Prognostic Factors for Survival and Relapse in ANCA-Associated Vasculitis with Renal Involvement: A Clinical Long-Term Follow-Up Study.

AIM: We describe the clinical pattern of ANCA-associated vasculitis (AAV) and assess long-term prognostic factors of patients and renal survival and relapse. METHODS: Data from 85 patients with renal biopsy-proven AAV at a single center with up to 20-year [median 16.2 years (95% CI 14.9-17.7)] follow-up were retrospectively collected. RESULTS: Overall, 55% of the patients had microscopic polyangiitis (MPA) and 45% had granulomatosis with polyangiitis (GPA). The histopathological classes were focal in 35%, crescentic in 26%, mixed in 20%, and sclerotic glomerulonephritis in 19% of the patients. As induction treatment, a combination of cyclophosphamide and corticosteroids was given to 82%, while a combination of azathioprine and corticosteroids was maintenance therapy in 79%. The twenty-year patient survival was 45%. In a multivariable analysis, age ≥58 years [hazard ratio (HR) 7.64, 95% CI 3.44-16.95] and myeloperoxidase (MPO) ANCA (HR 2.12, 95% CI 1.08-4.17) were associated with shorter patient survival time. Renal survival was 68% overall: 88% in focal, 71% in crescentic, 56% in mixed, and 37% in sclerotic class (p=0.01). Female sex (HR 0.26, 95% CI 0.10-0.73) was a predictor of improved renal survival, whereas GFR <30 ml/min and MPO-ANCA were associated with worse renal survival (HR 4.10, 95% CI 1.35-12.49 and HR 3.10, 95% CI 1.21-7.95, respectively). Relapse-free survival at 20 years was 10%. MPA was associated with a lower risk for relapse (HR 0.48, 95% CI 0.28-0.82). CONCLUSION: We confirmed the improved patient and renal survival in AAV patients with glomerulonephritis, while relapse remained the primary challenge. Histopathological classification may be relevant for survival.

Amyloidosis is frequently undetected in patients with rheumatoid arthritis.

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.

Increased urinary excretion of transforming growth factor-beta(1) in renal transplant recipients during cytomegalovirus infection.

AIMS: Cytomegalovirus (CMV) is a suggested risk factor for chronic allograft nephropathy, and transforming growth factor-beta (TGF-beta) is a key fibrogenic molecule in this process. CMV has been shown to induce the expression of TGF-beta and several cytokines. We analyzed the impact of CMV on urinary excretion of TGF-beta, ICAM-1, TNF-alpha and correlated findings with biopsy histology. MATERIAL: Urine samples from 46 renal transplant recipients were available for the study. Urine samples were taken when CMV infection was suspected, or for controlling of proteinuria or bacteriuria. METHOD: CMV was diagnosed by antigenemia and viral cultures. Patients with previous CMV infection were excluded from the analysis. Urine samples were analyzed by ELISA-method to detect the levels of TNF-alpha, ICAM-1 and TGF-beta(1). Banff '97 criteria were used for scoring of protocol biopsies taken 6 months after transplantation. RESULTS: At the time of the urine collection, 13/46 patients had CMV infection. Eight patients with no CMV infection were used as controls. TGF-beta(1) was significantly increased in the CMV group (samples taken mean 137+/-79 days post-transplantation) compared to controls (samples 139+/-64 days post-transplantation) (51.1+/-28.0 vs. 13.3+/-6.7 ng/mmol crea, p<0.001). No differences in the levels of other molecules were recorded. In the biopsies, interstitial fibrosis was significantly increased in the CMV group compared to controls. CONCLUSIONS: Urinary excretion of TGF-beta(1) was increased in patients during CMV infection. This was associated with increased fibrosis in the biopsies.

Persistent cytomegalovirus infection is associated with increased expression of TGF-beta1, PDGF-AA and ICAM-1 and arterial intimal thickening in kidney allografts.

BACKGROUND: Cytomegalovirus (CMV) is a suggested risk factor for the development of chronic allograft nephropathy. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) are important molecules in this process. We analysed the impact of persistent CMV infection in kidney allografts on the expression of growth factors, adhesion molecules and inflammation markers. METHODS: In a population of 172 renal transplant recipients, CMV was diagnosed in 82 patients by pp65 antigenaemia test and viral cultures. Biopsies taken after CMV infection were available from 48 of the 82 patients for the demonstration of CMV antigens by immunohistochemistry and in situ DNA hybridization. Biopsy material for further analyses was available from 16 CMV patients. Five patients with no previous CMV infection were used as controls. Biopsy histology was scored according to Banff 97 classification. RESULTS: In 11 out of 16 patients, persistent CMV antigens and/or DNA were demonstrated in the biopsy >2 months after the last positive finding in blood or urine. Increased expression of TGF-beta1 was recorded in tubuli and in arterial endothelium in biopsies with a positive CMV finding compared with controls. Also, the expression of PDGF-AA was increased in tubuli and somewhat in arterial endothelium in CMV-positive biopsies. The expression of intercellular adhesion molecule-1 (ICAM-1) was increased significantly in peritubular capillary endothelium. Vascular intimal thickening was increased in the biopsies with persistent CMV infection. CONCLUSIONS: Persistent CMV infection in kidney allografts was associated with increased vascular changes and increased expression of TGF-beta1, PDGF-AA and ICAM-1.

Predictors of renal allograft histologic damage progression.

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 > or =85 mmHg at biopsy had a higher difference between CADI score in protocol biopsies and CADI score in donor biopsies (DeltaCADI) 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 DeltaCADI correlated significantly with serum creatinine at hospital discharge, at 6 mo, and at 2 yr. DeltaCADI 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.

Increased urinary excretion of alpha1-microglobulin at 6 months after transplantation is associated with urinary excretion of transforming growth factor-beta1 and indicates poor long-term renal outcome.

BACKGROUND: Albumin and alpha1-microglobulin (alpha1M) are absorbed by two specific receptors in tubular epithelial cells. Any cell injury will disturb the reabsorption of these proteins, The increased urinary excretions of albumin or alpha1M could thus serve as a marker of subclinical graft lesions and as an early indicator of chronic allograft dysfunction. METHODS: We measured 24-hour urinary excretions of albumin, alpha1M, and transforming growth factor (TGF)-beta1 at 6 months after transplantation in 79 renal-graft recipients and recorded the changes in 24-hour creatinine clearance an average 51 (range 14-72) posttransplant follow-up months. RESULTS: At 6 months from transplantation, 46 of 79 (58%) patients were normoalbuminuric, 25 (32%) microalbuminuric, and 8 (10%) macroalbuminuric. In normoalbuminuric patients, urinary alpha1M/creatinine ratio was 10 times, and TGF-beta1/creatinine ratio approximately 5 times, higher than in the healthy subjects but lower than in albuminuric patients. In all patients, urinary alpha1M correlated with urinary TGF-beta1 (r=0.508, P<0.001), with albumin (r=0.220, P<0.05), and with the annual changes in 24-hour creatinine clearance (r=-0.273, P<0.05). During follow-up, renal function deteriorated in 20 of 33 (60%) patients with alpha1M/creatinine ratio greater than 5 mg/mmol, but only in 1 of 46 (2%) patients whose ratio was less than 5 mg/mmol (P<0.01), giving the ratio 5 mg/mmol or greater a 95% sensitivity to detect patients with poor long-term outcome. CONCLUSIONS: 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.

Decreased expression of vascular endothelial growth factor in idiopathic membranous glomerulonephritis: relationships to clinical course.

BACKGROUND: Membranous glomerulonephritis (MGN) has a variable clinical course, and factors that determine the prognosis are unknown. Our previous study suggested that urinary excretion of vascular endothelial growth factor (VEGF) is decreased in active MGN, but normalizes in remission. In the present study, VEGF protein and messenger RNA (mRNA) expression were investigated in this disease. METHODS: Twelve patients with clinically active and/or progressive MGN were studied by using urinary assays for VEGF and soluble VEGF receptor-1 (sVEGF-R1), semiquantitative scoring of serial renal biopsy specimens by using immunohistochemical staining for VEGF protein, and in situ hybridization for VEGF mRNA. Results were compared with healthy controls and normal parts of nephrectomized kidneys. RESULTS: Urinary VEGF excretion was decreased significantly (P < 0.001 versus controls) in MGN, but there was no difference in sVEGF-R1 excretion compared with healthy subjects. VEGF protein expression was diminished significantly in glomerular podocytes (P = 0.008), as well as in extraglomerular small arteries (P = 0.03) and arterioles (P = 0.008) in MGN. Total kidney VEGF score (the sum of scores of individual kidney compartments) also was decreased in MGN (P < 0.05) and remained low in repeated biopsies. Expression of VEGF mRNA localized predominantly to podocytes in normal kidneys was greatly reduced in MGN. CONCLUSION: Clinically active MGN is associated with diminished expression of VEGF protein and mRNA, mainly in podocytes, and expression remains depressed in persistently active and/or progressive disease. This is reflected by decreased urinary VEGF excretion. These findings point to potentially reversible podocyte injury and, together with our previous study, suggest that VEGF may have a protective role during the evolution of MGN.

Lymphomas diagnosed by percutaneous kidney biopsy.

BACKGROUND: Occult renal lymphoma clinically mimicking renal medical disease constitutes a diagnostic challenge to nephrologists, radiologists, and renal pathologists. The clinical and radiological findings, mostly nonspecific or inconclusive, seldom obviate the need for a kidney biopsy. METHODS AND RESULTS: We report 5 new cases of diffuse bilateral renal lymphoma diagnosed by percutaneous kidney biopsy, all presenting with acute renal failure (ARF) of unknown cause. Three cases showed an interstitial and 2 an intraglomerular/intravascular type of lymphomatous infiltration. All tumors were of B-cell lineage. Our cases add to 50 similar cases reported since 1980. Considering all 55 cases together, 39 (87%) of the 44 cases with interstitial and 5 of 11 (45%) of those with intraglomerular lymphoma presented with ARF. In contrast, 5 of 10 cases with intraglomerular but none with interstitial infiltration presented with nephrotic range proteinuria. All but 2 cases (95%) with ARF and interstitial lymphoma but none with ARF and intraglomerular lymphoma showed bilaterally enlarged kidneys. Signs of extrarenal lymphomatous involvement were detected in 24 cases (44%) at the time of kidney biopsy or shortly thereafter. However, in only 10 cases (18%), all with interstitial lymphoma, was a tumor suspected prior to biopsy, mainly based on radiographical evidence of enlarged kidneys. CONCLUSION: Both types of diffuse bilateral renal lymphoma may clinically mimic renal medical disease. ARF in interstitial and in intraglomerular lymphoma may be due to increased intrarenal pressure and intraglomerular obstruction, respectively. Percutaneous kidney biopsy provides the most expedient means of establishing the diagnosis. Differential diagnosis includes interstitial nephritis and proliferative glomerulonephritis.

Lower urinary-interleukin-1 receptor-antagonist excretion in IgA nephropathy than in Henoch-Schönlein nephritis.

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schönlein nephritis (HSN) share many clinical, histological and immunological features. It has been postulated that these two conditions have a common pathogenesis and that HSN might be a systemic form of IgAN. Activity of interleukin-1beta (IL-1beta) in urine has been found to be higher in IgAN and HSN patients than in healthy controls. Interaction between IL-1beta and interleukin-1 receptor antagonist (IL-1ra) plays a significant role in the regulation of inflammatory responses. We studied levels of urinary excretion of IL-1beta and IL-1ra in patients with IgAN and HSN. METHODS: Amounts of IL-1beta and IL-1ra excreted in 24-h urine samples collected from 241 IgAN, 26 HSN patients and from 33 healthy controls were determined. Results were expressed as cytokine/creatinine (ng/mmol) ratios. RESULTS: Urinary IL-1beta excretion by the IgAN and HSN patients was no greater than urinary IL-1beta excretion by healthy controls. Urinary IL-1ra excretion by the IgAN patients was lower than urinary IL-1ra excretion by healthy controls (P < 0.05) and by the HSN patients (P < 0.01). In both patients and controls women had significantly higher IL-1ra, IL-1beta excretion levels and IL-1ra/IL-1beta ratios. The differences in urinary excretions of IL-1ra by the healthy controls and by the IgAN and HSN patients were significant in both sexes. Excretion of IL-1beta or IL-1ra did not correlate with excretion of urinary protein, duration of the disease or any histopathological variable. However, histopathological changes in renal biopsy specimens from patients with IL-1ra/IL-1beta ratios above normal were significantly milder than in renal biopsy specimens from patients with low or normal IL-1ra/IL-1beta ratios. CONCLUSION: Urinary IL-1ra levels in IgAN patients were lower than urinary IL-1ra levels in healthy controls or HSN patients, a finding which may indicate that the two diseases have a different pathogenesis. Whether the male predominance in IgAN and HSN and the worse outcomes in males that have been reported previously in IgAN and HSN are connected with the lower excretion of IL-1ra and consequently lower IL-1ra/IL-1beta ratios in male patients than in female patients needs more thorough investigation.

Urinary amino-terminal propeptide of type III procollagen (PIIINP) as a marker of interstitial fibrosis in renal transplant recipients.

BACKGROUND: Interstitial fibrosis in the protocol biopsy specimens of transplanted kidneys is regarded as the most reliable predictor of future impaired renal function. Type I and III collagens are the main components of renal fibrosis. During the synthesis and deposition of type III collagen, an amino-terminal propeptide (PIIINP) of a molecular weight of 44 kDa is degraded from the collagen and secreted into surroundings. Increased circulating PIIINP has been shown to reflect ongoing fibrotic processes. METHODS: The extent of interstitial fibrosis in 6-month protocol biopsy specimens was recorded, and the urinary excretion of PIIINP in 24-hr urine specimens was measured in 79 graft patients. We also measured the urinary excretion of transforming growth factor (TGF)-beta 1, alpha(1)-microglobulin (alpha(1)M), and albumin and recorded the changes in creatinine clearance during 0.5 to 6 (mean, 4.3) posttransplant follow-up years. RESULTS: The urinary excretion of PIIINP was significantly lower in patients with no interstitial fibrosis compared with patients with mild or moderate interstitial fibrosis (P<0.01). The urinary PIIINP-to-creatinine ratio correlated closely with the extent of interstitial fibrosis (r=0.410, P<0.001), with TGF-beta 1-to-creatinine (r=0.585, P<0.001) and alpha(1)M-to-creatinine (r=0.438, P<0.001) but not with the albumin-to-creatinine ratio. There was a close correlation between urinary TGF-beta 1 and alpha(1)M (r=0.508, P<0.001), whereas no correlation was found between urinary and serum PIIINP or between urinary PIIINP-to-creatinine ratio and glomerular filtration rate (GFR). During the follow-up, the GFR decreased in 42% of patients with a PIIINP-to-creatinine ratio over 100 ng/mmol, but only in 8% of patients with a ratio less than 100 ng/mmol (P<0.01). CONCLUSIONS: 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.

The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients.

BACKGROUND: The role of cytomegalovirus (CMV) in chronic kidney allograft rejection remains controversial. The purpose of this study was to examine the impact of CMV infection on histopathologic changes in 6-month protocol biopsy specimens of kidney allografts. METHODS: Altogether, 52 renal allograft recipients were studied. CMV infection was diagnosed by CMV antigenemia test, viral cultures from blood and urine, or both. CMV was demonstrated in the biopsy specimens by antigen detection and hybridization in situ. Acute rejections were diagnosed by biopsy histology, and biopsy specimens were graded according to the Banff '97 classification. RESULTS: CMV infection was diagnosed in 41 patients. The 11 patients in whom CMV infection was not detected were used as controls. Acute rejection was diagnosed in 22 of 41 CMV patients and in 6 of 11 control patients. CMV was demonstrated in the biopsy specimens of 19 of 41 CMV patients. CMV was not associated with increased glomerular, tubular, or interstitial changes. However, the arteriosclerotic changes in small arterioles were significantly increased in the subgroup of patients where CMV was demonstrated in the graft as compared with controls (P<0.01). Analysis of the impact of acute rejection on arteriolar thickening showed that only a positive history of both acute rejection and CMV found in the graft was associated with significantly increased vascular changes compared with CMV-free recipients (P<0.05). CONCLUSIONS: Neither CMV nor acute rejection alone was associated with increased vascular or other histopathologic changes in 6-month protocol biopsy specimens of kidney allografts, but a previous history of both acute rejection and the presence of CMV in the graft was associated with increased vascular changes.