SllmnlaryImmunopathological evidence suggests that activation of the alternative pathway of complement (AP) is involved in membranoproliferative glomerulonephritis (MPGN) and in immunoglobulin A nephropathy. In this report we describe an AP dysfunction-associated factor that was isolated from the serum and urine of a patient with hypocomplementemic MPGN. Extensive glomerular deposits of C3, properdin, and of the terminal complement components were observed in the kidney of the patient. In her serum the AP hemolytic activity was virtually absent. When mixed with fresh normal serum, the patient's serum induced a 96% C3 conversion during a 30-min incubation at +37~ This activity was found to be due to a circulating factor that by immunochemical characterization proved to be a 46-kD monoclonal immunoglobulin X light (L) chain dimer (~L)-Purified ~,r, but not control ~, or Ic L chains from patients with L chain disease, activated the AP in a dose-and ionic strength-dependent manner. Functionally, XL was differentiated from C3 nephritic factor (an autoantibody against the AP C3 convertase, C3bBb) by its inability to bind to and stabilize the C3bBb enzyme. Instead, Jkr was observed to interact directly with the AP control factor H. Thus, hL represents a novel type of immunoglobulinrelated AP-activating factor with the capacity to initiate alternative complement pathway activation in the fluid phase.

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The median urinary TGF-beta 1 excretion (pg/mg creatinine) was significantly higher (1730; range 60-16,970) in MGN patients than in the healthy controls (300; 30-1330; P < 0.0001). In renal allograft recipients the excretion was 840 (250-3440; P < 0.0001 vs healthy controls), in IgA GN it was 1130 (30-4910; P = 0.039), and in proteinuric patients it was 39 (29-165; P = NS). In MGN but not in the proteinuric controls or renal allograft recipients, urinary TGF-beta 1 correlated with urinary albumin excretion (r = 0.86, P < 0.0001) but no correlation with renal function or the duration of the disease was found. Urinary TGF-beta 1 at renal biopsy correlated with interstitial cellular inflammation and its excretion 1 year before the biopsy correlated with indices of sclerosis/fibrosis. Immunosuppressive therapy significantly decreased urinary TGF-beta 1 from 2800 (1610-16,960) to 840 (170-1600) pg/mg creatinine (P = 0.028). Patients with persistent nephrotic syndrome and/or declining renal function had a higher initial TGF-beta 1 excretion (median 3680; 1830-7420 pg/mg creatinine) than those entering partial or complete remission (1060; 60-1960; P = 0.003) within 12 months from sampling.

These findings show that the urinary PIIINP-to-creatinine ratio reflects the ongoing fibrotic processes in the kidney. Tubular epithelial cell injury may initiate the fibrotic processes, and elevated concentrations of urinary TGF-beta 1 and alpha(1)M may associate with the increased production and deposition of collagen type III in the graft. We conclude that measurements of urinary excretion of PIIINP can be used as an early noninvasive indicator of renal fibrosis after kidney transplantation.

We show proximal tubular injury, measured by increased urinary alpha1M, to be present even in normoalbuminuric patients and to be associated with increased excretion of TGF-beta1 and with the annual deterioration of glomerular filtration rate. These findings show increased alpha1M/creatinine ratio to be an early and sensitive indicator of poor long-term outcome in renal-transplant patients.

The objective of this study was to analyze factors that are involved in the progression of renal allograft damage in the first 6 mo after transplantation. Donor and 6-mo protocol biopsies of 83 patients who received a renal transplant were classified using the Chronic Allograft Damage Index (CADI). Histologic changes were compared and correlated to clinical parameters at transplantation, at 6 mo, and annually over 2 yr. All CADI components increased significantly in the 6-mo posttransplantation period, except chronic vascular changes and the percentage of glomerulosclerosis. Total cholesterol and LDL-cholesterol at the time of biopsy correlated positively with mesangial matrix increase, and HDL cholesterol correlated negatively with vascular intima increase. High BP at biopsy was associated with tubular atrophy. Diastolic BP at biopsy correlated with 6-mo CADI (CADI-6). Patients with diastolic BP >85 mmHg at biopsy had a higher difference between CADI score in protocol biopsies and CADI score in donor biopsies (⌬CADI) and higher creatinine at 1 and 2 yr. CADI in donor biopsies (CADI-0) >1 was more frequently found in older (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01 to 1.14) and nontraumatic dead donors (OR, 3.89; 95% CI, 1.13 to 13.33). CADI-6 >3 was more frequently found in those with CADI-0 >1 (OR, 3.82; 95% CI, 1.19 to 12.21), older donors (OR, 1.05; 95% CI, 1.01 to 1.10), and number of AB mismatches (OR, 2.36; 95% CI, 1.09 to 5.10). CADI-0, CADI-6, and ⌬CADI correlated significantly with serum creatinine at hospital discharge, at 6 mo, and at 2 yr. ⌬CADI was affected by initial percentage of glomerulosclerosis (OR, 1.10; 95% CI, 1.02 to 1.19) and creatinine at hospital discharge (OR, 1.01; 95% CI, 1.00 to 1.02). Donor-related as well as nonimmunologic factors, such as hypertension and dyslipidemia, are associated with increased risk for renal allograft damage progression.

Prevalence of AA amyloid in rheumatoid arthritis (RA) is still unclear. The objective of this retrospective study was whether dedicated re-examination of autopsy tissues from RA patients increases the detection rate of amyloid compared to routine examination. Amyloid was re-examined in tissue samples and detection rate compared with original reports of 369 consecutively autopsied RA patients and 370 non-RA patients matched for sex, age, and year of autopsy between 1952 and 1991. Re-examination of 90% of the 739 cases showed doubling of the prevalence of amyloid compared with the original reports: from 18 to 30% in RA and from 2 to 4% in non-RA patients. In RA patients, cardiac amyloid was as frequent as renal amyloid. In RA patients with amyloid at re-examination, amyloidosis had been diagnosed before autopsy in 37%, and these patients had more inflammation and longer disease duration than RA patients without amyloid. Only 56% of RA patients with renal amyloid were known to have proteinuria. In conclusion, this autopsy study shows that amyloid in RA is a common finding which remains frequently undetected. In patients with active and long-lasting RA, a systematic search for amyloid may enable early diagnosis of amyloidosis, which will require effective suppression of inflammation.

Persistent CMV infection in kidney allografts was associated with increased vascular changes and increased expression of TGF-beta1, PDGF-AA and ICAM-1.