Elimination of enoxacin in renal disease.

The elimination of enoxacin was investigated in 15 subjects, 10 of whom were hospital outpatients with renal disease and varying degrees of renal impairment. Each was given enoxacin orally (200 mg b.i.d.) for 7 days. Blood specimens collected over 24 hours after the final dose of enoxacin and urine collected during the 12-hour dose interval after the final dose were assayed for enoxacin by HPLC. The elimination half-life of enoxacin increased with worsening renal function. In general, patients with diminished renal function had lower plasma enoxacin clearance values than had normal subjects, and a statistically significant correlation between apparent oral clearance and creatinine clearance was observed. Excretion of enoxacin by the kidney accounted for 26% to 72% of the apparent plasma clearance in normal subjects. This was markedly reduced in patients with severe renal failure.

Alpha blockade. An overview of efficacy data.

The antihypertensive effects of the alpha-adrenergic blocking agent prazosin have been studied extensively. Prazosin exerts a vasodilatory effect via selective competitive blockade of post-junctional alpha 1 adrenoceptors. Results of various other clinical trials suggest that the selective alpha 1-adrenoceptor antagonist prazosin has a significant impact on two of the three primary coronary heart disease risk factors. In the articles reviewed herein, prazosin is shown to be an effective agent when used alone or in combination with other agents. Stamler and co-workers showed that prazosin alone achieves successful control of blood pressure equal to that of hydrochlorothiazide. Inouye et al compared the effectiveness of prazosin with propranolol and hydrochlorothiazide and found all three drugs to be comparable. Okun reveals the efficacy of prazosin across the spectrum of hypertension--mild, moderate, and severe. Additionally, Okun's prazosin versus captopril study revealed equal efficacy between these two drugs. The long-term comparative data of Lowenstein and Neusy show prazosin and atenolol to be equally effective as monotherapy after one year.

Glomerular lesions after renal transplantation.

Significant changes in glomeruli on light microscopy has been observed in 27 of 109 cadaveric renal allografts which functioned beyond 6 months. Tissue was available for study from all but two allografts. The histologic lesions were classified as follows: recurrent glomeruloneophritis, 9 cases (3 focal scierosis, 2 mesangial immunoglobulin A[IgA] disease, 2 mesangiocapillary glomerulonephritis, 1 dense deposit disease, 1 familial nephritis); de novo glomerulonephritis, 1 case (diffuse proliferative glomerulonephritis with crescents); and glomerular change of uncertain etiology, 17 cases (10 mesangiocapillary, 5 focal scierosis, 1 focal proliferative and 1 mesangial proliferative). These lesions were not distinguishable on light, fluorescent and electron microscopy from those in patients with spontaneous renal disease. All patients with glomerular lesions had proteinuria, and all but 3 had microscopic hematuria. Glomerular lesions were not significantly associated with early clinical rejection episodes or HLA compatibility. Presensitization of HLA antigens was significantly related to the occurence of a nonrecurrent glomerular lesion. Vescoureteral reflux was significantly more frequent in those with glomerular change (14 of 24) than in those without (13 of 48). Glomerular lesions were associated with a higher rate of graft loss due to renal transplant failure; renal function in survivors was significantly worse than in those without glomerular lesions.

Role of the renal medulla in adrenocorticotrophin-induced hypertension in rats.

OBJECTIVES: The mechanism of hypertension induced by adrenocorticotrophin (ACTH) remains unclear. The antihypertensive renomedullary lipids are vasodilators and it has been proposed that a deficiency of these lipids may contribute to the hypertension produced by destruction of the renal papilla. The aim of the present work was to study ACTH hypertension in both control and chemically renomedullectomized rats. METHODS: Renomedullectomy was produced by single intraperitoneal injection of 2-bromoethylamine (BEA) at 400 mg/kg. RESULTS: BEA-treated rats all developed increases in water intake and urine volume, with loss of papillae and medullary and cortical fibrosis. There was a significant correlation between papillary ablation and systolic blood pressure (SBP). SBP in renomedullectomized rats was higher after ACTH than sham injection, and higher than after ACTH injection in intact rats. CONCLUSION: Chemical renomedullectomy with BEA did not block or attenuate the onset or magnitude of ACTH hypertension in the rat.

Effect of dietary calcium on the development of hypertension and hypertensive vascular lesions in DOCA-salt and two-kidney, one clip hypertensive rats.

OBJECTIVE: To examine the effect of modest changes in dietary calcium on systolic blood pressure (SBP) and myocardial and renal vascular lesions in Sprague-Dawley rats. DESIGN: Regular- (0.4%, by weight), high- (0.8%) or low-calcium (0.24%) diets were fed to normotensive control, deoxycorticosterone acetate (DOCA)-salt and two-kidney, one clip (2-K, 1C) hypertensive rats for 8 weeks. METHODS: Tail-cuff SBP and metabolic balance were measured once a week. At the end of the study the kidneys and hearts were collected for histological study. RESULTS: Dietary calcium had no effect on SBP in the DOCA-salt rats, but loading with calcium accelerated the rise in SBP in 2-K,1C rats (P < 0.01, high- versus regular-calcium diet). The high-calcium diet reduced the percentage medial area of intramyocardial arteries in the DOCA-salt and 2-K,1C hypertensive rats. The DOCA-salt rats on the low-calcium diet had a higher renal vascular lesions score than those on the regular- or high-calcium diet (P < 0.05). CONCLUSIONS: A high-calcium diet appears to prevent intramyocardial vascular wall thickening in DOCA-salt and 2-K,1C hypertensive rats, and a low-calcium diet aggravates renal vascular lesions in DOCA-salt hypertensive rats. These effects are not related simply to changes in blood pressure.

Malignant hypertension in Brattleboro (vasopressin-deficient) rats.

The role of arginine vasopressin (AVP) in malignant renal hypertension was investigated using the homozygous Brattleboro (vasopressin-deficient) rat. Brattleboro rats with complete aortic-ligature between the renal arteries developed malignant hypertension with the same frequency and severity as normal Long-Evans rats subjected to the same procedure. The Long-Evans hypertensive rats had significantly elevated plasma AVP levels. Plasma renin activity and plasma angiotensin II levels were significantly elevated in both Brattleboro and Long-Evans rats with malignant hypertension and the levels reached were equivalent in both groups. Thus, the renin-angiotensin system did not compensate for the lack of AVP in malignant hypertensive Brattleboro rats. Specific vascular lesions of fibrinoid necrosis were observed in a high percentage of rats with malignant hypertension, in both the Brattleboro and Long-Evans strains. We conclude that AVP does not play a primary role in the pathogenesis of malignant renal hypertension and, in particular, in the development of the vascular lesions of fibrinoid necrosis.

Adrenocorticotrophin-induced hypertension in the rat: haemodynamic, metabolic and morphological characteristics.

Adrenocorticotrophin (ACTH) administration has been systematically studied in man and sheep. It raises systolic blood pressure (SBP) in the rat, but this has been little studied. ACTH was injected once daily at 0.5 mg/kg for 12 days in male Sprague-Dawley rats (n = 19). Sham-injected animals were studied in parallel (n = 15). ACTH increased SBP from 94 +/- 4 to 121 +/- 4 mmHg (P less than 0.001), significantly greater (P less than 0.02) than sham injection. The SBP of ACTH-treated rats was significantly higher than that of sham-injected rats when the same animals were measured by both the tail-cuff method (ACTH, 126 +/- 3 mmHg; sham, 99 +/- 3 mmHg) and direct arterial cannulation (ACTH, 137 +/- 2 mmHg; sham, 123 +/- 3 mmHg): P less than 0.005 and P less than 0.001, respectively. There was a loss of body weight, and increased water intake and urine output in ACTH-treated animals compared with both control (P less than 0.001) and sham treatments (P less than 0.02). ACTH increased plasma [Na] (sham, 140 +/- 1 mmol/l; ACTH, 145 +/- 1 mmol/l; P less than 0.001) and urinary Na excretion compared with control (P less than 0.01) and sham injection (P less than 0.05), and also decreased plasma [K] (sham, 4.6 +/- 0.2 mmol/l; ACTH, 3.3 +/- 0.8 mmol/l; P less than 0.01) and increased urinary K excretion (P less than 0.01) compared with control. SBP in adrenalectomized animals (n = 10) was unchanged by ACTH. ACTH increased adrenal, renal, cardiac and brain weights compared with sham injection (P less than 0.05). There were no significant changes in vascular morphology, although ACTH treatment increased glomerular epithelial cell droplets and abolished the adrenal zona glomerulosa.

Urine cytologic profile in renal allograft recipients determined by monoclonal antibodies. Diagnosis of allograft rejection.

Controversy exists as to the type of cells present in the urine during renal allograft rejection. In order to resolve this controversy as well as to evaluate the value of urine sediment examination as a means of detecting AR, we quantitated the different cells present in urine during AR using an immunoperoxidase technique and monoclonal antibodies reactive with lymphocytes, monocytes, granulocytes, glomerular epithelial, tubular, and urothelial cells. Urine sediment (n = 176) was examined serially over 3 months in 15 transplant recipients. There were 12 episodes of early posttransplant acute tubular necrosis and 21 episodes of AR. It was possible to detect AR as well as to distinguish AR from ATN. Lymphocyte and tubular cell excretions were increased significantly during AR. Excretion of urothelial cells was also significantly increased during most episodes of AR suggesting that rejection of ureters occurs concomitantly with rejection of the kidneys.

Circulation immune complexes after renal transplantation.

The liquid phase C1q-binding assay was used as a measure of circulating immune complexes in 147 renal transplant recipients. Thirty-six patients were studied serially from the time of transplantation. Abnormal levels of C1q-binding activity (C1qBA) were most frequently detected in the first 6 months post-transplant. Although there was a statistically significant association of elevated C1qBA with rejection, the incidence of "false positives" and "false negatives" was high and particularly evident in serial studies. There was no evidence of association between C1qBA and the recipients' original renal diseases. Post-transplant monitoring of renal transplant recipients for circulating immune complexes by the C1q-binding assay is an unreliable guide to rejection.

Human renal allograft rejection is predicted by serial determinations of antibody-dependent cellular cytotoxicity.

The early recognition and prompt treatment of rejection may minimise damage to renal allografts. Preliminary studies showed whole blood effector cell function in a constant antibody-dependent cellular cytotoxicity (ADCC) assay system to be suppressed in recipients with stable renal function. To investigate the possible role of ADCC in the rejection process, serial estimates were performed in 29 consecutive recipients of cadaveric kidneys. The generation of ADCC, as measured in vitro, preceded the biochemical confirmation of an impending rejection episode by 3 to 5 days for 31 of 33 episodes experienced by 23 recipients. Statistical analysis (X2) demonstrated a highly significant correlation between ADCC generation as measured in vitro and subsequent episodes of graft rejection. In contrast, six recipients who did not experience rejection episodes during the first 3 months postgrafting showed no evidence of ADCC activity. Thus, ADCC may be used to identify rejection earlier than has previously been possible.

Diltiazem in renal allograft recipients receiving cyclosporine.

Of 113 cyclosporine-treated primary renal allograft recipients, 60 were randomized to receive standard therapy without diltiazem (ND) and 53 received standard therapy plus diltiazem (D). There was no difference in CsA blood levels between ND and D at all intervals between 3 and 24 months follow-up, yet the D group required 35% less CsA than the ND group (measured at 12 months). At all intervals to 24 months there was no difference in blood pressure, renal function (as measured by serum creatinine), or in the number of grafts lost between the 2 groups (ND, 4 lost; D, 3 lost). There was no significant difference in the total number of rejection episodes in the 2 groups (ND, 89 episodes; D, 71 episodes). However, the severity of rejection episodes was greater in the ND group as evidenced by a significant difference in the usage of OKT3 (ND, 17 courses; D, 8 courses of OKT3, P < 0.05). Of the biopsy-proven episodes of rejection, there were more episodes of vascular rejection in the ND group (ND, 14 episodes; D, 3 episodes, P = 0.005). The incidence of primary nonfunction was less in the D group (ND, 16 patients; D, 5 patients, P = 0.05). It was concluded that the use of diltiazem was associated with a markedly reduced requirement for CsA without any adverse effect on graft function or graft outcome. Diltiazem with CsA was associated with fewer episodes of primary nonfunction and less-severe rejection episodes and in particular fewer episodes of vascular rejection.

A prospective randomized trial of low-dose versus high-dose steroids in cadaveric renal transplantation.

Low-dose steroid regimens, in combination with azathioprine, have become increasingly common for immunosuppression of renal transplant recipients. The change from conventional high-dose steroid regimens was prompted by the results of several prospective trials that showed similar graft survivals with high-dose and low-dose steroids, but a lower incidence of steroid-induced complications in low-dose-steroid--treated patients. However, the number of patients entered into the trials was small, and consequently there remained a possibility that a clinically relevant difference in graft survival could have remained undetected. A multi-center prospective trial was performed to compare graft survival with high-dose (91 patients) and low-dose (98 patients) oral steroids in combination with azathioprine. There was significantly worse graft survival in the low-dose group. The difference was largely due to a poor graft survival in patients receiving low-dose steroids and azathioprine less than 1.75 mg/kg/day. Graft survivals were similar in the high-dose and low-dose steroid patients who received azathioprine doses of greater than 1.75 mg/kg/day. The results indicate that the combination of low doses of both steroids and azathioprine provides inadequate immunosuppression in renal transplantation, although higher doses of azathioprine allow the use of low-dose steroids without significantly more graft losses than with high-dose steroids.

Beta-adrenergic receptor blocking drugs in hypertension. With special reference to their use as initial therapy.

Beta-adrenergic receptor blocking agents have been receiving attention as first-line agents for the treatment of hypertension. However, a number of significant side effects of these drugs have been brought to light. The most important of these--increases in "atherogenic" lipid concentrations--may place treated persons at risk of coronary artery disease and myocardial infarction. Other side effects, including bronchospasm, heart failure, cold extremities, reduced insulin secretion and central nervous system effects, may preclude their use in many patients. However, because several major trials have shown that controlling blood pressure reduces the incidence of coronary heart disease and stroke, the use of antihypertensive therapy is likely to increase and to continue for longer periods. The physician must prescribe an agent with the fewest and most minor side effects. Alternatives to beta-blocking drugs, such as the alpha-receptor blocking agent prazosin, should be considered and evaluated because of the limiting side effect profile of beta blockers.

Effects of non-narcotic analgesics on the kidney.

Non-narcotic analgesics have acute and chronic effects on the kidney. Until quite recently chronic effects have received much more attention than acute effects. Renal papillary necrosis attributed to prolonged intake of analgesic compounds was first described from Switzerland in the 1950s, and subsequently in many countries including Scandinavia, Australia, Belgium and Canada. Renal papillary necrosis is now accepted as an effect of over-the-counter analgesic compounds and has also been recorded with many individual non-steroidal anti-inflammatory drugs (NSAIDs). Evidence suggests that uroepithelial tumours also occur as a complication of prolonged abuse of analgesic compounds. Clinical evidence associating renal papillary necrosis with compound analgesics and NSAIDs has been backed up by experimental evidence showing that these drugs cause renal papillary necrosis in animals. Acute effects of non-narcotic analgesics have been described mainly in association with aspirin and NSAIDs. In high renin states, including salt-depleted normal subjects, NSAID administration may be associated with an acute decrease in renal function, which is more obvious in patients who have underlying renal disease. Clinical syndromes which occur in association with NSAIDs include oedema, hyperkalaemia and acute renal failure and the acute nephrotic syndrome. Acute renal failure may be associated with acute interstitial nephritis and the nephrotic syndrome or may be due to acute tubular necrosis. Patients who have the nephrotic syndrome show fusion of foot processes of glomerular epithelial cells on electron microscopy as well as acute interstitial nephritis. Patients who suffer these episodes of acute renal function deterioration associated with NSAIDs recover slowly after withdrawal of the drugs, and the recovery may not be complete.

The treatment of resistant hypertension.

Resistant hypertension can be defined in terms of lack of blood pressure response to hypotensive agents, but there may be a big difference between standing and lying blood pressure levels. In general target organ damage and papilloedema improve if the standing blood pressure is controlled; however, progression can occasionally be documented when only the supine blood pressure remains uncontrolled. Resistant hypertension was a frequent phenomenon when ganglion blocking agents and hydrallazine were the only effective hypotensive agents. With the advent of the thiazides, effective control of the blood pressure became the exception rather than the rule; however, it was not until the advent of adrenergic blocking agents that reduction of supine blood pressures was regularly achieved. The addition of hydrallazine or prazosin to a combination of a thiazide and beta-adrenoreceptor blocking agent produces a further significant fall in the blood pressure lying and standing. This combination will control the blood pressure in most patients, but a few remain refractory to maximum doses and will require treatment with oral diazoxide or minoxidil. Both these powerful vasodilators are very effective in resistant hypertension. Oral diazoxide permits excellent control and allows a 10-fold reduction in the doses of other agents. Minoxidil usually needs to be combined with moderate doses of beta-blocking agents to reduce the marked reflex tachycardia. Only a 50% reduction in other hypotensive agents was achieved in patients treated with minoxidil and two patients proved resistant to minoxidil, but subsequently responded to oral diazoxide.

Glomerular size and glomerulosclerosis in Australian aborigines.

We have previously described the prevalence of glomerulomegaly in biopsy specimens from Australian Aborigines with renal disease, a phenomenon documented in a number of other indigenous populations. Many of the biopsy specimens showed variable degrees of focal and segmental glomerulosclerosis (FSGS). Correlations between glomerular size and FSGS have been described in various animal models, as well as studies of humans. The aim of this study is to determine whether a relation exists between glomerular volume and severity of FSGS in biopsy specimens from Australian Aboriginals in the Northern Territory and Aboriginal inhabitants of the Tiwi Islands (Bathurst Island and Melville Island, Northern Territory, Australia). Consecutive clinical biopsy specimens were obtained from 78 non-Tiwi and 72 Tiwi Aboriginals. Glomerular volume was estimated using the stereological method of Weibel and Gomez. FSGS was graded from 0 to 4; 0 indicates no sclerosis and 4 indicates severe sclerosis. A biphasic relationship between glomerular size and severity of FSGS was identified. As the severity of FSGS increased from grade 0 to grade 3, glomerular size also increased. For both populations studied, glomeruli scored as grades 1, 2, and 3 were approximately 50% (P< 0.001), 65% (P< 0.001), and 100% (P< 0.001) larger than normal glomeruli, respectively. However, in glomeruli with grade 4 FSGS, glomerular size decreased to the size of normal glomeruli. These results show a biphasic relationship between severity of FSGS and glomerular size in Australian Aborigines.

Treatment of mesangial immunoglobulin A glomerulonephritis.

Mesangial immunoglobulin A glomerulonephritis does not progress unless microscopic hematuria presents at levels over 100,000/mL, proteinuria presents at levels over 0.5 g in 24 hours, or hypertension is inadequately controlled. Hypertension, microscopic hematuria, and proteinuria all can be controlled; the evidence for control of these three risk factors is reviewed. The evidence for prevention of progression in mesangial immunoglobulin A glomerulonephritis is also reviewed.

HLA-DR and -DQ genotyping in anti-GBM disease.

Anti-GBM disease has been associated with the HLA genes of the major histocompatibility complex (MHC) in previous serological studies, with an increased incidence of HLA-DR2 in patients. In this study, 36 patients with anti-GBM disease were genotyped by restriction fragment length polymorphism (RFLP) analysis using cDNA probes for DRB, DQA, and DQB. The frequency of HLA-DRw15(Dw2), a split of DR2, was significantly increased in the patients compared with the controls (63.9 per cent versus 23.3 per cent, chi 2 = 22.4, p(corr) less than 0.0001), and all but one of the patients were positive for either DRw15(Dw2) or DR4 (p less than 0.0001). The frequencies of the remaining DR antigens were not decreased randomly, with a significant decrease in DR7 in the patient group (chi 2 = 8.6, p(corr) less than 0.05). The closely linked gene HLA-DQw6 was found to be significantly increased in frequency in the patients compared with the controls (p(corr) less than 0.0001). No correlations could be made between the genetic data and clinical features of the disease.

Immunocytologic dissection of the urine sediment using monoclonal antibodies.

A method to identify nucleated nonsquamous cells in urine using monoclonal antibodies and immunoperoxidase stain is described. Cells from washed deposits of midstream urine samples were transferred to gelatinized slides in a cytocentrifuge, air-dried, acetone fixed, and subjected to microwave irradiation. Slide preparations were then treated with monoclonal antibodies with the use of a four-layer peroxidase-antiperoxidase technique. It was possible to identify granulocytes, monocytes, lymphocytes, and renal epithelial and urothelial cells. This method was found to be helpful in determining the profiles of cells in urine in acute tubular necrosis, drug-related acute interstitial nephritis, and crescentic glomerulonephritis.

Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation.

OBJECTIVE: To determine the optimal method of measuring uterine artery waveforms with Doppler ultrasound when screening healthy nulliparas for subsequent development of preeclampsia and fetal growth retardation (FGR). METHODS: Color Doppler ultrasound was used to obtain uterine artery waveforms at 19-24 weeks' gestation in 458 nulliparas. In each uterine artery, the resistance index (RI), the ratio between peak systolic (A) and early diastolic (C) blood flow velocities (AC ratio) (a measure of the early notch in the uterine artery waveform), and placental position were recorded. The predictive values of these uterine artery Doppler measurements were evaluated for pregnancy complications. The major end points were preeclampsia and small for gestational age (SGA) infants. RESULTS: The best screening test for preeclampsia and SGA infants was the placental-side uterine artery RI or AC ratio above the 90th percentile for gestational age when the placenta was located on the left or right, and the highest RI or AC ratio when the placenta was midline. This method identified 51% of women with subsequent preeclampsia or SGA infants and had a positive predictive value of 29%. The test detected women with severe disease requiring delivery before 37 weeks with a sensitivity of 83% and specificity of 88%. However, the results were similar if the placental-side uterine artery RI was above an arbitrary cutoff of 0.56 or the AC ratio was above 2.05. A normal test predicted an uncomplicated pregnancy. CONCLUSIONS: Although abnormal uterine artery Doppler is associated with an increased risk of preeclampsia and FGR, the positive predictive values do not support its introduction as a routine screening test in nulliparous women.