Transient Proteinuria Research Articles

Podocyte Changes after Induction of Acute Albuminuria in Mice by Anti-Aminopeptidase A mAb

Administration of a specific combination of anti-aminopeptidase A (APA) mAb (ASD-37/41) in mice induces an acute albuminuria which is independent of angiotensin II, a well-known substrate of APA. In the present experiments, we examined whether binding of the mAb initiated changes in the podocytic expression of cytoskeleton (-associated), adhesion and slit-diaphragm proteins in relation to the time course of albuminuria. In addition, we measured ultrastructurally the extent of foot process retraction (the number of foot processes per µm GBM) and the width of the slit pore between the podocytes by morphometric methods. An injection of the mAb combination ASD-37/41 induced a massive but transient albuminuria that started at 6 h, and peaked at 8 h, after which it declined. However, even at day 7 after injection of the mAbs some albuminuria was present. Injection of the combination ASD-3/41 or saline did not induce an albuminuria. Notably, we observed changes in the staining of CD2AP and podocin, two slit-pore-associated proteins that coincided with the start of the albuminuria. Nephrin staining was reduced and podocytic actin staining became more granular only at a time albuminuria was declining (24 h). The number of foot processes per µm GBM was already decreased at 4 h with a further reduction thereafter. The width of the slit pore was unchanged at the time of peak albuminuria and gradually decreased thereafter. At day 7, podocytic foot process effacement was even more prominent although albuminuria was only slightly abnormal. Expression of CD2AP was still granular. We observed however a change toward normal in the expression of podocin. Injection of saline or ASD-3/41 had no effect on the expression of podocytic proteins, the number of foot processes or width of the slit pore. Our data show that the onset of albuminuria in the anti-APA model is related to alterations in CD2AP and podocin, proteins that are important for maintaining slit-diaphragm structure and podocytic function. Extended studies at day 7 demonstrated uncoupling of albuminuria, podocytic foot process effacement and CD2AP staining. Changes in podocin more closely paralleled changes in albuminuria.

Proteinuria after injection of human focal segmental glomerulosclerosis factor.

Recurrent focal segmental glomerulosclerosis (FSGS) is heralded by proteinuria that may remit after treatment with plasmapheresis or immunoadsorption. Study of recurrent FSGS has been hampered by lack of an animal model that exhibits a pattern of proteinuria that mimics human disease. We have obtained a component of FSGS patient plasma (FSGS factor) that increases glomerular albumin permeability (P(alb)) in vitro and causes transient proteinuria in vivo. Plasma fractions containing FSGS factor and comparable plasma fractions from normal donors were injected into normal male Sprague-Dawley rats. Urinary protein, albumin, and creatinine were measured at various time points. Additionally, plasma samples from test animals were collected after injection and tested for FS activity defined by increased P(alb). Finally, glomeruli were isolated from animals after injection and P(alb) of these glomeruli tested. Proteinuria and albuminuria were increased by 24 hr after injection with FSGS factor, and returned to baseline by 48 hr after injection. Injection with the same fraction of normal plasma had no effect on urinary protein. FSGS factor increased urinary protein in a dose-dependent manner. Serum collected from rats 15 or 60 min after injection with FSGS factor increased P(alb) of glomeruli in vitro, whereas serum collected 3 or more hours after injection had no effect. Glomeruli isolated from rats receiving injections with FSGS factor had increased in vitro P(alb) compared with glomeruli from rats injected with a fraction from normal plasma. We have demonstrated that a single injection of FSGS factor increases P(alb) and, causes transient albuminuria and proteinuria in rats. FS activity in the plasma of recipient rats is also transient. This is the first detailed description of the time course and dose-dependence of proteinuria caused by FSGS factor in an animal model.

Increased glomerular permeability in patients with nephropathia epidemica caused by Puumala hantavirus.

Nephropathia epidemica (NE) is the Scandinavian type of haemorrhagic fever with renal syndrome. Usually heavy transient proteinuria is present at the onset of the disease. We investigated glomerular permeability in eight patients with acute NE and in eight healthy controls. Six patients were followed for 1 year. The glomerular filtration rate (GFR) was determined by inulin clearance and effective renal plasma flow (ERPF) by para-aminohippurate clearance. GFR and ERPF were significantly reduced in NE patients during the acute phase compared with those in controls (P<0.001 and P<0.001, respectively). The filtration fraction (FF) was thus high, 0.37. The fractional clearances of albumin, IgG, and IgG(4) were markedly increased. As a sign of tubular dysfunction, increased urinary excretion of alpha(1)-microglobulin was observed in all patients. After 1 year, the GFR of the patients no longer differed from that of the controls. ERPF was lower and FF higher than those in controls (P=0.014 and P=0.009, respectively). The fractional clearances of albumin, IgG, and IgG(4) remained increased. The high-molecular fractional dextran clearances in the patients were significantly increased compared with controls during the acute phase. Computed analysis of glomerular membrane-pore structure showed that the "shunt-flow" was increased in the patients during the acute phase compared with the controls. There was a positive correlation between the FF and the shunt (r=0.768, P=0.026). In addition, fractional clearances of albumin and IgG correlated significantly with the shunt (r=0.810, P=0.015 and r=0.762, P=0.028, respectively). Renal involvement in the acute phase of NE is characterized by a markedly decreased GFR and ERPF. Increased glomerular permeability is associated with impairment of both the size- and charge-selectivity properties of the glomerular filter.

Proteinuria: potential causes and approach to evaluation.

Proteinuria may be associated with a renal or systemic disease, or it may be isolated. The latter occurs in asymptomatic patients without evidence of any disease or abnormality of the urine sediment. Isolated proteinuria may be subdivided into two broad groups: (1) benign forms, with a favorable-to-excellent prognosis and (2) persistent forms, some of which have a worrisome prognosis. Functional proteinuria may occur in disorders with altered renal hemodynamics, usually resolves, and is not associated with progressive renal disease. Idiopathic transient proteinuria is typically discovered on routine screening and usually disappears on subsequent testing. In idiopathic intermittent proteinuria, a significant number (50%) of urine samples exhibit abnormal rates of protein excretion. Although structural abnormalities may be observed on renal biopsy, progressive renal insufficiency is unusual. In orthostatic proteinuria, the rate of protein excretion completely normalizes in the recumbent position. Long-term studies show this to be a benign condition. In persistent isolated proteinuria, at least 80% of random urine samples exhibit abnormal protein excretion. This represents a heterogeneous group, but a significant proportion of these patients have prominent renal pathologic findings and progress to serious renal disease. Proteinuria with significant renal disease may be non-nephrotic or nephrotic range. The former does not exclude glomerular disease, but tubulointerstitial or vascular disorders are also likely when proteinuria is less than 2 g/24 hours. Patients with nephrotic-range proteinuria generally have a glomerular disorder. Distinction between benign and more ominous forms of proteinuria requires careful evaluation.

Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris

We sought to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of basic fibroblast growth factor (bFGF), administered as a single intracoronary injection, to subjects with stable angina pectoris secondary to coronary artery disease. bFGF, an angiogenic growth factor, has been shown to enhance collateral development in animal models of progressive coronary occlusion. To our knowledge, this study represents the initial introduction of parenteral bFGF into humans. This was a phase 1, randomized, dose-escalation trial of bFGF in 25 subjects with coronary artery disease and stable angina. Subjects were randomized 2:1 to a single dose of bFGF or placebo, injected into the left main coronary artery. bFGF doses ranged from 3 to 100 μg/kg, increasing in half-log increments. bFGF was generally well tolerated at doses of 3 to 30 μg/kg. Plasma clearance was 20 ± 2 ml/kg/min, with an elimination half-life of 85 ± 11 minutes. bFGF caused acute hypotension (≈10%) that did not appear to be dose-related through the dose range studied. Of the 9 subjects who received 30 to 100 μg/kg bFGF, 2 had sustained hypotension, mild to moderate in severity, lasting 1 to 3 days, and 3 subjects developed bradycardia hours to days after bFGF administration. bFGF dilated epicardial coronary arteries (7.4 ± 2.5% mean diameter increase, p <0.02). Transient mild thrombocytopenia and proteinuria were observed in some subjects in the 30-μg/kg cohort. No subject had signs suggesting systemic angiogenesis. Thus, intracoronary bFGF, at doses of 3 to 30 μg/kg, was generally well tolerated in subjects with stable angina.

A practical approach to proteinuria.

Proteinuria is defined as urinary protein excretion exceeding 150 mg/day. It may result from nonpathological (posture, fever, exercise) or pathological (glomerular or tubular) processes. Glomerular proteinuria is an early sign of kidney disease and may also play a role in the progression of glomerular damage. Asymptomatic proteinuria is common; it may be transient or persistent. Transient proteinuria is a benign condition and requires no evaluation. Persistent proteinuria can be the first sign of kidney disease. Persistent proteinuria commonly results from disorders associated with increased glomerular permeability such as nephrotic syndrome, glomerulonephritis (e.g., post-infectious, membranous, membranoproliferative, lupus, IgA), and genetic defects (Alport syndrome, mesangial sclerosis). Tubular disorders should also be considered. Evaluation for the underlying cause is traditional. Whether the early detection and evaluation of proteinuria prevents progressive disease is unknown.

Induction of Transient Proteinuria, Hematuria, and Glucosuria by Ethanol Consumption in Japanese Alcoholics

Urinalysis was carried out in 231 inpatients with alcohol dependence syndrome (215 males and 16 females). Fifty-nine patients (25.5%) showed proteinuria, 97 (42.0%) showed glucosuria, and 62 patients (26.8%) showed hematuria on admission. A total of 135 out of 231 patients (58.4%) showed abnormal urinalysis. Proteinuria was related to high blood pressure, high serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, uric acid, and triglyceride levels, and high urinary amylase concentration. Glucosuria was related to high serum glutamic-oxaloacetic transaminase concentration and a history of gastrectomy. Hematuria was related to high age and high urinary amylase levels. By chi-square test, there was a significant correlation between proteinuria and hematuria (p < 0.001) and between hematuria and glucosuria (p < 0.001), but no correlation was found between proteinuria and glucosuria. The incidence of diabetes mellitus was 10.8% (25 out of 231 patients), but transient hyperglycemia was observed in some patients without diabetes mellitus on admission. Elevated hemoglobin A1, hemoglobin A1c, and fructosamine concentrations were observed in patients with either impaired glucose tolerance or transient hyperglycemia, which suggested the presence of persistent hyperglycemia before admission. On discharge, only 12 out of 198 patients (6.1%) showed abnormal urinalysis. We report that heavy ethanol consumption induces transient abnormal urinalysis results in Japanese alcoholics.

Pseudo-proteinuria following gelofusine infusion.

Transient massive proteinuria following cardiopulmonary bypass surgery was observed. It was characterized and attributed to post-operative gelofusine infusion. Gelofusine was found to interfere with dye binding but not immunochemical assays of proteinuria. Proteinuria following gelofusine infusion may not reflect underlying glomerular pathology.

Early proteinuria in renal transplant recipients treated with cyclosporin.

To establish the risk profile for the development of proteinuria in the first months after renal transplantation and to disclose the prognostic significance of this finding. We conducted an observational historic cohort study. We conducted the study in a tertiary care hospital renal transplantation unit covering a potential population of approximately 2 million. We made extensive use of suboptimal donors. In our unit, 560 cadaveric renal transplants were performed between January 1988 and June 1997, under Cyclosporine immunosuppression, with a minimum follow up of 1 year. The risk profile analysis explored early clinical factors reported to be related to the late course of renal transplantation. The study of the prognostic significance of proteinuria included survival analysis and correlation with late markers of graft dysfunction, taking into consideration the intensity and persistence of early proteinuria. A multivariate approach was used in all cases. Early proteinuria was strongly associated with delayed graft function (odds ratio [OR] 1.03/day of dialysis), acute rejection (OR 1.7 for steroid-sensitive and 6.2 for steroid-resistant rejection), renal transplant to a hypersensitized recipient (OR 2.5), and pediatric (<5 years)(OR 4.1) or older (>60 years)(OR 3.0) donors. The predictive model for persistency of proteinuria was very similar, whereas transient proteinuria could not be adequately modeled. Increasing intensity of proteinuria was strongly associated with poor patient and graft survival. Persistent, but not transient, proteinuria supported this relationship. Proteinuria appearing early after renal transplantation is strongly associated with delayed graft function, acute rejection, and the use of pediatric or older donors. Whatever its background, proteinuria is a strong predictor of poor patient and graft survival. This effect is directly related to the intensity and persistence of the disorder.

Dose of compound A, not sevoflurane, determines changes in the biochemical markers of renal injury in healthy volunteers.

Administration of sevoflurane in a circle absorption system generates Compound A, a nephrotoxin in rats. Reports examining the potential of Compound A to produce renal injury in humans have provided conflicting results. We tested the possibility that there is a threshold to Compound A-induced renal injury in humans and that, above this threshold, renal injury increases with increasing doses of Compound A. Eleven volunteers received 3% sevoflurane for 8 h at 2 L/min, and three volunteers received 3% sevoflurane for 8 h at 4-6 L/min. We measured inspired and expired concentrations of Compound A and urinary excretion of albumin, alpha-glutathione-S-transferase (GST), and glucose. The median urinary excretion of albumin, glucose, and alpha-GST for the first 3 days after anesthesia increased significantly from preanesthetic values in the 2-L/min group. Compound A doses < 240 ppm-h resulted in normal urinary excretion of albumin, glucose, and alpha-GST. Five of seven subjects who received doses > 240 ppm-h had abnormal excretion of albumin, and six of seven had abnormal alpha-GST urinary excretion (P < 0.05). Urinary excretion of albumin, alpha-GST, and glucose was normal by 14 days after exposure. We conclude that sevoflurane administration for 8 h at 2 L/min results in albuminuria and enzymuria when the dose of Compound A exceeds 240 ppm-h. That is, a Compound A concentration of 30 ppm breathed for > or = 8 h may produce transient renal injury. We examined the dose-response relationship of sevoflurane/Compound A and urinary excretion of albumin, glucose, and alpha-GST. Sevoflurane exposure for 8 h at a 2-L/min inflow rate produces transient albuminuria and enzymuria in healthy volunteers when the dose of Compound A exceeds 240 ppm-h (30 ppm for 8 h).

Studies' Divergent Results

Studies' Divergent Results

Mucosal immunoregulation and inflammatory bowel disease: new insights from murine models of inflammation.

Membranous glomerulonephritis (MGN) is said to be caused by circulating autoantibodies against antigen(s) located to the epithelial side of the glomerular capillaries. Membranous glomerulonephritis with severe renal damage can be produced experimentally by injections of heterologous antibodies, but this model is obviously of questionable relevance. It can also be produced by immunizing the animal with antigen mixed with Freund’s adjuvant, but this model does not prove that the damage is exerted by antibodies because Freund’s adjuvant is nephrotoxic and is itself able to produce MGN. It has not yet been demonstrated experimentally that autologous antibodies alone can produce more than trace or transient proteinuria; and kidney biopsies in unselected humans have shown that MGN is a frequent finding in individuals with normal urine and normal renal function, indicating that a subepithelial formation of immune complexes is also harmless to humans. Severe glomerulonephritis without immune complex formation can easily be produced experimentally with many nephrotoxic chemicals. It is therefore suggested that the primary event in MGN, and probably other subgroups, is a toxic or allergic tubulointerstitial reaction to chemicals or drugs and that the formation of glomerular immune complexes is a later and secondary phenomenon. In agreement, renal function and the course in MGN and other glomerulonephritides are strongly correlated with the degree of tubulointerstitial damage, but totally unrelated to the degree of glomerular damage. The hypothesis explains why a large number of patients with endstage renal failure owing to glomerulonephritis have been heavily exposed to environmental pollutants.

The subepithelial formation of immune complexes in membranous glomerulonephritis may be harmless and secondary to toxic or allergic factors.

Membranous glomerulonephritis (MGN) is said to be caused by circulating autoantibodies against antigen(s) located to the epithelial side of the glomerular capillaries. Membranous glomerulonephritis with severe renal damage can be produced experimentally by injections of heterologous antibodies, but this model is obviously of questionable relevance. It can also be produced by immunizing the animal with antigen mixed with Freund's adjuvant, but this model does not prove that the damage is exerted by antibodies because Freund's adjuvant is nephrotoxic and is itself able to produce MGN. It has not yet been demonstrated experimentally that autologous antibodies alone can produce more than trace or transient proteinuria; and kidney biopsies in unselected humans have shown that MGN is a frequent finding in individuals with normal urine and normal renal function, indicating that a subepithelial formation of immune complexes is also harmless to humans. Severe glomerulonephritis without immune complex formation can easily be produced experimentally with many nephrotoxic chemicals. It is therefore suggested that the primary event in MGN, and probably other subgroups, is a toxic or allergic tubulointerstitial reaction to chemicals or drugs and that the formation of glomerular immune complexes is a later and secondary phenomenon. In agreement, renal function and the course in MGN and other glomerulonephritides are strongly correlated with the degree of tubulointerstitial damage, but totally unrelated to the degree of glomerular damage. The hypothesis explains why a large number of patients with endstage renal failure owing to glomerulonephritis have been heavily exposed to environmental pollutants.

Epitope-specific antibodies to the 43-kD glomerular membrane protein podoplanin cause proteinuria and rapid flattening of podocytes.

The 43-kD integral membrane protein podoplanin is localized on the surface of rat podocytes, and transcriptionally downregulated in rat puromycin nephrosis. In this study, a single intravenous injection of polyclonal rabbit anti-podoplanin IgG resulted in selective binding of IgG to the entire podocyte's surface. Some IgG produced by different rabbits rapidly induced transient proteinuria (approximately 350 mg/24 h at day 1, normal levels around day 5), whereas other IgG were ineffective. All anti-podoplanin IgG shared a common binding site at amino acids 39 to 47 (DDMVNPGLE), whereas IgG inducing glomerular damage specifically bound to an additional epitope at amino acids 74 to 79 (PIEELP), as observed by a SPOTs analysis on overlapping synthetic peptides. Proteinuria was not prevented by complement depletion or by treatment with the oxygen radical scavenger dimethylthiourea. Injection of Fab fragments failed to induce glomerular pathology, indicating that dimerization of podoplanin by divalent IgG was required. Proteinuria was paralleled by extensive flattening of foot processes that was also induced by blood-free perfusion of isolated rat kidneys with anti-podoplanin IgG. Thus, glomerular changes were due to direct interaction of distinct epitope(s) of podoplanin and divalent IgG. These results provide evidence that podoplanin plays a role in maintaining the unique shape of podocyte foot processes and glomerular permeability.

GENDER DIFFERENCES IN ACUTE N -(3,5- DICHLOROPHENYL)-2-HYDROXYSUCCINIMIDE (NDHS) AND N -(3,5-DICHLOROPHENYL)-2-HYDROXYSUCCINAMIC ACID (2-NDHSA) NEPHROTOXICITY IN FISCHER 344 RATS

N -(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide that induces nephrotoxicity as its major toxicity. NDPS is also a more potent nephrotoxicant in female than in male rats. The purpose of this study was to examine the nephrotoxic potential of the two NDPS metabolites N -(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N -(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) in agematched male and female Fischer 344 rats to determine if gender differences exist for the nephrotoxicity induced by the two NDPS metabolites. Rats (4 per group) were administered a single intraperitoneal (ip) injection of NDHS or 2-NDHSA (0.025 or 0.05 mmol/kg) or vehicle, and renal function was monitored for 48 h. Neither compound induced significant nephrotoxicity in male rats at the doses tested. However, in female rats both metabolites induced marked nephrotoxicity at the 0.05 mmol/kg dose level, and treatment with 0.025 mmol/kg 2-NDHSA induced some changes in renal function (transient diuresis, transient proteinuria, decreased organic ion accumulation). Little effect on renal function was induced in females by treatment with 0.025 mmol/kg NDHS. At toxic levels in female rats, the renal lesions were located primarily in the S2 and S3 segments of the proximal tubule. These results indicate that, like the parent compound, gender differences exist in the nephrotoxic potential of NDHS and 2-NDHSA. The results also suggest that in females, as in males, NDPS nephrotoxicity is mediated via NDHS and/or 2-NDHSA. However, it is not clear if the ultimate nephrotoxicant species following NDPS exposure is different in males and females or if the same ultimate nephrotoxicant species is produced in both species but handled differently by male and female kidneys. Thus, further studies are needed to determine the exact nature of the ultimate nephrotoxicant species and the mechanisms of the observed gender differences.

INJECTION OF PLASMA PROTEIN FRACTION FROM PATIENTS WITH FSGS CAUSES TRANSIENT PROTEINURIA IN RATS

156 Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by heavy proteinuria, progression to end-stage renal disease, and frequent recurrence in renal allografts. Early recurrence of proteinuria following transplantation and therapeutic effect of plasmapheresis suggest the presence of a causative factor in the circulation of some patients with FSGS. We have documented the presence of permeability activity in sera and plasma of patients with FSGS. Through a series of biochemical manipulations we have succeeded in partially purifying a substance from the plasma of patients with recurrent FSGS which markedly increases albumin permeability in our in vitro assay. The current studies were performed to document that injection of partially purified FSGS factor can cause proteinuria in rats, and that this effect is seen with plasma from different patients. The active fraction of FSGS plasma from Patient 1 (Fpf), 12 mg protein in 1 mL saline, or 12 mg of a comparable fraction of pooled normal human plasma fraction (Npf) was injected intravenously into male Sprague Dawley rats (250-350 g). This amount corresponds to the active protein fraction from about 40 mL of plasma. Urine was collected prior to injection and during 6-12 hour intervals for 2 days. Fpf caused an transient increase in urinary protein in every rat while Npf had no effect. Proteinuria was maximal at 12 hr while serum creatinine was unchanged. Proteinuria, expressed as mg protein/mg creatinine, is shown.TablePlasma from each of three additional patients was subjected to identical biochemical manipulations, and injected into rats in separate experiments. The active fraction from each of these patients caused proteinuria in rats at 12 hours. TableMean arterial pressure in rats injected with Fpf dropped significantly within 3 minutes and returned to normal by 10-15 minutes. Injection with a similar fraction of normal plasma had no effect on mean arterial pressure. In summary, Fpf from each of 4 patients with recurrent FSGS caused transient proteinuria in rats. This finding supports an etiologic role for a circulating factor in human FSGS. The model will be useful for studies of mechanisms of proteinuria and for trials of potential therapeutic agents in FSGS.

Glomerulonephritis in autopsy cases with hepatitis C virus infection.

The glomerular changes of 188 consecutive autopsy cases with hepatitis C virus (HCV) infection were studied. The glomerular changes were classified as follows: Category I: membranoproliferative glomerulonephritis (MPGN; 21 cases, 11.2%), 2) Category II: membranous nephropathy (MN; 5 cases, 2.7%), 3) Category III: mesangial proliferative glomerulonephritis (MesGN; 33 cases, 17.6%), 4) Category IV: mesangial thickening type without proliferative mesangial cell (MT; 44 cases, 23.4%), and 5) Category V: almost normal glomeruli (85 cases, 45.2%). Glomerulonephritis was defined as glomeruli with an increase in mesangial matrix or a thickening of the capillary walls in the glomeruli; categories I-IV corresponded to glomerulonephritis in this study. Multivariate analysis, using a multiple logistic model, indicated that glomerulonephritis with HCV infection was the most strongly correlated to the existence of esophagogastric varices. Abnormal urinalysis, that is transient or continuous microhematuria or proteinuria, was observed in only 23 (12.2%) cases. These results showed that in HCV-RNA positive patients with esophagogastric varices the possibility of glomerulonephritis should be considered.

Cationic dextran induces mesangioproliferative nephritis in rats independent of glomerular IgA deposition.

Dextran-induced mesangioproliferative glomerulonephritis in mice and, as recently reported, in rats is used as a model of IgA nephropathy. The pathogenetic role of the glomerular IgA deposits in this model, however, is unclear since IgG is often deposited in parallel. Lewis rats were immunized with cationic DEAE-dextran. Following this, rats received 5 x/week i.v. injections of 3 mg DEAE-dextran each, from days 20 to 80 and were then followed until day 120. Rats developed transient proteinuria (range 63-152 mg/24 h) and haematuria on day 80. Renal biopsies obtained at days 60, 80, 100 and 120 showed mild to severe mesangioproliferative changes at days 80 and 100 which did not persist at day 120. Electron-microscopy revealed mesangial immune deposits, signs of endothelial activation and vacuoles in mesangial cells and podocytes. Compared to normal, age-matched controls, in the nephritic rats significant (P < 0.05) increases were noted for glomerular total cellularity, alpha-smooth-muscle actin expression (a marker of activated mesangial cells), monocyte/macrophage counts, and matrix proteins. Using three different antibodies, no evidence of glomerular IgA deposition was detected at any time point. In contrast, glomerular IgG, IgM, C3, and occasional small C5b-9 deposits were present in nephritic rats. Circulating IgG but not IgA anti-dextran antibodies could be demonstrated in nephritic rats. The data confirm that mesangioproliferative glomerulonephritis can be induced in rats by immunization and chronic challenge with cationic dextran. Our data also show that in rats glomerular IgG deposition rather than IgA, appears to play an important pathogenetic role in this mesangioproliferative glomerulonephritis model.

Renal function after myocardial infarction and cardiac arrest in rats: role of ANP‐induced albuminuria?

Renal function was measured by clearance technique before and after acute myocardial infarction (MI) induced by left coronary artery ligation in male Sprague-Dawley rats. The animals were anaesthetized with halothane-nitrous oxide, paralysed with pancuronium and artificially ventilated. All parameters were stable throughout the experiment in sham-operated time control animals (n = 8). After MI, rats developed left ventricular dysfunction with increased left ventricular end-diastolic pressure and decreased mean arterial pressure. MI produced antidiuresis and antinatriuresis without changes in glomerular filtration rate (GFR), lithium clearance or renal albumin excretion (n = 8). The antidiuretic and antinatriuretic responses to MI were similar in rats with chronic bilateral renal denervation (n = 5). Three additional rats with chronic bilateral renal denervation had cardiac arrest and were resuscitated with cardiac massage, i.v. lidocaine and intracardiac adrenaline administration. These animals showed a transient increase in urine flow rate, sodium and albumin excretion with maximum 30-60 min after resuscitation, while GFR and lithium clearance were normal. Since cardiac ischaemia and sympathetic stimulation are strong stimuli for the release of atrial natriuretic peptide (ANP), we examined if ANP (0.25, 0.50, and 1.00 microg kg(-1) min(-1), n = 8 per dose) affects urinary albumin excretion. ANP increased dose-dependently the urine/plasma concentration ratio of albumin relative to inulin, which suggests that ANP increases the glomerular permeability for albumin. We conclude that MI causes stimulation of renal tubular sodium and water reabsorption by a mechanism which is independent of intact renal innervation. MI does not produce any change in renal albumin excretion in rats, but transient albuminuria may be observed in rats following cardiac arrest and/or manoeuvres used in cardiac resuscitation. Since ANP produces albuminuria, we speculate that ANP may be an important mediator of albuminuria in states with elevated plasma concentrations of ANP.

Administration of the bisphosphonate ibandronate (BM 21.0955) by intravenous bolus injection

Bisphosphonates (BPs) are used for the treatment of both benign and malignant diseases characterized by increased bone resorption. Because of their potential nephrotoxicity, currently available BPs have to be administered by slow intravenous infusion, with conventional doses requiring an infusion time of at least 2 h. In the present investigation, we evaluated the safety and efficacy of the new BP ibandronate as administered by intravenous bolus injection. On day 0, 15 normocalcemic breast cancer patients with bone metastases were treated with 3 mg of ibandronate injected intravenously over 60-120 s. Ibandronate treatment led to significant decreases in serum levels of calcium (p < 0.0001) and phosphate (p < 0.0001) and to subsequent increases in serum concentrations of parathyroid hormone (p <0.0001) and calcitriol (p <0.0001). Moreover, there was a significant reduction in the urinary excretion of calcium (p <0.0001), pyridinoline (p <0.001), and deoxypyridinoline (p < 0.0001). Three serious adverse events were observed: vomiting (WHO grade 3), pulmonary infection (WHO grade 2), and deterioration of a pre-existing impaired glucose tolerance (WHO grade 3). Only vomiting appeared to be related to administration of the drug. The most frequent nonserious adverse events were 10 cases of transient clinically asymptomatic hypocalcemia and 8 cases of asymptomatic hypophosphatemia. Serum levels of creatinine and urea nitrogen did not increase, nor did creatinine clearance deteriorate. When tested with the dipstick method, proteinuria was present in five (33%) patients prior to ibandronate treatment (median protein concentration, 30 mg/dl). Following the BP injection, seven (47%) patients showed slight (highest protein concentration, 30 mg/dl) transient proteinuria at at least one time point, of which six cases appeared in conjunction with leucocyturia and three with microhematuria. Side effects specific to aminosubstituted BPs (fever, reduction in white blood cell counts, and lymphocyte counts) were not seen in these 15 patients. In conclusion, a single intravenous injection of 3 mg of ibandronate significantly inhibited osteoclast activity as reflected by the decrease in serum calcium and in urinary parameters of bone resorption. Serum creatinine levels and estimates of creatinine clearance were not affected by therapy. However, before repeated bolus injections of ibandronate at this dosage can be recommended for further clinical trials, whether a relationship exists between the transient pathological urinary findings and injected ibandronate needs to be determined.