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Metastatic bacterial endophthalmitis is a rare but devastating complication of septicaemia. We present 3 recent cases occurring in dialysis patients. Septicaemic dialysis patients seem particularly prone to staphylococcal endophthalmitis which developed in the face of therapeutic serum concentrations of appropriate antibiotics in all 3 cases. Prompt treatment, including consideration of intravitreal antibiotics, is required if vision is to be preserved. Early signs of endophthalmitis should be actively sought in septicaemic dialysis patients, as they are easily overlooked.

We have examined the temporal and spatial distribution of myofibroblast-like cells, a phenotype with fibroblast and smooth muscle features, in an experimental model of renal infection. Escherichia coli organisms (10(5)) were inoculated directly into the renal cortex of Sprague-Dawley rats weighing 270 g. Saline was substituted in a control group. The animals were sacrificed at five time points up to day 24 (E. coli n = 8, controls n = 3 each interval). Myofibroblasts were identified by morphology and immunohistochemistry for alpha smooth muscle actin (alpha-SMA) and compared with staining for monocytes (ED-1), collagen III, and bromodeoxyuridine incorporation. Histological changes included a focal lesion in E. coli infected animals. Interstitial alpha-SMA staining was confined to spindle-shaped cells resembling myofibroblasts. The percent fractional area of alpha-SMA staining in the lesion increased from 0.12 +/- 0.09 at day 1 to 20.0 +/- 7.1 at day 3 (p0.005), decreasing progressively to 2.0 +/- 2.6 by day 24. This paralleled bromodeoxyuridine incorporation in myofibroblasts: 0.4 +/- 0.5 cells/0.25 mm2 at day 1, 105.0 +/- 36.3 at day 3, and 2.6 +/- 2.2 cells/0.25 mm2 at day 24. ED-1-positive cells increased from 374 +/- 200/0.25 mm2 at day 1 to 894 +/- 88 at day 3 (p0.01), declining to 230 +/- 108/0.25 mm2 by day 24. Intracellular collagen III and alpha-SMA stainings were colocalized at day 3. The fractional area of collagen III increased by day 24 (p0.05). In conclusion, myofibroblasts accumulate transiently during renal interstitial fibrosis and are derived at least in part from local proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-four children (≤15 years of age) with end-stage renal failure received 39 renal allografts between 1985 and 1991 and were treated with cyclosporin A (CyA), azathioprine and low-dose prednisolone (PNL). We aimed to withdraw PNL by 6 months after transplantation. Median duration of follow-up was 2 years 4 months (range 0.1 month to 6 years, 4 months). There were no deaths. Crude graft survival for living-related grafts (n=9) was 100%, although only 1 patient has been followed for >2 years. For cadaveric grafts (n=30), 1- and 5-year actuarial graft survivals were 90% and 79% respectively. At 12 months posttransplant, the median (range) glomerular filtration rate for all patients was 63 (19–109) ml/min per 1.73 m2 (n=25) and at 5 years was 48 (17–64) ml/min per 1.73 m2 (n=9). Complications observed included rejection episodes which occurred after discontinuation of PNL. Long-term (after 12 months), 28% of patients remain on PNL. Hypertension was present in more than 50% of patients. Severe CyA nephrotoxicity was not seen. Catch-up growth as determined by the change (Δ) in mean height standard deviation score (Ht-SDS) was noted at 1 year [ΔSDS/year=+0.60;P

The aim of this study was to assess the prevalence of human papillomavirus (HPV) DNA in women who had received a renal transplant and to compare this with two control groups. Women who had a functioning renal transplant for greater than 6 months (n = 69) were compared with women on maintenance dialysis (n = 89) and women with impaired renal function (creatinine 0.15-0.39 mmol/l) (n = 22). Women were excluded if they had had a hysterectomy, were older than 65 years, or were not yet sexually active. A questionnaire and cervical scrape were obtained from each participant. The cervical scrape was analysed for HPV DNA using PCR and the L1 consensus primers. The participation rate of transplant patients, dialysis patients and those with impaired renal function ('normal' group) was 69, 68, and 78% respectively. The characteristics of the three groups of women at enrollment were similar. No cytological abnormalities were present in the 'normal' population but 11 of 89 patients on maintenance dialysis and nine of 69 transplant patients had cytological abnormalities of atypia or greater (P = 0.08 and P = 0.07, for 'normal' compared to dialysis and transplant groups respectively). One (4.5%) of the 'normal' women had evidence of HPV DNA, while 18 (20%) of patients on maintenance dialysis and 15 (22%) of transplant patients were positive (P = 0.07 and P = 0.05, for 'normal' compared to dialysis and transplant groups respectively). This study suggests that not only transplant recipients but also dialysis patients may have a higher prevalence of risk factors (cytological abnormalities and HPV DNA) for the development of cervical cancer.

This paper prospectively evaluates 33 dual lumen, right atrial catheters inserted into either an external or internal jugular vein by open operation in 29 patients, of whom 15 required haemodialysis and 14 required temporary plasma exchange. The median (range) catheter survival in the haemnodialysis and plasma exchange groups was 108 days (7–334 days) and 61 days (10–116 days), respectively. Life table analysis demonstrated that overall catheter survival was 58% at 200 days. The main causes of catheter failure were infection (four cases), poor flow (three cases) and accidental removal (one case). Another nine catheters were removed electively because of maturation of alternative methods of vascular access (five cases). completion of plasma exchange treatment (three cases), or successful renal transplantation (one case). Long-term silastic catheters, inserted into the right atrium via a jugular vein. have distinct advantages over temporary subclavian vein catheters and external arteriovenous (AV) shunts; this form of access is the method of choice for hamodialysis and plasma exchange patients who require immediate and short- to medium-term vascular access.

To the Editor: Angiotensin-converting–enzyme (ACE) inhibitors have been shown to reduce proteinuria and slow the progression of renal disease.1 Although to date angiotensin II has been the focus of...

To the Editor: In response to Gallego, Fowler and van Gool's study of senior health service leaders' perceptions of decision making about new technologies,1 we would like to commend the authors' approach to clarifying the issues surrounding such an important clinical and corporate governance challenge in contemporary health care organisations. Introduction of new technologies into a health service requires consideration of a myriad of clinical governance factors, including safety, efficacy and appropriateness criteria, as well as credentialing and scope of practice for clinicians, implications for other staff within the health service, infection prevention and occupational health and safety. In addition, the corporate governance areas of financial viability and sustainability (including effectiveness and efficiency) are just as important to ensure that health leaders are advocating appropriately for the community when spending the valuable public health dollar.Melbourne Health has embraced such clinical and corporate governance challenges over the past 18 months by introducing a committee structure and framework to oversee the introduction of new technologies and clinical practices. The committee has been established within the Victorian Department of Human Services guidelines for establishing New Technologies Committees,2 and encompasses organisational considerations within the framework, including multidisciplinary (medical, nursing, allied health) and cross-organisational membership (clinical, quality and safety, finance, human resources, strategy, support services, environmental and Executive). The Committee framework is currently being assessed; however, preliminary issues and challenges arising from the evaluation are highlighted below.Benefits of the framework include:* providing clinicians with a clear pathway and expectations of requirements for new technologies to be approved;* a clear process to evaluate weighing risks/side effects compared with advantages of the procedure, and of comparing old technologies with the new technologies;* a clear link with medical administrative processes for credentialing and defining the scope of practice for medical staff;* provision of an ongoing audit process for evaluating clinical and financial/resource implications of the technology; and* chairmanship by an eminent, respected senior clinician within the organisation, to provide the translator/liaison between the clinicians and management. …

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.

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.

A therapeutic trial of plasma exchange was performed in 13 patients with documented progressive IgA nephropathy. Comparison of the rate of deterioration in renal function before, during, and after plasma exchange demonstrated significant improvement during plasma exchange. Seven patients had a slowed rate of deterioration by plasma exchange, but achieved a decrease in serum creatinine level. Favourable response was correlated with rapidity of deterioration preplasma exchange (P less than 0.01) and was apparent within 4 weeks of commencing therapy in those patients who responded. There was no overall difference between the deterioration rates pre- and postplasma exchange. In patients in whom creatinine decreased on plasma exchange, the initiation of subsequent dialysis was delayed.

Introduction Thrombotic Thrombocytopenic Purpura (TTP) is a cause of microangiopathic-haemolytic anaemia and thrombocytopenia, associated with renal and neurological dysfunction with thrombotic complications causing significant morbidity and mortality. Methods A restrospective single-institution analysis of patients with TTP treated between 1990–2005. Renal or bone marrow transplantation patients were excluded. Results Forty patients were identified. Aetiology was idiopathic 75% (n=30), connective tissue disease-related 12.5% (n=5), malignancy-related 5% (n=2) and pregnancy-related 7.5% (n=3). Presenting features: neurological 62.5% (n=25), renal impairment (creatinine>0.11 mmol/L) 76% (n=28), microangiopathic-haemolytic anaemia 97.5% (n=39) and thrombocytopenia 100% (mean platelet-count 42x10^9/L). Mean Hb 93 g/L and mean Lactose dehydrogenase (LD) 2517 U/L ( Conclusion TTP is associated with a significant relapse-rate (43%) and TTP-related mortality (16%) despite plasma-exchange. Delineation of patients at high risk of relapse following CR will potentially allow targetted treatment intensification. Treatment intensification is also clearly required for patients with refractory TTP and consideration may be given to other immunosuppressive agents, such the chimeric monoclonal anti-CD20 antibody, Rituximab, as a steroid-sparing agent and to potentially avoid splenectomy. We propose a central TTP registry is developed within Australia such that therapeutic strategies can be systematically evaluated in a multicentre setting.

Chronic atrophic pyelonephritis is associated with vesicoureteric reflux in infancy. Reflux disappears during childhood in 50% of cases. It is more commonly detected in infants (49%) and children (26%) with infection than in adults (4.4%). Severe reflux may persist in adults and is usually (94%) associated with scarring. Patients with end-stage renal failure due to pyelonephritis are much younger than patients with end-stage renal failure due to other causes. The incidence of reflux according to sex is equal in infancy, but after infancy both pyelonephritic scarring and reflux are far more common in females. Infection is the likely cause of progressive scarring in females. Hypertension is associated with chronic atrophic pyelonephritis. Proteinuria is the worst prognostic feature in patients with reflux nephropathy and pyelonephritic scarring. Intrarenal reflux determines the site of scarring. The role of surgical correction of vesicoureteric reflux remains uncertain, but meticulous control of infection appears to prevent progressive scarring.

A variety of fixatives and four immunohistochemical technics were compared for demonstration of binding of monoclonal antibodies to cell surface antigens in tissue sections. Three recently described monoclonal antibodies, directed against the human leukocyte-common antigen (PHM 1) and antigens present on mononuclear phagocytes (PHM 2, PHM 3), were used. Antigen stability to fixation and heat were first assessed by quantitating the resultant effect on binding of the monoclonal antibodies to a macrophage cell line in vitro, using a radiolabeled second antibody. All fixatives affected their binding, but least effect was seen with formaldehyde-based fixatives and ethanol. Sections of formaldehydeand ethanol-fixed lymph nodes were then labeled with monoclonal antibodies, and four developing methods were compared: indirect immunofluorescence, indirect immunoperoxidase, 3-layer heterologous peroxidase-antiperoxidase (PAP), and a 4-layer PAP technic. The 4-layer PAP proved to be the most sensitive technic since all three antibodies were localized successfully while both indirect technics only detected PHM 1, and the heterologous PAP method was not successful with any monoclonal antibody. The best combination of specific labeling and adequate morphology was seen with periodate-lysine-paraformaldehyde (PLP) fixation and the 4-layer PAP method. (

Three monoclonal antibodies have been made to identify cells of the human mononuclear phagocyte system in fluids and tissues. The first, PHM 1, recognises a surface antigen common to all leucocytes. The other 2 antibodies, PHM 2 and PHM 3, bind to monocytes and macrophages but not to polymorphonuclear cells (PMN). PHM 2 labels all monocytes, macrophages and a small population of T-cells. PHM 3 labels most monocytes and macrophages but no other blood cells. The application of these monoclonal antibodies to the identification of mononuclear phagocytes in blood and liver using an unlabelled antibody immunoperoxidase (PAP) technique is demonstrated.

Nine patients with various forms of glomerulonephritis were treated by repeated plasmapheresis which was combined with immunosuppression, and anticoagulant therapy. Improvement in renal function occurred in the seven patients in whom there had been rapid deterioration in renal function. Two patients with gradually deteriorating renal function failed to respond. Plasmapheresis may exert its beneficial effects both by depletion of circulating immune complexes or autoantibodies, and by depletion of important mediators of injury such as fibrinogen and complement.

Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists.BackgroundEndothelin (ET) may be a mediator of injury following ischemia-induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when administered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed.MethodsWe investigated the use of ETR antagonists, PD 156707 (ETA) and SB 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SB 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SB 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/Mφ), α-smooth muscle actin–positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen.ResultsAll ischemic groups of rats initially developed raised serum creatinine levels; however, no significant difference was observed between the groups (Kruskal–Wallis). Creatinines returned to preischemic values in all groups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/Mφ was significantly reduced in groups treated with ETR antagonists (P< 0.001). The presence of myofibroblasts was also significantly reduced in the antagonist-treated groups (P < 0.001). This was also paralleled by reduced quantities of collagen IV in the treated rat groups (P < 0.001). The interstitial area was also significantly greater in the saline group (P < 0.001). The amount of collagen III did not significantly differ between rat groups. Apoptosis was reduced (P < 0.001) by treatment with ETR antagonists, whereas proliferation was enhanced (P < 0.005). All non-ischemic groups showed no variation in any parameter studied at this time point.ConclusionsTreatment of ischemic ARF in the rat with ETR antagonists PD 156707 and SB 209670 attenuated cellular infiltration and matrix accumulation. An advantage of one antagonist over the other could not be determined in this study. The marked discrepancy between function and pathology (former unchanged, latter markedly improved) may be due to the time frame of this experiment, and longer outcome measures need to be assessed.

During a 10 year study of women with reflux nephropathy 20 women had plasma creatinine concentrations in the range 0.2-0.4 mmol/l (2.3-4.5 mg/100 ml). Six experienced pregnancies exceeding 12 weeks' gestation. Pregnancy was associated with rapid deterioration in function in all six, resulting in end stage renal failure in four women within two years after delivery despite adequate control of blood pressure. Of the 14 women who did not have a prolonged pregnancy, four had periods of uncontrolled hypertension, all of which were related to non-compliance or loss from follow up, or both. Uncontrolled hypertension was also associated with accelerated renal failure, and all four women progressed quickly to end stage renal failure. The remaining 10 women were observed for from five to 10 years; in all 10 renal function deteriorated slowly, and none reached end stage renal failure within seven years. It is concluded that pregnancy in patients with reflux nephropathy and moderately severe renal failure has a deleterious effect on renal function.

Serial renal biopsies for glomerular culture, histochemical staining for beta-glucuronidase, electron microscopy (EM) and light microscopy, were used to study macrophage involvement in experimental chronic immune complex (IC) glomerulonephritis (GN) induced in rabbits by daily intravenous injections of bovine serum albumin (BSA). In the 26 animals studied, proliferative GN of variable severity was induced, with mild disease in 5 animals, moderate proliferation in 15 and crescentic GN in 6. Macrophages first appeared in glomerular culture outgrowths during the 2nd and 3rd weeks, coincident with the onset of proteinuria and rising serum creatinine concentration. Large numbers of macrophages (in excess of 20 per glomerulus) were seen by the 5th weeks and persisted to the 9th week. The number of macrophages in outgrowths was not significantly greater in animals with crescentic disease. EM demonstrated macrophages in capillary loops, and in glomeruli with crescents, macrophages could be seen in the urinary space. Histochemical staining for beta-glucuronidase also demonstrated macrophages in the glomerular tuft and in crescents when present. These results indicate that macrophages constitute a considerable proportion of the glomerular hypercellularity seen in chronic IC glomerulonephritis.

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.

A case of renal infection with Mycobacterium chelonei is described. The infection probably occurred via haematogenous spread from an infected arteriovenous shunt in a uraemic woman. Prolonged treatment with intravenous cefoxitin combined with oral erythromycin and rifampicin eradicated the organism from the urine. Although renal function stabilised for one year, gradual deterioration to end-stage renal failure occurred.

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. Clinical Pharmacology and Therapeutics (1987) 41, 434–438; doi:10.1038/clpt.1987.53

In healthy nonpregnant adults, 30–130 mg of protein is excreted in the urine each day, the upper limit of normal being 150 mg/24 h [1]. This consists of albumin, small proteins such as ceruloplasmin, and various globulins. The filtration of a protein molecule is dictated by a variety of factors. These include the glomerular capillary wall structure and charge, the molecule’s size, charge and configuration, and hemodynamic factors. Most protein in the ultrafiltrate is reabsorbed in the renal tubules. The renal tubules also secrete some proteins, in particular Tamm Horsfall protein. The combined effect of glomerular filtration, tubular reabsorption, and tubular secretion determines the net urinary protein excretion.

SUMMARY— A technique for dissolving a. renal stone complicating an ileal conduit is described. Free ureteric reflux was present, which allowed retrograde irrigation of the stone by infusion of hemiacidrin solution into the ileal conduit. With careful attention to urine infection and the pressure within the system, this technique might be applicable to other patients in whom free ureteric reflux is present and pyelolithotomy, percutaneous nephrostomy or the passage of ureteric catheters is difficult.

Summary 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.

Four patients who presented with severe proliferative glomerulonephritis associated with linear deposition of IgG on the basement membrane have been treated by intermittent massive plasmapheresis. Two patients had all the features of Goodpasture's syndrome. In the other two cases, the characteristic renal lesion was present but there was no pulmonary involvement. In all cases, renal function improved after plasmapheresis while in two, renal function deteriorated after plasmapheresis was stopped. On of these patients responded to a second course of plasmapheresis but failed to respond to a third. This study supports previous reports of the value of plasmapheresis in patients with Goodpasture's syndrome and renal failure in whom recovery without plasmapheresis has not been recorded. The present study emphasizes the importance of continuing treatment for a period of weeks to permit prolonged remission. If treatment is withdrawn too early, rapid deterioration in renal function may result, and unless plasmapheresis is recommenced at once the renal failure may then prove irreversible.

SUMMARY Twenty-two patients with crescentic anti-GBM nephritis or Goodpasture's syndrome with renal impairment were reviewed. All patients were treated with a combination of plasma exchange and immunosuppression. Sixteen patients (73 per cent) showed improvement in renal function (> 30 per cent reduction in serum creatinine level) apparently in response to treatment, and nine patients (41 per cent) made long-term recoveries in renal function. The most important features carrying a bad prognosis were total anuria, and/or a very high percentage of glomeruli showing crescents (> 85 per cent) in the initial renal biopsy. Some patients with other so-called ‘bad’ prognostic features, including severely impaired renal function at presentation, oliguria and the need to institute dialysis had unexpected marked improvement in renal function and/or recovered renal function in the long term provided treatment with plasma exchange was begun promptly and maintained for a sufficient period to allow resolution of the disease process. Renal biopsies at the beginning and later proved to be an extremely valuable guide to the progress and outcome of the disease.

We examined the biopsy specimens of 62 patients with diabetic nephropathy to establish whether the myofibroblast (MF) has a role in progressive interstitial fibrosis and to ascertain whether a relationship existed between MF activity and severity of arteriolosclerosis. MF were identified by morphology and alpha smooth muscle actin (alpha SMA) immunostaining. Analysis of vascular injury was performed by counting the number of interstitial arterioles after staining endothelial cells with von Willebrand factor (VWF) antibody. Arteriosclerosis was quantified by using a computer-aided image analyzer to measure the arteriolar wall surface and total arteriolar surface area, and the ratio of wall to total surface area was expressed as the index of arteriosclerosis (IA). Fractional area of interstitium (IFA), alpha SMA, and collagen III (Coll III) were quantitated by point counting. Results were related to structural and functional parameters using rank correlation coefficients. There was a strong correlation between IFA and Coll III staining (r = 0.83; P0.001). The alpha SMA staining correlated with IFA (r = 0.56; P0.001) and Coll III (r = 0.47; P0.001), and there were significant correlations between alpha SMA and total urinary protein (r = 0.47; P0.001), renal function (plasma creatinine) at time of biopsy (r = 0.51; P0.001), and the percent change in plasma creatinine after 4 years (delta Cr) (r = 0.37; P = 0.01). The IA correlated significantly with Coll III (r = 0.29; P = 0.02), glomerular filtration rate (GFR) (r = 0.39; P = 0.008), and creatinine (r = 0.33; P = 0.01), but no correlation was observed between alpha SMA and IA (r = 0.16; P = 0.23) or IA and delta Cr (r = -0.04; P = 0.6). Strong correlations could be shown between arteriolar density, IFA (r = 0.75; P0.001), alpha SMA (r = -0.36; P = 0.034), and Coll III (r = -0.66; P0.0001). The MF appears to have a significant role in the progression of diabetic nephropathy. Ischemia secondary to arteriosclerosis may contribute to interstitial fibrosis through fibroblast modulation into MF.