328例肾脏疾病患者的肾脏病理分析

目的：了解近年经皮肾活检肾脏疾病患者的病理类型分布及其与临床症状的关系。方法：回顾分析2004年6月～2005年6月间因肾脏疾病住院行肾活检的患者的临床病理特点。结果：328例肾脏疾病中，原发性肾小球疾病257例（78．4％）、小管间质疾病16例（4．9％）、继发性肾脏病55例（16．8％）。原发性肾小球疾病中IgA肾病137例，占53．3％；继发性肾小球肾炎中狼疮肾炎、紫癜性肾炎和高血压肾损害较多，分别占32．7％、27．3％和18．2%；小管间质疾病以急性间质性肾炎为多，占68．8％。IgA肾病主要表现为蛋白尿并血尿；膜性肾病、高血压肾病主要表现为单纯性蛋白尿。单纯血尿主要病理类型是IgA肾病；单纯蛋白尿主要病理类型是IgA肾病和轻微病变。蛋白尿并血尿主要病理类型是IgA肾病、轻微病变和狼疮性肾炎；大量蛋白尿主要病理类型是轻微病变、IgA肾病和膜性肾病。结论：本组资料显示原发性肾小球疾病仍为我国最常见的肾脏疾病，其中以IgA肾病最常见；小管间质疾病发病率有增高，继发性肾脏病以狼疮肾炎最常见，其它特殊肾脏病有增加。     

Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study

BACKGROUND: Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. METHODS: Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. RESULTS: A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). CONCLUSION: The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.     

A new role for complement in experimental membranous nephropathy in rats.

The only established role for complement in mediating immunologic renal disease involves elaboration of leukochemotactic factors and neutrophil-dependent glomerular injury. In the passive Heymann nephritis (PHN) model of experimental membranous nephropathy, rats injected with sheep antibody to rat proximal tubular brush border antigen (Fx1A) form subepithelial deposits of sheep IgG and rat complement (C3), and develop heavy proteinuria after 5 d without glomerular inflammatory changes. To study the role of complement in mediating proteinuria in PHN, 16 rats were treated daily with cobra venom factor from before antibody injection to maintain C3 levels at < 10% of pretreatment values and compared to 16 untreated controls. Proteinuria at 5 d was abolished in C3-depleted rats (4 +/- 1, controls 70 +/- 15 mg/d, P < 0.001), although renal deposition of 125I-labeled antibody ws the same in both groups (188 +/- 35 vs. 191 +/- 22 microgram IgG/2 kidneys, P > 0.5). Nephritogenic doses of both the noncomplement-fixing F(ab')2 portion and the gamma 2 subclass of anti-Fx1A IgG produced subepithelial deposits of immunoglobulin without C3, but proteinuria did not occur despite glomerular deposition of up to 70 microgram/2 kidneys of gamma 2. However, glomerular deposition of as little as 60 microgram of gamma 1 produced C3 fixation in vivo and heavy proteinuria. No neutrophil exudate could be detected histologically in PHN from the time of antibody injection through development of proteinuria. Proteinuria in five PHN rats depleted of neutrophils to < 200/mm3 with antineutrophil serum was not reduced compared to six controls with normal neutrophil counts (34 +/- 9.6 vs. 25 +/- 10.4 mg/d, P > 0.5). These results demonstrate that proteinuria in the PHN model of membranous nephropathy is complement-dependent and strongly suggest a neutrophil-independent mechanism. Thus a new role for the complement system in mediating immunologic glomerular injury is identified.     

Role of the terminal complement pathway in experimental membranous nephropathy in the rabbit.

Our recent observations of a complement-mediated, cell-independent mechanism of altered glomerular permeability in rat membranous nephropathy suggested a possible role for the terminal complement pathway in the mediation of proteinuria in certain forms of glomerular disease. To directly determine whether the membranolytic terminal complement components (C5b-C9) are involved in glomerular injury, we studied the development of proteinuria in normal and C6-deficient (C6D) rabbits, in both of which a membranous nephropathy-like lesion develops early in the course of immunization with cationized bovine serum albumin (cBSA) (pI 8.9-9.2). C6 hemolytic activity of C6D was 0.01% that of control rabbits. After 1 wk of daily intravenous injections of cBSA, proteinuria developed in 71% of controls (median 154, range 1-3,010 mg/24 h, n = 24), whereas none of C6D were proteinuric (median 6, range 2-12 mg/24 h, n = 12, P less than 0.01). After 1 wk of cBSA, both groups had qualitatively identical glomerular deposits of BSA, rabbit IgG, and C3 on immunofluorescence microscopy, predominantly subepithelial electron-dense deposits on electron microscopy, and minimal glomerular inflammatory cell infiltration of glomeruli. Glomeruli were isolated from individual animals after 1 wk of cBSA and deposits of rabbit IgG antibody were quantitated by a standardized in vitro assay using anti-rabbit IgG-125I. Rabbit IgG deposits were found to be similar in control (29.8 +/- 13.2, range 12.7-48.6 micrograms anti-IgG/2,000 glomeruli, n = 6) and C6D rabbits (32.6 +/- 13.8, range 16.8-48.8 micrograms anti-IgG/2,000 glomeruli, n = 5, P greater than 0.05). After 2 wk, coincident with a prominent influx of mononuclear cells and neutrophils, proteinuria developed in C6D rabbits. These results document, for the first time, a requirement for a terminal complement component in the development of immunologic glomerular injury. Since the only known action of C6 is in the assembly of the membrane attack complex, these observations suggest that the membranolytic properties of complement may contribute to glomerular damage.     

Treatment of hepatitis B virus-associated nephropathy

Epidemiological studies have shown a relationship between hepatitis B virus (HBV) infection and development of proteinuria in some patients (most commonly children), with a predominance for male gender and histological findings of membranous nephropathy on renal biopsy. The presence of immune complexes in the kidney suggests an immune complex basis for the disease, but a direct relation between HBV and membranous nephropathy (or other types of glomerular diseases) remains to be proven. Clearance of HBV antigens, either spontaneous or following antiviral treatments results in improvement in proteinuria. Thus, prompt recognition and specific antiviral treatment are critical in managing patients with HBV and renal involvement. The present review focuses on treatment of HBV with special emphasis given to antiviral therapies, its complications, and dosing in patients with HBV-associated kidney disease.     

Quantitative assessment of urinary protein and enzyme excretion--a diagnostic programme for the detection of renal involvement in type I diabetes mellitus.

In an effort to establish a reliable programme for the clinical monitoring of renal involvement in patients with type-I diabetes mellitus, we quantified the urinary excretion of immunoglobulin G (IgG), transferrin (Tf), albumin (Alb), alpha 1-microglobulin (alpha 1MG), N-acetyl-beta-D-glucosaminidase (NAG), and total protein in 130 dipstick negative children and young adults with type-I diabetes. Eighty-five sex- and age-matched healthy persons served as a control group for the definition of the upper reference limits (95th centiles; micrograms min-1 1.73 m2): transferrin 1.4; albumin 16.6; total protein 27.1; NAG: 2.0 mU min-1 1.73 m2. Sex-related differences were detected for IgG (men: 3.8; women: 1.7) and alpha 1 MG (men: 6.0; women: 4.0 micrograms min-1 1.73 m2). The urinary excretion of IgG, Tf, alpha 1MG, NAG, and total protein was significantly higher in subjects with diabetes when compared to healthy controls (p < 0.01). Furthermore, 20 patients (15%) showed an elevated excretion of tubular markers (alpha 1MG and NAG), and 3 patients (2%) of at least two glomerular markers (Alb and/or Tf and/or IgG). Additionally, 18 individuals (14%) presented a mixed excretion pattern of both tubular and glomerular markers. These data suggest that the quantitation of both glomerular and tubular proteinuria provides a sensitive and cost-effective instrument for the non-invasive screening for renal involvement in patients with diabetes mellitus.     

Relationship between the urinary excretion of albumin and retinol-binding protein in insulin-dependent diabetics

The glomerular and proximal tubular function of the diabetic kidney was investigated. The urinary excretion (relative clearance) of albumin, a marker of glomerular function, and retinol binding protein (RBP), a low molecular weight (LMW) protein and marker of proximal tubular function, was determined in insulin-dependent diabetics. No correlation between the relative clearances of albumin and RBP was observed. LMW proteinuria without microalbuminuria was observed in 27 patients which suggests that tubular dysfunction may be an early stage in the development of diabetic nephropathy. Microalbuminuria was found in 16 patients while a mixed type of proteinuria (microalbuminuria and LMW proteinuria) was present in 56 patients several of whom had advanced nephropathy with elevated serum levels of RBP and creatinine. It is suggested that a combination of tubular and glomerular malfunction may be responsible for some cases of mixed proteinuria.     

Determination of urinary lysozyme for potential detection of tubular dysfunction in diabetic nephropathy

Seeking to study whether measurement of lysozyme (EC 3.2.1.17) in urine by a reliable radioimmunoassay can provide a suitable index of renal tubular function and how lysozymuria develops in temporal relation to proteinuria in diabetic nephropathy, we have compared the urinary excretion of lysozyme and beta 2-microglobulin with the 15-min excretion rate of phenolsulfonphthalein in 39 patients with Type 2 (non-insulin-dependent) diabetes and investigated the temporal relation between the onset of lysozymuria and proteinuria in 15 patients with Type 1 (insulin-dependent) diabetes. The concentrations of lysozyme and beta 2-microglobulin in urine increased in proportion to the decrease in the rate of excretion of phenolsulfonphthalein in these patients. The coefficient of correlation between lysozyme concentration and the 15-min excretion rate of phenolsulfonphthalein (r = -0.70) was higher than that between beta 2-microglobulin concentration and the 15-min excretion rate of phenolsulfonphthalein (r = -0.46). Abnormally high lysozymuria, suggesting the existence of tubular dysfunction, was demonstrated in six of the patients with Type 1 diabetes who showed no proteinuria or only a slight increase in urinary protein excretion. Lysozymuria may thus be added to a list of the indicators for diabetic nephropathy.     

Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis.

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous nephropathy. 10 d after injection of anti-Fx1A antibody, urinary protein excretion rate (Upr) in PHN was significantly higher than that of control. Micropuncture studies demonstrated reduced single nephron plasma flow and glomerular filtration rates, increased transcapillary hydraulic pressure difference, pre- and postglomerular resistances, and decreased ultrafiltration coefficient in PHN rats. Glomerular LTB4 generation from PHN rats was increased. Administration of the 5-LO activating protein inhibitor MK886 for 10 d markedly blunted proteinuria and normalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 receptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerulus were increased in PHN rats. In x-irradiated PHN rats, which developed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria. The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells.     

Acanthocytes in the urine: useful tool to differentiate diabetic nephropathy from glomerulonephritis?

OBJECTIVE: The presence of hematuria has been suggested to indicate nondiabetic nephropathy in diabetic patients with proteinuria. However, hematuria is frequently found in patients with biopsy-proven diabetic glomerulosclerosis without nondiabetic nephropathy. Urine microscopy allows discrimination of glomerular hematuria, which is defined as acanthocyturia (urinary excretion of acanthocytes, which are dysmorphic erythrocytes with vesicle-like protrusions), from nonglomerular hematuria. We hypothesized that acanthocyturia is an uncommon finding in diabetic nephropathy, which suggests the presence of a nondiabetic nephropathy in diabetic patients with proteinuria. RESEARCH DESIGN AND METHODS: Urine samples of patients with the clinical diagnosis of diabetic nephropathy (n = 68), of patients with biopsy-proven glomerulonephritis (n = 43), and of age-matched healthy control subjects (n = 20) were examined by phase-contrast microscopy for the presence of hematuria (>/=8 erythrocytes/ micro l) and acanthocyturia. Acanthocyturia of >/=5% (5 acanthocytes among 100 excreted erythrocytes) was classified as glomerular hematuria; acanthocyturia of 2-4% was classified as suspected glomerular hematuria. RESULTS: Hematuria was found in 62% of patients with the clinical diagnosis of diabetic nephropathy, in 84% of patients with glomerulonephritis, and in 20% of the healthy control subjects upon a single urine examination. In contrast, glomerular hematuria occurred in 4% of patients with diabetic nephropathy and in 40% of patients with glomerulonephritis (P < 0.001). CONCLUSIONS: In contrast to hematuria, acanthocyturia is uncommon in patients with the clinical diagnosis of diabetic nephropathy. In diabetic patients with proteinuria, the finding of acanthocyturia points to nondiabetic glomerulopathies, and renal biopsy should be considered.     

Inhibition of cyclooxygenases reduces complement-induced glomerular epithelial cell injury and proteinuria in passive Heymann nephritis

In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement induces glomerular epithelial cell injury and proteinuria, which is partially mediated by eicosanoids. Glomerular cyclooxygenase (COX)-1 and -2 are up-regulated in PHN and contribute to prostanoid generation. In the current study, we address the role of COX isoforms in proteinuria, using the nonselective COX inhibitor indomethacin and the COX-2-selective inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU). Four groups of rats with PHN were treated twice daily, from day 7 through 14 with vehicle, 1 mg/kg DFU, 10 mg/kg DFU, or 2 mg/kg indomethacin. Vehicle-treated rats with PHN showed significant proteinuria on day 14 (163 +/- 15 mg/d, n = 19), compared with normal rats (10 +/- 4 mg/d, n = 3, p < 0.001). Treatment with DFU (1 or 10 mg/kg) reduced proteinuria significantly (by ~33%), compared with vehicle, but to a lesser extent than indomethacin (56% reduction). Glomerular eicosanoid generation was reduced significantly in the DFU and indomethacin groups, compared with vehicle. There were no significant differences among vehicle- or DFU-treated groups in [(3)H]inulin clearance, or in glomerular expression of COX-1 and -2. DFU did not affect the autologous immune response. In cultured rat glomerular epithelial cells, COX inhibition reduced complement-induced cytotoxicity, and this reduction was reversed by the thromboxane A(2) analog 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F(2alpha) (U46619). Thus, in experimental membranous nephropathy, selective inhibition of COX-2 reduces proteinuria, without adversely affecting renal function. However, inhibition of both COX-1 and -2 is required to achieve a maximum cytoprotective and antiproteinuric effect.     

Urinary albumin excretion: a predictor of glomerular findings in adults with microscopic haematuria

BACKGROUND: Microscopic haematuria without proteinuria is a common clinical finding. When urological causes are excluded, usual findings on renal biopsy are IgA nephropathy (which can progress to end-stage renal failure) or thin basement membrane nephropathy (which has an excellent prognosis). A non-invasive test to discriminate between the two would be useful. Aim: To examine the value of measurement of urinary albumin excretion in discriminating glomerular causes of microscopic haematuria in patients without proteinuria on urine dipstick tests. DESIGN: Single-centre retrospective cross-sectional observational study. METHODS: Adult patients who underwent renal biopsy for microscopic haematuria over a 6-year period from January 1994 were identified. Study entry required normal renal function, no proteinuria detected by dipstick, and urinary albumin excretion <300 mg/24 h. Patients with IgA nephropathy had follow-up for a mean of 58 months after biopsy. RESULTS: Of 169 patients fulfilling study criteria, 119 (70%) had normoalbuminuria (<30 mg/24 h); 52 (30%) had microalbuminuria (30-299 mg/24 h). Of those with normoalbuminuria, 106 (89%) had thin basement membrane nephropathy or no glomerular abnormality. Thirteen (11%) had IgA nephropathy, and of 12 of these followed-up for a mean 64 months, none developed overt, dipstick-positive proteinuria. In contrast, 24 (48%) of those with microalbuminuria had IgA nephropathy, and of 22 followed-up for a mean 55 months, five developed overt proteinuria. DISCUSSION: Urinary albumin excretion is an indicator of likely glomerular findings in microscopic haematuria, and may influence whether a renal biopsy is necessary.     

妊娠致肾脏损害特点临床和肾活检病理的研究

目的　为探讨妊娠致肾脏损害的临床特点及病理特征。方法　对 46例妊娠致肾脏损害住院患者进行了临床和肾活检病理的分析研究。结果　 46例终止妊娠 3个月后仍有蛋白尿 ,合并肾功能不全者 2 6例 ( 56 .52 % ) ,肾活检免疫病理示 Ig G32例 ,Ig A36例 ,Ig M2 8例及 C338例肾小球血管袢及系膜区沉积 ;病理表现系膜增生性肾炎 2 8例、膜增生性肾炎 1 0例、局灶节段性肾小球硬化 6例、膜性肾病 2例 ,46例中合并小球硬化者 2 8例 ;胎儿死亡 36例 ( 76 .6 0 % )。结论　妊娠激发了免疫反应导致肾脏病变是肾小球疾病发病机制之一 ,积极诊治该类患者是临床不可忽视的问题。     

妊娠致肾脏损害特点临床和肾活检疫理的研究

目的：为探讨妊娠致肾脏损害的临床特点及病理特征,方法：对46例妊娠致肾脏损害住院患进行了临床和肾活检病理的分析研究,结果：46例终止妊娠3个月后仍有蛋白尿,合并肾功能不全26例（56．52％）,肾活检免疫病理示IgG32例,IgA36例,IgM28例及C338例肾小球血管袢及系膜区沉积;病理表现系膜增生性肾炎28例,膜增生性肾炎10例,局灶节段性肾小球硬化6例,膜性肾病2例,46例中合并小球硬化28例,胎儿死亡36例（76．60％）,结论：妊娠激发了免疫反应导致肾脏病变是肾小球疾病发病机制之一,积极诊治类患是临床不可忽视的问题。     

Significance of serum IgA levels and serum IgA/C3 ratio in diagnostic analysis of patients with IgA nephropathy

Diagnostic analysis of clinical markers including serum IgA levels and serum IgA/C3 ratio in patients with IgA nephropathy is described. One hundred patients with IgA nephropathy (IgA nephropathy group) and 100 patients with other primary glomerular diseases (non-IgA nephropathy group) were examined. The analysis was performed to distinguish between these two groups using four clinical markers: 1) more than five red blood cells in urinary sediments, 2) persistent proteinuria (urinary protein of more than 0.3 g/day), 3) serum IgA levels of more than 315 mg/dl, and 4) a serum IgA/C3 ratio of more than 3.01. Patients with three or four clinical markers were easily diagnosed as having IgA nephropathy in this study. Furthermore, there was a significant difference in these clinical markers between the good prognosis and relatively good prognosis groups (Groups I and II) and the relatively poor prognosis and poor prognosis groups (Groups III and IV) of IgA nephropathy patients. It appears that the presence of microscopic hematuria and/or persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratio are useful for distinguishing IgA nephropathy from other primary renal diseases. It is postulated that these clinical markers are also useful for diagnosis of IgA nephropathy without renal biopsy.     

Tamm-Horsfall protein in Balkan endemic nephropathy

It is suggested that Tamm-Horsfall protein, a specific renal glycoprotein, may be involved in the pathogenesis of some renal diseases. In cadmium nephropathy and Fanconi syndrome (primary tubular diseases of the kidney) an increased excretion rate of Tamm-Horsfall protein has been observed. Balkan endemic nephropathy is a chronic tubulointerstitial disease of unknown etiology, most probably a primary disease of the kidney tubules with secondary reaction of the interstitial tissue. Investigation of Tamm-Horsfall proteinuria in Balkan endemic nephropathy has shown that subjects living in the area where this condition is prevalent have a significantly higher Tamm-Horsfall protein /creatinine ratio than those living in the control area where the condition has not been observed. Differences in this ratio among diseased, suspect and subjects "at risk" were not observed, despite differences in their glomerular filtration rates. But excretion of Tamm-Horsfall protein per litre of glomerular filtrate was significantly different among diseased, suspect and subjects "at risk" and significantly higher compared to control subjects. a relatively significant correlation was obtained between Tamm-Horsfall protein excretion rate and glomerular filtration rate as measured by creatinine clearance in both control and subjects living in the area of Balkan endemic nephropathy. Determination of Tamm-Horsfall protein in urine together with determination of proteinuria by electrophoresis on cellulose acetate membranes as a screening procedure, and by SDS -electrophoresis in polyacrylamide gell may be useful laboratory tests in detecting this nephropathy.     

Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome.

1. To elucidate the mechanisms by which cyclosporin A diminishes proteinuria, we studied 20 patients with severe nephrotic syndrome. Biopsy-established pathologies included minimal change disease (n = 5), membranous glomerulopathy (n = 6), membranoproliferative glomerulonephritis (n = 5) and focal segmental glomerulosclerosis (n = 4). Before, at the end of a 90 day course of cyclosporin A, and finally 1 month after stopping cyclosporin A we determined 24 h protein excretion. Measurements of glomerular filtration rate, effective renal plasma flow, fractional clearance rates of albumin and immunoglobulins with different charges and the transglomerular sieving of uncharged dextrans of broad size distribution were used to study the effects of cyclosporin A on renal perfusion and the glomerular filtration barrier. The findings were analysed with a theoretical model of solute transport. 2. Among the different forms of glomerulopathy the response to low-dose cyclosporin A (trough levels 32.0-36.9 ng/ml) varied markedly. In minimal change disease, proteinuria decreased from 9.5 +/- 3.1 to 1.3 +/- 0.2 g/24 h (mean +/- SEM, P less than 0.01). This response was due to restoration of the charge selectivity of the glomerular barrier. The depressed value of the glomerular permeability coefficient also returned to normal. Glomerular filtration rate, effective renal plasma flow and renal vascular resistance did not change. Proteinuria returned after stopping cyclosporin A, although it did not reach pretreatment levels. In membranous glomerulopathy, proteinuria fell from 9.9 +/- 1.5 to 1.8 +/- 0.3 g/24 h (P less than 0.01). Changes in protein excretion and dextran sieving were compatible with an increase in glomerular permselectivity and a decrease in filtrate flow through the 'shunt' pathway. Glomerular filtration rate was maintained, although effective renal plasma flow fell significantly. Proteinuria relapsed after stopping cyclosporin A. In membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis proteinuria did not respond to cyclosporin A, although cyclosporin A exerted important haemodynamic effects. 3. In minimal change disease and membranous glomerulopathy cyclosporin A exerts its beneficial effects on proteinuria through changes in the properties of the glomerular barrier, resulting in increased charge and size selectivity, respectively.     

The natural history of membranous nephropathy in the West of Scotland

Membranous nephropathy was diagnosed in 54 patients between January 1975 and June 1983 in the Royal Infirmary, Glasgow. It was the commonest cause of the nephrotic syndrome and, with IgA nephropathy, the commonest primary glomerular disease. A cause was found in 10 patients. The last seven patients diagnosed were enrolled in the MRC trial. The natural history of the remaining 37 patients with idiopathic membranous nephropathy was studied. After an average observation period of 64 months, 50 per cent had stable renal function with or without proteinuria and 50 per cent had progressive renal failure or had died of other causes (five patients). Of the factors examined only heavy proteinuria and hypertension were significantly more common in patients who developed progressive renal failure. No patient who entered remission relapsed. Vascular complications were an important cause of morbidity and mortality. Incidence of events of arterial occlusion was significantly higher in these patients compared with patients with IgA nephropathy. Treatment of patients with membranous nephropathy should, therefore, be judged not only by its efficacy in preventing progressive renal failure, but also by its effect on vascular disease and by its toxicity.     

Enhanced urinary excretion of albumin and beta 2 microglobulin in essential hypertension induced by atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) was given as an intravenous bolus injection (2.0 micrograms kg-1) to 12 essential hypertensive patients (EH) and 10 normotensive control subjects (C) in order to study the effect of ANP on urinary excretion of albumin and beta 2-microglobulin, and on glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF). After the ANP injection, urinary excretion of albumin increased significantly (p less than 0.01) in EH from 7.3 micrograms min to 125 micrograms min (medians) and in C from 2.9 micrograms min-1 to 8.1 micrograms min-1 (p less than 0.05). Urinary excretion of beta 2-microglobulin increased in EH from 70 ng min-1 to 1022 ng min-1 (p less than 0.01) and in C from 118 ng min-1 to 170 ng min-1 (p less than 0.01). The increase in urinary excretion of both albumin (p less than 0.01) and B2-microglobulin (p less than 0.01) was significantly more pronounced in EH than in C. GFR and RPF were almost unchanged in both groups. FF rose to the same degree in the two groups. The increase in fractional excretion of sodium and in urine volume after ANP was enhanced in EH. It is concluded that ANP in pharmacological doses increased urinary excretion of albumin and beta 2-microglobulin to a considerably larger extent in essential hypertensive patients than in normotensive control subjects.     

Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy.

Podocyte injury is believed to contribute to glomerulosclerosis in membranous nephropathy. To identify the factors involved, we investigated the effects of basic fibroblast growth factor (bFGF), a cytokine produced by podocytes, on rats with membranous nephropathy (passive Heymann nephritis [PHN]). All rats received a daily i.v. bolus of 10 microg bFGF or vehicle from days 3-8 after PHN induction. In proteinuric PHN rats on day 8, bFGF injections further increased proteinuria. Podocytes of bFGF-injected PHN rats showed dramatic increases in mitoses, pseudocyst formation, foot process retraction, focal detachment from the glomerular basement membrane, and desmin expression. bFGF injections in PHN rats did not alter antibody or complement deposition or glomerular leukocyte influx. bFGF-injected PHN rats developed increased glomerulosclerosis when compared with control PHN rats. Also, bFGF induced proteinuria and podocyte damage in rats injected with 10% of the regular PHN-serum dose. None of these changes occurred in bFGF-injected normal rats, complement-depleted PHN rats or rats injected with 5% of the regular PHN serum dose. These divergent bFGF effects were explained in part by upregulated glomerular bFGF receptor expression, induced by PHN serum. Thus, bFGF can augment podocyte damage, resulting in increased glomerular protein permeability and accelerated glomerulosclerosis. This bFGF action is confined to previously injured podocytes. Release of bFGF from glomerular sources (including podocytes themselves) during injury may represent an important mechanism by which podocyte damage is enhanced or becomes self sustained.