Lack of effect of captopril on glomerular hyperfiltration in normoalbuminuric normotensive insulin-dependent diabetic patients

The aim of the present study was to evaluate the effects of captopril on the glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) of normoalbuminuric normotensive insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Eleven normoalbuminuric (UAER < 30 micrograms/min) patients (age: 34.3 +/- 4.6 years: diabetes duration: 9.5 +/- 6.4 years) participated in the study. Six patients were considered to be hyperfiltering (GFR > or = 134 ml/min/ 1.73m2). GFR (51Cr-EDTA single injection technique), extracellular volume (ECV; distribution volume of 51Cr-EDTA), UAER (RIA) and metabolic and biochemical parameters were measured at baseline, after 6 weeks on captopril (25 mg p.o. twice daily) and after 6 weeks off captopril. Plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood volume (51Cr red cell labeled) were measured at baseline and after 6 weeks on captopril. The baseline clinical and laboratory characteristics of hyperfiltering and normofiltering IDDM patients were similar. GFR did not change during the study (144.1 +/- 28.8; 139.7 +/- 21.8; 132.8 +/- 29.9 ml/min/1.73 m2) either in patients with hyperfiltration (164.6 +/- 20.7; 153.8 +/- 18.3; 148.6 +/- 31.0 ml/min/1.73 m2; n = 6) or without hyperfiltration (119.6 +/- 11.1; 123.2 +/- 11.9; 113.8 +/- 14.4 ml/min/1.73 m2; n = 5). Also, ECV (22.2 +/- 3.6; 21.5 +/- 4.3; 21.5 +/- 3.5 L/1.73 m2), UAER (3.9 [0.4-22.1]; 4.0 [0.2-11.4]; 3.7 [2.0-26.2] micrograms/min), systolic (112 +/- 13; 105 +/- 10; 111 +/- 11 mmHg) and diastolic (76 +/- 12; 72 +/- 9; 73 +/- 12 mmHg) blood pressure did not change. No difference in blood volume (60.8 +/- 10.4; 62.3 +/- 8.4 ml/kg) or plasma aldosterone (10.4 +/- 4.9; 7.7 +/- 3.8 ng/dl) was observed between baseline values and values after captopril use. PRA increased (2.4 [0.4-22.1]; 12.9 [2.2-41.1]ng/ml/h) at the end of 6 weeks on captopril (P = 0.002). Fasting plasma glucose, glycated hemoglobin, fructosamine, plasma cholesterol and potassium, 24 h urinary urea and sodium were similar during the study. These results were unchanged when patients with and without hyperfiltration were analyzed as separate groups. From baseline to the end of 6 weeks on captopril there was no correlation between change in GFR and change in glycated hemoglobin (r = 0.02, P = 0.96), systolic (r = 0.23; P = 0.49) and diastolic (r = -0.32, P = 0.32) blood pressure, urinary urea (r = 0.21; P = 0.53) and UAER (r = -0.16; P = 1.00). In conclusion, captopril has no effect on the GFR and UAER of normoalbuminuric normotensive IDDM patients irrespective of the presence of glomerular hyperfiltration.     

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.     

Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus

Progression of diabetic nephropathy from the stage of macroproteinuria with near-normal renal function until start of dialysis was compared in 16 patients with type I and 16 patients with type II diabetes mellitus. The mean creatinine clearance at the beginning of the study was 89 +/- 13 ml/min/1.73 m2 in patients with type I and 81 +/- 6 ml/min/1.73 m2 in those with type II diabetes. Dialysis was started after a mean interval of 77 (44-133) months, when creatinine clearance had decreased to 8 +/- 2 ml/min/1.73 m2 in type I diabetic patients. The respective figures for type II diabetic patients were 81 (40-124) months and 7 +/- 2 ml/min/1.73 m2. The mean rate of decrease in creatinine clearance was 1.05 +/- 0.45 ml/min/month in type I and 0.91 +/- 0.41 ml/min/month in type II diabetes. The mean rate of decrease was 1.46 +/- 0.30 ml/min/month in type I diabetic patients with a systolic BP > 160 mmHg versus 0.80 +/- 0.42 ml/min/month with < 160 mmHg (P < 0.01). In the type II diabetics the respective figures were 1.38 +/- 0.40 ml/min/month versus 0.78 +/- 0.15 ml/min/month (P < 0.01). During the observation period the prevalence of coronary heart disease increased from 6 to 50% in type I and from 31 to 87% in type II diabetes. In conclusion, the rate of progression of diabetic nephropathy during the predialytic phase is similar in type I and type II diabetes; BP adversely affects the rate of progression to the same extent in both groups.     

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.     

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%.     

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.     

Proteinuria is still useful for the screening and diagnosis of overt diabetic nephropathy

OBJECTIVE: To assess the performance of urinary total protein measurements in timed 24-h urine collection (24-h UP) and in a diurnal random urine specimen (RUS) for the screening and diagnosis of overt diabetic nephropathy. RESEARCH DESIGN AND METHODS: A total of 167 diabetic patients (20 type 1 and 147 type 2 diabetic patients; 78 women and 89 men), aged 20-84 years, collected 217 timed 24-h urine specimens. Albumin was measured by immunoturbidimetry, total protein by sulfosalicylic acid technique, and creatinine by Jaffe's method. According to the timed 24-h urinary albumin excretion rate (UAER), samples were divided into three groups: normoalbuminuric (NORMO) (UAER < 20 micrograms/min; n = 84), microalbuminuric (MICRO) (UAER 20-200 micrograms/min; n = 78), and macroalbuminuric (MACRO) (UAER > or = 200 micrograms/min; n = 55). Eighty-six patients also collected 105 RUSs (NORMO, n = 47; MICRO, n = 37; MACRO, n = 21), and urinary protein concentration (UPC) and urinary protein-to-creatinine ratio (UPCR) were measured. The receiver operating characteristics (ROC) curve approach was used to analyze the performance of the diagnostic tests. RESULTS: Spearman's coefficient of correlation of 24-h UAER versus 24-h UP was 0.95 (P < 0.001), and of 24-h UAER versus UPC and UPCR were 0.77 and 0.72, respectively (P < 0.001). The calculated areas (+/- SEM) under the ROC curve for the diagnosis of over diabetic nephropathy were 0.9987 +/- 0.001 for 24-h UP, 0.9926 +/- 0.006 for UPC, and 0.9751 +/- 0.014 for UPCR. In the ROC curves, the first points with 100% sensitivity were 541 mg (95.7% specificity) for 24-h UP, 431 mg/l (92.9% specificity) for UPC, and 0.2 (76.2% specificity) for UPCR. CONCLUSIONS: Measurements of proteinuria presented almost perfect accuracy for the screening and diagnosis of overt diabetic nephropathy. Protein measurement in spot urine is a reliable and simple method for the screening and diagnosis of overt 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.     

Measurement of glomerular filtration rate by the 99mTc-DTPA renogram is less precise than measured and predicted creatinine clearance

The work was devised to compare measurements of glomerular filtration rate (GFR) by technetium-99m-diethylenetriaminepentacetic acid (99mTc-DTPA) renogram to those by creatinine clearance (measured and predicted by Cockroft and Gault) and by inulin clearance. A total number of 65 individuals were enrolled: 15 healthy controls and 50 patients with renal disease. Compared to inulin clearance used as the gold standard, 99mTc-DTPA overestimated at low and underestimated at high GFRs. 99mTc-DTPA measurements were less precise than creatinine clearance except for individuals with GFR >100 ml/min x 1.73 m2. Measured creatinine clearance had the highest correlation coefficient with inulin clearance, 99mTc-DTPA clearance the lowest. In correlation analyses, 81.5% of the interindividual variability for measured creatinine clearance could be explained by true differences in inulin clearance; this value dropped to 59.1 and 57.4% for predicted creatinine clearance and 99mTc-DTPA, respectively. In patients with GFR <25 ml/min x 1.73 m2, all 99mTc-DTPA measurements were out of the 95% confidence interval for the inulin measurement. It can be inferred that 99mTc-DTPA clearance from the renogram is less precise than measured and predicted creatinine clearance.     

Radioisotopic evaluation of renal function in cyclosporine-treated pediatric and adult renal transplant recipients and their living donors. A study of 152 donor-recipient pairs

Renal function was studied in 2 groups of renal transplant recipients and their donors by technetium-99m diethylenetriamine pentaacetic acid and a gamma camera. The pediatric group (group A) comprised 40 children and their adult kidney donors. The adult group (group B) consisted of 112 consecutive adult renal transplant recipients and their adult donors. All patients received kidneys from living donors and were given the same immunosuppression protocol (PRED plus CSA). Donor glomerular filtration rate (GFR) was determined before nephrectomy and at a mean period of 30 (range 10-50) months after nephrectomy. The graft GFR was measured at 1, 3, 6, and 12 months and at the most recent follow-up visit. Moreover, the functional reserve of the graft was assessed by infusion of dopamine and an amino acid. The postnephrectomy GFR of donors in groups A and B were 74 +/- 18 and 72 +/- 20 ml/min/1.73 m2, respectively. The GFR of pediatric recipients was significantly lower than that of adult recipients at corresponding time points along the course of follow-up. The mean values of graft GFR were 47.6 +/- 20 and 63.8 +/- 29.6 ml/min/1.73 m2 for pediatric and adult recipients, respectively (P < 0.001). Moreover, the graft functional reserve was significantly lower in pediatric recipients. These data demonstrate that adult kidneys transplanted into pediatric recipients have lower GFR than those transplanted into adults, despite corrections for body surface area. Although the reason for this phenomenon is unknown, the observation may have important implications for management of pediatric recipients.     

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:     

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.     

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.     

Quantitative bone histology in children with chronic renal failure

Quantitative bone histology (on undecalcified sections following double tetracycline labeling), radiographs, and biochemistry were studied in 47 children, ages 1 to 17 years, with glomerular filtration rates (GFR) below 80 ml/min/1.73m2. The earliest histologic change was an increased osteoid surface accompanied by increased osteoblast and tetracycline surfaces. However, significant bone disease (increased osteoclastic surface, fibrosis, increased osteoid area, increased mineralization lag time, and reduced tetracycline uptake at osteoid surfaces) occurred only at GFR below 30 ml/min/1.73m2. Radiographs and alkaline phosphatase were normal in 25% of children with significant bone disease; parathyroid hormone was increased in 48% of children without bone disease. Thus, these noninvasive investigations were poor predictors of disease presence. GFR was the most sensitive indicator because bone disease occurred only at GFR below 30 ml/min/1.73m2 and was present in all children with GFR below 20 ml/min/1.73m2. It was concluded that bone histology is required for early detection of bone disease and is an essential tool in experimental studies of renal osteodystrophy. However, because the level of GFR will indicate the presence or absence of bone disease in most children, bone biopsy can be avoided generally in clinical practice.     

The localisations in liposomal membranes of the tetrahydrofuran ring moieties of the annonaceous acetogenins, annonacin and sylvaticin, as determined by 1H NMR spectroscopy

We studied 34 apparently healthy children and 2 propositi from kindreds with familial juvenile hyperuricaemic nephropathy (FJHN) - a disorder characterised by early onset, hyperuricaemia, gout, familial renal disease and a similarly low urate clearance relative to glomerular filtration rate (GFR) [fractional excretion of uric acid (FEur) 5.1+/-1.6%] in young men and women. In addition to the propositi, 17 asymptomatic children were hyperuricaemic -- mean plasma urate (368+/-30 micromol/l), twice that of controls (154+/-41 micromol/l). Eight of them had a normal GFR ( > 80 ml/min per 1.73 m2), and 11 renal dysfunction, which was severe in 5. The FEur in the 14 hyperuricaemic children with a GFR > 50 ml/min was 5.0+/-0.5% and in the 5 with a GFR < or =50 ml/min was still low (11.5+/-0.2%) compared with controls (18.4+/-5.1%). The 17 normouricaemic children (185+/-37 micromol/l) had a normal GFR (>80 ml/min) and FEur (14.0+/-5.3%). The results highlight the dominant inheritance, absence of the usual child/adult difference in FEur in FJHN and presence of hyperuricaemia without renal disease in 42% of affected children, but not vice versa. Since early allopurinol treatment may retard progression to end-stage renal failure, screening of all relatives in FJHN kindreds is essential.     

Schistosoma mansoni: a comparison of mouse and rat worms with respect to host antigens detected by the technique of transfer into hamsters

Quantitative bone histology (micromorphometry of undecalcified sections, analysis under polarized light; fluorescence microscopy with tetracycline double labelling) as well as serum and urinary chemistry (creatinine clearance, parathyroid hormone, ionized Ca, bone phosphatase, pH), were studied in 50 patients with incipient to advanced (glomerular filtration rate, 80 to 6 ml/min x 1.73 m2 renal insufficiency. In incipient renal failure, indirect evidence of parathyroid hormone excess was found in the skeleton (empty osteoclastic lacunae, woven osteoid). Osteoclastic surface resorption was abnormally high when GFR fell below 50ml/min x 1.73 m2. With the tetracycline double-labelling technique, a mineralization defect was demonstrable in many but not all patients.     

Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy

The aim of our study was to evaluate whether inhibition of ACE (lisinopril 10-20 mg/day) can reduce the rate of decline in kidney function more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50-100 mg/day), usually in combination with a diuretic. We performed a prospective, randomized, parallel study for 42 months, double blind for the first 12 months and single blind thereafter. Forty-three (21 lisinopril and 22 atenolol) hypertensive NIDDM patients with diabetic nephropathy were enrolled. Data from 36 patients (17 lisinopril and 19 atenolol, 60 +/- 7 years of age, 27 men) who completed at least 12 months of the study period are presented. At baseline, the two groups were comparable: glomerular filtration rate (51Cr-EDTA plasma clearance) was 75 +/- 6 and 74 +/- 8 ml x min(-1) x 1.73 m(-2), mean 24-h ambulatory blood pressure (A&D TM2420) was 110 +/- 3 and 114 +/- 2 mmHg, and 24-h urinary albumin excretion rate was 961 (range 331-5,727) and 1,578 (476-5,806) mg/24 h in the lisinopril and atenolol groups, respectively. The mean follow-up time was similar, 37 and 35 months in the lisinopril and atenolol groups, respectively. Mean ambulatory blood pressure was equally reduced in the two groups, 12 +/- 2 and 10 +/- 2 mmHg in the lisinopril and atenolol groups, respectively. Glomerular filtration rate declined in a biphasic manner with a faster initial (0 to 6 months) change of 1.25 +/- 0.49 and 0.81 +/- 0.29 ml x min(-1) x month(-1) followed by a slower sustained decline (6 to 42 months) of 0.59 +/- 0.10 and 0.54 +/- 0.13 ml x min(-1) x month(-1) in the lisinopril and atenolol groups, respectively. No significant differences were observed in either initial or sustained decline in glomerular filtration rate between the two groups. Urinary albumin excretion was reduced (% reduction of baseline) more in the lisinopril than in the atenolol group, at 55 (95% CI 29-72) and 15% (-13 to 34), respectively (P = 0.01). In conclusion, the relentless decline in kidney function characteristically found in hypertensive NIDDM patients with diabetic nephropathy can be reduced equally effectively by two antihypertensive treatments, the beta-blocker atenolol and the ACE inhibitor lisinopril.     

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)     

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.