Proteinuria in membranous lupus nephritis: the pathology is in the podocyte.

BACKGROUND: Patients with membranous lupus glomerulonephritis (MLN) can present with a broad range of urine protein excretion. The glomerular lesion underlying this functional abnormality has been presumed to be immune complexes which aggregate in the subepithelial area. However, the amount of proteinuria often fails to correlate with the quantity of immune deposits demonstrable on fluorescent and electron microscopy. The purpose of this study is to determine the correlation of alterations of the morphologic components of the glomerular capillary wall with the amount of proteinuria in MLN. DESIGN: We conducted a retrospective clinicopathologic study of patients with lupus nephritis (n=236). In those with pure MLN and proteinuria (n=20), the degree of immune aggregates in the capillary walls and mesangium was detailed using fluorescent and electron microscopy. The degree of foot process effacement (FPE) was detailed using electron microscopy. RESULT: Eleven patients had nephrotic range proteinuria (≥ 3 g proteinuria/g creatinine (g/g)) and nine demonstrated subnephrotic range proteinuria (<3 g/g) (nephrotic, 8.3 ± 5.1 g/g vs. subnephrotic, 1.63 ± 0.83 g/g, p=0.001). All patients demonstrated peripheral capillary wall granular deposits by immunofluorescence microscopy, and the degree of moderate (2+) to severe (3+) deposition was not different (nephrotic, 8/11, 73% vs. subnephrotic, 5/9, 55%, p=0.64). By electron microscopy, FPE (88.6 ± 11% vs. 48.3 ± 36.1%, p=0.002) and foot process width (1798 ± 736 nm vs. 1000 ± 333 nm, p=0.008) was greater in the nephrotic group compared with subnephrotic. There were no other histopathologic differences between the groups. CONCLUSIONS: In patients with MLN, a distinguishing morphologic feature of those with nephrotic range proteinuria is diffuse visceral epithelial cell FPE. We conclude that nephrotic range proteinuria in patients with MLN may be a manifestation of concomitant glomerular visceral epithelial cell dysfunction.

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis.

AIMS/HYPOTHESIS: The content of heparan sulphate is reduced in the endothelium under hyperglycaemic conditions and may contribute to the pathogenesis of atherosclerosis. Heparanase-1 (HPR1) specifically degrades heparan sulphate proteoglycans. We therefore sought to determine whether: (1) heparan sulphate reduction in endothelial cells is due to increased HPR1 production through increased reactive oxygen species (ROS) production; and (2) HPR1 production is increased in vivo in endothelial cells under hyperglycaemic and/or atherosclerotic conditions. METHODS: HPR1 mRNA and protein levels in endothelial cells were analysed by RT-PCR and Western blot or HPR1 enzymatic activity assay, respectively. Cell surface heparan sulphate levels were analysed by FACS. HPR1 in the artery from control rats and a rat model of diabetes, and from patients under hyperglycaemic and/or atherosclerotic conditions was immunohistochemically examined. RESULTS: High-glucose-induced HPR1 production and heparan sulphate degradation in three human endothelial cell lines, both of which were blocked by ROS scavengers, glutathione and N-acetylcysteine. Exogenous H(2)O(2) induced HPR1 production, subsequently leading to decreased cell surface heparan sulphate levels. HPR1 content was significantly increased in endothelial cells in the arterial walls of a rat model of diabetes. Clinical studies revealed that HPR1 production was increased in endothelial cells under hyperglycaemic conditions, and in endothelial cells and macrophages in atherosclerotic lesions. CONCLUSIONS/INTERPRETATION: Hyperglycaemia induces HPR1 production and heparan sulphate degradation in endothelial cells through ROS. HPR1 production is increased in endothelial cells from a rat model of diabetes, and in macrophages in the atherosclerotic lesions of diabetic and non-diabetic patients. Increased HPR1 production may contribute to the pathogenesis and progression of atherosclerosis.

The prognosis of severe lupus nephritis based on the Modification of Diet in Renal Disease (MDRD) study estimated glomerular filtration rate.

The level of renal function at biopsy is predictive of outcome in patients with severe lupus nephritis (SLN). While renal function has been based on serum creatinine (SCr) alone, measuring the estimated glomerular filtration rate (eGFR) utilizing the Modification of Diet in Renal Disease (MDRD) Study equation has been found to be more accurate. The MDRD eGFR (ml/min/1.73 m(2)) at biopsy was calculated in 86 patients with SLN and patients were categorized based on eGFR: ≥60 (33 pts), 59-30 (33 pts) and <30 (20 pts). An eGFR was <60 in 18% of patients with a normal SCr. After 120 ± 65 months of follow-up, attainment of a complete remission (76% versus 30% versus 10%, p < 0.0001) and patient survival without end-stage renal disease (ESRD; 10 year survival: 85% versus 45% versus 14%, p < 0.0001 overall) was highest in patients with an eGFR ≥60 and lowest in those with an eGFR <30. The long-term prognosis for patients with severe lupus nephritis and an eGFR ≥60 was extremely good. Since the prognosis for patients with an eGFR <60 was poor even in those patients with a normal SCr, renal function is more accurately determined by the MDRD eGFR.

Gamma G globulin subgroup composition of the glomerular deposits in human renal diseases.

36 renal biopsies from patients with nephritis were studied for glomerular localization of the heavy chain subgroups of immunoglobulin G (IgG or gammaG). The deposition pattern of these subgroups was selective and did not reflect the normal serum concentration of these proteins. gammaG2, which comprises 18% of normal serum gammaG, was the predominant or unique subgroup deposited in five cases of lupus nephritis and four biopsies with other forms of nephritis associated with granular gammaG deposits. gammaG3, which normally makes up only 8% of the serum gammaG, was the dominant subgroup seen in one biopsy of lobular glomerulonephritis. Patients with linear gammaG deposits generally had a selective absence of gammaG3 and often had large amounts of gammaG4 (normally 3% of the serum gammaG) deposited. The deposition of complement components C1q, C4, and C3 was variable. One biopsy had only gammaG2 and no complement components in the deposits and had no neutrophile leukocyte infiltration. This latter observation correlates well with the poor ability of gammaG2 to fix complement in vitro. Similarly, deposits containing large amounts of gammaG4, which does not fix complement, also tended to have less inflammatory infiltrate than deposits devoid of this subgroup. The selective deposition of monotypic or restricted gammaG subgroups on the glomerulus supports the likelihood that the gammaG represents antibody. The nature of the subgroup involved in the deposit may represent one variable in the determination of the inflammatory and morphological picture that evolves in human glomerulonephritis.

Regulated expression of the tyrosine hydroxylase gene by epidermal growth factor.

The addition of epidermal growth factor (EGF) to cultures of the rat PCG2 pheochromocytoma cell line increased the level of RNA coding for tyrosine hydroxylase (TH). A region of DNA containing 5'-flanking sequences of the TH gene was fused to a heterologous gene and transfected into a rat anterior pituitary cell line, GH4. The TH gene sequences from +27 to -272 contained information sufficient for the induction of TH by EGF. Two regions within this TH DNA were extensively homologous to the EGF regulatory element of the rat prolactin gene.

Interaction of polycations with cell-surface negative charges of epithelial cells.

The interaction between various polycations and cultured glomerular epithelial cells was studied by cell electrophoresis. It was shown that the glomerular epithelial cell presents a negatively charged surface which imparts a zeta potential of -29.0 +/- 1.5 mV at the peripheral layer of the plasma membrane. The pH at which the GEC charge became 50% reduced (pKa) was determined to be 3.0. A variety of polycations of various sizes and fixed and flexible geometries were tested for their capacity to neutralize the cell charge. All the polycations except cytochrome c and lysozyme were capable of completely neutralizing the cell. Cytochrome c could maximally neutralize only 50% of charge and lysozyme only 72% of charge. However, reduced and 'relaxed' molecules of cytochrome c and lysozyme efficiently neutralized the cell surface, as did larger sized 'flexible' polylysines. On the basis of these findings, we conclude that all polycations are not equal in their capacity to neutralize the cell surface. Flexible molecules in contrast to molecules with rigid structures were more effective in neutralizing the cell. This may likely be due to the exposure and availability of more cationic groups in a flexible molecule which results in stabilization of interaction with cells.

Laryngeal complications in a patient with inactive systemic lupus erythematosus.

Laryngeal complications in systemic lupus erythematosus (SLE) are rarely described. They range from hoarseness to life-threatening respiratory distress. To our knowledge, previous reports describe laryngeal involvement with SLE occurring only during periods of active disease. We saw a patient with inactive SLE in whom hoarseness and exertional dyspnea developed as a result of arytenoiditis and vocal cord paresis during steroid tapering. The condition responded dramatically to readjustment of her steroid dosage. Involvement of the larynx with SLE is a potentially life-threatening complication and may occur in patients with either active or inactive disease. It is an indication for close observation and steroid therapy in patients with SLE.

Review of the overall experience of captopril in hypertension.

The pharmacologic profile of the angiotensin-converting enzyme inhibitor, captopril, is described. After reviewing the total clinical experience of captopril from the world literature and manufacturer's files, a small subgroup of clinically complex patients at particular risk of side effects and in whom the drug must be used with caution is characterized. Evidence is available that demonstrates that lower doses (150 mg/day or less, with modest doses of diluretic agents) are effective in both short- and long-term therapy, while the incidence of side effects is substantially reduced. With this background information, the benefit-risk ratio is substantially improved and the use of captopril as a primary agent in the management of hypertension may be considered.

An economic analysis of captopril in the treatment of diabetic nephropathy. The Collaborative Study Group.

OBJECTIVE: The results of a recent clinical trial. The Effect of ACE inhibition on Diabetic Nephropathy, demonstrated that captopril reduced the rate of renal failure, end-stage renal disease (ESRD), and death in patients with IDDM and nephropathy. The purpose of this study was to determine the cost-benefit and cost-effectiveness of captopril as a therapy in patients with IDDM as well as the potential savings for all patients with diabetes and nephropathy. RESEARCH DESIGN AND METHODS: We used the results from a randomized, placebo-controlled trial comparing captopril (207 patients) with placebo (202 patients), whose purpose was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy to develop a model of medical treatment for patients before progression to ESRD. To model the course of illness after progression to ESRD and to extend the model to patients with NIDDM, we used data from the U.S. Renal Data System and published literature. Medical resource cost data were based predominantly upon Medicare reimbursement levels, published wholesale drug prices, and surveying health care providers. The economic model uses a payer perspective to estimate direct cost. The cost to society (indirect cost) associated with lost patient productivity due to ESRD was also estimated. Using this information, we predicted the costs incurred annually and over a lifetime if patients with IDDM and NIDDM and overt nephropathy were treated with either placebo or captopril. We also constructed a model of the overall prevalence of diabetic nephropathy to estimate the aggregate savings in total U.S. health care expenditures. RESULTS: Treatment with captopril resulted in an absolute direct cost savings or benefit of $32,550 per patient with IDDM over the course of a lifetime compared to treatment with placebo. For patients with NIDDM, the direct cost savings totaled $9,900 per patient. Absolute savings were found for indirect costs as well: $84,390 per patient with IDDM and $45,730 per patient with NIDDM. If captopril therapy were initiated in 1995 for patients with either IDDM or NIDDM and nephropathy, the aggregate health care cost savings (i.e. direct cost savings alone) would be $189 million a year for the year 1999 and $475 million a year in 2004, the present value of cumulative health care cost savings for these 10 years would be $2.4 billion. CONCLUSIONS: The use of captopril in diabetic nephropathy will provide significant savings in health care costs; in addition, it will result in savings in indirect cost, which reflects the broader societal benefit.

The prognosis of focal segmental glomerular sclerosis of adulthood.

We describe 46 adults with idiopathic focal segmental glomerular sclerosis (FSGS). The mean age was 36.9 years (range, 15 to 80 years). Males represented 61%, and 65.2% were white. Hypertension was a presenting feature in 63% and 32.6% had microscopic hematuria. Twenty-nine patients had nephrotic proteinuria (greater than or equal to 3.0 g/24 h) at presentation, and 13 had renal insufficiency (serum creatinine concentration greater than 1.5 mg/dl). A mean follow-up of 59.8 months (range, 3 to 255 months) was obtained. In addition to segmental sclerosis, glomerular hyalinosis was observed in 65.3% of biopsies, and this was similar irrespective of the severity of proteinuria. Sixteen of the 29 patients with nephrotic proteinuria received prednisone therapy (60 mg/day) for at least 1 month. Three received cytotoxic agents in addition. A response to therapy was observed in 50%, 5 achieving a complete remission and 3 a partial remission. No patient with non-nephrotic proteinuria received prednisone therapy. The clinical course of each patient was evaluated based on the slope calculated by the linear regression method using the inverse of serum creatinine from the time of presentation to follow-up. Patients with non-nephrotic proteinuria had a better prognosis than nephrotics (P less than .05). Nephrotic patients responding to therapy had a better course than non-responders or patients not treated (P less than 0.01). At the time of last follow-up, 8 patients had progressed to end-stage renal disease, 6 of whom had presented with nephrotic proteinuria. No patient responding to therapy had progressed to end-stage renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus.

Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) or proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc). A significant negative correlation was found between the presence of this C1q-binding material and subepithelial electron-dense deposits, suggesting that the presence of this material contributed to the absence of subepithelial immune deposits. Large-molecular-weight C1qSP-binding material was also present, mainly in sera from patients with proliferative lesions. Furthermore, highly positive correlations were found between immune deposits in interstitial blood vessels and peritubular areas, and the concentrations of C1qSP-binding IgG and rapidly sedimenting IgG in density gradient analysis. Overall, these findings are consistent with the hypotheses that circulating immune complexes contribute to the pathogenesis of glomerulonephritis and interstitial nephritis in patients with SLE, and that 6.6S C1q-binding IgG plays a role in the proliferative lesions of lupus glomerulonephritis.

Immunotactoid glomerulopathy.

We present 11 patients with immunotactoid glomerulopathy, a new syndrome characterized clinically by proteinuria (11/11), microscopic hematuria (9/11) and hypertension (9/11). The patients consisted of six females and five males, aged 25 to 59 years (mean, 44.6). Proteinuria was the presenting feature and the reason for renal biopsy in all patients. The diagnosis of immunotactoid glomerulopathy was established at renal biopsy by the presence of glomerular extracellular microtubules composed of immune reactants. All the biopsies studied by immunofluorescence (10 cases) had glomerular deposits of IgG and C3. In three biopsies studied with IgG subclass specific antisera, only one patient had monoclonal immunoglobulin deposits (IgG3 kappa). In six cases the glomerular deposits were analyzed for light chains. In three the deposits contained kappa only, and three consisted of both kappa and lambda. In two cases the immune aggregates were confined to the mesangium, and in the remaining eight cases, the deposits were present in the mesangium and the glomerular basement membranes. Electron-dense deposits composed of microtubules were present in the same distribution within the glomerulus as the immune reactants. The microtubules had a uniform diameter in each biopsy, but they varied in size from case to case. They were approximately the same size in eight cases (mean, 22.3 +/- 3 [SD] nm). Three cases had much larger microtubules: 34.2 nm, 35.4 nm, and 48.9 nm in diameter. Although the 22.3-nm microtubules resembled amyloid in their appearance, glomerular distribution and random orientation in the tissue, they were more than twice the diameter of amyloid (8.9 nm), and Congo red and thioflavin T stains for amyloid were negative. Similar microtubular structures have been described in patients with cryoglobulinemia, SLE and paraproteinemia, but these diseases were excluded in our patients on clinical, serologic and in some cases histologic grounds. More important, none of our patients had clinical or histochemical evidence of amyloidosis, an entity which may be confused with immunotactoid glomerulopathy on a morphologic basis. Follow-up, from 22 to 94 months (mean, 52.6) was obtained in all 11 patients, and 2 clinical courses were noted. Six patients had progressive deterioration of renal function, with five requiring dialysis. This group had severe hypertension (4/6) and nephrotic-range proteinuria (5/6) at some point in their course. The remaining five patients with stable renal function had proteinuria of less than 2.0 g/24 hr in most cases (4/5), and none had severe hypertension. This dichotomy correlated with the distribution of immunotactoids.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulmonary hemorrhage in systemic lupus erythematosus.

The clinicopathological features of four patients with systemic lupus erythematosus and pulmonary hemorrhage are described. Our study confirms that pulmonary hemorrhage may be a dominant clinical expression of lung involvement in this disease. Its clinical manifestations are usually quite characteristic. However, hemoptysis may be absent. Radiographically, bilateral alveolar infiltrates resembling pulmonary edema or infection may be seen. Pulmonary hemorrhage was a major contributing factor to the death of three of our patients. The possible pathogenetic mechanisms responsible for pulmonary hemorrhage in our patients and other patients previously recorded in the literature are reviewed. Evidence supporting an immune complex pathogenesis is presented. Our immunopathological and ultrastructural studies demonstrate deposition of immune aggregates in the lungs in the alveolar septa, large blood vessels, and bronchioles in a manner similar to that which has been observed in the experimental serum sickness model of immune complex mediated pulmonary injury. The histological abnormalities, although nonspecific, are consistent with this interpretation, and collectively show diffuse alveolar lining cell and endothelial cell injury. However, an immune complex pathogenesis may not completely explain the occurrence of pulmonary hemorrhage in SLE. Other factors, including bleeding disorders, pulmonary infection, oxygen toxicity, and the "shock lung" syndrome, may also have contributed to lung hemorrhage in some of these patients.

Persistence of clinical and serologic activity in patients with systemic lupus erythematosus undergoing peritoneal dialysis.

To determine whether patients with systemic lupus erythematosus undergoing long-term peritoneal dialysis have persistent clinical and serologic remissions, the clinical courses of eight patients with end-stage renal disease in whom peritoneal dialysis was begun at Rush-Presbyterian-St. Luke's Medical Center between 1981 and 1986 were analyzed. Patients were followed for a mean of 90.1 +/- 28.8 months before dialysis and 20.8 +/- 4.7 months after the initiation of dialysis. Disease activity was quantified for each individual in terms of "flares" per year before and after the initiation of peritoneal dialysis, the means of which were 0.66 +/- 0.46 and 0.94 +/- 0.28, respectively. Comparison of these rates showed no statistical difference. Seven of the eight patients had at least one flare while receiving peritoneal dialysis, all of which required prednisone therapy (mean 31.3 mg per day). The clinical manifestations included fever, rash, myalgias, anemia, leukopenia, serositis, and cerebritis. Eighty-eight percent of these flares had associated worsening of serologic results. Prednisone was discontinued in only one patient at any time during peritoneal dialysis. This experience reveals that patients with lupus continue to show clinical and serologic disease activity and require maintenance prednisone therapy while receiving long-term peritoneal dialysis.

Immune complex deposition and coronary vasculitis in systemic lupus erythematosus. Report of two cases.

Extramural coronary arteries were examined in two patients with systemic lupus erythematosus (SLE). Coronary vasculitis was found in both patients. One patient with clinically and serologically inactive SLE had died suddenly and was found to have a myocardial infarction secondary to the coronary vasculitis. Immunopathologic studies demonstrated immune reactants in the walls of inflamed and noninflamed arterial segments in a pattern consistent with immune complex aggregates. Immunologic injury secondary to immune complex deposition may be responsible for the development of coronary disease in patients with SLE. This has been demonstrated in experimental animals but not in humans. Although this is an uncommon complication of SLE, it represents a cause of sudden death and a potentially treatable lesion in this patient population. Its occurrence may be related to the deposition of immune aggregates in the walls of coronary vessels.

Immunopathology of cardiac lesions in fatal systemic lupus erythematosus.

Immunopathologic studies were performed on cardiac tissue obtained at autopsy in 10 patients with severe systemic lupus erythematosus (SLE). The immunopathologic findings were correlated with histopathologic and clinical evidence of cardiac injury, and with clinical and serologic features of SLE. Immune reactants were demonstrated by direct immunofluorescence in nine patients in a granular deposition pattern suggesting immune complex aggregates. Histologic and gross anatomic findings of inflammation were generally more focal than was the distribution of immune reactants. Most of the immune deposits were present in the walls of the blood vessels of myocardium (eight of 10) or pericardium (two of three). In one patient with Libman-Sacks endocarditis, immunoglobulin and complement components were present in the valve stroma and the vegetations. The immune deposits around epicardial nerve fibers in two patients with severe neurologic manifestations contained immunoglobulin E(IgE). In general, the most intense and widespread immune deposits were observed in patients with persistently increased serologic and clinical evidence of activity of their systemic disease. These results suggest a role for immune complex deposition in the pathogenesis of the cardiac lesions of SLE.

Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo.

1. Ro 32-3555 (3(R)-(cyclopentylmethyl)-2(R)-[(3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl)methyl]-4-oxo-4-piperidinobutyrohydroxamic acid) is a potent, competitive inhibitor of human collagenases 1, 2 and 3 (Ki values of 3.0, 4.4 and 3.4 nM, respectively). The compound is a selective inhibitor of collagenases over the related human matrix metalloproteinases stromelysin 1, and gelatinases A and B (Ki values of 527, 154 and 59 nM, respectively). 2. Ro 32-3555 inhibited interleukin-1 alpha (IL-1 alpha)-induced cartilage collagen degradation in vitro in bovine nasal cartilage explants (IC50 = 60 nM). 3. Ro 32-3555 was well absorbed in rats when administered orally. Systemic exposure was dose related, with an oral bioavailability of 26% at a dose of 25 mg kg-1. 4. Ro 32-3555 prevented granuloma-induced degradation of bovine nasal cartilage cylinders implanted subcutaneously into rats (ED50 = 10 mg kg-1, twice daily, p.o.). 5. Ro 32-3555 dosed once daily for 14 days at 50 mg kg-1, p.o., inhibited degradation of articular cartilage in a rat monoarthritis model induced by an intra-articular injection of Propionibacterium acnes. 6. Ro 32-3555 is a potential therapy for the treatment of the chronic destruction of articulating cartilage in both rheumatoid and osteoarthritis.

A clinical trial in type 2 diabetic nephropathy.

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.