The significance of focal and segmental hyalinosis and sclerosis (FSHS) and nephrotic range proteinuria in IgA nephropathy.

Between 1971 and 1991, 845 patients were diagnosed as having IgA glomerulonephritis on renal biopsy performed. These patients were followed for a mean period of 53 months post biopsy (range 0-336 months). By the end of follow up 147 (17%) of patients have developed chronic renal failure (Cr > 0.2 mmol/l) or end-stage renal failure. Presenting creatinine > 0.12 mmol/l, hypertension, nephrotic range, age > 40 years and male gender, all correlated strongly on univariate analysis with the development of chronic renal failure or kidney disease (all p < 0.0001). However, a number of patients developing chronic renal failure or end-stage renal failure already had renal impairment (creatinine > 0.12 mmol/l at presentation). A separate comparison was performed of patients presenting with creatinine < 0.12 mmol/l and either developing chronic failure or end-stage renal failure within 5 years of biopsy (n = 18) and those with creatinine still < 0.12 mmol/l after 5 years follow up (n = 186). Of the 18 patients who deteriorated 6 (35%) were nephrotic at presentation and 9 (56%) had focal hyalinosis and sclerosis on renal biopsy. This compared with 5 (3%) patients with nephrotic range proteinuria and 16 (10%) patients with focal hyalinosis and sclerosis among the 186 patients who did not deteriorate (p < 0.0001). The sensitivity and specificity of the presence of either or both factors in predicting deterioration was calculated at 65% and 87% respectively. Thus in patients with normal renal function at presentation the presence of nephrotic range or focal hyalinosis and sclerosis are strong predictors of adverse clinical outcome.

Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease.

In a retrospective cohort study of women with renal disease in pregnancy we investigated if: 1. low dose aspirin reduced the prevalence of preeclampsia and improved fetal outcome compared to no anticoagulant therapy. 2. heparin plus low dose aspirin and/or dipyridamole reduced the prevalence of preeclampsia and improved fetal outcome compared to i. no treatment ii. low dose aspirin alone. Women with renal disease were allocated into 3 groups according to the treatment received during their pregnancies: I. no prophylactic heparin or antiplatelet drugs, n = 76 II. prophylactic low-dose aspirin 75(50-150)mg, n = 27 III. prophylactic subcutaneous heparin 10,000 (5000-12,500) IU b.d. combined with low-dose aspirin 50 (50-150)mg and/or dipyridamole 400 (200-400)mg, n = 44. Preeclampsia and fetal outcome was analysed according to treatment group. Preeclampsia was less common in the heparin group (2.3%) compared with 27.6% in the no treatment group [O.R. 0.06 (0.01-0.30)] and 25.9% in the aspirin group [O.R. 0.07 (0.01-0.38)]. Women on aspirin, who developed preeclampsia, delivered later in pregnancy [35.4 (33-38.2) weeks] than preeclamptic women on no treatment [29 (22-38) weeks], p = 0.04. There was a trend to reduced perinatal deaths in the heparin + antiplatelet drug group, [2.3%; O.R., 0.17 (0.02-1.4)] and in the aspirin group [0%, O.R., 0.13 (0.01-2.3)] compared with 11.7% perinatal deaths in the no treatment group. Heparin with anti-platelet drugs may prevent preeclampsia in high risk women with renal disease. Further investigation in a randomized trial is indicated.

Renal biopsy as an outpatient procedure.

We evaluated the safety and efficacy of outpatient renal biopsy by prospectively comparing outpatient and inpatient renal biopsies in which patients were given the choice between having the procedure as an inpatient or an outpatient. Three hundred fifty renal biopsies were performed between January 1992 and August 1994; 118 patients had the procedure as an outpatient and 232 patients had the procedure with discharge planned for the following day. There was no difference between the two groups in terms of patient age, sex, or renal function. The complication rate for the two groups was not significantly different, with two inpatients having loin pain and one having macroscopic hematuria compared with one outpatient having loin pain and one having macroscopic hematuria. The biopsies provided samples of comparable size. We conclude that outpatient renal biopsy is a safe procedure and provides adequate tissue samples.

A prospective study of cortical scarring in acute febrile pyelonephritis in adults: clinical and bacteriological characteristics.

Previous reports have demonstrated lesions on computerized axial tomography (CT), and nuclear scintigraphy (DMSA) in acute pyelonephritis (PN). We undertook a prospective study of all patients presenting to our hospital with PN over 40 months. Patients who fulfilled diagnostic criteria, were treated with intravenous antibiotics. Excluding two who were pregnant, all patients had imaging by intravenous urography (IVU), CT and DMSA during their admission. Urine samples were collected prior to treatment. Patients without IVU evidence of cortical scarring but with parenchymal defects on CT and/or DMSA underwent a repeat DMSA three or more months after the acute episode. Of the 164 patients, 142 were female. E. coli was found in 116 patients. Forty-six patients had an abnormality on IVU. Of the 106 patients without IVU evidence of cortical scarring, 59 had a defect on CT and/or DMSA. Late DMSA scans in 35 of these 59 patients showed a persistent abnormality in 77%. E. coli characteristics such as P-fimbriae and Type 1 fimbriae were not predictive of acute imaging abnormalities. Inhibition of E. coli growth by the addition of EDTA was highly predictive of acute CT and DMSA abnormalities with a sensitivity of 83.3% and a specificity of 82.8%. Acute pyelonephritis is often associated with acute CT and/or DMSA abnormalities which may evolve into renal cortical scars. Acute scan abnormalities can be predicted by the presence of E. coli which were susceptible to EDTA in culture. Late scarring could not be predicted by clinical features, response to treatment or antibiotic used.

Uterine artery waveform as a predictor of pregnancy outcome in women with underlying renal disease.

To investigate the use of uterine artery flow velocity waveforms in predicting gestational hypertension (GH), preeclampsia (PE) and intrauterine growth retardation (IUGR), Colour Doppler ultrasound of the uterine arteries was performed at 19-24 weeks gestation in 51 women with known renal disease. On four consecutive waveforms, peak systolic (A), end-diastolic (B) and early diastolic (C) velocities were measured. Resistance index (RI) was calculated as (A-B)/A, and the severity of the waveform notch expressed as the AC ratio (A/C). Gestational hypertension was defined as a blood pressure (BP) > or = 140/90 mmHg with an increase of at least 15 mmHg in diastolic BP. PE included women with gestational hypertension and proteinuria > 300 mg/24 h or a doubling of early gestation protein excretion. IUGR was defined as a birthweight less than the 10th percentile for gestation. RI and/or AC ratio in 14 women (27%) exceeded the 90th percentile for gestational age of our low risk control population. Of the women with an abnormal test, 11 (79%) developed complications, 8 (57%) developed GH or PE, 3 (21%) IUGR alone, 2 (14%) GH and IUGR, and in one women intrauterine fetal death of an IUGR infant occurred, and 3 (21%) had an uncomplicated pregnancy. Of the women with a normal test, 34 (92%) had an uncomplicated pregnancy, and only 3 (8%) developed GH or IUGR. In summary, uterine artery waveform indices at 19-24 weeks gestation may be useful for the prediction of pregnancy complications in woman with underlying renal disease.

Randomized controlled trial of cyclophosphamide, warfarin and dipyridamole in idiopathic membranous glomerulonephritis.

40 patients with idiopathic membranous glomerulonephritis were randomized to receive either no treatment or a regime of cyclophosphamide for 6 months, and warfarin and dipyridamole for two years. During the two years of the trial there was no significant deterioration in renal function in either group. A significantly greater improvement in urinary protein excretion was, however, observed at all time points in the treatment group. Plasma albumin was also significantly higher in the treatment group at 18 and 24 months. As progressive deterioration in renal function in membranous glomerulonephritis is associated with persistent heavy proteinuria these results suggest a beneficial effect of treatment.

Lupus nephritis and pregnancy.

Sixty-four pregnancies in 41 women with biopsy proven lupus nephritis between 1965 and 1991 were analysed to record fetal and maternal outcome and identify risk factors for poor outcome. Of 65 fetuses, 22 (34 per cent) were lost (including therapeutic abortions), 19 (30 per cent) were live born but premature (less than or equal to 36 weeks gestation) and 24 (37 per cent) were term. Fetal loss after 20 weeks gestation was 19 per cent. Twelve per cent of 25 fetuses whose birthweight was recorded were small for gestational age. Maternal renal function deteriorated in 19 per cent of pregnancies but was irreversible post-partum in only one woman (2 per cent). Hypertension was recorded in 44 per cent of pregnancies, developed early (less than or equal to 32 weeks gestation) in 28 per cent and was severe in 13 per cent. Treated hypertension predated 17 per cent of pregnancies and in 6 per cent (included in the overall incidence of hypertension) exacerbation occurred during pregnancy despite continued anti-hypertensive medication. Nine women (22 per cent) who developed de novo hypertension in pregnancy had permanent hypertension post-partum. Increased proteinuria was recorded in 48 per cent of pregnancies and was irreversible post partum in 5 per cent. Comparison of pregnancies occurring before or after diagnosis was made by renal biopsy failed to show any significant difference in fetal outcome. Pregnancies occurring after the diagnosis of glomerulonephritis were associated with a significantly lower incidence of maternal hypertension, early hypertension, severe hypertension and increased proteinuria. The presence of the circulating lupus anticoagulant was clearly associated with a significantly high fetal loss rate although the incidence of maternal complications did not differ significantly between mothers positive or negative for lupus anticoagulant.

PIP: 64 pregnancies were analyzed in 41 women with biopsy-proven lupus nephritis between 1965-91; fetal and maternal outcome were evaluated and risk factors for poor outcome were identified. Of 65 fetuses, 22 (34%) were lost (including therapeutic abortions). 19 (30%) were liveborn but premature (or= 36 weeks gestation) and 24 (37%) were term. Fetal loss after 20 weeks gestation was 195. 12% of 25 fetuses whose birthweight was recorded were small for gestational age. Maternal renal function deteriorated in 19% of the pregnancies but was irreversible postpartum in only 1 woman (2%). Hypertension was recorded in 44% of pregnancies, developed early (or= 32 weeks gestation) in 28%, and was severe in 13%. Treated hypertension predated 17% of the pregnancies and in 6% (included in the overall incidence of hypertension) exacerbation occurred during pregnancy despite continued antihypertensive medication. 9 women (22%) who developed de novo hypertension in pregnancy had permanent hypertension postpartum. Increased proteinuria was recorded in 485 of pregnancies and was irreversible postpartum in 5%. The comparison of pregnancies occurring before or after diagnosis was made by renal biopsy and failed to show any significant difference in fetal outcome. Pregnancies which occurred after the diagnosis of glomerulonephritis were associated with a significantly lower incidence of maternal hypertension, early hypertension, severe hypertension, and increased proteinuria. The presence of circulating lupus anticoagulant was clearly associated with a significantly higher fetal loss rate although the incidence of maternal complications did not differ significantly between mothers positive or negative for lupus anticoagulant.

Whole-cell and single-channel currents across the plasmalemma of corn shoot suspension cells.

Whole-cell sealed-on pipettes have been used to measure electrical properties of the plasmalemma surrounding protoplasts isolated from Black Mexican sweet corn shoot cells from suspension culture. In these protoplasts the membrane resting potential (Vm) was found to be -59 +/- 23 mV (n = 23) in 1 mM Ko+. The mean Vm became more negative as [K+]o decreased, but was more positive than the K+ equilibrium potential. There was no evidence of electrogenic pump activity. We describe four features of the current-voltage characteristic of the plasmalemma of these protoplasts which show voltage-gated channel activity. Depolarization of the whole-cell membrane from the resting potential activates time- and voltage-dependent outward current through K(+)-selective channels. A local minimum in the outward current-voltage curve near Vm = 150 mV suggests that these currents are mediated by two populations of K(+)-selective channels. The absence of this minimum in the presence of verapamil suggests that the activation of one channel population depends on the influx of Ca2+ into the cytoplasm. We identify unitary currents from two K(+)-selective channel populations (40 and 125 pS) which open when the membrane is depolarized; it is possible that these mediate the outward whole-cell current. Hyperpolarization of the membrane from the resting potential produces time- and voltage-dependent inward whole-cell current. Current activation is fast and follows an exponential time course. The current saturates and in some cases decreases at membrane potentials more negative than -175 mV. This current is conducted by poorly selective K+ channels, where PCl/PK = 0.43 +/- 0.15. We describe a low conductance (20 pS) channel population of unknown selectivity which opens when the membrane is hyperpolarized. It is possible that these channels mediate inward whole-cell current. When the membrane is hyperpolarized to potentials more negative than -250 mV large, irregular inward current is activated. A third type of inward whole-cell current is briefly described. This activates slowly and with a U-shaped current-voltage curve over the range of membrane potentials -90 less than Vm less than 0 mV.

Primary glomerulonephritis and pregnancy.

Three hundred and ninety-five pregnancies undertaken by 238 women with primary glomerulonephritis between 1962 and 1987 were analysed to record fetal and maternal outcome and identify risk factors for a poor outcome. Of 398 fetuses, 26 per cent were lost (including therapeutic abortions), 24 per cent surviving infants were premature (less than or equal to 36 weeks gestation) and 51 per cent were term. Excluding therapeutic abortions, 20 per cent of fetuses were lost, 15 per cent after 20 weeks gestation. Fifteen per cent of 237 fetuses whose birth weight was recorded were small for gestational age: Deterioration in maternal renal function was seen in 15 per cent of pregnancies and in 5 per cent of women failed to resolve post partum. Only four women had impaired renal function recorded in the first-trimester and two of these were known to have renal impairment before pregnancy. Hypertension was recorded in 52 per cent of pregnancies, developed early (less than or equal to 32 weeks gestation) in 26 per cent and was severe in 18 per cent. Treated hypertension pre-dated 12 per cent of pregnancies and in 7 per cent (included in the overall incidence of hypertension) exacerbation occurred during pregnancy despite continued antihypertensive medication. Forty-four women (18 per cent) who developed de novo hypertension in pregnancy had permanent hypertension postpartum. Increased proteinuria was recorded in 59 per cent of pregnancies and was irreversible in 15 per cent of women. Comparison of pregnancies which occurred before or after renal biopsy revealed a significantly higher fetal loss rate after 20 weeks gestation in those pregnancies undertaken before the diagnosis of renal disease, and a significantly higher incidence of hypertension and increased proteinuria. Impaired renal function, early or severe hypertension or nephrotic range proteinuria was significantly associated with increased fetal loss, prematurity and fewer full-term infants. There was no significant difference in fetal outcome or maternal complications in pregnancy in patients with treated hypertension before pregnancy and those who were normotensive in the first-trimester. The highest incidence of fetal and maternal complications occurred in patients with primary focal and segmental hyalinosis and sclerosis and the lowest in non-IgA diffuse mesangial proliferative glomerulonephritis. The presence of severe vessel lesions on renal biopsy was associated with a significantly higher total fetal loss and fetal loss after 20 weeks gestation.

Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.

Twenty-seven patients presenting to the Royal Melbourne Hospital between 1968 and 1988 with mesangiocapillary glomerulonephritis type II with intramembranous dense deposits (dense-deposit disease, DDD) are analyzed. Patients were divided into two groups on the basis of whether renal function deteriorated (14 patients) or remained stable (13 patients). At presentation or during the course of the disease, heavy proteinuria, macroscopic hematuria, and high quantitative urinary red cell or white cell counts characterized patients with progressive disease. Patients with crescents on their initial renal biopsy or with large numbers of polymorphs in glomerular capillaries corresponding with sterile pyuria were more likely to have deterioration of renal function. The average time from onset of symptoms to development of end-stage renal disease was over 16 years. The patient's clinical course could not be anticipated by serum complement profiles, the presence of C3 nephritic factor, or partial lipodystrophy. Pregnancy did not affect the course of the disease. Six patients underwent renal transplantation and the disease recurred on renal biopsy in four. However, only two individuals lost renal allografts due to recurrent DDD.

Immunoperoxidase identification of nucleated cells in urine in glomerular and acute tubular disorders.

Nucleated nonsquamous cells in urine of patients with crescentic glomerulonephritis (CN), noncrescentic glomerulonephritis (NCN), acute tubular necrosis (ATN) and drug related acute interstitial nephritis (AIN) were identified using monoclonal antibodies and immunoperoxidase stain. Cell viability was determined by trypan blue permeability. CN was distinguishable from NCN by total cell numbers exceeding 30,000/ml (p less than 0.001) and counts of granulocytes exceeding 10,000/ml (p less than 0.05), monocytes exceeding 3,000/ml (p less than 0.001), T4 lymphocytes exceeding 1,500/ml (p less than 0.001), T8 lymphocytes exceeding 1,500/ml (p less than 0.001), glomerular epithelial cells exceeding 4,000/ml (p less than 0.001), proximal tubular cells exceeding 8,000/ml (p less than 0.001), loop of Henle cells exceeding 1,500/ml (p less than 0.01) and urothelial cells exceeding 1,500/ml (p less than 0.05). AIN was distinguishable from ATN by total cell numbers exceeding 75,000/ml (p less than 0.001) and counts of granulocytes exceeding 150,000/ml (p less than 0.001), monocytes exceeding 5000/ml (p less than 0.001), T4 lymphocytes exceeding 3,000/ml (p less than 0.01), T8 lymphocytes exceeding 2,500/ml (p less than 0.01) and cell viability exceeding 60% (p less than 0.05). Proximal tubular, loop of Henle, distal tubular/collecting duct and urothelial cells were present in high numbers in CN, ATN and AIN. CN can be distinguished from NCN, and ATN can be distinguished from AIN by identifying and quantifying the nucleated cells present in the urine.

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.

Detection of bladder bacteriuria in patients with acute urinary symptoms.

Quantitative culture of midstream urine fails to yield a significant microorganism in many patients with acute urinary symptoms. We cultured bladder urine, obtained by aspiration, from symptomatic adults with equivocal findings on standard testing of midstream urine for low numbers of conventional uropathogens and fastidious bacteria. We found 561 (31%) of 1817 women and 36 (12%) of 300 men to be culture positive. Five hundred eighty-one (70%) of 830 isolates were fastidious bacteria; 191 (34%) of 561 culture positive women and 0 of 36 culture-positive men had polymicrobic bacteriuria. Bacterial counts were less than 10(5) colony-forming units/mL in 67% of samples; 204 of 406 patients with single-species infections had increased leukocyte counts in urine. Patients with symptoms of urinary tract infection who are culture negative on standard testing may harbor fastidious bacteria or low numbers of conventional uropathogens in the bladder. In these patients, culture of bladder aspiration urine for low counts and fastidious species is necessary to diagnose bacteriuria.

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.