The effects of quinolones on xanthine pharmacokinetics.

Caffeine, theobromine, and theophylline are among the most widely consumed compounds in beverages and in pharmaceutical preparations. These methylxanthine alkaloids are metabolized by similar pathways involving demethylation and hydroxylation that are predominantly cytochrome P-450 mediated. In vivo and in vitro evidence suggests that the cytochrome P-450 isozymes involved in the demethylation pathways are distinct from the cytochrome P-450 isozymes involved in the hydroxylation pathways. Although distinctions can be made between demethylation and hydroxylation pathways, the evidence suggests that these different cytochrome P-450 isozymes are under common regulatory control. Any drug inhibiting the family of cytochrome P-450 isozymes involved in the metabolism of the methylxanthines would, therefore, be expected to have a similar effect on theophylline, theobromine, and caffeine. A number of quinolones, including enoxacin, pipemidic acid, ciprofloxacin, norfloxacin, and pefloxacin, have been shown to reduce the clearance of theophylline, while lomefloxacin has no effect on theophylline or caffeine clearance. It has been hypothesized that only fluoroquinolones that form a 4-oxo-metabolite inhibit theophylline clearance. Lomefloxacin, which does not form a 4-oxo-metabolite, would therefore not be expected to inhibit the clearance of theophylline or caffeine. In contrast, ciprofloxacin, which does form a 4-oxo-metabolite, has been shown to reduce theophylline and caffeine clearances by about one third. Another hypothesis for the differences among quinolones suggests that quinolones that have a greater impact on theophylline clearances are more stereochemically similar to theophylline. Substitutions at position 8 on the quinolone nucleus (as in lomefloxacin) would result in stearic hindrance and decrease the structural similarity to theophylline.

Tinidazole pharmacokinetics in severe renal failure.

The single-dose pharmacokinetics of intravenously and orally administered tinidazole were studied in normal subjects and patients with severe chronic renal failure. The clearance of tinidazole was also measured in patients on regular haemodialysis. After intravenous administration the mean elimination half-life of tinidazole was 17.1 +/- 2.3 (SD) hours in the normal subjects and 16.9 +/- 4.9 hours in patients with renal failure; the mean apparent volumes of distribution were 0.80 +/- 0.09 L/kg and 0.69 +/- 0.09 L/kg, respectively. Following oral administration the mean elimination half-life was 15.6 +/- 1.6 hours in the normal subjects and 18.4 +/- 3.5 hours in patients with renal failure; there were no statistically significant differences in these pharmacokinetic parameters. There was no accumulation of the major metabolite (hydroxymethyl tinidazole) in normal subjects or in patients with renal failure. Tinidazole clearance during haemodialysis was 71 +/- 7.7 ml/min. In the presence of renal failure no modification of tinidazole dosage would appear to be necessary. Tinidazole should be administered in full dosage following haemodialysis.

Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations.

Tolbutamide hydroxylation has been investigated in human liver microsomes. Anti-human liver NADPH-cytochrome P-450 reductase IgG inhibited hydroxytolbutamide formation and this metabolite was not formed when NADPH-generating system was omitted from microsomal incubations. Tolbutamide hydroxylation followed Michaelis-Menten kinetics, consistent with the involvement of a single form of cytochrome P-450 in this reaction. Mean apparent Km and Vmax values for hydroxytolbutamide formation were 120 +/- 41 microM and 0.273 +/- 0.066 nmol min-1 mg-1, respectively. A range of clinically used drugs and xenobiotics used as probes for cytochrome P-450 activity in laboratory animals was screened for inhibitory effects on hydroxytolbutamide formation. Caffeine, paraxanthine, theophylline, theobromine, debrisoquine, erythromycin, phenacetin, propranolol, aminopyrine, benzo(a)pyrene and 7-ethoxycoumarin were all found not to inhibit tolbutamide hydroxylation. In contrast, sulphaphenazole, phenylbutazone, nifedipine, verapamil, cimetidine, aniline, dextropropoxyphene and mephenytoin were competitive inhibitors of tolbutamide hydroxylation. The respective apparent Ki values for these compounds were 0.12 microM, 11 microM, 15 microM, 118 microM, 140 microM, 182 microM, 225 microM and 375 microM. Sulphinpyrazone inhibited tolbutamide hydroxylation with atypical kinetics. The in vitro data is in good agreement with in vivo drug interactions with tolbutamide. The data also confirm that tolbutamide hydroxylation is not associated with the cytochromes P-450 responsible for methylxanthine metabolism or with the form responsible for the polymorphic oxidation of debrisoquine.

Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies.

Anti-human NADPH-cytochrome P-450 reductase inhibited all theophylline metabolic pathways confirming the involvement of cytochrome P-450 isozymes in the metabolism of theophylline. Tolbutamide, debrisoquine, mephenytoin, theobromine, phenylbutazone, sulphaphenazole and sulphinpyrazone did not inhibit theophylline metabolism by human liver microsomes. Verapamil and dextropropoxyphene were non-selective competitive inhibitors of theophylline metabolism. Cimetidine and caffeine selectively inhibited the two demethylations as Ki values for these two pathways were lower than for the 8-hydroxylation pathway. The effects of nifedipine, propranolol and alpha-naphthoflavone were atypical. The degree of inhibition by propranolol reached a plateau, which was greater for the two demethylations than for the 8-hydroxylation. Alpha-naphthoflavone (ANF) at low concentrations inhibited the demethylations to a greater extent than the 8-hydroxylation. At higher concentrations ANF activated all pathways, with this effect being most marked for the 8-hydroxylation. Nifedipine inhibited the theophylline demethylations but not the 8-hydroxylation. In some livers the 8-hydroxylation was markedly activated. The results confirm that there are at least two distinct cytochrome P-450 isozymes involved in theophylline metabolism, one isozyme being involved with the demethylations and a different isozyme involved in the 8-hydroxylation pathway. Preliminary correlation studies suggest that the human orthologue to the rabbit polycyclic hydrocarbon inducible P-450 Form 4 may be involved in the N-demethylations of theophylline.

Lansoprazole pharmacokinetics differ in patients with oesophagitis compared to healthy volunteers.

AIM: To compare the pharmacokinetics of lansoprazole in patients with reflux oesophagitis and in healthy volunteers, after a single dose and at steady-state. PATIENTS AND METHODS: A 30 mg dose of lansoprazole was administered orally daily for 7 days in eight healthy male volunteers aged 21-24 years, and in 16 patients aged 29-65 years with grade 2 or 3 reflux oesophagitis. The pharmacokinetics were assessed over the 24 h dose interval following the first dose and again after the 7th dose. RESULTS: Within both the patient and volunteers groups, there were no significant differences between day 1 and day 7 in any of the pharmacokinetic parameters including maximum concentration (Cmax), area under the concentration-time curve (AUC), and terminal half-life of elimination (t(1/2)). However, on both days 1 and 7, values were significantly higher in the patients than in the healthy volunteers. On day 7, Cmax was 1343 ng/mL in patients compared with 765 ng/mL in healthy volunteers, AUC was 3458 ng.h/mL vs. 1350 ng.h/mL and t(1/2) was 1.62 h vs. 0.90 h. CONCLUSION: The differences in results for the pharmacokinetics reflect reduced lansoprazole clearance in the patient group. Other research has not found a difference in pharmacokinetics when comparing healthy volunteers with patients with acid-related disorders. The difference in lansoprazole clearance in this study may be related to a variety of factors that are different in patients compared with young normal volunteers, such as age, gender, other drugs, and reduced general well-being.

Serum profiles and safety of intermediate-dose (500-1,000 mg) methotrexate following IV and IM administration.

Despite extensive clinical experience with methotrexate there is no consensus of opinion as to the ideal method of administration. This study tested the hypotheses that intermediate-dose (500-1,000 mg) methotrexate can safely by administered to outpatients as an IM injection, and that similar serum profiles of methotrexate result from IM and IV administration. Fourteen patients received 500 mg methotrexate, and nine of these received 1,000 mg as an IM injection. Methotrexate levels at 24 and 48 h were below the levels at which toxicity can be expected. Six patients received 500 mg both IM and IV and 1,000 mg both IM and IV. Serum methotrexate profiles over 48 h were similar following both IM and IV administration. This study showed no evidence of significant toxicity in terms of bone marrow, gastrointestinal, or renal impairment.

Quinolone pharmacokinetics.

Fluoroquinolones have broad antibacterial spectra and are active against most Gram-negative and many Gram-positive species. They exhibit excellent oral bioavailability, extensive tissue penetration, low protein binding, and a long elimination half-life. This review compares and contrasts the pharmakonetics of some quinolone antibiotics - especially pefloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, fleroxacin and lomefloxacin - in terms of their adsorption, distribution, metabolism, elimination, and interactions with other drugs and with food. In addition, the pharmacokinetics of these agents in the elderly and in patients with renal or hepatic impairment is discussed. The fluoroquinolones are established as a major class of antibiotics in the treatment of infections but pharmacokinetics factors should be considered when deciding on the most appropriate of these agents to use in individual patients.

Abnormal glycine betaine content of the blood and urine of diabetic and renal patients.

In normal human plasma the concentrations of the renal osmolyte, glycine betaine, are usually between 20 and 70 mumol/l, in adult males (median 44 mumol/l) higher than in females (34 mumol/l). Concentrations are lower in renal disease (median 28 mumol/l) and normal in diabetes. Urinary excretion of glycine betaine shows no sex difference and is frequently elevated both in renal disease and in diabetes (medians: normal, 6.2, renal 12.3 and diabetes, 39.7 mmol/mol creatinine). The elevation in diabetes does not strongly correlate with known renal disease, nor with either urinary microalbumin or plasma creatinine. There is no correlation with glycated haemoglobin. The positive correlation with the excretions of another renal osmolyte, sorbitol, was highly significant in diabetic subjects. In the diabetic group there was also a significant negative correlation between plasma glycine betaine and urine microalbumin.

Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia.

In an ambulatory population of diabetic subjects (Type 1 and Type 2), the urine excretion of the renal osmolyte, glycine betaine, was compared to known markers of glycemic control, renal dysfunction and to the excretion of related betaines, including trigonelline, proline betaine, carnitine and acetyl-carnitine. Of the 85 subjects, 20 patients had urine glycine betaine concentrations above the reference range for normal subjects. Plasma glycine betaine concentrations were within reference ranges for normal subjects. Patients with elevated glycine betaine excretion tended to have lower plasma glycine betaine concentrations, but this did not reach statistical significance. One way analysis of variance found excretion is independent of treatment, duration of diagnosed diabetes, blood pressure and body mass index (BMI). An association between glycine betaine excretion and glycemic control was observed with statistically significant correlations occurring with both plasma glucose (r = 0.43, P < 0.001) and glycated haemoglobin (HbA1c) (r = 0.35, P < 0.005). The excretion of carnitine, acetyl-carnitine and proline betaine were related to glycine betaine excretion (r = 0.49, P < 0.001; r = 0.40, P < 0.001; r = 0.27, P < 0.05, respectively). Urine carnitine and acetyl-carnitine concentrations were also related to plasma glucose concentrations (r = 0.30, P < 0.01). Increased urine retinol binding protein concentrations (RBP), a marker of proximal tubular dysfunction, correlated with elevated urine glycine betaine excretion and plasma HbA1c (r = 0.28, P < 0.01). These results suggest poor glycemic control is associated with the increase in urine glycine betaine, carnitine, acetyl-carnitine and RBP excretion in diabetic patients. However, < 50% of the observed increase in glycine betaine excretion has been accounted for by the variables measured, suggesting other unidentified processes may also be involved.

Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia.

Diabetes mellitus subjects, type 1 and type 2, have increased glycine betaine excretion compared to normal subjects that correlated with plasma glucose and HbA(1C) concentrations. The current study was undertaken to determine whether elevated glucose concentration directly increases glycine betaine excretion in an animal model. Non-pregnant female Coopworth sheep received an intravenous glucose load (12.5,25 and 50% w/v; rate 200 ml/h) for 6 h followed by a 12 h physiological saline washout (0.9% w/v). Plasma and urine samples were analyzed for glycine betaine and glucose. Urine volumes and osmolality were also measured. Using the non-parametric Kruskal Wallis analysis of variance test we found no difference in glycine betaine excretion between glucose loaded and saline infused control animals (P=0.861). However, a significant negative correlation (r=-0.28, P<0.001) was observed between urine osmolality and glycine betaine excretion independent of treatment. We conclude that acute elevations of plasma glucose concentrations did not result in increased glycine betaine excretion and is therefore unlikely to be directly responsible for elevated glycine betaine excretion observed in diabetes mellitus subjects.

Activation of the food-derived mutagen 2-amino-3-methylimidazo[4, 5-f]quinoline by human-liver microsomes.

The ability of human-liver microsomes to metabolically activate the food-derived heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and the model mutagen, 2-aminofluorene (AF), has been investigated using Salmonella typhimurium TA98. In 6 subjects tested the number of revertants produced by 0.1 micrograms IQ per mg microsomal protein varied from 11, 830 +/- 320 to 42, 830 +/- 290 (mean +/- SD). With the same livers and a dose of 10 micrograms AF per plate the number of revertants varied from 15,770 +/- 1600 to 29,380 +/- 810 per mg microsomal protein. Metyrapone and alpha-naphthoflavone caused differential inhibition of the mutagenesis of both IQ and AF indicating the involvement of different forms of cytochrome P450 in the metabolic activation of these amines in human-liver microsomes. In presence of human-liver microsomes IQ produced no detectable increase in mutations at the hypoxanthine phosphoribosyl transferase locus in lymphocytes and caused no increase in micronuclei formation at realistic exposure levels.

Effect of lacidipine, a dihydropyridine calcium antagonist on renal function of hypertensive patients with renal insufficiency.

There are few studies on the use of dihydropyridine calcium antagonists in hypertensive patients with moderate renal insufficiency. We undertook an open study on the effects on renal function, albumin excretion and blood pressure of the slow-onset, long-acting dihydropyridine calcium antagonist, lacidipine, in 14 patients with stable, chronic renal insufficiency (mean assessed GFR 0.78 ml/s, range 0.50-1.17 ml/s) and moderate hypertension. Following a 2 week washout phase, lacidipine was administered for 24 weeks in a dose of 2 mg/day with the dose being titrated at 2 weekly intervals to a maximum of 6 mg/day in order to achieve adequate blood pressure control. Frusemide was introduced if blood pressure was not controlled on the maximum lacidipine dose. Blood pressure, creatinine clearance, 24 h urinary albumin excretion and plasma creatinine and albumin concentrations were measured at regular intervals throughout the study. Isotopic GFR was determined at the end of the washout period and at week 24. Lacidipine was not very effective in controlling blood pressure and had an adverse effect on renal function. In 3 patients with an incipient nephrotic syndrome this necessitated withdrawal from the study. Mean GFR of the 10 patients who completed the study decreased from 0.69 ml/s/1.73 m2 at baseline to 0.56 ml/s/1.73 m2 at week 24 (p = 0.006) with a decline in GFR being observed in 9 of these patients. The decrease in GFR was greatest in patients with poorly controlled blood pressure. An insignificant increase in mean urinary albumin excretion occurred during the study with this increase being observed only in patients with albuminuria > 1 g/24 h at baseline. These findings indicated that systemic hypertension altered glomerular hemodynamics and that the vasodilatation of pre-glomerular vessels which followed introduction of the calcium antagonist may have exacerbated this situation. The withdrawal of an angiotensin converting enzyme inhibitor during the washout period may have contributed to these changes. We suggest that renal function should be monitored closely in patients with renal insufficiency when a calcium antagonist is being used to control blood pressure, particularly in those with either marginal blood pressure control, significant albuminuria or an incipient nephrotic syndrome.

Clinical audit of the use of renal biopsy in the management of isolated microscopic hematuria.

Whether renal biopsies are indicated for the investigation of microscopic hematuria is a subject of debate. In this retrospective study we evaluated our use of renal biopsy in patients who presented between 1985 and 1995 with microscopic hematuria but without proteinuria, hypertension or renal insufficiency. Of 111 patients, 75 had a renal biopsy. Histological diagnoses included thin membrane nephropathy (TMN) (36%), IgA nephropathy (IgAN) (23%), non-IgA mesangioproliferative glomerulonephritis (MPGN) (9%), mild glomerular abnormalities (11%), focal global glomerulosclerosis (FGS) (4%) and normal (17%). After 85 patients had been followed for a mean of 43 months there were no deaths, 3 patients had proteinuria (IgAN 2, no biopsy 1), 1 had proteinuria and renal insufficiency (immune negative MPGN) and 11 were hypertensive (TMN 3, IgAN 2, normal 2, FGS 1, no biopsy 3). Hematuria resolved in 23 patients. Only 11 patients were still attending the nephrology clinic and 27% of the patients who were advised to continue annual follow-up with family doctors had not done so. In summary, the information obtained from renal biopsy rarely altered clinical management. Hypertension developed in 13% of the patients followed but it was not predicted by the biopsy result. Although a renal biopsy will usually be diagnostic it is difficult to justify in patients who have isolated microscopic hematuria.

DMSA renal scans in adults with acute pyelonephritis.

The 99mTc-DMSA scan is accepted as the most sensitive imaging modality for detecting areas of renal parenchymal scarring. More recently the DMSA scan has also been shown to be of value in imaging areas of renal parenchymal involvement in both children and adults with acute pyelonephritis. We assessed the acute DMSA scan findings in a consecutive series of 81 patients hospitalized with acute pyelonephritis. Acute pyelonephritis was diagnosed if the patient had a fever of > 37.8 degrees C, loin pain or tenderness and infected urine (99% Escherichia coli). Patients had a blood culture taken (8 positive), as well as a hematological (leukocytosis 75%) and biochemical screen, C-reactive protein (CRP) (increased in 57 of 66 [86%]) and urinary tract ultrasonography. If the initial DMSA scan was abnormal it was repeated after three months and in some instances again at six months. If persisting defects were noted an intravenous urogram was then undertaken. Of the 81 patients, 37 (46%) had an abnormality on the DMSA scan. Nineteen had a single defect, 12 multifocal defects, five features suggestive of pre-existing renal parenchymal scarring (all later shown to have reflux nephropathy) and one a shrunken kidney. Those patients with an abnormal scan had a higher CRP concentration than those with a normal scan. Of the 31 patients who had either a focal or multifocal defect on their initial DMSA scan there was adequate follow-up on 24 patients. In 18 of these the defects had resolved by six months (usually within three months), while of the remainder, three were shown to have reflux nephropathy, one had a large single renal cyst and another an area of parenchymal calcification. Fifty-three of 76 patients (70%) had normal ultrasonography. In adults with acute pyelonephritis, the DMSA scan may prove to be the most useful renal imaging procedure.

Prospective, randomized, controlled study comparing two dosing regimens of gentamicin/oral ciprofloxacin switch therapy for acute pyelonephritis.

Aminoglycosides are drugs of choice for severe gram-negative urinary tract sepsis. Recent evidence suggests that they are just as efficacious, but less nephrotoxic and ototoxic, if given as a single daily dose rather than in divided doses. We considered that a single, large dose of an aminoglycoside followed by oral therapy with a different antibiotic might be equally effective and possibly less toxic. This randomized, controlled study compared a single large i.v. dose (10 mg/kg) of gentamicin (S) with a standard multiple dose regimen (M) of gentamicin (2.5 mg/kg i.v. stat and then computer generated divided doses aiming for peak and trough concentrations of 8 and 1.5 mg/l respectively) for the treatment of patients with suspected acute pyelonephritis requiring hospitalization for parenteral antibiotic treatment. All patients were switched to oral ciprofloxacin either four hours after the S dose or when clinically appropriate in the M regimen. For all patients the total duration of treatment was five days. Fifty-three patients (48 women; mean age 32 yr) were enrolled. Clinical and bacteriological efficacy could be assessed in 41 patients. Thirteen of 16 in the S arm and 24 of 25 in the M arm were clinically cured and the other four clinically improved. Fifteen of 16 in the S arm and 23 of 25 in the M arm were cured bacteriologically (sterile urine 7-10 days after treatment). In 41 patients high tone audiometry was carried out before or very soon after the start of treatment, and again at the end of treatment. Ototoxicity (> or = 10 dB loss in > or = 2 frequencies in both ears) was observed in 3 of 18 in the S group (17%) and 7 of 23 in the M group (30%) (NS). Other side-effects and toxicity were mild and not different between groups. Substantial cost savings occurred in the S group. In summary, a large single dose of gentamicin was comparable in efficacy and toxicity to a standard regimen, but cheaper and more convenient to use.

Cost-benefit analysis and prediction of 24-hour proteinuria from the spot urine protein-creatinine ratio.

AIM: A prospective cross-sectional study was performed on 170 patients with various glomerular diseases to study the accuracy of predicting 24-hour proteinuria from the spot urine protein-creatinine ratio (Up/Uc). A cost-benefit analysis was performed for the New Zealand health economic system to obtain the best cut-off values for proteinuria. SUBJECTS, METHODS AND RESULTS: Two spot urine samples (Up/Uc1 and Up/Uc2) were collected on the same day as the collection of a 24-hour urine. A randomly chosen subsample of 50 patients provided a second set of urine samples. The correlation and precision of agreement between the two methods were examined. The predictive intervals were calculated for derived 24-hour proteinuria. The level of agreement was evaluated by the Bland-Altman method and concordance analysis. The limits of agreement were evaluated against the clinical limits of agreement. A cost-benefit analysis (CBA) was performed to obtain the optimum operating points on receiver operating characteristic (ROC) curves for the best decision threshold. Correlations of r = 0.97 and 0.99 were observed between Up/Uc1, Up/Uc2 and 24-hour proteinuria, respectively. The 95% predictive intervals were wide. A high concordance correlation coefficient was obtained. The most of the differences between the two methods fell within the clinical limits of agreement. The Up/Uc1 of 0.26 and 3.20 represent the best thresholds to detect normal and nephrotic proteinuria, respectively. CONCLUSIONS: Despite wide confidence intervals, a good correlation and precision of agreement were demonstrated between the two methods across the whole range of proteinuria, regardless of the level of renal function. The difference between the two methods was less than the biological variability in the protein excretion and its measurement, enabling the methods to be used interchangeably. The optimum thresholds for abnormal and nephrotic range proteinuria were obtained.

A comparison of the safety and efficacy of mibefradil and nifedipine SR in patients with renal disease and hypertension.

The antihypertensive efficacy and safety of mibefradil and nifedipine SR were compared in 143 patients with chronic renal failure and mild-to-moderate hypertension in a multicenter, double-blind, randomized, parallel-design study. At treatment week 12, a significantly greater decrease in sitting diastolic blood pressure (SDBP) was seen with mibefradil than with nifedipine SR (12.8 mmHg vs 8.1 mmHg, respectively; p = 0.014). A significantly greater number of mibefradil-treated patients achieved normalization of SDBP by week 12 (62% vs 37%; p < 0.01). The changes in renal function parameters and the incidence of adverse events were similar in both groups. In this population, 12 weeks of treatment with mibefradil were more effective than nifedipine SR for lowering blood pressure and had similar effects on renal function parameters.

Long term complications following renal transplantation.

The long term complications of renal transplantation were assessed in 36 patients who had lived for 10 or more years with a functioning renal transplant. Thirty-three patients were alive with a mean plasma creatinine of 0.13 mmol/L (SD 0.07). A 62 year old women died from a myocardial infarction 11 years after transplantation and two women developed chronic rejection and returned to dialysis after 17 years. Nineteen patients have required antihypertensive therapy, five have suffered ischaemic heart disease and two a cerebrovascular event. Malignancy has developed in 13 patients, with four having two or more organs involved. Skin cancers (9 squamous cell, 4 basal cell) were present in all 13 patients and recurred in six. The other malignancies included carcinoma of cervix (2), cervix and bladder (1) and thyroid (1). Three patients have required parathyroidectomy for autonomous hyperparathyroidism, two splenectomy for hypersplenism, and one bilateral hip replacement for avascular necrosis of the femoral heads. The development of hypertension, vascular disease and malignancy are the most important long term complications after renal transplantation. Strategies must be formulated to reduce the morbidity and mortality from these causes.

Pregnancy in renal transplant recipients: the Christchurch experience.

AIM: Assess the pregnancies of our female renal transplant recipients and to document long term maternal and fetal outcome. METHODS: Between 7 June 1972 and 31 December 1992 112 females had at least one renal transplant. Sixty-four of these 112 women were in the reproductive age and had a functioning graft. RESULTS: Nine women had 16 pregnancies which resulted in 11 live births and three first trimester abortions. Two unplanned pregnancies were terminated. Mean age at transplantation was 17.2 yr [range 16-22.5 yr] and mean interval from transplant to pregnancy was 6.8 yr [range 1.8-9.0 yr]. Prednisone and azathioprine were used in all patients and cyclosporin in five. For seven of the successful pregnancies plasma creatinine remained < or = 0.10 mmol/L. One of these women developed allograft nephropathy 5 years after delivery and returned to dialysis 9 years later. For the other four successful pregnancies the preconception plasma creatinine was 0.12-0.14 mmol/L. The woman with two successful pregnancies had a halving of glomerular filtration rate during the second pregnancy, but it has remained stable for 15 years; one was poorly compliant with her immunosuppressive regimen and reached endstage renal failure two years after delivery; one developed cyclosporin nephrotoxicity, but 18 months later renal function was stable after a dosage reduction. Ten infants were delivered by caesarean section, four of them urgently. Three babies were preterm and five growth retarded. One died of sudden infant death syndrome at four months. All other infants developed normally. CONCLUSION: There is no contraindication to pregnancy in female transplant recipients who have stable graft function and controlled blood pressure. Management of such pregnancies should be by shared obstetrical/nephrological/paediatric care.

Long term follow up of patients with IgA nephropathy.

AIM: To assess the long term outcome of patients with IgA nephropathy. METHOD: The outcome of 151 patients (120 male; mean age 32.5, median age 29.6, SD 15.4 years; 146 Caucasian) with biopsy-proven IgA nephropathy. The patients were enrolled between 30 April 1973 and 21 August 1992. RESULTS: Ninety-five (63%) of the patients presented with microscopic haematuria, with or without proteinuria and/or renal insufficiency. At presentation renal insufficiency was present in 34% and hypertension in 48% of patients. During a mean follow up period of 63.3 months (range 0-233 months) 12 patients have reached end stage renal failure, five have died of a nonrenal cause and 25 were lost to follow up. The actuarial renal survival rate was 92.6% at five years and 91.1% at both 10 and 15 years. A significantly poorer renal survival rate was seen in those patients with a plasma creatinine > or = 0.12 mmol/L, hypertension, a serum albumin of < 35 g/L, or a 24 hour urinary albumin excretion > or = 1.0 g at presentation, and this became apparent within the first few years of follow up. CONCLUSIONS: The long term outcome of IgA nephropathy is better than previously reported. Those patients with a poor prognosis can be identified with considerable certainty at presentation.