Lupus glomerulonephritis with thrombotic microangiopathy

Well-documented cases of systemic lupus erythematosus (SLE) with thrombotic microangiopathy (TMA) are rare. Renal biopsy in a 25-year-old woman with SLE who was in renal failure demonstrated proliferative lupus glomerulonephritis with arteriolar thrombosis and the arterial intimal changes of TMA. No staining of vessels for immunoglobulins or complement was found by direct immunofluorescence. Fibrillar and flocculent deposits were seen in the widened and rarefied subendothelial space in a small artery and two glomeruli, one of which also contained electron-dense deposits. The vascular findings, which are those of TMA, are distinct from the immune complex vasculopathy of SLE.     

Necrotizing arteritis in a human immunodeficiency virus-infected patient with lupus-like glomerulonephritis

Human immunodeficiency virus (HIV)-associated lupus-like glomerulonephritis (GN) is a chronic immune complex disease occurring in HIV-infected patients. Although the light, immunofluorescence, and electron microscopy findings indicate features of lupus nephritis, no evidence of systemic lupus erythematosus (SLE) is observed in the affected patients. We present the case of a 45-year-old Caucasian woman with HIV infection who was admitted to the hospital with a nephrotic syndrome 10 years after the HIV diagnosis. A renal biopsy revealed HIV-associated lupus-like GN and necrotizing arteritis affecting two interlobular arteries. Necrotizing arteritis is a type of renal vasculopathy associated with SLE, but has not been reported previously in HIV-associated lupus-like GN. In this case, necrotizing arteritis was found to be a histological feature common to both HIV-associated lupus-like GN and SLE. This histological finding reinforces the resemblance between HIV-associated lupus-like GN and nephritis caused by lupus.     

Is there a pathogenetic role of hepatitis B virus in lupus nephritis?

In view of the widely disputed frequency with which hepatitis B surface antigen (HBsAg) is found in the sera and kidney biopsy specimens of patients with systemic lupus erythematosus (SLE), serologic screening of HBsAg and immunofluorescence studies for HBsAg and hepatitis B core antigen in renal biopsy specimens were performed in 45 patients with SLE. Five of the 45 patients with SLE had HBs antigenemia, and the prevalence was not significantly different from that of the general population in Hong Kong. The renal biopsy findings of these five patients showed lupus nephritis in two and features suggestive of hepatitis-induced glomerulonephritis in three. Our findings do not support an increased prevalence of HBsAg in sera or kidney of patients with SLE, and hepatitis B virus is unlikely to have a pathogenetic role in SLE in areas where both SLE and HBs antigenemia are common.     

Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature.

Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephrotic-range proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis.     

Infantile case of early manifestation of SLE-like symptoms in complete C1q deficiency

C1q deficiency is a rare complement deficiency in the early part of the complement cascade. Patients with C1q deficiency have severe recurring life-threatening infections and systemic lupus erythematosus (SLE)-like symptoms. We report on a boy with recurrent life-threatening infections and SLE-like recurrent skin conditions before 2 years of age. Immunological studies revealed an undetectable level of C1q. No abnormality was observed in the urine, but renal biopsy showed segmental granulonephritis. However, the changes observed were atypical for SLE nephritis. This case of C1q deficiency was unusual because the SLE-like symptoms appeared earlier than that normally seen in complement deficiency. Therefore, this case provides insights into the development of autoimmune disease, particularly in the early phase of component deficiency, and in managing renal disease that may develop in the future.     

Resolution of HBV infection occurs sooner than recovery of renal disease in adult serum HBsAg‐negative HBV–associated glomerulonephritis

Most cases of hepatitis B virus–associated glomerulonephritis (HBV‐GN) occur in children and present with serum HBsAg positivity. Few studies have investigated adult patients with HBV‐GN who are serum HBsAg‐negative. This study aimed to determine the clinical and pathological features of adult patients with HBV‐GN who are serum hepatitis B surface antigen (HBsAg)‐negative. Clinical, pathologic, and laboratory findings were collected and analyzed in a cohort of 27 adult patients with HBV‐GN who were serum HBsAg‐negative upon diagnosis. The study population included mostly men of middle age (40‐59 years). Clinically, patients presented with nephrotic syndrome. Serum immunoglobulin G levels were low, whereas serum immunoglobulin M, immunoglobulin A, complement C3 (C3), and complement C4 (C4) levels as well as liver and renal function tests were normal in most or all patients. Among the 27 patients, 21 tested positive for HBV antibodies. Membranous nephropathy was the dominant pathological form on kidney biopsy. In addition, only a few patients showed a “full house” staining pattern and renal immune deposit of complement C1q (C1q). Serum HBsAg‐negative HBV‐GN may represent a late stage of HBV infection. We recommend routine testing for HBV markers on renal biopsy in regions where HBV is prevalent, even when tests for serum HBV markers are negative.     

Hepatitis B virus surface antigen in glomerular immune complex deposits of patients with systemic lupus erythematosus

In view of a high prevalence of hepatitis B virus infection in the Malaysian population, indirect immunofluorescence examination for hepatitis B surface antigen (HBsAg) was routinely performed on renal biopsy specimens at the University Hospital, Kuala Lumpur, over a 3-year period. Examination of renal tissue from 259 patients, including 47 with systemic lupus erythematosus (SLE), revealed 43 cases with HBsAg in glomerular immune complexes. A significantly high proportion (30/43) of these were SLE patients. The deposits were granular in nature, situated in both the capiliary walls and mesangium and associated with immunoglobulin deposition. Morphological patterns of lupus nephritis involved were focal pro-liferative (one case), diffuse proliferative (23 cases) and membranous (six cases). None of these patients showed clinical evidence of liver disease. The significance of these findings remains uncertain, but the possibility exists that the hepatitis B virus may have a role in the pathogenesis of SLE in the tropics where both SLE and HBs antigenaemia are common.     

Absence of interferons-alpha and -gamma in renal lesions of systemic lupus erythematosus and membranous glomerulonephritis

Frozen kidney biopsy sections from nine patients with systemic lupus erythematosus (SLE) as well as many other renal diseases, including IgA nephropathy, membranous nephritis, and minimal change nephrotic syndrome, were negative for interferons -alpha and -gamma by immunofluorescence. Lupus patients studied included several subjects with marked serum elevations of interferon activity as well as others with low or negative serum interferon levels. Isolated glomerular eluates prepared from normal and SLE kidneys showed no functional interferon activity by virus plaque inhibition assay. Components of normal as well as SLE serum showed no direct binding to interferon -alpha or -gamma by ELISA assays.     

Lupus-specific kidney deposits of HSP90 are associated with altered IgG idiotypic interactions of anti-HSP90 autoantibodies

Previous studies have shown that autoantibodies to heat shock protein 90 (HSP90) are elevated in a significant proportion of patients with systemic lupus erythematosus (SLE) who are more likely to have renal disease and a low C3 level. Using samples from 24 patients, we searched for glomerular deposits of HSP90 in renal biopsy specimens from seven patients with lupus nephritis and 17 cases of glomerulonephritis from patients without SLE. Positive glomerular immunofluorescent staining for HSP90 was observed in six of seven cases of SLE and positive tubular staining in two of seven SLE patients. The staining for HSP90 was granular in nature and was located in subepithelial, subendothelial and mesangial areas. None of the non-SLE renal biopsies revealed positive staining for HSP90 deposition. Further we showed the presence of anti-HSP90 IgG autoantibodies in IgG from sera of patients with SLE as well as in normal human IgG (IVIg). In normal IgG this autoreactivity could be adsorbed almost completely on F(ab')2 fragments from the same IgG preparation, coupled to Sepharose and could be inhibited by the effluent obtained after subjecting normal IgG to HSP90 affinity column. These findings indicate that anti-HSP90 natural autoantibodies are blocked by idiotypic interactions within the IgG repertoire. Unlike natural autoantibodies, anti-HSP90 IgG from SLE patients' sera were only moderately adsorbed on F(ab')2 fragments of normal IgG. These results demonstrate that immunopathogenesis of lupus nephritis is associated with HSP90 (as an autoantigen) and that the pathology is associated with altered idiotypic regulation of the anti-HSP90 IgG autoantibodies.     

Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) on kidney tissue from systemic lupus erythematosus (SLE) patients

The aim of this study was to evaluate the expression of TIM-3 in renal tissue from patients with systemic lupus erythematosus (SLE) and patients without SLE, and to evaluate the difference of TIM-3 expression between them. A total of 272 patients with SLE as SLE group and 62 patients without SLE as control group were enrolled in the present study. Patients with SLE accepted percutaneous renal biopsy. We examined the expression of TIM-3 in renal tissue and the serological parameters in serum from all enrolled cases. The expression of TIM-3 and serological parameters were compared between the different groups. Positive staining of TIM-3 protein was seen in 97.1 % patients with SLE (264 out of 272), but 95.2 % negative staining in the cases without SLE (59 out of 62), only 3 out of 62 patients in control group were positive staining of TIM-3. There were significant differences between two groups in almost all serological markers which reflect SLE activity. There was a nearly positive correlation between pathological manifestations and expression degree of TIM-3. High immuno-reactivity of TIM-3 was found to be significantly correlated with serological grade (p < 0.001), but there was the phenomenon in control group. The results showed that there was the expression of TIM-3 in renal tissue from the patients with SLE, but rarely expression in cases without SLE. Expression of TIM-3 was associated with the diseases’ activity.     

Experience in the diagnosis of glomerulonephritis using combined light microscopical, ultrastructural and immunofluorescence techniques--an analysis of 134 cases.

The contribution of electron and immunofluorescence microscopy to renal biopsy diagnosis is illustrated by the results obtained in a personal series of patients with various types of glomerulonephritis. Introductory notes on the ultrastructure of the glomerular capillary and on immunological processes are also included. Immunofluorescent staining has particular value in demonstrating IgG-containing deposits in early membranous glomerulonephritis at a stage when ordinary microscopy is inconclusive. It is capable of throwing light on the mechanism of glomerular damage in severe extracapillary proliferation and in some cases of recurrent haematuria, but is less successful in separating minimal change disease from proliferative processes. Electron microscopy reveals the precise site of immune deposits and fibrin together with basement membrane changes, the microtubular structures common in SLE, and other details. It is concluded that for the accurate diagnosis of kidney disease it is essential to supplement light microscopy by one, or preferably both these methods.     

Lupus nephritis: When and how often to biopsy and what does it mean?

Renal disease is a frequent complication of SLE which can lead to significant illness and even death. Today, a baseline renal biopsy is highly recommended for all subjects with evidence of lupus nephritis. Biopsy allows the clinician to recognize and classify different forms of autoimmune lupus glomerulonephritis, and to detect other glomerular diseases with variable pathogenesis which are not directly related to autoimmune reactivity, such as lupus podocytopathy. Moreover, not only glomerular diseases, but other severe forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy may be detected by biopsy in lupus patients. Thus, an accurate definition of the nature and severity of renal involvement is mandatory to assess the possible risk of progression and to establish an appropriate treatment.The indications to repeat biopsy are more controversial. Some physicians recommend protocol biopsies to recognize the possible transformation from one class to another one, or to identify silent progression of renal disease, others feel that good clinical monitoring is sufficient to assess prognosis and to make therapeutic decisions. At any rate, although any decision should always be taken by considering the clinical conditions of the patient, there are no doubts that repeat renal biopsy may represent a useful tool in difficult cases to evaluate the response to therapy, to modulate the intensity of treatment, and to predict the long-term renal outcome both in quiescent lupus and in flares of activity.     

Immunopathology of lupus nephritis

When patients with systemic lupus erythematosus (SLE) present with urinary abnormalities, a renal biopsy is usually needed to rule out or confirm lupus nephritis. Renal biopsy is also needed to define the type of renal manifestation as different entities are associated with different outcomes; hence, renal biopsy results shape lupus management. But why does lupus nephritis come in different shapes? Why do patients with SLE often show change over time in class of lupus nephritis or have mixed forms? How does autoimmunity in SLE evolve? Why does loss of tolerance against nuclear antigens preferentially affect the kidney? Why are immune complex deposits in different glomerular compartments associated with different outcomes? What determines crescent formation in lupus? In this review, we discuss these questions by linking the latest information on lupus pathogenesis into the context of the different classes of lupus nephritis. This should help the basic scientist, the pathologist, and the clinician to gain a more conceptual view on the immunopathology of lupus nephritis.     

ANA negative (Ro) lupus erythematosus with multiple major organ involvement: a case report

Anti-nuclear antibody (ANA) negative systemic lupus erythematosus (SLE) occurs in about 4-13% of SLE cases. A small group of ANA negative SLE patients with positive anti-Ro antibodies usually present with typical vasculitic skin lesions which can be associated with photosensitivity, renal disease, congenital heart block or neonatal lupus. We present a case of a persistently ANA negative patient who presented with joint pain, rashes, mouth ulcer and alopecia. Clinical diagnosis of systemic lupus erythematosus was made even though ANA was negative. She was started on steroids and went into remission. Later, she developed several episodes of convulsions associated with fever and prominent vasculitic lesions. The patient was also found to have microscopic hematuria, proteinuria, anemia and thrombocytopenia. Renal biopsy showed lupus nephritis class 1B. Due to the prominent skin lesions, we performed anti-extractable nuclear antigens (ENA) antibodies test and anti-Ro turned out to be positive. The final diagnosis was ANA negative SLE (Ro lupus) with cutaneous, renal, musculoskeletal, hematological and cerebral Involvement.     

Nephrotic syndrome in a patient with IgA deficiency-associated mesangioproliferative glomerulonephritis

A case of mesangioproliferative glomerulonephritis in a 55-year-old woman with selective IgA deficiency and serum antinuclear antibodies who presented with nephrotic syndrome is described. The patient did not have clinical or laboratory features of systemic lupus erythematosus (SLE) other than antinuclear antibodies. Histology of the patient's renal biopsy revealed a mesangioproliferative glomerulonephritis and direct immunofluorescence showed that paramesangial deposits contained predominant IgM with lesser IgG, C3 and C1q. These findings are identical to those previously described in a form of glomerulonephritis associated with IgA deficiency and would be atypical for lupus nephritis. Glomerulonephritis is not a well recognized complication of IgA deficiency, though it has been rarely reported in the literature. This case provides further evidence that IgA deficiency is associated with a unique immune complex-mediated glomerulopathy with characteristic immunopathological and ultrastructural features. It is the first reported case to present with nephrotic syndrome.     

Expanding the pathologic spectrum of light chain deposition disease: a rare variant with clinical follow-up of 7 years.

We report an unusual histologic manifestation of light chain deposition disease in a 69-year-old female patient, who presented with nephrotic syndrome and an increased serum creatinine. The renal biopsy findings by light and electron microscopy suggested a glomerulonephritis with massive immune-complex deposition, such as lupus nephritis. However, the overall clinical scenario was inconsistent with lupus. Subsequent tests revealed multiple myeloma confirmed by bone marrow biopsy and identification of a monoclonal kappa light chain immunoglobulin by serum and urine immunoelectrophoresis and immunofixation. Additional immunohistochemistry of the first biopsy also demonstrated strong kappa light chain staining of the glomerular capillary walls and mesangium but not lambda light chain or IgG staining. The patient responded well to therapy and was asymptomatic until nearly 7 years later. A repeat biopsy revealed similar findings to the first biopsy with the addition of immunofluorescence microscopy, which confirmed the prominent kappa light chain staining of the glomeruli, tubular basement membranes, and interstitium with corresponding electron-dense deposits visualized by electron microscopy. This case represents an unusual histologic variant of light chain deposition disease, which to our knowledge has not been previously described and further expands the wide clinicopathologic spectrum within the diagnostic entity of light chain deposition disease.     

Guinea pig complement fixation by tissues from hypocomplementaemic renal diseases

Recently many studies have been done to identify complement pathway activation in renal tissue from patients with renal disease. We examined whether tissues obtained by renal biopsy from such patients would fix guinea pig complement. Nine out of 15 patients with systemic lupus erythematosus (SLE), 4 out of 7 patients with mesangiocapillary glomerulonephritis (MCGN), and 2 out of 7 cases with acute glomerulonephritis (AGN) fixed guinea pig C3. We found that tissues from 5 out of 9 guinea pig C3-positive SLE cases fixed guinea pig C4, while none of the guinea pig C3-positive tissues from patients with MCGN or AGN fixed guinea pig C4. These guinea pig C3-positive renal tissues were further studied for interaction with C4-deficient guinea pig serum, EDTA guinea pig serum, heated guinea pig serum, and EGTA Mg2+ guinea pig serum. The results indicated that activation of both the alternate and classical complement pathways occurred with tissues from patients with SLE, while activation of the alternate pathway occurred with MCGN and AGN. Results for tissues from AGN and MCGN patients indicated the presence of C3 convertase and protease which interacted with guinea pig C3.     

False-negative anti-DNA antibody activity in infantile systemic Lupus erythematosus (SLE)

A 2.5-month-old previously healthy female infant presented with serositis, nephrotic syndrome, progressive renal failure, anemia, and thrombocytopenia. Renal biopsy revealed a proliferative glomerulonephritis with glomerular and extraglomerular deposits of IgG, IgM, C3, and Cl_q by direct immunofluorescence (IF) techniques. Skin biopsy was positive for IgG and C3 deposits in the dermal-epidermal junction by IF. Despite strong clinical and pathological criteria for systemic lupus erythematosus (SLE), tests for antinuclear and anti-DNA antibodies were negative. Circulating immune complexes (CICs) were detected in three separate assay systems. Immunochemical analysis of isolated CICs showed that anti-DNA antibody was present. Analysis of kidney biopsy material by antigen-specific solubilization techniques showed antibodies reactive with ds-DNA in the kidney. These studies confirm that SLE may be a cause of the congenital nephrotic syndrome and that negative SLE serologies may be secondary to binding of available antibody by excess antigen. Analysis of CICs may be helpful in confirming the diagnosis of SLE in seronegative patients.     

Relationship between antibodies to dsDNA and to soluble cellular antigens and histologically defined glomerulonephritis in patients with SLE

To better define the relationships between circulating autoantibodies and renal involvement in systemic lupus erythematosus (SLE), antibodies to both dsDNA and soluble cellular antigens were detected in sera from a large series of SLE patients. Significantly higher dsDNA binding activities and lower complement levels at onset were found in patients with renal disease; however, this was uniquely due to subjects with diffuse or focal proliferative glomerulonephritis. Patients with membranous nephropathy (MGN) showed very low dsDNA binding activities (6/9 of them being negative for dsDNA antibodies) and normal mean C3 and C4 levels. A comparison between patients with proliferative nephritis and patients without renal involvement with high dsDNA binding activities revealed significantly lower complement levels in the former group. No significant difference was observed in the prevalence of antibodies to soluble cellular antigens between patients with or without renal disease; however, nRNP antibody was two-fold more frequent in patients with MGN than in all other subgroups. This study highlights the close relationship between concurrently high anti-dsDNA and low complement levels and proliferative glomerulonephritis in SLE, and suggests that subjects with MGN may represent a subgroup of SLE patients showing peculiar serological features. Different mechanisms possibly involved in the pathogenesis of MGN in SLE are discussed.     

Mannose binding lectin deposition in skin of lupus erythematosus patients: A case series

Introduction

Mannose binding lectin (MBL) has been linked to predisposition to systemic lupus erythematosus (SLE) and to disease activity. Some studies found deposits of MBL in glomerular tissue of patients with lupus nephritis. There is no research about the deposition of MBL in skin.

Materials and methods

Skin biopsies from lesional and non lesional skin of 4 discoid lupus erythematosus (DLE) and 10 SLE patients were submitted to immunofluorescence staining for IgG, IgA, IgM, C3, C4, C1q, C5b-9 and MBL. Charts were reviewed for demographic, clinical and serological data. Patients with SLE had disease activity measured by SLEDAI.

Results

MBL was found only in SLE lesional skin and its presence showed an association trend towards higher disease activity. Deposition of C5b-9 occurred in vessels only in patients with SLE (70%) and in the two patients with kidney involvement.

Conclusions

MBL deposition was found in the lesional skin of SLE patients but not in SLE non lesional skin nor in DLE patients, and it seems to be less frequent and less strong than observed in the kidneys biopsies, suggesting that the complement participation in the pathophysiology of SLE process may not be the same in these two clinical manifestations.