Lupus-like membranous nephropathy: Is it lupus or not?

BACKGROUND: Membranous glomerulonephritis is typically classified as idiopathic or secondary to systemic lupus erythematosus (SLE), hepatitis B, drugs, toxins, other infections, or malignancy. Not infrequently in some patients without a definite diagnosis of SLE, pathologic features of secondary membranous nephropathy are seen e.g., mesangial and/or subendothelial deposits, tubuloreticular inclusions, and full house immunofluorescence. In these patients, there is uncertainty about the etiology, response to therapy, and prognosis of membranous GN. METHODS: We retrospectively reviewed the charts of 98 patients with membranous GN at San Francisco General Hospital and John Stroger Hospital of Cook County over a 10-year period. Data were collected and analyzed using SPSS.18. RESULTS: Thirty-nine (40 %) had idiopathic membranous GN (Group 1), thirty-six (37 %) had lupus membranous GN (Group 2) and twenty-three (23 %) had some pathological features of secondary membranous GN, but no definite etiology of membranous GN (Group 3). At baseline (at time of renal biopsy) and after mean follow-up of 3.5 years, the average serum creatinine (in mg/dL) in Group 1 was (1.6 ± 1.0 versus 1.6 ± 1.7), Group 2 was (1.8 ± 2.5 versus 1.2 ± 0.9) and Group 3 was (1.1 ± 0.4 versus 1.27 ± 0.83), respectively. For the same time points, the average urine protein to creatinine ratio (g/g) in Group 1 was (9.8 ± 7.1 versus 5.7 ± 6.7), Group 2 was (4.2 ± 3.9 versus 1.7 ± 2.2), and Group 3 was (7.4 ± 5.7 versus 3.1 ± 3.8). In addition, during the follow-up period, eleven of 39 (28 %) in Group 1, two of 36 (6 %) in Group 2, and three of 23 (13 %) in Group 3 progressed to end-stage renal disease and were started on dialysis. CONCLUSIONS: It appears that patients with lupus membranous GN have better renal prognosis than patients with idiopathic membranous GN. The renal prognosis for patients with pathological features of lupus membranous but no diagnosis of systemic lupus (lupus-like membranous GN) falls in between. Further studies are needed to determine if Group 3 patients can (a) definitively be classified as true idiopathic membranous GN or lupus membranous GN or (b) they have a separate disease from either M-type phospholipase A2 receptor membranous nephropathy or systemic lupus-induced membranous nephropathy.

Use of observation followed by outpatient stress testing in chest pain patients with prior coronary artery disease history: An evaluation of prognostic utility.

OBJECTIVE: To determine the outcomes of patients with chest pain (CP) and prior history of coronary artery disease (CAD) managed with observation followed by outpatient stress myocardial perfusion imaging (MPI). METHODS: Retrospective analysis of patients with CP managed with observation followed by outpatient stress MPI, comparing cardiovascular (CV) event rates stratified by CAD history. RESULTS: 375 patients were included: 111 with and 264 without a CAD history. All patients underwent outpatient stress MPI within 72 h of observation. MPI identified patients at risk for CV events. However, while patients with negative MPI and without a CAD history had very low rates of short- and long-term CAD events (0.8%, 0.8%, and 1.3% at 30 days, 1 year, and 3 years, respectively), event rates of those with a negative test but a CAD history were significantly higher (2.6%, 5.3%, and 6.6% at 30 days, 1 year and 3 years, respectively; p = 0.044 and p = 0.034 compared to CAD- patients at 1 year and 3 years, respectively). In a multivariable logistic regression model, a positive MPI proved to be an independent predictor of long-term CV events in patients with CP and prior CAD. CONCLUSION: Observation followed by stress MPI can effectively risk stratify CP patients with prior CAD for CV risk. These patients are at increased risk of CV events even after a low-risk stress MPI study. Patients presenting with CP and managed with a strategy of observation followed by a negative stress MPI warrant close short- and long-term monitoring for recurrent events.

Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth.

Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Coexpression of the monocytic growth factor colony-stimulating factor (CSF)-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and antiapoptosis during regeneration of renal tubules. Here, we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were coexpressed in RCCs and TECs proximally adjacent to RCCs. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and epidermal growth factor signaling in RCCs. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R, and epidermal growth factor expression in RCCs. Furthermore, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCCs.

The Oxford classification of IgA nephropathy: a retrospective analysis.

BACKGROUND/AIMS: The Oxford classification of IgA nephropathy (IgAN) assesses the presence of mesangial hypercellularity ≥50% (M1 vs. 0), endocapillary proliferation (E1 vs. 0), segmental glomerulosclerosis (S1 vs. 0), tubular atrophy/interstitial fibrosis >25 or 50% (T1 or 2 vs. 0), and has been reported as having prognostic value. We studied the clinical significance of the classification in our adult patients with IgAN. METHODS: Retrospective study of 54 patients with biopsy-proven IgAN seen from 1983 to 2009. The correlation between the Oxford classification and baseline renal function was assessed. The primary endpoint was a 50% reduction in eGFR or end-stage renal disease. Predictors for progression to the endpoint were determined by multivariate analyses. RESULTS: Patients were 41 ± 15 years of age with a serum creatinine of 1.5 ± 0.8 mg/dl, eGFR of 61 ± 24 ml/min/1.73 m(2), and proteinuria of 2.0 ± 1.6 g/day. Oxford classifications were as follows: M1 = 72%, E1 = 20%, S1 = 81%, and T1 = 13%/T2 = 22%. During the follow-up of 5.8 ± 4.8 years, 19% of patients reached the primary endpoint. While the Oxford classification was associated with progressive renal disease, only the T score (T0, T1, T2) was predictive of outcome with 6, 29, and 50% of patients (p = 0.002) reaching the primary endpoint. The 10-year renal survival for T0, T1, and T2 was 100, 50, and 17%, respectively (p < 0.001). By multivariate analysis, the hazard ratio for reaching the primary endpoint was 32 for patients with T ≥1 versus T0 (p = 0.01). CONCLUSIONS: In our experience, the Oxford classification predicts progressive renal disease, but the degree of tubulointerstitial fibrosis was the only feature independently predictive of outcome.

Pathogenetic features of severe segmental lupus nephritis.

BACKGROUND: Accumulating evidence supports the notion that the pathogenesis of severe lupus glomerulonephritis is multifactorial and not solely an immune complex-mediated glomerular disease. Alternate mechanisms for glomerular destruction may exist. METHODS: We conducted a retrospective clinicopathologic analysis of 213 patients with lupus nephritis. Twenty-six patients had severe segmental glomerulonephritis (SSGN) and 15 patients had diffuse proliferative glomerulonephritis (DPGN). Patients with pure mesangial lupus nephritis [mesangial glomerulonephritis (MesGN)] (N = 13) were used as histologic controls. The degree of immunologic activity detailed by histologic data including light, fluorescent (IF) and electron microscopy (EM) on kidney biopsies and clinical data from patients with severe lupus nephritis were analysed. RESULTS: Biopsies from patients with SSGN had fewer glomeruli with wire loops (3 +/- 6% versus 35 +/- 34% P = 0.005) and hyaline thrombi (0.8 +/- 3% versus 16 +/- 22%, P = 0.02) compared to DPGN. The amount of IgG by IF was less in SSGN lesions compared to DPGN lesions, and IgG was absent in 30% of the SSGN group compared to none of the DPGN group (P = 0.04). There was no difference in mesangial deposits among the three groups (SSGN, DPGN and MesGN). The EM data supported the IF data. Anti-neutrophil cytoplasmic antibodies (ANCA) were essentially negative in all three groups and the C3 values tended to be lower in DPGN compared to SSGN (48 +/- 15 mg/dl versus 60 +/- 26 mg/dl, P = 0.09). CONCLUSIONS: The findings in DPGN involve a classic immune complex-mediated glomerulonephritis as demonstrated by the abundant immune aggregates witnessed in the peripheral capillary wall. In contrast, a paucity of peripheral immune aggregates is seen in SSGN implying a different pathogenesis. Our data support a mechanism of glomerular injury in SSGN that is separate from the generally accepted unitary concept of immune complex deposition in lupus nephritis.

Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis.

Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas(lpr)) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas(lpr) mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas(lpr) mice. Using mutant MRL-Fas(lpr) strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC(low)CD11b(+)), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC(low)CD11b(+)Ly6C(high)) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b(+)CSF-1R(+) or CD68(+)) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.

A case of lymphangioleiomyomatosis with membranous nephropathy and likely systemic lupus.

Membranous glomerulonephritis is most often idiopathic, but it can be secondary to systemic lupus erythematosus, viral hepatitis, and drugs. A number of malignancies have also been associated with membranous glomerulonephritis, although a causal link has not been established yet. A young patient with lymphangioleiomyomatosis is described who developed massive proteinuria and was found to have membranous glomerulonephritis on renal biopsy. There were many pathological features and some clinical features that suggested the patient also suffered from systemic lupus erythematosus.

Value of a complete or partial remission in severe lupus nephritis.

BACKGROUND AND OBJECTIVES: The value of a complete remission in severe lupus nephritis is well known but little is known about the impact of a partial remission in this patient population. The purpose of this study was to evaluate the long-term prognosis of achieving a complete or partial remission in a well-defined group of patients with severe lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 86 patients with diffuse lupus glomerulonephritis were reviewed for assessment of the value of a partial remission (50% reduction in baseline proteinuria to < or =1.5 g/d and < or =25% increase in baseline creatinine) and complete remission (proteinuria < or =0.33 g/d and serum creatinine < or =1.4 mg/dl) on outcomes compared with patients who did not attain a remission. These well-characterized patients were entered into a prospective therapeutic trial conducted by the Collaborative Study Group and were followed for more than 10 yr. RESULTS: All biopsies showed diffuse lupus nephritis. A complete remission was attained in 37 (43%) patients, a partial remission in 21 (24%) patients, and no remission in 28 (32%) patients. Baseline clinical and serologic features were similar among the groups, but patients with a complete remission had a lower serum creatinine and chronicity index compared with patients with partial or no remission. The patient survival at 10 yr was 95% for complete remission, 76% for partial remission, and 46% for no remission. The renal survival at 10 yr was 94% for complete remission, 45% for partial remission, and 19% for no remission, and the patient survival without end-stage renal disease at 10 yr was 92% for complete remission, 43% for partial remission, and 13% for no remission. CONCLUSION: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no remission.

The prognosis and pathogenesis of severe lupus glomerulonephritis.

BACKGROUND: The International Society of Nephrology/ Renal Pathology Society classification (ISN/RPS) of lupus glomerulonephritis (GN) divides diffuse GN (>/=50% involvement) into diffuse segmental (IV-S) and diffuse global GN (IV-G). This division tests whether the pathogenesis and clinical outcomes are the same as when similar patients are classified using the World Health Organization (WHO) classification into severe segmental (WHO III >/=50%) and diffuse global (WHO-IV) GN. METHODS: Thirty-nine renal biopsies with WHO class IV and 44 with WHO III >/= 50% were reclassified using the ISN/RPS and were correlated with pathogenesis and outcome. RESULTS: There were 22 biopsies with ISN/RPS class IV-S. ISN/RPS class IV-G comprises two morphologically discrete classes of renal biopsies: 39 biopsies originally classified as WHO class IV (WHO-IV) and 22 that switched from WHO III >/=50% to ISN/RPS class IV-G (IV-Q). We will analyze IV-S, IV-Q and WHO-IV separately. WHO-IV had significantly more immune aggregate deposition than IV-S and IV-Q. WHO-IV had lower serum complements C3 (P = 0.05) and C4 (P = 0.05) than patients with IV-Q. Patients with WHO-IV had more remissions (56%) than IV-Q (23%) (P = 0.01), and stable renal function at the last follow-up was less frequent in patients with IV-Q (18%) than IV-S (50%, P = 0.05) and WHO-IV (62%, P = 0.001). Renal survival and renal survival without end-stage renal disease were different when the patients were diagnosed as WHO classes III >/=50% and IV, but the outcomes for ISN/RPS class IV-S and IV-G (WHO-IV plus IV-Q) were not different. CONCLUSIONS: WHO III >/=50% and WHO-IV lupus GN are not congruent with ISN/RPS IV-S and IV-G. The ISN/RPS minimizes pathological and outcome differences between classes IV-S and IV-G which results in the loss of informational content from the renal biopsies. ISN/RPS does not detect pathogenetic or clinical differences among patients with severe lupus GN.

The pathology of lupus nephritis.

An international working group of clinicians and pathologists met in 2003 under the auspices of the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) to revise and update the 1982 and 1995 World Health Organization classification of lupus glomerulonephritis. This article compares and contrasts the ISN/RPS classification and the antecedent World Health Organization classifications. Although systemic lupus erythematosus is the prototypical systemic immune-complex disease, several non-immune-complex mechanisms of glomerular injury and dysfunction have been proposed, and this article summarizes the evidence supporting the pathogenic mechanisms of lupus vasculitis, glomerular capillary thrombosis, and lupus podocytopathy. The most significant and controversial feature of the ISN/RPS classification is the separation of diffuse glomerulonephritis into separate classes with either segmental (class IV-S) or global (class IV-G) lesions. Several groups have tested the prognostic significance of this separation, and this article discusses the implications of these studies for the ISN/RPS classification.

Severe lupus nephritis: racial differences in presentation and outcome.

This study assessed whether certain clinicopathologic variables could explain the impact of race on outcome in 86 patients who had severe lupus nephritis and were available for long-term follow-up after participating in a prospective, controlled, clinical trial. Fifty-four (63%) patients were white, 21 (24%) were black, and 11 (13%) were categorized as other. The proportion of patients with anti-Ro, anti-nRNP, and anti-Sm was significantly greater among black patients. Biopsies with segmental active proliferative and necrotizing lesions that involved >or=50% of glomeruli +/- membranous glomerulonephritis (class III >or=50%+/-V) were significantly more common (white 44%, black 76%, other 36%; P < 0.05) and diffuse proliferative glomerulonephritis +/- membranous glomerulonephritis (class IV+/-V) was less common (white 54%, black 24%, other 64%) among black patients. Attainment of a remission was greatest among white patients (white 52%, black 29%, other 27%; P = 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV+/-V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P = 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P = 0.015) were significantly poorer in black patients. Predictors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class III >or=50%+/-V lesions, and failure to achieve a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were associated with more aggressive renal disease and resulted in worse outcomes than white patients.

Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis.

BACKGROUND: A 42-year-old man presenting with flank pain was found to have renal failure with severe hypocomplementemia and eosinophilia. INVESTIGATIONS: Physical examination, laboratory testing, renal ultrasonography, and renal biopsies. DIAGNOSIS: Acute immune-complex-mediated tubulointerstitial nephritis. MANAGEMENT: Immunosuppressive therapy with 1 mg/kg/day prednisone.

Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding.

We describe a case of lipoprotein glomerulopathy, the second ever reported from the United States, in a Mexican man with a hitherto undescribed mutation in the apolipoprotein E gene (substitution of proline for arginine at position 147 [Arg147Pro]). In this patient, glomerular basement membranes showed double contours and circumferential mesangial extensions, suggesting that deposition of lipids could be injurious to endothelial cells. Immunofluorescence staining of thrombi was positive for apolipoprotein E and B. To study the reason for lipid deposition in glomeruli, we incubated normal human kidney sections with serum from the patient and a healthy control. Apolipoprotein E from the patient's serum showed binding to the glomerular capillary wall, but the control did not, suggesting enhanced binding of the mutated apolipoprotein E to glomerular capillaries. Apolipoprotein E genotyping by means of restriction endonuclease digestion of polymerase chain reaction-amplified genomic DNA showed it to be of the wild-type E3/E3.

Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients.

The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter-driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression.

Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs.

Despite clinical and experimental data suggesting a direct relationship between antineutrophil cytoplasmic antibodies (ANCAs) and disease activity in patients with microscopic polyangiitis (MPA), the causal relationship between perinuclear ANCAs specific for myeloperoxidase (MPO-ANCA) and disease manifestations has been controversial. We describe the case of a woman with a history of pulmonary-renal syndrome caused by MPA whose disease became clinically and serologically active during pregnancy. Forty-eight hours after delivery, the newborn developed pulmonary hemorrhage and abnormalities in renal function. The newborn's cord blood showed an immunoglobulin G MPO-ANCA level identical to that of the mother's serum, indicating passive transfer of the antibody to the neonate. Our findings represent the first human model supporting the interpretation that MPO-ANCAs were immunopathogenic.