Renal Involvement in the Antiphospholipid Syndrome (APS)—APS Nephropathy

Although the kidney represents a major target organ in antiphospholipid syndrome (APS), renal involvement in APS was poorly recognized until recently. The most well-recognized renal manifestations of APS are the renal artery thrombosis/stenosis, renal infarction, hypertension, renal vein thrombosis, end-stage renal disease, increased allograft vascular thrombosis, some types of glomerular disease, and a small-vessel vaso-occlusive nephropathy, recently defined as APS nephropathy. APS nephropathy was first described in primary APS patients, characterized by acute thrombotic lesions in glomeruli and/or arterioles (thrombotic microangiopathy) and chronic vascular lesions such as fibrous intimal hyperplasia of arterioles and interlobular arteries, organized thrombi with or without recanalization, and fibrous arterial and arteriolar occlusions or focal cortical atrophy. APS nephropathy was also detected in further studies including patients with systemic lupus erythematosus (SLE)-related APS and SLE/non-APS patients with positive antiphospholipid antibodies, independently of lupus nephritis. The same histologic lesions, especially thrombotic mictroangiopathy, were also observed in patients with catastrophic APS. The most frequent clinical and laboratory characteristics of APS nephropathy in all the above groups of patients are hypertension (often severe), proteinuria (ranging from mild to nephrotic range), hematuria, and acute or chronic renal insufficiency.     

Histopathology,ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded.     

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.     

Renal Manifestations in 2007 Korean Patients with Beh?et's Disease

Purpose

Behçet''s disease (BD) theoretically affects all sizes and types of blood vessels and results in multi-organ involvement. However, renal BD has not been fully characterized, though the kidneys are histologically rich in blood vessels.

Materials and Methods

A total of 2007 patients who fulfilled the diagnostic criteria for BD were enrolled in this study. We reviewed the medical records and test results of the BD patients and used univariate and multivariate logistic regression analyses to determine the clinical significance of renal involvement in BD.

Results

Among the 2007 BD patients, we noted hematuria in 412 (20.5%) and proteinuria in 29 (1.4%). Univariate analysis showed that the BD patients with hematuria were predominantly female and older, had higher erythrocyte sedimentation rates (ESRs), and more frequently presented with genital ulcerations. BD patients with proteinuria had higher ESR levels compared to BD patients without proteinuria. In the multivariate analysis, age, sex, and ESR were found to be significantly associated with hematuria in BD patients, whereas only ESR was associated with proteinuria in BD patients. We also found that IgA nephropathy was the most common pathologic diagnosis in 12 renal BD patients who underwent renal biopsies.

Conclusion

We suggest that routine urinalysis and serum renal function tests be performed for the early detection of renal BD, especially in older female BD patients with recurrent hematuria, high ESR levels, and frequent genital ulcers, as well as in BD patients with proteinuria and high ESR levels.     

68例维吾尔族IgA肾病患者MBL基因多态性与临床病理相关性分析

目的 探讨甘露糖结合凝集素(mannose-binding lectin,MBL)基因第54位密码子多态性与维吾尔族IgA肾病患者临床和病理的关系.方法 应用PCR-RFLP方法对68例维吾尔族IgAN患者进行MBL多态性检测,并与患者临床和病理特点进行相关性分析.结果 ①维吾尔族IgAN中表现为蛋白尿的患者突变型等位基因GAC的发生频率显著高于表现为单纯血尿的患者(P＜0.05);②维吾尔族IgAN中表现为复合性免疫沉积的患者等位基因GAC的发生频率显著高于表现为单纯免疫沉积的患者(P＜0.05).结论 MBL突变型等位基因GAC与维吾尔族IgAN 蛋白尿发生和免疫复合沉积相关.     

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.     

Early hyperbaric oxygen therapy attenuates disease severity in lupus-prone autoimmune (NZB x NZW) F1 mice

The effects of hyperbaric oxygen (HBO(2)) therapy on the immune system are reported including potential changes to the CD4/CD8 ratio and a decreased proliferation of lymphocytes during exposure. The immunosuppressive effect of HBO(2) had been suggested to be applicable for the treatment of certain autoimmune diseases. (NZB x NZW) F1 hybrid mice, the unique lupus-prone mice, have been used for elucidating the pathogenesis of SLE. To investigate the effect of HBO(2) on NZB/W F1 lupus-prone mice, 32 female mice were divided into four groups. Three groups of mice were treated with HBO(2) (2.5 atm abs (ATA) for 90 min daily over 2 weeks) starting at (A) 3 months, (B) 6 months, or (C) 8 months of age, while the remaining group (D) served as control. Animals were followed until 11 months of age. Experimental parameters included life span, proteinuria, peripheral lymphocytes, anti-dsDNA antibody titers, and renal histopathology. HBO(2) treatment resulted in increased survival, decreased proteinuria, alterations in lymphocyte-subset redistribution, reduced anti-dsDNA antibody titers, and amelioration of immune-complex deposition in groups A and B. Our data demonstrated that HBO(2) therapy attenuated disease severity in NZB/W F1 mice. HBO(2) treatment may be of use in the clinical treatment of lupus patients and would benefit from further study.     

Intraglomerular tubular epithelial cells. A marker of glomerular hematuria

The occurrence of intraglomerular tubular epithelial cells (ITEC) was investigated in 202 consecutive renal biopsy specimens and were present in 111 (55%). Minimal, focal, or diffuse glomerular diseases were all represented. Of the patients with ITEC 110 (99%) had gross or microscopic hematuria, either alone or associated with proteinuria; however, ITEC were found only in one of 79 proteinuric patients with no documented hematuria. Intraglomerular tubular epithelial cells did not occur in four patients with drug-induced interstitial nephritis and microscopic hematuria, or in 11 normal controls. The pathogenesis of ITEC is not known, but our data indicate that the phenomenon is almost constantly found in association with glomerular hematuria. Identification of ITEC, therefore, should help to confirm the glomerular origin of hematuria when histologic alterations are minimal.     

Fabry病肾病临床病理分析

目的阐明具有肾脏损害的Fabry病的临床病理特点。方法回顾性分析3例具有肾损害的Fabry病患者的临床表现,并对其肾活检组织进行免疫荧光、光镜及超微结构观察。结果3例患者均出现血尿、蛋白尿;光镜下肾小球足细胞体积增大,空泡变性,肾小管上皮也可出现上述改变;电镜下肾小球足细胞胞质内可见大量嗜锇性髓鞘样包涵体—圆形或卵圆形,明暗相间呈板层状,大小为0.3～10μm,外有单位膜包绕。结论具有肾脏损害的Fabry病患者临床上可出现蛋白尿、血尿,晚期常发展为肾功能衰竭。肾小球足细胞胞质内出现嗜锇性髓鞘样包涵体是Fabry病肾病特征性的形态学改变。     

Glomerulonephritis Associated with Sarcoidosis

Clinical findings and structural alterations in the kidneys of 6 patients with sarcoidosis and an associated glomerulonephritis are described. Five of the 6 patients manifested the nephrotic syndrome during some phase of their illness. Additional clinical evidence of renal disease included persistent microscopic hematuria (5 patients), hypertension (4 patients) and progressive renal failure (3 patients). Glomerular pathology varied and included proliferative glomerulonephritis (3 patients), membranous glomerulonephritis (1 patient), and chronic glomerulonephritis (2 patients). In 2 patients sequential examination of the kidney was possible, with renal biopsies preceding autopsy examination by 3 and 6 years, respectively. Glomerular pathology had progressed in severity in each case. Immunofluorescent studies in 2 patients revealed patterns of glomerular antibody localization consistent with immune complex disease. Electron microscopic studies of 1 revealed membranous changes characterized by electron-dense subepithelial and intramembranous deposits. Totally unexpected were virus-like intraendothelial structures in the glomeruli identical to those previously reported in systemic lupus erythematosus. Since current evidence suggests that the pathogenesis of both membranous and proliferative types of glomerulonephritis is immunologic, it should not be surprising that sarcoidosis, a disease which quite possibly results from an immune response to a disseminated antigen(s), should occasionally include glomerulonephritis as a part of its histologic expression.     

CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE

CR1 and CR2 expression is decreased by approximately 50% on B cells of patients with systemic lupus erythematosus (SLE). Expression is also decreased in the MRL/lpr murine model of SLE prior to the development of clinical disease, suggesting that this alteration may play a role in pathogenesis. To determine whether the decrease in receptor levels affects the development of SLE, we analyzed MRL/lpr mice in which CR1/CR2 expression was altered by gene targeting. Mice from each cohort (Cr2+/+, Cr2+/-, and Cr2-/-) were analyzed biweekly for the development of proteinuria and autoantibodies. Kidneys were examined at 12 and 16 weeks for evidence of immune complex deposition and renal disease. Deficiency of CR1/CR2 did not affect survival or development of renal disease as measured by proteinuria. Mice deficient in CR1/CR2 had significantly lower levels of IgG3 rheumatoid factor (RF) and total serum IgG3, suggesting a specific defect in production of IgG3 in response to endogenous autoantigens. Since IgG3 RF has been associated with the development of vasculitis in this model, we examined the mice for alterations in development of this clinical manifestation. Although there was no difference in the development of ear necrosis among the three groups, renal arteritis was not identified in any of the Cr2+/- mice, whereas it was present in 20% of the Cr2+/- and 40% of the Cr2+/+ mice. Finally, significantly higher levels of IgA were seen in the glomeruli of Cr2+/- mice compared to Cr2+/- or Cr2+/+ mice, suggesting that CR1/CR2 are involved in either the regulation of IgA production or the clearance of IgA immune complexes. Together these data support the concept that alterations in CR1/CR2 expression or function affect the regulation of autoantibody production and/or clearance and may have clinical consequences.     

血管紧张素Ⅱ受体拮抗剂联合中成药治疗 慢性肾炎蛋白尿的研究进展

慢性肾炎基本临床表现为蛋白尿、血尿、高血压、水肿,其中蛋白尿是加速肾小球硬化、促进肾功能恶化的重要因素之一,且蛋白尿水平越高,导致肾脏病进展的速度越快,因此积极降低蛋白尿是肾脏病治疗的关键。血管紧张素Ⅱ受体拮抗剂除降压作用外,还有降低患者蛋白尿水平及肾脏保护作用,为进一步减少慢性肾炎蛋白尿,在应用ARB基础上加用中成药亦可获得疗效进行综述。     

Immune-complex glomerulonephritis associated with cytomegalovirus infection.

Histologic and immunopathologic studies were performed at autopsy on the kidneys of a patient in whom hematuria and proteinuria developed in association with cytomegalovirus (CMV) pneumonitis. Light microscopic examination of the kidneys revealed focal mesangial proliferative glomerulonephritis. Immunofluorescent microscopy revealed a granular deposition of IgG, IgA, C3, and C4, mainly in the mesangium. CMV antigens were also demonstrated in a similar immunofluorescent pattern. Glomerulus-bound immunoglobulins were eluted and demonstrated to contain antibodies to CMV antigens. These findings suggest that in some patients who have CMV infection immune-complex glomerulonephritis is induced by glomerular deposition of CMV antigen-antibody complexes.     

Beneficial effect of captopril on systemic lupus erythematosus-like disease in MRL lpr/lpr mice

MRL lpr/lpr (MRL/l) mice exhibit a disease similar to systemic lupus erythematosus (SLE) in humans. To investigate the influence of antihypertensive treatment on this disease, four groups of MRL/l mice were treated with the angiotensin-converting enzyme inhibitor captopril (n = 25), with the sympathetic blocker bretylium (n = 15), and with cyclophosphamide (n = 10). Thirty-five mice did not receive any treatment and served as controls. Survival rate, blood pressure, incidence of proteinuria and hematuria, renal pathology, lymphoid hyperplasia and dermatitis were studied. The survival at the age of 36 weeks was significantly improved by captopril as compared to controls (60 vs. 25%, p = 0.035). The cyclophosphamide group showed no mortality at that time and the bretylium group did not differ from the control group. Captopril and bretylium reduced systolic blood pressure significantly while cyclophosphamide was without effect. Captopril and cyclophosphamide diminished significantly the glomerular damage with less proliferative changes and a decreased incidence of proteinuria. The bretylium-treated animals also exhibited an improved renal pathology index but they did not differ from the controls with respect to proteinuria and hematuria. Lymphoid hyperplasia and dermatitis were decreased only by captopril and cyclophosphamide. It is concluded that captopril improves survival in SLE disease of MRL/l mice, counteracting lymphoid hyperplasia, renal disease, dermatitis and decreasing arterial blood pressure.     

Serum concentrations of immunoglobulins E and G and α2-macroglobulin in childhood renal disease

Serum concentrations of IgE, IgG, and α₂-macroglobulin (α₂M) were determined in 67 children with renal disease and in appropriate controls. IgE concentrations were significantly elevated in patients with renal disease and proteinuria, including those with minimal change nephrotic syndrome (MCNS). IgG concentrations were lower and α₂M concentrations higher in patients with proteinuria than in patients without proteinuria. In 16 patients with nephrotic syndrome who had a decrease in proteinuria with therapy, there was a concomitant decrease in mean serum IgE level. All nine with MCNS had a decrease in serum IgE following therapy whereas eight of the nine had a concomitant increase in serum IgG. The findings suggest the possibility that IgE may play an etiologic role in the proteinuria of childhood nephrotic syndrome, and that both elevated serum IgE and proteinuria may represent unusual responses to antigens that are seldom identified. Elevations of IgE secondary to lowered IgG or to entirely nonspecific alterations in IgE metabolism in proteinuric renal disease are other possibilities. Further studies to elucidate the role of IgE in renal disease, including the nature of the altered metabolism of this immunoglobulin, are warranted.     

Thin glomerular basement membrane disease: light microscopic and electron microscopic studies.

Benign recurrent hematuria usually indicates a good prognosis. This condition is associated with abnormally thin glomerular basement membranes. Of 680 renal biopsy cases in which lower urinary tract disease had been excluded by careful study, 25 cases from seven children and eighteen adults met the criteria for thin glomerular basement membrane disease, placing the incidence of the disease at 3.7%. The mean patient age was 32.4 years and the male to female ratio was 1 to 5.3. The primary finding was microscopic hematuria in eighteen patients and gross hematuria in five patients. Among eighteen patients who had microscopic hematuria, one patient also exhibited proteinuria and one patient suffered from acute renal failure due to acute drug-induced interstitial nephritis. Proteinuria was only found in one patient. All of the patients had normal renal function, with the exception of one who suffered from acute renal failure. The duration of hematuria from the time of detection to the date of biopsy ranged from 3 months to 30 years with a mean interval of 56.6 months. No apparent evidence of familial hematuria in any patient was noted. Under light microscopy most glomeruli were normal. However, five cases showed focal global sclerosis. Under immunofluorescence microscopy seventeen cases were negative for all immunoglobulins, for complement, and for fibrinogen. Eight cases showed nonspecific mesangial deposition of fibrinogen and/or IgM. Ultrastructurally, extensive diffuse thinning of the GBM was a constant finding. The mean thickness of the GBM was 203.2 +/- 28.3 nm (n = 25); the thickness in adult (201.4 +/- 27.5 nm; n = 18) did not differ from that in children (208.1 +/- 32.0 nm; n = 7).     

褪黑素对系统性红斑狼疮样小鼠的影响

为了观察褪黑素 (MT )对CJ S13 1所致的SLE样小鼠改变的影响并探讨其作用机制。采用空肠弯曲菌CJ S13 1和CFA混合免疫动物 ,诱导SLE样小鼠改变。结果表明MT 0 0 1、 0 10、 1 0mg/kg/d× 2 8d ,ig能部分或完全拮抗血清抗ssDNA和组蛋白IgG型自身抗体水平的升高 ,抑制ConA及LPS诱导的淋巴细胞增殖反应的增强 ,降低动物尿蛋白水平 ,减轻肾组织病变程度。提示一定剂量的MT对SLE样小鼠改变具有一定的保护作用。     

Proteinuria predicts relapse in adolescent and adult minimal change disease

OBJECTIVE:

This study sought to outline the clinical and laboratory characteristics of minimal change disease in adolescents and adults and establish the clinical and laboratory characteristics of relapsing and non-relapsing patients.

METHODS:

We retrospectively evaluated patients with confirmed diagnoses of minimal change disease by renal biopsy from 1979 to 2009; the patients were aged >13 years and had minimum 1-year follow-ups.

RESULTS:

Sixty-three patients with a median age (at diagnosis) of 34 (23-49) years were studied, including 23 males and 40 females. At diagnosis, eight (12.7%) patients presented with microscopic hematuria, 17 (27%) with hypertension and 17 (27%) with acute kidney injury. After the initial treatment, 55 (87.3%) patients showed complete remission, six (9.5%) showed partial remission and two (3.1%) were nonresponders. Disease relapse was observed in 34 (54%) patients who were initial responders (n = 61). In a comparison between the relapsing patients (n = 34) and the non-relapsing patients (n = 27), only proteinuria at diagnosis showed any significant difference (8.8 (7.1-12.0) vs. 6.0 (3.6-7.3) g/day, respectively, p = 0.001). Proteinuria greater than 7 g/day at the initial screening was associated with relapsing disease.

CONCLUSIONS:

In conclusion, minimal change disease in adults may sometimes present concurrently with hematuria, hypertension, and acute kidney injury. The relapsing pattern in our patients was associated with basal proteinuria over 7 g/day.     

Benign familial hematuria

Fifty children had benign familial hematuria. They were from 43 families showing neither deafness, heavy proteinuria, nor chronic renal failure and had a nonprogressive course. Light microscopy of renal biopsy specimens showed little or no glomerular changes. Immunofluorescence showed no significant glomerular deposits of immunoglobulins or complement components, but deposition of C3 in the arteriolar walls was observed in 21 of the 39 patients examined. Electron microscopy demonstrated widespread attenuation of the glomerular basement membrane (GBM) in 19 patients, focal attenuation in 22, and normal GBM in nine. These observations suggest that patients with benign familial hematuria are heterogeneous and that the thin GBM may be related to hematuria.