The incidence of biopsy-proven glomerulonephritis in Australia.

BACKGROUND: There is limited population-based epidemiological data on renal disease. An insight into the spectrum of clinically significant glomerulonephritis can be obtained from renal biopsy diagnoses. This is a descriptive report of biopsy-proven glomerulonephritis within a defined population. METHODS: A retrospective review of the pathology reports of all native renal biopsies performed in the Australian state of Victoria in 1995 and 1997 was undertaken. Trends in the average annual age- and sex-specific incidence rates for biopsy-proven glomerulonephritis were calculated. Comparisons were made with the incidence of end-stage renal disease due to glomerulonephritis confirmed on renal biopsy. RESULTS: The most common glomerulonephritides in adults are IgA disease, focal glomerulosclerosis, lupus nephritis and vasculitis, and in children are lupus nephritis, focal glomerulosclerosis, IgA disease and minimal change disease. A male predominance is seen for all glomerulonephritides, except lupus nephritis, in both adults and children. An increase in incidence of disease with age, particularly in males, is seen for vasculitis and focal glomerulosclerosis. The most common glomerulonephritides on renal biopsy are reflected in the most common causes of end-stage renal disease due to glomerulonephritis. CONCLUSIONS: This review has provided population-based descriptive epidemiological data on clinically significant glomerulonephritis. This data provides important clues for further studies relating to the identification of risk factors for the various types of glomerulonephritis.

Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial.

Angiotensin-converting enzyme inhibitors delay progression of renal disease in different animal models of nephropathy. We tested this treatment modality in 70 hypertensive patients with severe renal disease of various etiologies. We report a double-blind study of the effect of 5 mg enalapril once daily compared with placebo in patients with nondiabetic severe chronic renal impairment (plasma creatinine 2.8 to 6.8 mg/dL; mean creatinine clearance 15 mL/min/1.73 m2) followed for up to 2 years. Efficacy parameters were the slopes of 51Cr-EDTA clearance, reciprocal of plasma creatinine, creatinine clearance, and the effect on urinary protein excretion. Thirty-one patients completed 2 years of treatment (12 in the enalapril group and 19 in the placebo group). Two patients died from nonrenal causes (one patient each in the enalapril and placebo groups), 16 patients commenced dialysis (seven in the enalapril group and nine in the placebo group), and eight patients were discontinued due to adverse events (five in the enalapril group and three in the placebo group). Eleven patients were discontinued because they were noncompliant, uncooperative, or moved (nine in the enalapril group and two in the placebo group). Two enalapril-treated patients were dropped from the study due to protocol deviations. Importantly, the statistical approach in this study evaluated all patients, regardless of the duration of treatment. A mixed-effects linear model and intention to treat analysis, taking into account the number of observations per patient, indicated that enalapril significantly reduced the rate of deterioration of renal disease: glomerular filtration rate (P = 0.038), reciprocal of plasma creatinine (P = 0.017), or creatinine clearance (P = 0.031). The renal protective effects of enalapril were shown to be in addition to its antihypertensive effect when blood pressure was held constant. Proteinuria was reduced by enalapril (P = 0.007) and was slightly increased in the placebo-treated patients (P = 0.051). The difference between these two groups was highly significant (P = 0.002). In conclusion, enalapril retarded the progression of chronic renal failure, as assessed by changes in glomerular filtration rate, creatinine clearance, and 1/plasma creatinine, and reduced proteinuria in patients with nondiabetic severe chronic renal insufficiency.

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.

Prevention of progression in non-diabetic chronic renal failure.

We have performed separate randomized prospective controlled studies on the effects of protein-restricted diet and angiotensin converting enzyme (ACE) inhibition on the rate of progression of non-diabetic renal failure. Renal function was assessed by creatinine clearance, reciprocal of plasma creatinine concentration and 51Cr-EDTA clearance. A protein-restricted diet (0.4 g per kg) resulted in a significantly lower rate of progression, as assessed by the slope of these parameters with time, when compared with a standard diet. ACE inhibition, when assessed by a mixed effect model, also significantly reduced the rate of progression. The many variables involved hinder trials of therapies directed against progression in non-diabetic renal failure.

Kidney transplantation from living related donors: a 19-year experience.

OBJECTIVE: To determine the outcome of patients with end-stage chronic renal failure treated by live donor renal transplantation at the Royal Melbourne Hospital and Royal Children's Hospital between 1973 and 1991, during which time two distinct immunosuppressive regimens were used. DESIGN: Data about live donor renal transplant recipients were retrieved from the Australian and New Zealand Dialysis and Transplantation Association Registry, to which we have submitted data on all transplant recipients at six monthly intervals since the commencement of our dialysis and transplant programs. PATIENTS: Seventy-two patients with chronic renal failure who received live donor renal transplants during the 19 years from February 1973 to February 1992 were included. MAIN OUTCOME MEASURES: Patient survival, transplant survival, transplant function, change in prednisolone requirements, and duration of hospital stay. RESULTS: The first 32 patients were treated with immunosuppressive regimens based on combinations of prednisolone and azathioprine ("dual therapy"), while the next 40 patients were treated with combinations of cyclosporin, prednisolone and azathioprine ("triple therapy"). Survival of patients in each group five years after transplantation was 97%. Actuarial graft survival at 5, 10 and 15 years in the dual therapy group was 58%, 52% and 47%, compared with a 5-year actuarial graft survival in the triple therapy group of 96%. There was no statistically significant difference in renal transplant function between the two groups within the first 6 years after transplantation. Twelve of 26 patients (46%) treated initially with triple therapy were able to stop treatment with prednisolone within 12 months of transplantation. Median hospital stay was 12 (range, 6-35) days during the period 1973-1985 and 8 (range, 5-20) days for the 1985-1992 period. CONCLUSION: Live donor renal transplantation has provided a highly satisfactory means of treating patients with end-stage chronic renal failure in the short and long term. Our recent experience indicates that excellent patient and graft survival and adequate renal function can be achieved by treating live donor renal transplant recipients with a triple immunosuppressive regimen of low dose cyclosporin, prednisolone and azathioprine.

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.

Glomerulosclerosis and hyalinosis in rabbits.

Histological appearances of remnant kidney in female New Zealand white rabbits undergoing left nephrectomy at 6 mths were studied. All 20 rabbits had evidence of previous Encephalitozoon cuniculi (E. cuniculi) infection. Half of the 10 uninephrectomized and 10 control animals completed 3 pregnancies before sacrifice (15 mths). Twelve of 30 kidneys at sacrifice showed focal and segmental hyalinosis and sclerosis (FSHS), a lesion not previously reported in rabbits. Four of 5 kidneys in both uninephrectomized pregnant and uninephrectomized virgin animals showed FSHS compared with 2 of 10 in both control pregnant and non-pregnant rabbits (p = 0.0026). More glomeruli were sclerosed in control pregnant (median 3.5%) than non pregnant animals (median 0.4%) (p < 0.005). Median right kidney weights per kilogram body weight were greater in previously nephrectomized animals (3.9 gm/kg) than controls (2.6 gm/kg), (p < 0.001). Absolute glomerular area was increased in hypertrophied kidneys, however, after correction for kidney weight, glomerular area was smaller in previously uninephrectomized animals than controls (p < 0.0001).

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.

Preservation of renal function in chronic renal failure.

Mechanisms of progression of chronic renal failure (CRF) have been well documented in the rat but may not be relevant in man. Factors which may modify clinical CRF include underlying disease, diet, hypertension, intercurrent events, and adverse or beneficial effects of drug therapy. It has been argued that progression in many forms of renal disease is inexorable below a certain level of renal function. In other diseases, eg primary malignant hypertension, analgesic nephropathy, function frequently improves in both the short and long term with appropriate management. Thus knowledge of the nature of the underlying disease is essential in assessing progression. The value of diet in preserving renal function has been debated, particularly the relative roles of protein and phosphate control. In our own unit, a prospective randomized study showed a benefit of protein restriction. Development of accelerated hypertension is an important cause of progression of renal disease and clinical and experimental evidence supports the view that non-accelerated hypertension is also a factor in progression, amenable to treatment. Various intercurrent events may accelerate progression and function may be lost permanently following sepsis, urinary tract obstruction, renal arterial or venous obstruction, hypotension and in some cases pregnancy. Numerous drugs can have deleterious effects on the kidney. The possibility that converting enzyme inhibitors might preserve renal function is attracting attention but in view of their side effects their place in therapy should be determined by prospective controlled studies in which the above factors are carefully considered.

Morphology of renal parenchymal culture in collagen gels.

Explants of rabbit renal parenchyma have been grown in primary tissue culture suspended within hydrated collagen gels. Light and phase contrast microscopic analysis of the first 17 days in culture is described. Pieces of NZW rabbit renal parenchyma were suspended in collagen gels and bathed in supplemented RPMI 1640 medium and incubated at 37 degrees C in 5% CO2 in air. Tubules demonstrated a fine granularity by phase contrast microscopy and glomeruli appeared as red spheres. Blebs formed at the sides and ends of the explant and a monolayer outgrowth of tightly packed polygonal cells occurred from day 4. Histologically an immediate phase of necrosis was followed by regeneration whereby tubules became lined with a confluent epithelium composed of a single layer of flat to cuboidal-shaped cells sitting on an intact tubular basement membrane (TBM). Intraluminal casts of organized cellular debris as well as material presumed to be Tamm Horsfall protein were present. Glomeruli demonstrated collapsed capillary loops. The interstitium became widened by eosinophilic material. The tissue surface contained epithelial cells arranged in places into sac-like structures enclosing a space.

Reflux nephropathy and primary vesicoureteric reflux in adults.

We have studied the clinical features and course of adults with reflex nephropathy and/or primary vesicoureteric reflux, paying particular attention to the differences between males and females, and the presenting features that influence prognosis. In our series of 293 patients, females outnumbered males in the ratio 5:1 and most presented with urinary infection, whereas males most commonly presented with features of renal damage such as proteinuria, hypertension or renal failure. Males more commonly had bilateral scarring and persistent reflux. One hundred and forty-seven patients were followed for two years or more (range 2-19 years); deterioration in renal function occurred in 55 (37 per cent). Risk factors for a rise in plasma creatinine were, in descending order, the presence of proteinuria, an elevated plasma creatinine concentration, bilateral scarring, male sex and the presence of hypertension. Stepwise multiple regression analysis showed that the independent risk factors were proteinuria, elevated plasma creatinine concentration and hypertension; gender and the presence of persistent reflux had no independent influence on the course of renal failure.

Double-blind study of dilevalol and captopril, both in combination with hydrochlorothiazide, in patients with moderate to severe hypertension.

Sixty-one patients (41 men, 20 women) aged 29-73 years, with moderate to severe hypertension, were enrolled in a multicentre study to compare the efficacy, safety, and tolerability of dilevalol (D) and captopril (C). At the end of the baseline period, supine diastolic blood pressure (SuDBP) was 105-140 mm Hg on hydrochlorothiazide (HCTZ) 25 mg once daily and placebo t.i.d. Patients were randomly assigned to D + HCTZ (n = 29) or C + HCTZ (n = 32) and entered phase II titration of D (100-800 mg b.i.d.) or C (12.5 mg b.i.d. to 50 mg t.i.d.). If SuDBP was greater than 99 mm Hg, hydralazine was added (25 mg once daily to 50 mg b.i.d.). If SuDBP was less than or equal to 99 mm Hg, patients entered phase III, a 3-month maintenance period. Demographic profiles were not significantly different between the two groups. Baseline supine BP (mean +/- SEM) was similar in the two groups (D + HCTZ: 182 +/- 3/112 +/- 1; C + HCTZ: 179 +/- 4/113 +/- 1 mm Hg), as was baseline standing BP (D + HCTZ: 175 +/- 3/114 +/- 2; C +/- HCTZ: 173 +/- 4/113 +/- 1 mm Hg). At the end of phase II, there were no significant differences between treatments with respect to the changes in BP from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of protein restriction on the progression of renal insufficiency.

Dietary protein intake may be an important determinant of the rate of decline in renal function in patients with chronic renal insufficiency. We conducted a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment. The study lasted 18 months and included 64 patients with serum creatinine concentrations ranging from 350 to 1000 micromol per liter. The patients were randomly assigned to follow either a regular diet or an isocaloric protein-restricted diet (0.4 g of protein per kilogram of the body weight per day). Blood-pressure levels and the balance between calcium and phosphate were similar in the two groups. End-stage renal failure developed in 9 of the 33 patients (27 percent) who followed the regular diet during the study, as compared with 2 of the 31 patients (6 percent) who followed the protein-restricted diet (P less than 0.05). The mean (+/- SE) glomerular filtration rate, as measured by the clearance of 51Cr bound to EDTA, fell from 0.25 +/- 0.03 to 0.10 +/- 0.05 ml per second (P less than 0.01) in the group on the regular diet, whereas it fell from 0.23 +/- 0.04 to 0.20 +/- 0.05 ml per second (P not significant) in the group on the protein-restricted diet. We conclude that dietary protein restriction is effective in slowing the rate of progression of chronic renal failure.

Morphometric analysis of pre-eclampsia in women biopsied in pregnancy and post-partum.

The importance of endothelial cell swelling and subepithelial deposits in producing capillary wall thickening in women with pre-eclampsia is controversial. In this study renal biopsy tissue from 16 women with a diagnosis of pre-eclampsia was analyzed morphometrically. Women biopsied during pregnancy (N = 6) showed substantial, electron-dense subendothelial deposits in capillary loops, but these were rare or absent in women (N = 10) biopsied post-partum (P less than 0.01). Endothelial cell swelling was present in both groups of patients to an equal degree. Mesangial cell interposition occurred but was not the dominant feature, and was similar in both pregnancy and post-partum biopsies. The median percentage per patient occupied by basement membrane was similar for both groups. Subendothelial deposits appear to resolve early in the post-partum period.

Idiopathic membranous glomerulonephritis: long-term follow-up in 139 cases.

The clinical course of 139 patients (77 male, 62 female) with idiopathic membranous glomerulonephritis is reviewed. The median duration of follow-up was 52 months; 45% and 25% were followed for more than 5 and 10 years respectively. The median age at presentation was 36. Fifty-four percent of patients had the nephrotic syndrome at presentation. Half of the patients were treated at some stage with cyclophosphamide or corticosteroids. During the course of follow-up some deterioration in renal function occurred in only 20% of patients. The patients who suffered deterioration in renal function were mainly male and had significantly worse renal function and a higher incidence of the nephrotic syndrome than the other patients at presentation. Only 7 male patients (5%) developed terminal renal failure during follow-up and one female presented in terminal renal failure. Survival was 88% and 81% at 5 and 10 years. The median predicted (or actual) time for development of terminal renal failure in patients with progressive deterioration was 7.3 years. These data are in accord with other recently published series which have described a relatively benign prognosis for idiopathic membranous glomerulonephritis.

Morphometric aspects of reflux nephropathy.

We have studied the relationships between renal size, glomerular hypertrophy and sclerosis and renal function in adults with reflux nephropathy. A digitizer was used to measure the renal surface areas in intravenous pyelogram films. This was then corrected for patient size by dividing by the area of the first three lumbar vertebrae. In renal biopsies, glomerular surface area and the proportion of segmentally and globally sclerosed glomeruli were measured and compared with a control group of 17 renal donors. Of 57 patients studied, 45 had intravenous pyelogram films and 32 had renal biopsy tissue available from the time of presentation, 20 had both. Thirty-one were followed for two years or more (median 6 years, range 2 to 11 years). There were positive correlations between corrected renal size and renal function, and inverse correlations between these and maximum glomerular size, the proportion of sclerosed glomeruli and vascular wall thickness. Proteinuria correlated best with the proportion of segmentally sclerosed glomeruli. As a prognostic guide, the strongest correlations were between rate of functional decline and percent segmental sclerosis, urine protein excretion and creatinine clearance at presentation. These studies confirm expected relationships between renal size, glomerular size and renal function and suggest that the severity of segmental sclerosis is a major factor in eventual decline into renal failure.

Serum sickness nephropathy in the rat using cationized albumin: effect of preimmunization and antigen dose.

A model of glomerulonephritis induced in preimmunized rats with cationic albumin is described. Extensive glomerular immune complex formation and a severe nephrotic syndrome occurred within 5 days of commencement of daily intravenous injections. Severity of disease was markedly influenced by the degree of preimmunization and, to a lesser extent, by the dose of cationic albumin administered. Immune deposits, although initially confined along the capillary loops, were seen at all sites in the glomerulus. This study confirms that, in rats, the use of cationic antigens accelerates the development of 'serum sickness' nephropathy but preimmunization is necessary to produce significant disease.

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.