. SETTINGS: Steno Diabetes Center, a tertiary referral centre. MAIN OUTCOME MEASURES: Loss of kidney function according to birth weight and weight/length ratio at birth. RESULTS: There was no correlation in univariate analysis between birth weight or weight/length ratio and rate of decline in GFR, neither in men nor in women. Furthermore, the 27 patients with birth weights below the 20th centile had a rate of decline in GFR [median (range)] similar to the 134 patients above: 2.6 (-4.7; 9.6) vs. 3.4 (-2.3; 19.3) mL min(-1) year(-1), respectively (NS). A multiple regression analysis revealed that albuminuria, arterial blood pressure, and haemoglobin A1C during follow-up showed a significant correlation with the decline in GFR [R2 (adjusted) = 0.34], whereas birth weight and birth weight/length ratio did not. CONCLUSIONS: Our study does not suggest that weight at birth is associated with progression of established diabetic nephropathy in type 1 diabetic patients, whilst several other potential modifiable risk factors were identified.

Progression of diabetic nephropathy: role of plasma homocysteine and plasminogen activator inhibitor-1.

Among patients with diabetic nephropathy, the decline in glomerular filtration rate (GFR) varies substantially, ranging from 2 to 20 mL/min per year. Identification of predictors of progression in diabetic nephropathy is important. Plasma total homocysteine (tHcy) rises with urinary albumin excretion rate in diabetes, and plasminogen activator inhibitor-1 (PAI-1) has been correlated with increased matrix accumulation in various glomerulopathies. In this prospective observational cohort study, we evaluated the importance of baseline tHcy and PAI-1 as predictors of the rate of decline in GFR. Baseline tHcy and PAI-1 were measured in 157 type 1 diabetic patients with diabetic nephropathy (92 men; mean age, 41 +/- 10 years; mean diabetes duration, 27 +/- 8 years; median GFR, 80 mL/min/1.73 m(2) [range, 23 to 143 mL/min/1.73 m(2)]). Hereafter, GFR was measured yearly with a plasma clearance technique for at least 3 years (median, 7 years [range, 3.0 to 8.3 years]). The mean rate of decline in GFR was 3.7 +/- 0.3 mL/min per year. A linear regression analysis revealed a borderline significant relationship between rate of decline in GFR and tHcy (P = 0.069) and PAI-1 (P = 0.087). Analysis of the rate of decline in GFR and tertiles of tHcy and PAI-1 revealed that increasing levels of tHcy were correlated with a significantly faster decline in GFR (P = 0.025), whereas increasing levels of PAI-1 were not. After adjustment for other well-established risk factors for progression of nephropathy in a multiple linear regression analysis, however, neither tHcy levels nor PAI-1 levels were independent predictors of rate of decline in GFR.

Remission of nephrotic-range albuminuria in type 1 diabetic patients.

OBJECTIVE: To evaluate the cumulative incidence of nephrotic-range albuminuria (NRA), the frequency of remission, and the impact on progression, we analyzed data from a prospective cohort study of type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: All of the albuminuric type 1 diabetic patients (n = 321, 121 women), who had at least yearly measurements of glomerular filtration rate (GFR) with a (51)Cr-EDTA plasma clearance technique and were followed for at least 3 years, were evaluated. NRA, defined as persistent albuminuria >2,500 mg/24 h, occurred in 126 patients (35 women) aged (mean +/- SD) 34 +/- 8 years, with duration of diabetes 22 +/- 8 years and follow-up time from onset of NRA (median [range]) 8.7 (3.0-20.9) years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year. RESULTS: The cumulative incidence of NRA was 39%. Remission was induced in 28 of 126 (22%) patients; 21 were predominantly treated with ACE inhibitors, 7 with non-ACE inhibitor medications. Remission lasted 3.6 (1.0-18.1) years. More women (37%) than men (16%) obtained remission (P = 0.01). In the remission group compared with the no-remission group, mean arterial blood pressure (mean +/- SEM) was reduced (102 +/- 1 vs. 106 +/- 1 mmHg, P < 0.01), the rate of decline in GFR was diminished (3.8 +/- 0.6 vs. 7.5 +/- 0.5 ml x min(-1) x year(-1), P < 0.001), and serum cholesterol was lower (5.3 +/- 0.2 vs. 6.1 +/- 0.1 mmol/l, P < 0.01) during the whole follow-up period. No difference in glycemic control was found between groups (HbA(1c) 9.2 vs. 9.4%, NS). CONCLUSIONS: In contrast to observations made before the use of antihypertensive treatment, our prospective observational study suggests that aggressive antihypertensive treatment with and without ACE inhibitors can induce long-lasting remission in a sizeable fraction of type 1 diabetic patients with NRA. The group of patients obtaining remission is characterized by slow progression of diabetic nephropathy and improved cardiovascular risk profile.

Evolving strategies for renoprotection: diabetic nephropathy.

A cumulative incidence of diabetic nephropathy of 25-40% has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients. Diabetic nephropathy has become the leading cause (25-44%) of end-stage renal failure in Europe, the United States and Japan. Until the early 1980s, no renoprotective treatment was available for use in diabetic nephropathy. Death occurred on average 5-7 years after the onset of persistent proteinuria. It should be recalled that development of treatment modalities occurred in reverse order: in the early 1980s, antihypertensive treatment of diabetic nephropathy was introduced, and in the early 1990s, primary and secondary prevention with improved glycaemic control and angiotensin-converting enzyme inhibition. The two main treatment strategies for primary prevention of diabetic nephropathy are improved glycaemic control and blood pressure lowering, particularly using drugs such as angiotensin-converting enzyme inhibitors. Megatrials and meta-analyses have clearly demonstrated the beneficial effect of both the above-mentioned treatment modalities. Secondary prevention, that is, treatment modalities applied to diabetic patients with high risk of development of diabetic nephropathy (e.g. those with microalbuminuria) has been documented, applying angiotensin-converting enzyme inhibitors in both type 1 and type 2 diabetic patients. Furthermore, improved metabolic control reduces the risk of progression. In special cases (such as pancreas transplantation) even reversal of diabetic glomerular lesions has been documented. Antihypertensive treatment of patients with overt nephropathy induces a reduction in albuminuria, a reduction in the rate of decline of glomerular filtration rate, delays development of end-stage renal failure and improves survival. Many potential treatment modalities in preventing and treating diabetic nephropathy are presently being evaluated.

Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively.

BACKGROUND: Diabetic nephropathy is a chronic, progressive kidney disease with a mean rate of decline of in glomerular filtration rate (GFR) of 10 to 12 mL/min/year (natural history). The introduction of aggressive antihypertensive treatment has improved the renal prognosis during the last decades. To examine whether remission and regression of diabetic nephropathy are possible in type 1 diabetic patients, we analyzed data from a prospective observational cohort study that was started in 1983. METHODS: We measured GFR with a 51Cr-EDTA plasma clearance technique every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. Blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol were measured every three to four months during the study. In total, 271 patients received antihypertensive treatment, 179 patients predominantly with angiotensin-converting enzyme inhibitors. Remission was defined as albuminuria <200 microg/min sustained for at least one year and a decrease of at least 30% from preremission levels (surrogate endpoint), and regression as a rate of decline in GFR (DeltaGFR) equal to the natural aging process: < or =1 mL/min/year during the entire observation period (principal end point). RESULTS: The total number of patients who obtained remission was 92 (31%), with a duration of remission of [median (range)] 3.4 (1.0 to 14.1) years, and regression 67 (22%). The patients were stratified in quintiles by the average value of office mean arterial blood pressure (mean +/- SE): 93 +/- 0.5, 99 +/- 0.2, 103 +/- 0.1, 107 +/- 0.2, and 113 +/- 0.4 mm Hg. The prevalence of patients obtaining remission/regression was 58/42, 33/32, 25/11, 20/20, and 17/7% in each quintile, respectively. Spontaneous remission and regression occurred in 10 and 14 patients from the persistent normotensive group (N = 30), none of whom had ever received antihypertensive treatment. In all 301 consecutive patients, the (mean +/- SE) DeltaGFR was 4.0 +/- 0.2 mL/min/year during the investigation period. CONCLUSIONS: Our study suggests that aggressive antihypertensive treatment in type 1 diabetic patients can induce remission and regression in a sizable fraction of patients with diabetic nephropathy. Lower arterial blood pressure, reduced albuminuria, and better glycemic control were predictors of regression of diabetic nephropathy.

Progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy is a major cause of renal failure. The decline in glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20, with a median of 12 mL/min/year. The risk factors of losing filtration power (progression promoters) have not been clearly identified. Furthermore, information on optimal arterial blood pressure, glycemic control, and cholesterol levels are lacking. METHODS: We measured GFR with (51)Cr-EDTA plasma clearance technique, blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy recruited consecutively during 1983 through 1997. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. In total, 271 patients received antihypertensive treatment at the end of the observation period. RESULTS: Mean arterial blood pressure was 102 +/- 0.4 (SE) mm Hg. The average decline in GFR was 4.0 +/- 0.2 mL/min/year and even lower (1.9 +/- 0.5 mL/min/year) in the 30 persistently normotensive patients, none of whom had ever received antihypertensive treatment (P < 0.01). A multiple linear regression analysis revealed a significant positive correlation between the decline in GFR and mean arterial blood pressure, albuminuria, glycosylated hemoglobin A(1c), and serum cholesterol during follow-up (R(adj)(2) = 0.29, P < or = 0.001). No threshold level for blood pressure, glycosylated hemoglobin A(1c), or serum cholesterol was demonstrated. A two-hit model with mean arterial blood pressure and glycosylated hemoglobin A(1c) below and above the median values (102 mm Hg and 9.2%, respectively) revealed a rate of decline in GFR of only 1.5 mL/min/year in the lowest stratum compared with 6.1 mL/min/year in the highest stratum (P < 0.001). CONCLUSIONS: The prognosis of diabetic nephropathy has improved during the past decades, predominantly because of effective antihypertensive treatment. Genuine normotensive patients have a slow progression of nephropathy. Several modifiable variables have been identified as progression promoters.

Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy.

BACKGROUND: Growth factors have been suggested to play a role in the development and progression of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. The aim of the present study was to investigate plasma levels of VEGF in a large cohort of type 1 diabetic patients with diabetic nephropathy and in long-standing type 1 diabetic patients with persistent normoalbuminuria, and to evaluate VEGF as a predictor of nephropathy progression. METHODS: We measured VEGF with an enzyme-linked immunosorbent assay (ELISA) technique in 199 type 1 diabetic patients with diabetic nephropathy (122 males, age 41 +/- 10 years, diabetes duration 28 +/- 8 years), glomerular filtration rate (GFR) (median [range]) 75 [10-143] mL/min/1.73 m2, and in 188 long-standing type 1 diabetic patients with persistent normoalbuminuria (115 males, age 43 +/- 10 years, diabetes duration 27 +/- 9 years). One hundred fifty-five of the proteinuric patients were followed for at least 3 years after baseline examination with yearly GFR measurements. RESULTS: Plasma levels of VEGF were significantly increased in patients with nephropathy as compared to the normoalbuminuric group; (median [range]): 45.7 [22.0-410] versus 27.1 [22.0-355] ng/L, respectively, P < 0.001. This difference was ascribed to elevated VEGF levels in nephropathic men: 51.8 [22.0-410] versus 22.0 [22.0-308] ng/L, P < 0. 001. No differences were found between women with and without nephropathy: 37.8 [22.0-325] versus 36.6 [22.0-335] ng/L, NS. In proteinuric patients with GFR above and below the median value, there was no difference in the level of VEGF, NS. Plasma VEGF was below the detection limit (22.0 ng/L) in 60 patients with nephropathy and 93 patients with normoalbuminuria, P < 0.001. The mean rate of GFR decline was 3.5 (SE: 0.4) mL/min/year, and the following baseline variables acted as predictors of progression: albuminuria, mean arterial blood pressure and male gender. Hemoglobin A1c and plasma VEGF did not act as predictors. No significant differences between patients with and without proliferative retinopathy were detected. CONCLUSIONS: Our data suggest that VEGF is elevated early in the course of diabetic nephropathy in men with type 1 diabetes mellitus. Baseline albuminuria, arterial blood pressure and male gender was predictors of diabetic nephropathy progression, while plasma VEGF and Hemoglobin A1c did not contribute. The importance of VEGF in the initiation of diabetic nephropathy remains to be established.

Spleen emptying and venous hematocrit in humans during exercise.

The spleen may release pooled erythrocytes to the general circulation during strenuous conditions such as heavy exercise. Most of our knowledge of this reservoir function of the spleen derives from animal studies, and the splenic contribution to the circulating blood volume in humans has been regarded as unimportant. We recorded the erythrocyte content in the human spleen during graded bicycle exercise to maximal working capacity. In five normal adults 99mTc-labeled autologous erythrocytes were injected intravenously, and the subjects were placed on bicycles with the back against a gamma camera focusing on the spleen. During increasing exercise the splenic erythrocyte content decreased linearly, and at maximal work load it had been reduced to a mean of 34.2% (range 44-26%) of the initial count rate at supine rest. Concomitantly norepinephrine and epinephrine in plasma increased gradually, whereas neuropeptide Y increased only at maximal exercise. A rise in hematocrit from a mean of 44.6 to 48 was observed, but the autotransfusion of erythrocytes from the spleen only partly explains the rise in hematocrit during physical activity.