Time as a risk factor in diabetic nephropathy.

Eighteen individuals with IDDM (type I) and diabetic nephropathy in whom the initial glomerular filtration rate (GFR) was reduced but not below 60 ml/min per 1.73 m2 were observed for an average of 3 yr. The rate of further decline of GFR was found to range between -2 and 21 ml/min/yr. The duration of diabetes until the GFR was first found to be reduced varied between 14 and 33 yr and was not correlated to the ensuing rate of decline in GFR (r = -0.13). In 10 individuals who developed uremia 40 yr or more after onset of IDDM, the development of persistent proteinuria was followed by hypertension and increased serum creatinine 2 yr later and by terminal uremia after an average of 8 yr. This is also the normal time span for individuals who develop terminal uremia after shorter duration of diabetes. We conclude that the course of clinical diabetic nephropathy is not more favorable in individuals with late onset of this complication and that there is no point at which a person with diabetes can be considered to be spared from developing diabetic nephropathy.

Decreased urinary histamine metabolite after successful PUVA treatment of urticaria pigmentosa.

The effect of PUVA therapy on pruritus, the skin mast cell population and histamine metabolism has been studied in 3 patients with urticaria pigmentosa and manifestations of systemic mastocytosis. Relief of itch was found concomitant with a significant decrease of the major histamine metabolite 1-methyl-4-imidazoleacetic acid in the urine. The decrease occurred during the first 2 mo after starting PUVA therapy and was sustained during an observation period of 3 mo after discontinuation of the treatment. At this time a reduction of the number of mast cells was found in skin biopsy specimens. No evidence of acute histamine release in association with PUVA treatment was obtained. These results suggest that this effective new treatment for urticaria pigmentosa reduces the histamine turnover in the skin by inhibiting mast cell proliferation.

Studies on histamine metabolism in mastocytosis.

The urinary excretion of histamine and its main metabolite, 1-methyl-4-imidazoleacetic acid (MeImAA), was determined in 30 adult patients with the clinical diagnosis of urticaria pigmentosa (UP). Clinical and laboratory investigations including skin histology, bone marrow examination, and scintigraphy of the skeleton, liver, and spleen revealed systemic manifestations in 14 cases. Among the 16 cases with dermal proliferation of mast cells only 3 cases classified as telangiectasia macularis eruptiva perstans (TMEP). All patients with systemic mastocytosis and UP excreted increased amounts of MeImAA in the urine while normal amounts were found in 2 of the patients with TMEP. A significant correlation existed between MeImAA excretion and the extent of mast cell infiltration in skin and internal organs. No such correlation was found for urinary histamine. Urinary MeImAA but not histamine is therefore considered a useful indicator of systemic involvement by reflecting the size of the mast cell histamine pool. The main symptom of the patients was pruritus, which was moderate to severe in 17 and mild or absent in 13 cases. Gastrointestinal symptoms were present in 14 patients. However, there was no obvious correlation between the excretion of MeImAA and any of the symptoms recorded. Neither was the severity of pruritus correlated to the histamine content of the skin, which was measured in both lesional and unaffected skin in 23 of the patients. Thus, symptoms possibly caused by histamine in mastocytosis patients are not directly related to urinary histamine metabolite excretion or tissue histamine content.

Histidine decarboxylase expression and histamine metabolism in gastric oxyntic mucosa during hypergastrinemia and carcinoid tumor formation.

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

Effect of captopril on renal hemodynamics in the treatment of resistant renal hypertension.

The effects of 6 weeks of treatment with captopril on the renal hemodynamics of 16 patients with treatment-resistant renal hypertension (six had diabetic nephropathy, seven had other renal parenchymatous disease, and three had renovascular disease) were studied. Significant changes in glomerular filtration rate, filtration fraction, plasma renin activity, urinary aldosterone, and mean blood pressure were noted in the patients with renal parenchymatous disease, but not in those with diabetic nephropathy. Renal blood flow remained unchanged in all patients. Captopril was well tolerated.

Histamine formation from 14 C-L-histidine in man.

1. (14)C-L-histidine was given i.v. to one normal subject and two patients with chronic myelocytic leukaemia. Urinary excretion of histamine and two of its metabolites methylhistamine and methylimidazoleacetic acid, total as well as (14)C-labelled, was measured, as well as blood (14)C-histamine. In addition the total urinary and pulmonary elimination of (14)C was followed.2. Total (14)C elimination was high during the first days, then declined slowly except for a plateau at the 10th-14th day in the two patients. There was a measurable elimination even after some months.3. (14)C-histamine appeared in the blood of the leukaemic patient, whereas in the normal subjects the values were hardly measurable.4. The leukaemic patients excreted much more of the two (14)C-labelled histamine metabolites than the normal subject. The difference in excretion of the (14)C-labelled metabolites was largest around the 12th day after the infusion of (14)C-L-histidine.5. The results indicate that the leukaemic patients formed at least 20 times more histamine daily than the normal subject.

Consensus report on quality control of quantitative measurements of renal function obtained from the renogram: International Consensus Committee from the Scientific Committee of Radionuclides in Nephrourology.

Among all the physiological indices that can be quantified using renography, measurement of renal function is the most basic. These measurements are used to make critical clinical management decisions and, as such, their reliability needs to be quality assured. This article seeks to address each aspect of the renography procedure, with particular emphasis on the effect on measurement of relative renal function. Estimation of individual kidney function is mentioned, but only briefly. A consensus approach was adopted, overseen, and directed by a chairman appointed by the Scientific Committee of the International Radionuclides in Nephro-Urology Group. The chairman selected the panel of experts from eight different countries based on their practical experience in the field. Where evidence exists to support the various recommendations it is given. Otherwise, the stated guidance represents the considered opinion of a body of experts, based on long experience and unpublished data. Some necessary compromises were made to account for the fact that renography is seldom performed solely with the purpose of measuring relative renal function. The technicalities of renography have always been a source of debate in nuclear medicine, which is reflected by the fact that a consensus could simply not be reached on a small number of issues. The structure of the report ensures that these are clearly indicated. This should serve to highlight gaps in our current knowledge, thus helping to direct future research. It is envisaged that the recommendations will be revised on a 2-year cycle to ensure that they remain up to date. An "open" process will be used to encourage participation and ownership. It is hoped that promotion of these guidelines, suitably complemented by audit processes, will raise standards in the practice of gamma camera renography.

Consensus on renal cortical scintigraphy in children with urinary tract infection. Scientific Committee of Radionuclides in Nephrourology.

A questionnaire related to cortical scintigraphy in children with urinary tract infection was submitted to 30 experts. A wide consensus was reached on several issues related to planar images: 99mTc dimercapto succinic acid (DMSA) appears as the most appropriate tracer for renal imaging; dynamic tracers are considered to be inferior, in particular 99mTc diethylenetriaminepentaacetate, which is not recommended. The general opinion is that DMSA scintigraphy is not feasible with a minimal dose below 15 MBq, whereas the maximum dose should not be higher than 110 MBq. The dose schedule generally is based on body surface area, and sedation is only exceptionally given to children. Images are obtained 2 to 3 hours after injection, preferably with high resolution collimators; pinhole images are used by only half of the experts. Posterior and posterior oblique views are used by most of the experts, and the posterior view is acquired in supine positions. At least 200.000 kcounts or 5 minute acquisition is required for nonzoomed images. As a quality control, experts check the presence of blurred or double outlines on the DMSA images. Color images are not used and experts report on film or directly on the computer screen. As far as normal DMSA images are concerned, most experts agree on several normal variants. Hydronephrosis is not a contraindication for DMSA scintigraphy but constitutes a pitfall. Differential renal function generally is measured, but no consensus is reached whether or not background should be subtracted. Most of the experts consider 45% as the lowest normal value. A consensus is reached on some scintigraphic aspects that are likely to improve and on some others that probably represent persistent sequelae. There is a wide consensus for the systematic use of DMSA scintigraphy for detection of renal sequelae, whereas only 58% of the experts are systematically performing this examination during the acute phase of infection.

Felodipine. A calcium-inhibiting vasodilator in refractory hypertension.

12 patients with primary hypertension not adequately controlled on combined treatment with diuretics, beta-adrenergic blocking drugs and hydralazine were included in the study. The patients were hospitalised and hydralazine discontinued. The diuretic and beta-blocking medication was given about 1 hour prior to the short term experiments and, following baseline measurements, an oral solution of felodipine (0.075-0.1 mg/kg) was ingested. Cardiac output was measured (dye dilution technique) and continuous monitoring of intra-aortic blood pressure (brachial artery) was performed. In 10 patients, changes in renal plasma flow (para-aminohippuric acid clearance) and glomerular filtration rate (51Cr-EDTA-clearance) were followed over a short period, and in 6 patients repeated after 5 to 7 months. Plasma renin activity (radioimmunoassay of angiotensin I) was followed, as was plasma concentration of felodipine. A significant hypotensive response was seen only 15 minutes after intake of felodipine. The maximal response occurred after 30 minutes when mean arterial blood pressure was reduced by 24% (from 132 to 102 mm Hg). There was a linear relationship between the change in mean arterial blood pressure and log plasma concentration of felodipine. Cardiac output increased from 5.1 +/- 1.5 to 6.6 +/- 2.6 L/min (p less than 0.01), partly because of increased heart rate from 56 +/- 7.9 to 65 +/- 9.5 beats/min (p less than 0.01) and partly due to increased stroke volume from 93 +/- 25 to 103 +/- 34 ml/beat (p less than 0.05). Renal plasma flow increased significantly (p less than 0.05) from 343 +/- 138 ml/min to 391 +/- 154 ml/min and 400 +/- 149 ml/min, while glomerular filtration rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of felodipine in hypertensive patients with reduced renal function.

The new calcium antagonist felodipine with a pronounced arteriolar dilating capacity was used to treat 11 patients with severe hypertension resistant to treatment (4 with essential hypertension, 5 with renoparechymatous hypertension, 2 with renovascular hypertension). Mean glomerular filtration rate for 10 patients was 34 +/- 27 ml/min/1.73 m2 body surface area (51Cr-EDTA clearance) before felodipine. One patient was on haemodialysis treatment. Mean arterial blood pressure in the outpatient clinic was 206 +/- 39/119 +/- 18 mm Hg in spite of treatment with 3 or more antihypertensive drugs. All but 2 patients had been given an angiotensin converting-enzyme inhibitor without success. All vasodilating agents were discontinued and the following morning 5 to 10 mg felodipine was given orally. This resulted in a reduction of average supine blood pressure from 190/110 mm Hg to 150/90 mm Hg during the first hour. The antihypertensive effect was unchanged during 6 hours and the drug was subsequently administered twice or three times a day. Mean systolic and diastolic blood pressure after 1 month was 155 +/- 19/91 +/- 12 mm Hg. Eight patients showed a favourable long term response with a mean systolic and diastolic blood pressure of 154 +/- 17/89 +/- 6mm Hg after 6 months. One patient died from his underlying disease after 2 months and 1 patient discontinued treatment because of ankle oedema after 6 weeks. In the long term treated patients with glomerular filtration rates greater than 15 ml/min/1.73m2 all but 1 showed an improved renal function by 26 +/- 19% (n = 5) after initiation of felodipine therapy. In 2 cases with very low glomerular filtration rate (6 to 7 ml/min/1.73m2) the deterioration of renal function continued after felodipine, but at a slower rate. It is concluded that felodipine decreased blood pressure dramatically in patients with severe hypertension where a majority of the cases had been resistant to a previous therapy. The drug appeared safe also in advanced renal insufficiency.

Felodipine in combination with a beta-blocker and a diuretic in chronic treatment of patients with refractory primary hypertension.

The acute antihypertensive effects of the dihydropyridine calcium antagonist, felodipine, were investigated in 12 male patients aged 43 to 64 years with uncontrolled blood pressure on combined treatment with a thiazide diuretic, a beta-blocker and hydralazine. Central and renal haemodynamics were monitored after acute oral administration (0.075 mg/kg) of felodipine in combination with the beta-blocker and diuretic. Six patients were continued on long term oral felodipine (mean dose 20 +/- 24 mg/day) in combination with the other drugs for 6 to 18 months. Ambulatory blood pressure was measured repeatedly and renal function re-examined once during long term felodipine therapy. In the 6 patients on long term therapy, systolic blood pressure was reduced from 190 +/- 17 to 149 +/- 24 mm Hg and diastolic blood pressure from 116 +/- 12 to 89 +/- 14mm Hg (p less than 0.001). No significant change in heart rate was observed (65 +/- 4 vs 62 +/- 10 beats/min). Renal plasma flow significantly increased from 284 +/- 97 to 425 +/- 131 ml/min/m2 (p less than 0.01) but glomerular filtration rate was unchanged (72 +/- 20 vs 80 +/- 22 ml/min/m2). Hence, the filtration fraction was significantly reduced and normalised in all patients (0.26 +/- 0.04 vs 0.20 +/- 0.03) [p less than 0.05]. Bodyweight was unchanged. It is concluded that felodipine is a highly potent vasodilator with a favourable effect on renal function and is suitable for long term therapy in patients with severe primary hypertension.

Clinical evaluation of felodipine in patients with refractory hypertension.

The calcium antagonist, felodipine, was used to treat 21 patients with severe uncontrolled hypertension: 13 had renoparenchymatous hypertension, 5 essential hypertension and 3 renovascular hypertension. Mean arterial blood pressure of patients was 195 +/- 8/122 +/- 3mm Hg in spite of treatment with 3 or more antihypertensive drugs. The majority of the patients (n = 17) were treated with an ACE inhibitor. Mean glomerular filtration rate (GFR) for 20 patients was 39 +/- 6 ml/min/1.73m2 body surface area (Cr-EDTA clearance) before felodipine administration. All patients had an immediate blood pressure fall after 5-10mg of felodipine administered orally. This fall persisted when the drug was given 2 or 3 times daily in combination with previous medication except the former vasodilating drugs. 15 patients are on long term treatment with felodipine and their blood pressure after 1 year (n = 14) was 152 +/- 4/89 +/- 2mm Hg. Patients with moderately impaired renal function and no signs of progressive kidney disease (n = 8) improved their GFR significantly after 1 year on felodipine. Six patients stopped felodipine therapy within 3 months (4 because of adverse reactions, 1 died of scleroderma and 1 became normotensive after the start of dialysis treatment). In patients with renoparenchymatous disease and documented progressive deterioration of renal function the addition of felodipine did not prevent a decline in filtration rate but did slow the rate of deterioration (from 9 +/- 2 to 5 +/- 1 ml/min/year).(ABSTRACT TRUNCATED AT 250 WORDS)

The role of gastric resection in the management of multicentric argyrophil gastric carcinoids.

A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.

Effects of prostacyclin infusion on renal function during cardiopulmonary bypass.

Infusion of prostacyclin inhibits platelet activation during cardiopulmonary bypass (CPB) but also results in systemic arterial hypotension. Therefore, the effects of CPB and prostacyclin on renal function were studied in 36 male patients undergoing aortocoronary bypass. Nineteen patients (Group 1) received prostacyclin, 50 ng per kilogram of body weight per minute, during CPB, and 17 patients (Group 2) served as controls. There was pronounced hypotension in Group 1 only. Urine production during CPB averaged 88 +/- 140 ml and 2,306 +/- 1,112 ml in Groups 1 and 2, respectively. No patient had renal failure. Glomerular filtration rate (GFR), as measured by clearance of chromium 51-labeled ethylenediaminetetraacetic acid, was increased in Group 1 from 86 +/- 14 to 99 +/- 22 ml/1.73 m2/min (p less than 0.05) the day after operation, but remained unchanged in Group 2 (81 +/- 15 to 82 +/- 21 ml/1.73 m2/min). The increased GFR in Group 1 can be regarded as an expected adaptation to the change in body fluids after CPB. Therefore, the unchanged GFR in Group 2 must be regarded as caused by insufficient adaptation or impaired renal function. Proximal tubular function was evaluated by determination of beta 2-microglobulin in urine. In both groups, urinary beta 2-microglobulin and the ratio of urinary beta 2-microglobulin to urinary creatinine were increased the day after operation. The hypotension in Group 1 did not exacerbate the damage to tubular function.

The bone marrow in urticaria pigmentosa and systemic mastocytosis. Cell composition and mast cell density in relation to urinary excretion of tele-methylimidazoleacetic acid.

The bone marrow sections from five normal subjects and 18 patients with mastocytosis were examined to establish criteria to distinguish urticaria pigmentosa from systemic mastocytosis. Nine patients had increased numbers of mast cells in bone marrow sections stained with a long toluidine blue staining technique specific for mast cells, whereas five patients exhibited increased numbers of mast cells on May-Grünwald-Giemsa-stained smears of bone marrow. A positive correlation between the number of mast cells in sections of the bone marrow and the urinary excretion of the main histamine metabolite tele-methylimidazoleacetic acid was found. In ten of the examined bone marrow specimens, focal lesions containing mast cells, lymphocytes, and eosinophils appeared. The presence of these focal lesions together with either an increased number of mast cells in bone marrow sections and/or increased urinary excretion of telemethylimidazoleacetic acid is considered diagnostic of systemic mastocytosis. No patient exhibited myeloproliferative condition or other major hematologic abnormality.

Treatment of chronic urticaria with PUVA or UVA plus placebo: a double-blind study.

Chronic urticaria is a disease for which the available range of treatment modalities is limited. Ultraviolet radiation has recently been shown to affect histamine release from mast cells. We therefore studied the effects of PUVA and UVA on chronic urticaria. Nineteen patients took part in the study, which was designed as a randomized double-blind study. Eleven patients received PUVA, and 8 received UVA plus a placebo. In the PUVA group, 7 patients showed improvement, 3 noticed no change, and 1 became worse. In the group that received UVA plus placebo, 5 patients experienced an improvement, whereas the other 3 showed no change. The differences between the groups were not statistically significant. However, the probability of achieving this degree of improvement in both groups just by chance is less than 1%. Consequently, the improvement noted could have been due to either UVA alone or a placebo effect. It is concluded that PUVA is not better than UVA in the treatment of chronic urticaria.

Effects of Prostaglandin Synthetase Inhibitation on Captopril-Induced Changes in Renal Function in Bartter's Syndrome.

Three patients with Bartter's syndrome were studied under metabolic ward conditions. Renal function and the renin-angiotensin system were evaluated in three different settings: before and during captopril treatment and during administration of captopril and indomethacin. Captopril induced renal vasodilation with an increase in renal plasma flow by 23%. The addition of idomethacin abolished this change. Captopril increased the release of renin and the concentration of angiotensin II in plasma decreased without being completely normalized. Indomethacin thereafter reduced plasma concentration of renin, which was, however, still higher than the control level. The plasma concentration of angiotensin II did not change significantly. In conclusion, prostaglandin synthetase inhibition annihilated the effect of captopril on renal hemodynamics and renin release.

Effects of extra-renal background subtraction and kidney depth correction in the measurement of GFR by gamma camera renography.

99Tcm-DTPA gamma camera renography was performed in 83 patients with a wide range of renal function. An uptake index (UI) proportional to the single kidney glomerular filtration rate (GFR) was calculated from the renograms according to two different algorithms, one based on a blood background taken from a region of interest (ROI) over the heart (method I), and the other a modification of that procedure including an extra-renal background subtraction (method II). The extra-renal background was defined by a ROI closely surrounding the kidney, making the separation between the extra-renal background and intra-renal blood background possible. Method II was further evaluated by comparing the results without and with correction for kidney depth (method III), the skin-kidney distance being measured by sonography. Calculated UI from the renograms was compared with measured 51Cr-EDTA plasma clearance as the reference method. Method I overestimated GFR at low kidney function. Addition of the extra-renal background subtraction (method II) eliminated that error and correction for kidney depth improved the accuracy (the standard error of the estimate was reduced from 18.2 min-1 to 12.3 min-1). It is concluded that the measurement of GFR by gamma camera renography is improved by these additional operations.

Gamma camera renography with 99Tcm-DTPA: the impact of variations in input plasma curve on estimated GFR.

In an attempt to improve the reliability in estimating glomerular filtration rate (GFR) from gamma camera renography without blood sampling, we have investigated the impact of plasma input region of interest (ROI) size and location and the effect of the time delay between the circulation peak in the renal curves and in the plasma curve. An uptake index (UI) was calculated using plasma ROIs of five different sizes (8-56 cm2) and compared with measured 51Cr-EDTA clearance. The spread of the estimated GFR was not affected by the variations in plasma ROI size but different relations were obtained between UI and GFR. The plasma ROI markedly affected the estimated GFR (a deviation of 3.5 cm from the maximal region led to an overestimation of the GFR of 36%). Furthermore, the most reliable GFR estimate (S.D. 10.5 ml min-1) was achieved by including the whole circulation peak in the calculation time interval of the time delay-adjusted renogram, except the first frame. The time delay adjustment also enabled the calculation of a factor alpha, which represents the ratio between the blood volume within the renal ROI and that within the plasma input ROI. An abnormal alpha/UI ratio would suggest an unreliable GFR estimation.

Reliability of ACE inhibitor-enhanced 99Tcm-DTPA gamma camera renography in the detection of renovascular hypertension.

Twenty consecutive patients with renovascular hypertension, proven by cure or improvement of hypertension at 1-year follow-up after percutaneous transluminal angioplasty or surgical repair, were studied before intervention by means of gamma camera renography with 99Tcm-diethylenetriaminepentaacetic acid (99Tcm-DTPA) at baseline and after angiotensin-converting enzyme (ACE) inhibition. Sixteen patients underwent bilateral renal vein catheterization for measurement of renal vein renin release and extraction ratios of para-amino-hippurate (PAH) and 51Cr-EDTA before and after acute ACE inhibition. With the limit for a significant change in relative side distribution of 5% or more after ACE inhibition on gamma camera renography 13 patients responded (Group 1), while seven patients (Group 2) had unchanged side distribution. Glomerular filtration rate (GFR), measured with 99Tcm-DTPA, in the affected kidney decreased in Group 1 from 26 +/- 16 ml min-1 to 11 +/- 12 ml min1 (P < 0.0005), while GFR was unchanged in the affected kidney in Group 2, 26 +/- 13 ml min-1 versus 29 +/- 13 ml min-1. Extraction ratios of PAH and 51Cr-EDTA for the affected kidney in Group 1 decreased from 80 +/- 18 to 73 +/- 21% (P < 0.05) and from 16 +/- 5 to 7 +/- 5% (P < 0.005), respectively, while in Group 2 the PAH extraction ratio was not significantly changed, 86 +/- 5 versus 81 +/- 14%, but the 51Cr-EDTA extraction ratio for the affected kidney also decreased from 16 +/- 3 to 8 +/- 4% (P < 0.005). All patients had lateralization of renal vein renin to the affected kidney.(ABSTRACT TRUNCATED AT 250 WORDS)