Urinary albumin excretion rate and glomerular filtration rate in single-kidney type 2 diabetic patients

OBJECTIVE: To evaluate the urinary albumin excretion rate (UAER) and the glomerular filtration rate (GFR) of single-kidney type 2 diabetic patients (SKD) and of single-kidney non-diabetic patients (SKN). RESEARCH DESIGN AND METHODS: Patients who had only one kidney for at least 5 years, with no renal disease or hypertension at the time of the nephrectomy and with no calculus or systemic disease at the time of the evaluation, were included in this controlled cross-sectional study A total of 20 SKD (8 men, age 62 +/- 9 years; diabetes duration 8.5 +/- 7 years), 17 SKN (2 men, age 57 +/- 13 years), and 184 type 2 diabetic patients who were matched to the single-kidney diabetic group for age, sex, and BMI were studied. UAER was measured by immunoturbidimetry in timed 24-h sterile urine, and GFR was determined by the 51Cr-EDTA single-injection method. RESULTS: SKD patients presented a higher proportion (8 of 20, 40%) of microalbuminuria (UAER 20-200 microg/min) than SKN patients (3 of 17, 17.6%) and type 2 diabetic patients (37 of 184, 20%). SKD patients presented a higher proportion of macroalbuminuria (UAER >200 microg/min; 6 of 20, 30%) than SKN patients (1 of 17, 6%) but were similar to type 2 diabetic patients (43 of 184, 23%). The GFRs of normoalbuminuric SKN (71.7 +/- 21.4 ml x min(-1) x 1.73 m(-2)) and SKD patients (73.0 +/- 21.5 ml x min(-1) x 1.73 m(-2)) were similar but higher than the one-kidney GFR (GFR / 2) of the age-, sex-, and BMI-matched normal individuals (50.5 +/- 9.0 ml x min(-1) x 1.73 m(-2)) and normoalbuminuric type 2 diabetic patients (54.0 +/- 11.6 ml x min(-1) x 1.73 m(-2)). CONCLUSIONS: Increased GFR related to single-kidney status confers an increased risk of developing renal disease in the presence of diabetes.     

Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN)

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.     

Immune response to glycated and oxidized LDL in IDDM patients with and without renal disease

OBJECTIVE: To study autoantibodies to oxidized and glycated LDL in IDDM patients with and without diabetic nephropathy and in nephropathy-related macroangiopathy RESEARCH DESIGN AND METHODS: The study included 101 IDDM patients with a long duration of diabetes and 54 healthy subjects. Patients were divided into two groups according to their median urinary albumin excretion rate (AER); the normoalbuminuric group had AER <20 microg/min and the albuminuric group >200 microg/min. The groups were matched for age and BMI, and the two diabetic groups were matched for duration of diabetes and glycemic control. Antibodies against oxidized LDL (using malondialdehyde-modified LDL as the antigen) and against glycated LDL were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean antibody levels against glycated LDL were higher in IDDM patients (0.305 +/- 0.399) than in healthy subjects (0.166 +/- 0.22 optical density [OD]; P = 0.019), but levels did not differ significantly between normoalbuminuric and albuminuric IDDM patients (0.258 +/- 0.354 vs. 0.388 +/- 0.459, respectively). Among the three groups, antibody levels to oxidized LDL did not differ. IDDM patients showed an inverse correlation between antibodies to oxidized LDL and HbA1 (r = -0.211, P = 0.04). The antibody levels to glycated and oxidized LDL did not differ among albuminuric IDDM patients with or without clinical macroangiopathy. CONCLUSIONS: Antibodies to glycated and oxidized LDL do not seem to associate with diabetic nephropathy or nephropathy-related macroangiopathy.     

Synthesis of the esterified cerebroside in the epidermis of guinea pigs

BACKGROUND: The level of glomerular filtration rate (GFR) and its determinants in non-insulin-dependent diabetes mellitus (NIDDM) are currently controversial. DESIGN OF THE STUDY: We measured GFR and effective renal plasma flow (ERPF) in 121 consecutive NIDDM without evidence of overt diabetic nephropathy. Age varied from 28 to 70 years, 61.2% were women and known duration of NIDDM was 0-37 years. Hypertension was detected in 36.4% of patients and 47.8% had microalbuminuria. RESULTS: An inverse correlation was found between GFR and age, but not with known duration of NIDDM: It was a weak correlation (r = -0.41) but statistically significant (P < 0.001). The other variables considered were not significant by multiple stepwise regression analysis, but patients with lower GFR tended to have diabetic retinopathy more frequently. GFR was lower in hypertensive compared to normotensive patients (123 +/- 28.4 versus 136 +/- 32.5 ml/min/1.73 m2; P < 0.05), but was not different between patients with normal and elevated albumin excretion rate. ERPF also had an inverse correlation with age (r = -0.45, P < 0.001). CONCLUSION: We conclude that (i) age should be considered as a confounding variable when evaluating GFR in patients with NIDDM, and (ii) the age-dependent decline in GFR may mask hyperfiltration in the early stages of diabetic nephropathy in NIDDM:     

Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands

PURPOSE: To evaluate the usefulness of Doppler ultrasonography (US) in the diagnosis of hyperfiltration in patients with insulin-dependent diabetes mellitus (IDDM). MATERIALS AND METHODS: Eighty-one consecutive patients with IDDM were studied. All patients were normotensive and had normal creatinine and blood urea nitrogen levels. The glomerular filtration rate (GFR) was evaluated by means of plasma clearance of chromium-51 ethylenediaminetetraacetic acid, urinary albumin excretion, US evaluation of renal volume, and Doppler evaluation of resistance index (RI) in the renal interlobar arteries. The patients were divided according to GFR into the following groups: those with hyperfiltering kidneys (group 1, n = 40) and those with normofiltering kidneys (group 2, n = 41). RESULTS: The median renal volume was 351 mL (95% CI = 337 mL, 379 mL) in group 1 and 318 mL (95% CI = 300 mL, 335 mL) in group 2 (P = .005). The number of patients with microalbuminuria was significantly lower in group 1 than in group 2 (P = .02). The median RI was significantly lower in group 1 (0.55; 95% CI = 0.53, 0.57) than in group 2 (0.57; 95% CI = 0.56, 0.59) (P = .04). An RI of less than 0.5, a renal volume greater than 410 mL/m2, and the absence of microalbuminuria were independent predictors of hyperfiltration. An RI of less than 0.5 and a renal volume greater than 410 mL/m2 showed high specificity (98% and 95%, respectively) and poor sensitivity (25% and 23%, respectively) in the diagnosis of hyperfiltration in IDDM patients. CONCLUSION: Both RI and renal volume showed correlation with GFR, but neither parameter is sufficiently sensitive in screening for hyperfiltration in IDDM patients.     

Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus

Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.     

Renal reserve is normal in adults born with unilateral renal agenesis and is not related to hyperfiltration or renal failure

This study was carried out to examine the renal hemodynamic response in adult patients with single kidneys born with unilateral renal agenesis. A group of 21 patients with unilateral renal agenesis were divided into three groups according to their glomerular filtration rate (GFR): 112 +/- 3 ml/min x 1.73 m2 in group A, 68 +/- 3.2 ml/min x 1.73 m2 in group B, and 40.7 +/- 3.3 ml/min x 1.73 m2 in group C. Mean arterial blood pressure was significantly higher in the patients of group C who were also proteinuric. The renal hemodynamic response to an oral protein load (2 g/kg of protein as beefsteak) was normal in all groups and unrelated to hyperfiltration or to renal failure and proteinuria. The study indicates that in patients with renal agenesis, the hemodynamic response to a protein challenge is similar to that of kidney donors, renal transplant recipients and uninephrectomized patients. The paper also demonstrates that the renal response to a protein challenge is inadequate to identify patients with renal agenesis who are at risk of developing renal disease. Finally, in renal agenesis with renal disease, creatinine clearance overestimated the GFR by an average of 32.7%.     

Proximal tubular basement membrane width in insulin-dependent diabetes mellitus

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.     

Cloning of the rat brain cDNA encoding for the SLC-1 G protein-coupled receptor reveals the presence of an intron in the gene

OBJECTIVE: Glomerular filtration rate (GFR) can be estimated in patients with renal disease from plasma creatinine concentration, age, sex, and body weight according to the formula of Cockcroft and Gault. The hypothesis that this method can be improved when tubular secretion of creatinine is inhibited by cimetidine was studied in NIDDM patients. RESEARCH DESIGN AND METHODS: In 30 outpatients with NIDDM and normo- (n = 10), micro- (n = 9), or macroalbuminuria (n = 11), GFR was measured as the urinary clearance during continuous infusion of 125I-labeled iothalamate. Plasma creatinine concentration was analyzed with an enzymatic assay before and after 800 mg t.i.d. oral cimetidine was given during a 24-h period. RESULTS: Plasma creatinine rose in all patients after cimetidine administration and, as a consequence, the clearance calculated with the Cockcroft-Gault formula fell. The ratio of this formula and GFR decreased from 1.16 +/- 0.20 to 0.97 +/- 0.16 (means +/- SD). This ratio tended to be smaller in the normo- (0.93) than in the micro- (0.98) and macroalbuminuric (1.00) groups. Also, 20 patients with a BMI < 30 kg/m2 had a smaller ratio than those with a BMI > 30 kg/m2 (0.92 vs. 1.07; P < 0.05). Bland and Altman analysis showed a difference of the Cockcroft-Gault formula and GFR of 12.0 +/- 17.4 ml.min-1 (1.73 m2)-1, which decreased to -3.8 +/- 14.8 ml.min-1.(1.73 m2)-1. The same analysis of 24-h creatinine clearance with urine collection and GFR showed larger standard deviations. CONCLUSIONS: GFR can be estimated in an acceptable way from plasma creatinine concentration after cimetidine administration in outpatients with NIDDM. Despite a nonsignificant underestimation in normoalbuminuric and overestimation in overweighted patients, this method is superior to 24-h creatinine clearance with outpatient urine collection.     

Effect of intensive treatment on diabetic nephropathy in patients with type I diabetes

We evaluated the long-term effect of an intensive treatment of diabetic nephropathy (anti-hypertensive drugs, low protein diet, multiple insulin injections to achieve a good metabolic control) on glomerular filtration rate (GFR) and albumin excretion rate (AER). Fourteen type I diabetic patients (mean age 45 +/- 9.5 years, mean duration of diabetes 23.5 +/- 7.3 years, 8 males/6 females) with glomerular filtration rate < 70 ml/min-1/1.73 m2 and albumin excretion rate > 30 micrograms/min were treated intensively for 36 months. This intensive treatment consisted of multiple insulin injections, antihypertensive therapy with ACE inhibitors and a low-protein diet (0.8 g/kg body wt/day.) Renal function was evaluated as GFR and AER. HbA1c mean value decreased significantly from 8.7 +/- 0.8% to 6.5 +/- 0.5% (P < 0.0002). GFR rose from 58 +/- 12 ml/min-1/1.73 m2 to 84 +/- 11 ml/min-1/1.73 m2 (P < 0.0008). AER decreased from 208 micrograms/min (range: 73 to 500) to 63.8 micrograms/min (range 15 to 180; P < 0.05). Systolic and diastolic blood pressure decreased respectively from 144 +/- 26 mm Hg to 120 +/- 15 mm Hg and from 89 +/- 9 mm Hg to 75 +/- 8 mm Hg (P < 0.01). We obtained a rise of GFR and a reduction of proteinuria after three years of this treatment. We suggest that this intensive treatment in all patients with early stage diabetic nephropathy may be effective in slowing the progression to renal failure.     

Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.     

Renal reserve filtration capacity in growth hormone deficient subjects

In normal subjects, the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) acutely increase in response to infusion of amino acids and to low doses of dopamine. It is uncertain whether circulatory growth hormone (GH) is a permissive factor for these stimulatory effects. GFR and ERPF (constant infusion technique using 125I-iothalamate and 131I-hippuran, respectively) were measured before and during the infusion of dopamine and amino acids in 8 GH deficient subjects. The clearance study was repeated during concomitant administration of octreotide to investigate whether this somatostatin analogue would modify the amino acid and dopamine-induced renal haemodynamic changes. Dopamine increased baseline GFR from 89 +/- 3 (mean +/- SEM, n = 8) to 102 +/- 4 ml min-1 1.73 m-2 and ERPF from 352 +/- 19 to 476 +/- 26 ml min-1 1.73 m-2, P less than 0.001 for both. During amino acid infusion GFR and ERPF increased to 108 +/- 3 and 415 +/- 23 ml min-1 1.73 m-2, respectively, P less than 0.001 for both. Octreotide did not significantly decrease baseline and dopamine-stimulated renal haemodynamics but lowered the amino acid-stimulated GFR (98 +/- 4 ml min-1 1.73 m-2, P less than 0.05) and ERPF (381 +/- 18 ml min-1 1.73 m-2, P less than 0.05). Basal plasma glucagon concentrations were not suppressed by octreotide, whereas the amino acid-induced increments in plasma glucagon were partially inhibited. It is concluded that GH is not a necessary factor for the stimulatory effects of amino acids and dopamine on renal haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of angiotensin-converting enzyme inhibitors on proteinuria in chronic glomerulonephritis

The effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.     

Effect of changes in daily protein intake on renal function in chronic renal insufficiency: differences in reaction according to disease entity

Protein restriction is advocated in patients with chronic renal insufficiency (CRI) in an attempt to slow down further renal function deterioration, with the most obvious effect in patients with chronic glomerulonephritis (GN) and diabetic nephropathy, and much less in other disease entities, such as adult polycystic kidney disease (APKD), tubulointerstitial nephritis (TIN) and nephrosclerosis (NS). The mechanism by which protein restriction slows down the progression of renal failure remains unclear. Decline of hyperfiltration has been implicated. Whether long-term protein restriction in patients with CRI is associated with a decrease in hyperfiltration is not clear. We studied the effects of prolonged protein intake variation (isocaloric diets in 4-week periods of low (goal: 30-40 g protein daily) and high protein intake (goal: 80-90 g daily) on renal function in 51 patients with CRI. Patients were divided into subgroups according to the underlying renal disease (GN, n = 17; APKD, n = 9; TIN, n = 12; NS, n = 13). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured at the end of each study period. Overall, GFR rose from 39 (9-90) to 46 (9-100) ml/min/1.73 m2 (median and ranges, p < 0.01), and ERPF from 158 (39-558) to 171 (32-676) ml/min/1.73 m2 (p < 0.01). GFR rose significantly in GN (15%, range -23 to 51%), APKD (5%, range -10 to 33%), and NS (8%, range -8 to 25%). ERPF only rose significantly in GN (14%, range -45 to 47%) and APKD (9%, range -9 to 25%).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation

BACKGROUND: Due to their vasodilatory effect, calcium antagonist may have a renoprotective against cyclosporin (CsA)-induced nephrotoxicity and rise in blood pressure (BP) seen in renal transplantation. METHODS: In order to evaluate the effect of the calcium antagonist felodipine on renal function and BP during cyclosporin treatment, 79 CsA-treated renal transplant recipients were investigated during the first 3 months after transplantation in a randomized, double-blind, placebo-controlled study with two parallel groups. Felodipine (ER tablets, 10 mg) or placebo was given prior to transplantation and each day during the study period. The patients were assessed twice, i.e. at 4-6 weeks and at 10-12 weeks after transplantation. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by constant infusion technique. Tubular function was estimated from clearance of lithium. RESULTS: At 6 weeks after transplantation, felodipine caused a significantly higher RPF [felodipine: 219 +/- 70 ml/min; placebo: 182+/-56 ml/min (mean+/-1 SD); P=0.03]. No differences were found in GFR, filtration fraction (FF), tubular sodium handling, or sodium excretion. Felodipine lowered BP significantly. At 12 weeks after transplantation, felodipine caused a significantly higher GFR (felodipine: 49+/-18 ml/min; placebo: 40+/-16 ml/min; P=0.05) and RPF (felodipine: 225+/-77 ml/min; placebo: 175+/-48 ml/min; P<0.01). No difference was found in FF. Felodipine lowered BP significantly. No differences were found with regard to duration of primary anuria, hospitalization time, number of rejection episodes, plasma creatinine day 7 post-transplant, or treatment doses of CsA. CONCLUSIONS: It is concluded that in renal transplant recipients treated with CsA, felodipine significantly increased both GFR and RPF 3 months after transplantation when compared with placebo, despite a concomitant lowering of BP. A possible antagonizing affect of felodipine against CsA-induced nephrotoxicity in these patients is suggested.     

Left atrial "stunning" following radiofrequency catheter ablation of chronic atrial flutter

Patients with autonomic neuropathy are more susceptible to insulin-induced hypotension than normal subjects, but the mechanisms are unclear. We quantitated the hemodynamic and metabolic effects of two doses of i.v. insulin (1 and 5 mU/kg.min, 120 min each) and several aspects of autonomic function in 28 patients with insulin-dependent diabetes mellitus (IDDM) and in 7 matched normal subjects under standardized normoglycemic conditions. The autonomic function tests included those predominantly assessing the integrity of vagal heart rate control (the expiration inspiration ratio during deep breathing and high frequency power of heart rate variability) and tests measuring sympathetic nervous function (reflex vasoconstriction to cold and blood pressure responses to standing and handgrip). During hyperinsulinemia, heart rate increased less (2 +/- 1 vs. 6 +/- 2 beats/min; P < 0.04) and diastolic blood pressure fell more (-3.1 +/- 1.2 vs. 0.9 +/- 2.1; P = NS) in the patients with IDDM than in the normal subjects. Forearm vascular resistance decreased significantly in the patients with IDDM [by -7.1 +/- 1.4 mm Hg/(mL/dL.min); P < 0.001 for high vs. low dose insulin], but not in the normal subjects (-0.1 +/- 2.5 mm Hg/(mL/dL.min; P = NS). Reflex vasoconstriction to cold was inversely correlated with the decreases in diastolic (r = -0.51; P < 0.005) and systolic (r = -0.59; P < 0.001) blood pressure and forearm vascular resistance (r = -0.53; P < 0.005), but not with the change in heart rate. The expiration inspiration ratio was, however, directly correlated with the insulin-induced change in heart rate (r = 0.63; P < 0.001), but not with diastolic or systolic blood pressure or forearm vascular resistance. Whole body (48 +/- 2 vs. 67 +/- 5 mumol/kg.min; P < 0.005) and forearm (44 +/- 4 vs. 67 +/- 8 mumol/kg.min; P < 0.05) glucose uptake were significantly lower in the IDDM patients than in the normal subjects. The latter could be attributed to a defect in the forearm glucose arterio-venous difference (1.5 +/- 0.1 vs. 2.2 +/- 0.2 mmol/L, respectively; P < 0.01), but not in blood flow. We conclude that both impaired vagal heart rate control and sympathetic nervous dysfunction exaggerate the hemodynamic effects of insulin in patients with IDDM and could contribute to insulin-induced hypotension.     

Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease

Patients with renal disease who smoke have a poor renal functional prognosis, but the mechanisms involved have not been explored. In this controlled study, the effects of smoking and sham smoking were compared in 15 healthy normotensive volunteers. All were occasional smokers and abstained from smoking for 48 h as documented by urinary cotinine measurements. These data were compared with those of seven patients with biopsy-confirmed IgA glomerulonephritis, also occasional smokers. Renal clearance examinations were obtained after hydration in the supine position before and while smoking two cigarettes or sham cigarettes in random order on 2 consecutive days. GFR and effective renal plasma flow were determined using In111-diethylenetriamine penta-acetic acid and 131I-hippurate with a dual tracer infusion clearance technique. In an ancillary study with six volunteers, the effect of smoking was compared with the effect of nicotine-containing chewing gum. In healthy volunteers, sham smoking caused a minor but significant increase of mean arterial pressure (MAP) and GFR with no significant change of effective renal plasma flow, filtration fraction (FF), or renovascular resistance. Smoking caused a significant and more marked increase of MAP (from baseline 92.8+/-8.98 to 105+/-7.78 mmHg) and heart rate (from 61.7+/-7.52 to 86.4+/-9.87 min(-1)), accompanied by a significant increase in arginine vasopressin (from 1.27+/-0.72 to 19.9+/-27.2 pg/ml) and epinephrine (from 37+/-13 to 140+/-129 pg/ml). During smoking, GFR decreased in all but one volunteer (from 120+/-17.7 to 102+/-19.3 ml/min per 1.73 m2), and this was accompanied by a significant decrease of FF (from 21.3+/-4.24 to 17.4+/-3.41%) and an increase in renovascular resistance (from 97.6+/-27.2 to 108+/-30.4 mmHg x min/ml per 1.73 m2). These findings were reproduced with nicotine-containing chewing gum. In contrast, when patients with IgA glomerulonephritis smoked, a similar increment in MAP was noted, the changes of FF were not uniform, and a small but consistent increase of urinary albumin/creatinine ratio was observed. An additional 20 volunteers were subjected to the smoking arm of the study for statistical evaluation of the GFR change in patients. The difference between the change of GFR between all volunteers (n = 35) and patients (n = 7) was significant (P < 0.005). It is concluded that the known effects of smoking and nicotine on the sympathetic nervous system and on systemic hemodynamics are accompanied by significant acute changes in renal hemodynamics and albuminuria. These findings are of interest because of the known effects of smoking on progression of renal disease.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking. METHODS: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS). CONCLUSION: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.     

Donor age and graft function

We evaluated survival and renal function of cadaveric donor grafts according to donor age. The median age of the pediatric donors was 7.0 (0.7-16) years in 46 patients [median age 11.8 years (range) 3-16.8 years]. The median age of the adult donors was 34.4 (19-54) years in 59 patients [median age 12.1 years (range) 7-17.3 years]. Thirty patients were treated with azathioprine and prednisolone and 75 with cyclosporine A and prednisolone. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were determined by the clearances of 51chromium-EDTA and 125iodine-hippurate 1-48 months after kidney transplantation. There was no difference in graft survival between pediatric and adult grafts. There were also no differences in GFR in patients receiving grafts from pediatric or adult donors; 2-3 months after transplantation the GFR in recipients of pediatric grafts was 62 +/- 20 ml/min per 1.73 m2 compared with 61 +/- 21 in those receiving adult grafts. The ERPF in recipients of adult grafts was significantly higher in the 1st month after transplantation: 486 +/- 239 versus 362 +/- 158 ml/min per 1.73 m2. From the 4th to the 6th month after transplantation this difference disappeared: the ERPF of grafts from pediatric donors was 279 +/- 131 ml/min per 1.73 m2 compared with 273 +/- 123 ml/min per 1.73 m2 in grafts from adult donors. Using the single-kidney GFR and ERPF on an age-matched group of probands with minor diseases as references, 2-3 months after transplant the mean GFR of grafts from pediatric donors increased to 118% +/- 51%, whereas the GFR of adult donor grafts fell to 60% +/- 22% over the same period. After 4-6 months the ERPF in pediatric grafts was 96% +/- 55% compared with 50% +/- 22% in adult grafts. We conclude that graft survival and function in children with either a pediatric or an adult graft may not differ because graft function adapts to the requirement of the recipient.     

Managing complex orthodontic problems: the use of implants for anchorage

In congestive heart failure captopril modifies the left ventricular filling pattern mainly by unloading the heart. We investigated whether the structural characteristics of the left ventricle may influence the acute effects of captopril on this pattern in patients with untreated hypertensive (H group, 6 patients) or idiopathic (I group, 14 patients) cardiomyopathy. We evaluated changes of pulsed Doppler mitral flow, of systemic arterial and wedge pulmonary pressures 40 min after 25 mg captopril administered sublingually, and correlated these changes with the M-mode echocardiographic relative wall thickness index (h/r). Baseline mean arterial pressure (H = 137 +/- 20 mm Hg, mean +/- SD, I = 95 +/- 19 mm Hg; p < 0.001), and h/r (H = 0.38 +/- 0.03, I = 0.28 +/- 0.09; p < 0.05) were greater in the high blood pressure group; wedge pressure, echocardiographic biplane ejection fraction, and Doppler indexes of the left ventricular filling were similar in the two populations. After captopril, ejection fraction did not change significantly, mean arterial pressure decreased significantly in hypertensive patients (H group, baseline = 137 +/- 20, captopril = 119 +/- 10, p = 0.02; I group, baseline = 95 +/- 19, captopril = 90 +/- 24, p = nonsignificant), and the wedge pressure was reduced by the same extent in both groups (H group, baseline = 27.7 +/- 3, captopril = 21 +/- 7, p < 0.05; I group, baseline = 20 +/- 12, captopril = 15 +/- 8, p < 0.05). In the H group early mitral flow increased [(E wave integral) x (mitral annulus area)] by 38 +/- 15%, and was almost steady in the I group (-1.3 +/- 30%; group H vs. I = p < 0.01); late mitral flow [(A wave integral) x (mitral annulus area)] showed a pattern exactly opposite to this (H = +0.4 +/- 40%, I = +38 +/- 19; p < 0.01). In the whole population there was a significant correlation between the early/late flow ratio variations and baseline h/r (r = 0.6, p < 0.05). In chronic congestive heart failure, changes in left ventricular filling with captopril are related to h/r: a higher index, as recorded in the H group, is associated with "true normalization' of the filling pattern after captopril; a lower index, as recorded in the I group, is associated with "pseudonormalization' despite a similar decrease of left ventricular filling pressure.