High risk of ischemic heart disease in patients with lupus nephritis.

OBJECTIVE: To investigate the occurrence of ischemic heart disease (IHD) in a cohort of 104 Danish patients with biopsy-proven lupus nephritis (LN). METHODS: Information on all hospitalizations in Denmark for IHD between 1977 and 2006 was obtained from the Danish National Hospital Register. Occurrence of IHD after date of first renal biopsy in the LN cohort was compared to the occurrence of IHD in the general population by calculation of standardized ratios of observed to expected events (O:E ratios) for different manifestations of IHD registered during inpatient and outpatient hospital visits. RESULTS: The median duration of followup was 14.7 (range 0.1-30.0) years. Thirty-one first-time hospitalizations for IHD occurred in the cohort, yielding an overall O:E ratio for IHD of 6.8 (95% CI 4.6-9.7). Increased risks were found for angina pectoris (O:E ratio 6.0, 95% CI 3.0-11), myocardial infarction (O:E ratio 7.9, 95% CI 3.8-15), and other IHD-related diagnoses combined (O:E ratio 6.9, 95% CI 3.3-13). A high IHD risk was observed for patients aged < 31 years at time of first renal biopsy (O:E ratio 17.1, 95% CI 9.1-29) and for patients aged 30-39 years during followup (O:E ratio 42.3, 95% CI 21-76). Patients undergoing chronic renal replacement therapy also had a pronounced risk of IHD (O:E ratio 19.4, 95% CI 7.8-40). CONCLUSION: LN is associated with markedly increased morbidity from IHD. Our findings indicate that patients with early-onset LN have a disturbingly high risk of IHD compared to the general population.

Virtual microscopy: an evaluation of its validity and diagnostic performance in routine histologic diagnosis of skin tumors.

Digitization of histologic slides is associated with many advantages, and its use in routine diagnosis holds great promise. Nevertheless, few articles evaluate virtual microscopy in routine settings. This study is an evaluation of the validity and diagnostic performance of virtual microscopy in routine histologic diagnosis of skin tumors. Our aim is to investigate whether conventional microscopy of skin tumors can be replaced by virtual microscopy. Ninety-six skin tumors and skin-tumor-like changes were consecutively gathered over a 1-week period. Specimens were routinely processed, and digital slides were captured on Mirax Scan (Carl Zeiss MicroImaging, Göttingen, Germany). Four pathologists evaluated the 96 virtual slides and the associated 96 conventional slides twice with intermediate time intervals of at least 3 weeks. Virtual slides that caused difficulties were reevaluated to identify possible reasons for this. The accuracy was 89.2% for virtual microscopy and 92.7% for conventional microscopy. All κ coefficients expressed very good intra- and interobserver agreement. The sensitivities were 85.7% (78.0%-91.0%) and 92.0% (85.5%-95.7%) for virtual and conventional microscopy, respectively. The difference between the sensitivities was 6.3% (0.8%-12.6%). The subsequent reevaluation showed that virtual slides were as useful as conventional slides when rendering a diagnosis. Differences seen are presumed to be due to the pathologists' lack of experience using the virtual microscope. We conclude that it is feasible to make histologic diagnosis on the skin tumor types represented in this study using virtual microscopy after pathologists have completed a period of training. Larger studies should be conducted to verify whether virtual microscopy can replace conventional microscopy in routine practice.

Long-term mortality and renal outcome in a cohort of 100 patients with lupus nephritis.

OBJECTIVE: To evaluate the long-term mortality and renal outcome in a cohort of Danish patients with lupus nephritis (LN) and to identify outcome predictors among findings registered at the time of the first renal biopsy. METHODS: The cohort consisted of 100 patients diagnosed with LN (World Health Organization classes I-VI) between 1971 and 1995 and followed for a median duration of 14.7 years (range 0.01-36.9 years). Standardized mortality ratios (SMRs) were calculated on the basis of national age-, sex-, and calendar-year period-specific death rates. RESULTS: Thirty-seven deaths occurred in the cohort, corresponding to an overall SMR of 6.8 (95% confidence interval [95% CI] 4.9-9.4). Excess mortality was observed throughout followup. The SMR estimates were 9.0 (95% CI 4.7-17.1), 6.2 (95% CI 4.0-9.5), and 6.6 (95% CI 3.1-13.8) for patients diagnosed during the calendar-year periods 1971-1979, 1980-1989, and 1990-1995, respectively. The cumulative renal survival after 5, 10, and 20 years of followup was 87%, 83%, and 73%, respectively. The risk of end-stage renal disease (ESRD) did not decrease significantly across calendar-year periods. Systolic blood pressure >or=180 mm Hg, focal segmental nephritis, and advanced sclerosing nephritis were identified as baseline predictors of death in multivariate regression analyses, while systolic blood pressure >or=180 mm Hg, serum creatinine level >or=140 mumoles/liter, and diagnostic delay predicted progression to ESRD. CONCLUSION: LN is associated with excess long-term mortality, and patients may progress to ESRD even after prolonged followup. Our analyses indicate that focal segmental histopathology at disease onset constitutes an important risk factor for death among LN patients. Moreover, our data underscore the importance of early intervention, blood pressure control, and long-term followup in LN.

The renal metallothionein expression profile is altered in human lupus nephritis.

INTRODUCTION: Metallothionein (MT) isoforms I + II are polypeptides with potent antioxidative and anti-inflammatory properties. In healthy kidneys, MT-I+II have been described as intracellular proteins of proximal tubular cells. The aim of the present study was to investigate whether the renal MT-I+II expression profile is altered during lupus nephritis. METHODS: Immunohistochemistry was performed on renal biopsies from 37 patients with lupus nephritis. Four specimens of healthy renal tissue served as controls. Clinicopathological correlation studies and renal survival analyses were performed by means of standard statistical methods. RESULTS: Proximal tubules displaying epithelial cell MT-I+II depletion in combination with luminal MT-I+II expression were observed in 31 out of 37 of the lupus nephritis specimens, but not in any of the control sections (P = 0.006). The tubular MT score, defined as the median number of proximal tubules displaying this MT expression pattern per high-power microscope field (40x magnification), was positively correlated to the creatinine clearance in the lupus nephritis cohort (P = 0.01). Furthermore, a tubular MT score below the median value of the cohort emerged as a significant predictor of a poor renal outcome in renal survival analyses. Thus, patients with a tubular MT score < 1.0 had a 6.2-times higher risk of developing end-stage renal disease than patients with a tubular MT score >or= 1.0 (P = 0.03). CONCLUSION: Lupus nephritis is associated with significant alterations in renal MT-I+II expression. Our data indicate that important prognostic information can be deduced from the renal MT-I+II expression profile in systemic lupus erythematosus patients with nephritis.

Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure.

OBJECTIVE: To evaluate the prognostic significance of clinical and renal biopsy findings in an unselected cohort of patients with systemic lupus erythematosus (SLE) and nephritis. METHODS: Ninety-one patients with lupus nephritis were included in the study. Renal biopsies were classified according to the WHO criteria and examined for the presence of active and chronic histological changes. Predictors of endstage renal disease (ESRD) were identified by univariate and multivariate analyses. RESULTS: The median followup time was 6.1 years (0.1-30.0 yrs). In all cases, immunosuppressive treatment was initiated or intensified within one month following renal biopsy. The cumulative incidence of ESRD after 1, 5, and 10 years was 3.5%, 15%, and 17%, respectively. A variety of clinical and biopsy findings including several histological markers of chronic renal damage were identified as univariate predictors of ESRD. In multivariate regression analyses, duration of nephritis symptoms > 6 months prior to biopsy, s-creatinine > 140 micromol/l, diffuse proliferative glomerulonephritis, and tubular atrophy emerged as the strongest combination of independent risk factors (relative hazard ratios: 9.3, 5.6, 8.9, and 3.1, respectively). CONCLUSION: Our results confirm the negative prognostic impact of hypercreatininemia, class IV histopathology, and tubular atrophy in lupus nephritis. Our data show that delay between onset of nephritis and renal biopsy constitutes an important risk factor of ESRD. Patients with SLE should have kidney biopsy as soon as clinical signs of nephritis are evident in order to accelerate treatment decisions and minimize risk of inflammation-induced irreversible kidney damage.

Impaired glomerular and tubular function as a short-term effect of sirolimus treatment in the rat.

AIMS: To investigate acute and short-term effects of sirolimus (SRL) on glomerulo-tubular function, blood pressure (BP), and renal morphology in the rat. METHODS: Male Sprague-Dawley rats, weighing initially 140-180 g were treated with SRL in three series: SRL 0.2, 0.4, or 0.8 mg/kg/day intraperitoneally for up to 28 days after skin allo-transplantation from Lewis donors (to establish a dosage with significant immunosuppressive effect). SRL 0.4 mg/kg intravenously (acute effects). SRL 0.4 mg/kg/day intraperitoneally for 7 days (short-term effects). Inulin, lithium (C(Li)) and sodium clearance, and intra-arterial BP were measured in conscious catheterized rats. Morphological kidney studies were completed after post-mortem fixation. RESULTS: Maximum immunosuppressive effect was achieved with SRL 0.4 mg/kg/day. SRL acutely increased GFR and C(Li), whereas fractional proximal reabsorption (PFR) declined. In the short-term study SRL had opposite effects on GFR and C(Li), unaffected proximal tubular reabsorption and PFR, raised BP, diminished food consumption, and slower increase in body weight. Morphological changes were non-specific. CONCLUSION: In a dosage giving maximum immunosuppressive effect, SRL revealed acute effects on glomerular and proximal tubular function thus indicating increased outflow from the proximal tubules whereas one week of SRL treatment produced a change resembling the known nephrotoxic effects of the calcineurine inhibitors.

Kidney function and morphology after short-term combination therapy with cyclosporine A, tacrolimus and sirolimus in the rat.

BACKGROUND: Sirolimus (SRL) may supplement calcineurin inhibitors in clinical organ transplantation. These are nephrotoxic, but SRL seems to act differently displaying only minor nephrotoxic effects, although this question is still open. In a number of treatment protocols where SRL was combined with a calcineurin inhibitor indications of a synergistic nephrotoxic effect were described. The aim of this study was to examine further the renal function, including morphological analysis of the kidneys of male Sprague-Dawley rats treated with either cyclosporine A (CsA), tacrolimus (FK506) or SRL as monotherapies or in different combinations. METHODS: For a period of 2 weeks, CsA 15 mg/kg/day (given orally), FK506 3.0 mg/kg/day (given orally) or SRL 0.4 mg/kg/day (given intraperitoneally) was administered once a day as these doses have earlier been found to achieve a significant immunosuppressive effect in Sprague-Dawley rats. In the 'conscious catheterized rat' model, the glomerular filtration rate (GFR) was measured as the clearance of Cr(EDTA). The morphological analysis of the kidneys included a semi-quantitative scoring system analysing the degree of striped fibrosis, subcapsular fibrosis and the number of basophilic tubules, plus an additional stereological analysis of the total grade of fibrosis in the cortex stained with Sirius Red. RESULTS: CsA, FK506 and SRL all significantly decreased the GFR. A further deterioration was seen when CsA was combined with either FK506 or SRL, whereas the GFR remained unchanged in the group treated with FK506 plus SRL when compared with treatment with any of the single substances. The morphological changes presented a similar pattern. The semi-quantitative scoring was significantly worst in the group treated with CsA plus SRL (P<0.001 compared with controls) and the analysis of the total grade of fibrosis also showed the highest proportion in the same group and was significantly different from controls (P<0.02). The FK506 plus SRL combination showed only a marginally higher degree of fibrosis as compared with controls (P=0.05). CONCLUSION: This rat study demonstrated a synergistic nephrotoxic effect of CsA plus SRL, whereas FK506 plus SRL was better tolerated.