[Quality of life of the elderly patient on dialysis]. / La qualita' della vita nell'anziano in dialisi.

When elderly patients with end-stage renal disease start dialysis their quality of life, and particularly the emotional aspects of it, are very similar to those of age-matched controls. However, as the treatment becomes chronic the quality of life will decline not only with regard to the physical aspects (due to comorbidities) but also the emotional aspects. Dialysis-related stress episodes and the peculiar interrelationships in the dialysis facility setting may cause psychological discomfort which on the one hand reduces the patient's quality of life and on the other may unfavorably impact on the family and the health-care personnel. An integrated psychological approach involving the patient from the beginning of dialysis throughout the treatment process as well as the healthcare personnel and the family can reduce the patient's psychological discomfort, thereby improving quality of life.

[Nephrogenic systemic fibrosis]. / Fibrosi nefrogenica sistemica.

Nephrogenic systemic fibrosis (NSF) is a new, rare, and severe disease occurring in patients with renal failure who have been exposed to gadolinium. The pathogenesis of NSF is not completely known. In fact, the first warning about a significant relationship between NSF and gadolinium (a contrast medium used in magnetic resonance imaging) was only issued in 2006. No cases of NSF have been reported in Italy to date. A nationwide investigation should therefore be carried out to assess the real prevalence of NSF within the Italian uremic population. Furthermore, we need guidelines to reduce the risk of NSF in renal patients undergoing MRI with contrast medium.

Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.

BACKGROUND: Patients with Type 2 diabetes and albuminuria are at high risk to progress to end-stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end-point data are available. METHODS: Two multicentre, double-masked, randomized placebo controlled trials were designed to study the renoprotective potential of sulodexide. The Sulodexide Microalbuminuria Trial examined the efficacy of sulodexide given over 26 weeks in 1000 patients with Type 2 diabetes, hypertension and microalbuminuria. The Sulodexide Overt Nephropathy Trial examined the efficacy of sulodexide in 2240 patients with Type 2 diabetes, hypertension and proteinuria > or = 900 mg/24 h. RESULTS: The primary outcome of The Sulodexide Microalbuminuria Trial was (i) conversion to normoalbuminuria and at least a 25% decrease in the urinary albumin creatinine ratio (UACR), or (ii) at least a 50% reduction in UACR. The primary outcome of The Sulodexide Overt Nephropathy Trial was time to a composite end point of doubling of serum creatinine or ESRD. CONCLUSIONS: The sulodexide nephropathy programme will document whether therapy with sulodexide confers renal protection in Type 2 diabetes and nephropathy.

Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes.

The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P<0.01). No change from base line values was observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8-hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not change from baseline with simvstatin, whereas a decrease was observed with cholestyramine treatment (simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/1.73 m(2), P<0.01). AER decreased in Group 1 (P<0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.

Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy.

We recently observed that the course of glomerular filtration rate (GFR) rapidly declines in a subgroup of Type 2 diabetic patients (D) with abnormalities of albumin excretion rate (AER) and typical diabetic nephropathy, despite tight blood pressure control. The aim of this study was to evaluate whether amelioration of blood glucose control, using insulin, improves the course of GFR. GFR decay was measured by spline modeling analysis of the plasma clearance rate of 51CR-EDTA, assessed every 6 months. We identified two groups of D using morphometric analysis of renal biopsy, who had values of glomerular basement membrane (GBM) and fractional mesangial volume (Vv mes/glom) respectively below (Group A: 38) or above (Group B: 50) the mean+2SD of values found in 27 kidney donors (GBM: 389 nm; Vv mes/glom: 0.25), as previously described in detail. Median AER was similar at base line in the 2 groups (109 microg/min, 29-1950, in Group A, 113 microg/min, 37-1845, in Group B; n.s.). Conventional metabolic therapy (sulphonylureas and/or biguanides) was used both in Group A and B during a 3 year follow-up period (Period 1). Group B was further divided in two subgroups with body mass index below (Group B, a) and above (Group B, b) the value of 30 kg/m2. Mean +/- SD HbA1c was 8.2 +/- 1.6% in Group A, 8.3 +/- 1.7% in Group B (a) (n.s.) and 9.1 +/- 1.7% in Group B (b) (n.s.). Tight blood pressure control was achieved and maintained using angiotensin converting enzyme inhibitors and/or beta blockers and/or calcium antagonists and/or thiazides. The mean arterial blood pressure (MAP) was 92 +/- 3 mmHg in Group A and 91 +/- 4 mmHg in Group B (n.s.). GFR decay was significantly greater in Group B than in Group A (Group A vs B: +1.21 +/- 0.71 vs -5.86 +/- 1.61 ml/min/1.73 m2/year). Median AER significantly rose in Group B (177 microg/min, p<0.05 vs base line) but not in Group A (134 microg/min, n.s.) during the third year of follow-up. Groups A and B were then followed over 4.1 years (range 3.1-4.4) (Period 2) maintaining the above described antihypertensive regimen, resulting in MAP values similar to those described during Period 1. Group A patients were treated with the same conventional glycemic control during Period 2. Group B (a) was conversely treated with intensive insulin therapy to achieve a HbA1c value below 7.5% (3 daily injections of regular and 1 or 2 daily injections of intermediate acting insulin associated with metformin 500 mg twice daily in 64% of the patients). Group B (b) patients were only treated by metformin (850 mg thrice daily) to achieve a HbA1c value below 7.5%. HbA1c decreased below the 7.5% target value in Group B (a) (7.0 +/- 1.6%, p<0.01 vs Period 1), but not in Group B (b) (8.0 +/- 1.6%, p<0.05 vs Period 1) and in Group A (8.3 +/- 1.7%, n.s. vs Period 1). The GFR decay of Group B, a during Period 2 was lower than that during Period 1 (Period 1 vs Period 2: -5.9 +/- 1.8 vs -1.8 +/- 0.7 ml/min/1.73 m2/year, p<0.01). GFR decay during Period 2 was similar to that observed during Period 1 in Group A (Period 1 vs Period 2: +1.21 +/- 0.71 vs +0.7 +/- 0.6 ml/min/1.73 ml/year, n.s.) and in Group B (b) (Period 1 vs Period 2: -4.4 +/- 0.71 vs -4.2 +/- 0.6 ml/min/1.73 m2/year, n.s.). Median AER did not significantly change in the fourth year of Period 2 , either in Group A or B (Group A vs B: 141 vs 152 microg/min, n.s.). In conclusion, our findings seem to suggest that amelioration of blood glucose control is attained both by insulin and metformin intensive treatment, but only insulin decreases and maintains HbA1c levels below 7.5%. These pattens of HbA1c appear to be a threshold value in order to significantly blunt GFR decay in a subgroup of Type 2 diabetic patients with typical diabetic glomerular lesions, who are less responsive to tight blood pressure control alone. Conversely, the cohort of patients with less severe diabetic glomerulopathy steadily show constant GFR patterns, despite similar abnormalities of albumin excretion rate, and HbA1c average values above 7.5%.

Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate.

Heterogeneity in renal structure has been described in type 2 diabetic patients with both microalbuminuria and proteinuria; in fact, only a subset of type 2 diabetic patients have the typical diabetic glomerulopathy. However, it is currently unknown whether abnormalities in albumin excretion rate (AER) have a different renal prognostic value depending on the underlying renal structure. Aims of this study were: 1) to study the course of renal function in type 2 diabetic patients with altered AER; 2) to evaluate the relationship between the course of glomerular filtration rate (GFR) and renal structure; and 3) to evaluate the relationship between the course of GFR and baseline AER levels, metabolic control, and blood pressure levels during a follow-up period of 4 years. A total of 108 type 2 diabetic patients, 74 with microalbuminuria (MA) and 34 with proteinuria (P), were recruited into a prospective study that encompassed: 1) a baseline kidney biopsy with morphometric measurements of glomerular parameters; 2) intensified antihypertensive treatment for an average 4-year period (blood pressure target <140/90 mmHg); and 3) determinations of GFR at baseline and every 6 months. Mean (+/- SD) GFR significantly decreased from baseline in both MA (-1.3+/-9.4 [95% CI -3.51 to +0.86], P < 0.05) and P (-3.0+/-13.0 ml x min(-1) x 1.73 m(-2) per year [-7.71 to +1.61], P < 0.01). However, the changes in GFR were quite heterogeneous. Thus, on the basis of percent GFR change per year from baseline (delta%GFR), both MA and P patients were defined as progressors or nonprogressors when they were below or above the median, respectively. Baseline parameters of glomerular structure had a strong influence on the course of GFR. Indeed, the odds ratios of being progressors significantly increased across the quartiles of baseline glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(mes/glom)], being 2.71 and 2.85 higher, respectively, in the fourth quartile than in the first quartile (P < 0.01 for both). Conversely, nonprogressors outnumbered progressors in the first quartile of GBM width (odds ratio: 2.14, P < 0.05) and in the first quartile of Vv(mes/glom) (odds ratio: 2.28, P < 0.01). Baseline albumin excretion rate (AER) did not influence delta%GFR; in fact, the number of progressors did not increase across quartiles of baseline AER among either MA or P. Similarly, mean blood pressure levels during follow-up (and intensified antihypertensive therapy) did not affect the course of GFR: the number of progressors and nonprogressors did not change across quartiles of mean blood pressure. In contrast, HbA1c during follow-up had an impact on delta%GFR: the odds ratio for being a progressor increased across quartiles of HbA1c, particularly for the highest quartile (HbA1c >9.0%). In conclusion, the course of renal function is heterogeneous in type 2 diabetic patients with microalbuminuria or proteinuria. In fact, a subset of patients has a rapid decline in GFR over a 4-year follow-up period; these patients have more advanced diabetic glomerulopathy and worse metabolic control than the remaining patients, whose GFR remains stable. These two cohorts are otherwise undistinguishable as regards the degree of AER at baseline and tight blood pressure control. Kidney biopsy has an important prognostic role in these patients. Thus, tight blood pressure control, when not associated with satisfactory glycemic control, is unable to prevent rapid GFR decline in type 2 diabetic patients with typical diabetic glomerulopathy.

Water and its effects when drunk cold. The Physician's view (1576-1751).

Starting with Baldassare Pisanelli's book Trattato della natura de' cibi et del bere, published in Venice in 1586, the controversies that have kept physicians busy over the centuries regarding the relative importance of water in human health are traced. These controversies were of considerable importance as the Latin word for water 'aqua' is derived from the phrase 'a qua vinimus' (from whence we come). However, until the studies of Nicolas Lemery, one of the most important pharmacologists of the 18th century, the controversies were debated using more theoretical, philosophical arguments. Lemery's studies shifted the debates from those based on philosophical arguments to more physiologically and scientifically based arguments.

Giovan Battista Morgagni, a pioneer of clinical nephrology.

In the 18th century, Giovanni Battista Morgagni was the first to propose that specific signs and symptoms are linked to particular anatomical changes at autopsy and that these changes were the cause of the disease. This paper describes the report by Morgagni wherein he linked the anatomic findings at autopsy, specifically atrophied kidneys, with the signs and symptoms of a disease now known as uremia. From these findings, Morgagni felt that he had identified the factors responsible for the disease as well as its clinical course.

Efficacy of antihypertensive therapy in decreasing renal and cardiovascular complications in diabetes mellitus.

The mechanism underlying the pathogenesis of microangiopathy and macroangiopathy in diabetes mellitus is hypothesized to be chronic hyperglycaemia. However, the values of blood glucose at which chronic diabetic complications develop at the renal and cardiac level are quite different. It is not clear whether this is due to different responses of kidney and heart tissues to the metabolic challenge of diabetes, or to the simultaneous role of other mechanisms contributing differently to the pathogenesis of chronic diabetic complications in renal and cardiac tissues. One of these mechanisms could be the simultaneous occurrence of arterial hypertension along with hyperglycaemia in diabetic patients. We reviewed the available evidence in the recent medical literature and provide information on the relationships between hyperglycaemia and cardiovascular and renal complications in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). The majority of reports indicate that the values of blood glucose appearing to be at threshold level for the development of cardiovascular complications are significantly lower than those determining renal complications (5.4 vs 10.0 mmol/l blood glucose concentrations 2 h after an oral glucose tolerance test). This was the case both in cross-sectional and prospective studies and also in intervention studies aimed at decreasing blood glucose concentrations by using strict metabolic control methods (The Diabetes Control and Complications Trial Research Group), which succeeded in delaying the rate of occurrence of microangiopathic complications at the kidney and retinal level but not so effectively at the cardiac level. Therefore, alternative therapeutic or supplementary strategies to blood glucose control should be adopted in diabetes to prevent diabetic complications. To date, the most effective approach, from our point of view, is antihypertensive therapy in order to prevent end-stage renal disease. We extensively reviewed the available literature which reported comparisons between angiotensin-converting enzyme inhibitors (ACE inhibitors) and calcium channel blockers (CCBs) in the treatment of arterial hypertension in diabetes. Intensified antihypertensive therapy achieving a blood pressure level below 130/85 mmHg has been shown to be useful in decreasing the rate of occurrence of chronic diabetic complications in diabetes mellitus. Both ACE inhibitors and CCBs have been shown to significantly improve the course of renal function in diabetic patients with incipient and overt nephropathy.

Renal function in noninsulin-dependent diabetes mellitus patients treated with angiotensin-converting enzyme inhibitors and calcium channel blockers.

BACKGROUND: Data have not shown consistent effects with calcium channel blockers on the course of renal function in patients with noninsulin-dependent diabetes mellitus (NIDDM) who have hypertension alone or in association with renal damage. The differences between the antiproteinuric effects of subclasses or formulations of calcium channel blockers and the heterogeneity of renal lesions may contribute to the discrepancy in these data. Clinical studies conducted by the authors and other recent data that describe the course of renal dysfunction in hypertensive NIDDM patients treated with antihypertensive agents are reviewed. Renal structural changes were also evaluated. RESULTS: Most available data indicate that angiotensin-converting enzyme inhibitors and dihydropyridine and nondihydropyridine calcium channel blockers produce similar effects on glomerular filtration rate. In one study of patients achieving intensified, strict control of blood pressure (target<140/85 mmHg) with either cilazapril or amlodipine, glomerular filtration rate declined by 2.03+/-0.66 ml/ min/1.73 m2 per year and 2.01+/-0.71 ml/min/1.73 m2 per year, respectively, in the subgroup with normoalbuminuria and by 2.15+/-0.69 ml/min/1.73 m2 per year and 2.33+/-0.83 ml/min/ 1.73 m2 per year, respectively, in the subgroup with microalbuminuria. Renal lesions in NIDDM patients were found to be structurally heterogeneous and glomerular filtration rate appeared to decline only in patients with renal structural changes typical of NIDDM. CONCLUSIONS: The extent of blood pressure control, rather than the method by which this is accomplished, is the most important factor in determining the evolution of incipient nephropathy in hypertensive NIDDM. The kidneys of microalbuminuric NIDDM patients are structurally heterogeneous with less than one-third of patients having 'typical' diabetic nephropathology.

Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM. The Italian NIDDM Nephropathy Study Group.

Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER+) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER+. We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER+ [Prob-NIDDM-(AER+)], 78 had AER-[Prob-NIDDM-(AER-)], 74 siblings of Prob-NIDDM-(AER+), and 113 siblings of Prob-NIDDM-(AER-) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER+, in siblings of Prob-NIDDM-(AER+) adjusted for age, hypertension, glycated haemoglobin A1c and other confounding variables was 3.94 (95% confidence intervals: 1.93-9.01) as compared to siblings of Prob-NIDDM-(AER-). The 74 siblings of Prob-NIDDM-(AER+) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER-) (14 vs 2%; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER+ and 36 non-diabetic siblings of 27 NIDDM probands with AER-. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER+) than in siblings of Prob-NIDDM-(AER-) [median = 13.5 (range 0.5-148) vs 6.6 (range 1-17) micrograms/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER+ and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM.

Renal structure and function in non-insulin dependent diabetic patients with microalbuminuria.

We have recently described heterogeneity in renal structure in non-insulin-dependent diabetic patients (NIDDM) with microalbuminuria (MA; defined as albumin excretion rate from 20 to 200 micrograms/min). Thus, at variance with IDDM patients, "typical" diabetic glomerulopathy by light microscopy is observed only in a third of NIDDM with MA (Category II, CII). Further, despite persistent MA, 30% of NIDDM have normal or near normal renal structure (Category I, CI). Another one-third shows "atypical" patterns of renal injury with absent or mild diabetic glomerular changes, associated with disproportionately severe tubulointerstitial lesions and/or arteriolar hyalinosis and global glomerular sclerosis (Category III, CIII). The aims of this study were to evaluate whether similar patterns of renal lesions could be confirmed in a larger group of NIDDM with MA and to investigate tubular function in order to understand the mechanisms underlying MA in NIDDM patients. Renal biopsies were performed in 53 NIDDM with MA. Categories I, II and III were found in 41%, 26% and 33% of NIDDM with MA, respectively. All 8 patients with proliferative diabetic retinopathy were in CII. We also studied the urinary daily excretion rate of alpha 1-microglobulin (alpha 1 m), a low molecular weight protein, which is a useful indicator of tubular function. alpha 1 m was markedly increased only in CII patients (CI vs. CII vs. CIII: 6.2 +/- 1.2 vs. 13.7 +/- 2.1 vs. 7.3 +/- 0.9 mg/day, ANOVA, P < 0.01). In conclusion, we confirm that there is heterogeneity in renal structure in NIDDM patients with MA. This heterogeneity is not due to renal diseases other than diabetes. Increased alpha 1 m and proliferative retinopathy are useful indicators of the subgroup of MA NIDDM patients with typical diabetic glomerulopathy. It is suggested that diabetic microangiopathy explains the simultaneous occurrence of typical diabetic glomerulopathy, proliferative retinopathy and tubular dysfunction in a subgroup of NIDDM patients with MA.

Patterns of renal injury in NIDDM patients with microalbuminuria.

Microalbuminuria predicts overt nephropathy in non-insulin-dependent diabetic (NIDDM) patients; however, the structural basis for this functional abnormality is unknown. In this study we evaluated renal structure and function in a cohort of 34 unselected microalbuminuric NIDDM patients (26 male/8 female, age: 58 +/- 7 years, known diabetes duration: 11 +/- 6 years, HbA1c: 8.5 +/- 1.6%). Systemic hypertension was present in all but 3. Glomerular filtration rate (GFR) was 101 +/- 27 ml.min-1.1.73 m-2 and albumin excretion rate (AER) 44 (20-199) micrograms/ min. Light microscopic slides were categorized as: C I) normal or near normal renal structure; C II) changes "typical" of diabetic nephropathology in insulin-dependent diabetes (IDDM) (glomerular, tubulo-interstitial and arteriolar changes occurring in parallel); C III) "atypical" patterns of injury, with absent or only mild diabetic glomerular changes associated with disproportionately severe renal structural changes including: important tubulo-interstitial with or without arteriolar hyalinosis with or without global glomerular sclerosis. Ten patients (29.4%) were classified as C I, 10 as C II (29.4%) and 14 as C III (41.2%); none of these patients had any definable non-diabetic renal disease. GFR, AER and blood pressure were similar in the three groups, while HbA1c was higher in C II and C III than in C I patients. Diabetic retinopathy was present in all C II patients (background in 50% and proliferative in 50%). None of the patients in C I and C III had proliferative retinopathy, while background retinopathy was observed in 50% of C I and 57% of C III patients. In summary, microalbuminuric NIDDM patients are structurally heterogeneous with less than one third having "typical" diabetic nephropathology. The presence of both "typical" and "atypical" patterns of renal pathology was associated with worse metabolic control, suggesting that hyperglycaemia may cause different patterns of renal injury in older NIDDM compared to younger IDDM patients.

Plasma clearance rate of 51Cr-EDTA provides a precise and convenient technique for measurement of glomerular filtration rate in diabetic humans.

It has not yet been fully clarified whether the plasma or renal clearance approach is the most reliable to investigate GFR in humans. The study presented here aimed to compare plasma decay with renal clearance of 51Cr-EDTA in 27 diabetic patients with patterns of renal function broadly dispersed in a wide range of values. Moreover, the comparison was also performed with renal clearance of nonlabeled iothalamate in a subgroup of 17 patients. A biexponential function was found to fulfill statistical and heuristic criteria for the modeling analysis of plasma 51Cr-EDTA decay with 19 samples after bolus intravenous 51Cr-EDTA injection. Individual GFR values from 51Cr-EDTA plasma clearance highly correlated with those from renal clearance (r2 = 0.977, P < 0.0001), but resulted on average about 2.5 mL.min-1.1.73 m-2 higher (66.8 +/- 6.5 mL.min-1.1.73 m-2 (mean +/- SE) versus 64.3 +/- 6.4, P < 0.02). This difference remained relatively constant from patients with normal renal function to those with impaired renal function, suggesting that the plasma clearance is slightly less accurate than renal clearance approach because of a constant extrarenal clearance rate. In the subgroup studied, a similar difference was found between GFR values from 51Cr-EDTA plasma clearance (84.7 +/- 7.3) and renal clearance of iothalamate (82.8 +/- 7.3), although not statistically significant (P = 0.4). Individual GFR values well correlated (r2 = 0.913, P < 0.0001). The precision and reproducibility of the experimental approaches were assessed by comparing three coefficients of variation: (1) CVb of the bolus injection, because of measurement errors; (2) CVc of the continuous infusion, which additionally includes errors of urine volume measurement and physiological variability in the same day; and (3) CVr of repeated measurements by using bolus injection, which also accounts for physiological variability in different days. CVc of iothalamate and 51Cr-EDTA infusions were 7.5 +/- 1.9% and 7.4 +/- 1.2% respectively. CVb and CVr of bolus injection of 51Cr-EDTA were 2.6 +/- 0.3% and 3.5 +/- 0.8% respectively. CVb and CVr of bolus injection of 51Cr-EDTA, but not CVc of iothalamate and 51Cr-EDTA infusions were twofold to tenfold lower than the percent yearly change reported in IDDM and NIDDM patients. More particularly, CVr was significantly less than CVc. In order to make the test less cumbersome, a reduced sampling schedule with seven samples was designed and validated. GFR measured with seven samples was 66.1 +/- 6.4 (P = 0.1 when compared with the full 19-sample schedule) with a CVb of 3.5 +/- 0.5%. This seven-sample protocol was not different from that obtained with the previously described simplified method of Brøchner-Mortensen (63.9 +/- 6.8, P = 0.16), yet yielding a statistically more accurate estimate (coefficient of variation for Brøchner-Mortensen method = 12.1 +/- 2.9, P = 0.004). Moreover, only bolus injection, along with modeling analysis of plasma clearance rate, allows the accurate measurement of the extracellular fluid volume, an important parameter in diabetic patients. It was concluded that the reduced seven-plasma sample protocol is able to detect as small as 4 to 5% changes per year in a single patient. Moreover, it provides precise and accurate estimate of GFR in diabetic patients with hyperfiltration, who are postulated to be at higher risk to develop renal damage.

Effects of angiotensin converting enzyme inhibitors and calcium antagonists on atrial natriuretic peptide release and action and on albumin excretion rate in hypertensive insulin-dependent diabetic patients.

Abnormalities in sodium homeostasis and in atrial natriuretic peptide (ANP) behavior could play a role in determining and accelerating the development of glomerular hypertension, hypertension, and microalbuminuria in insulin-dependent diabetes. The aim of the present study was to investigate in 32 hypertensive insulin-dependent diabetic patients (HD) with an altered albumin excretion rate the natriuretic response and ANP release to saline load (2 mmol/kg 90 min, and the effects angiotensin converting enzyme inhibitor therapy 2.5 to 5.0 mg cilazapril, once daily), and calcium antagonists (sustained release verapamil: 120 to 240 mg Isoptin Press, once daily, and long acting nifedipine: 20 to 40 mg Adalat AR, twice daily) on sodium homeostasis and albumin excretion rate. Eight normal subjects matched for sex, age, and weight served as controls. The 32 HD patients showed a blunted response in ANP release and sodium excretion during saline infusion in comparison with controls. The cilazapril and verapamil treatments were tested in 16 of the 32 HD patients and were both effective in ameliorating natriuretic and ANP response to saline load and in decreasing albumin excretion rate. The combined cilazapril and verapamil treatment further improved both these parameters in these patients, although blood pressure levels were comparable. The other 16 HD patients underwent sequential verapamil and nifedipine treatment. Verapamil was more effective than nifedipine in improving natriuresis and ANP release to saline load and in lowering the albumin excretion rate. The results of the present study demonstrate that sodium homeostasis and ANP release are altered in hypertensive nephropathic patients, and both cilazapril and verapamil are more effective than nifedipine in ameliorating natriuresis, ANP release, and albumin excretion rate.