Light chain nephropathy in a 19-month-old boy with AIDS.

A 19-month-old boy with AIDS developed clinically unexplainable proteinuria. Biopsied renal tissue was examined by light microscopy, transmission electron microscopy, and immunofluorescence. Findings included an increase of mesangial matrix with occasional nodular sclerosis, mesangial hypercellularity, and glomerular deposits of kappa and lambda light chains. There were deposits of kappa, but not lambda, light chains in the arteriolar walls, and around the tubular and interstitial capillary basement membranes. Quantitative urinary immunoelectrophoresis revealed an extremely high urinary concentration of kappa light chain. These changes are diagnostic of light chain nephropathy. The rarity of light chain nephropathy in childhood and its occurrence in a patient with AIDS make this case unusual.     

Light Chain Nephropathy in a 19-mo nth-old Boy with AIDS

A 19 month old boy with AIDS developed clinically unex-plainable proteinuria. Biopsied renal tissue was examined by light microscopy, transmission electron microscopy, and immunofluorescence. Findings included an increase of mesangial matrix with occasional nodular sclerosis, mesan-gial hypercellularity, and glomerular deposits of kappa and lambda light chains. There were deposits of kappa, but not lambda, light chains in the arteriolar walls, and around the tubular and interstitial capillary basement membranes. Quantitative urinary Immunoelectrophoresis revealed an extremely high urinary concentration of kappa light chain. These changes are diagnostic of light chain nephropathy. The rarity of light chain nephropathy in childhood and its occurrence in a patient with AIDS make this case unusual.     

Single light chain subclass (kappa chain) immunoglobulin deposition in glomerulonephritis

Renal glomerular disease characterized by the deposition of immunoglobulin light chains or monoclonal immunoglobulins was demonstrated by immunofluorescence microscopy in 11 patients. The most common histopathologic findings were those of mesangiocapillary glomerulonephritis, but considerable variability was observed. Lesions resembling diabetic glomerulosclerosis and amyloidosis were seen in some patients. Immunofluorescence findings in seven patients showed concomitant, equally intense staining for kappa light chain and immunoglobulin heavy chain (IgG or IgA), indicative of monoclonal immunoglobulin deposition. Specimens in the remaining cases stained predominantly for kappa light chain alone. In six cases the histologic and ultrastructural pattern was similar to that of type I mesangiocapillary glomerulonephritis. In three cases linear deposits were present, predominantly in subendothelial and inner glomerular basement membranes and, to a lesser degree, in mesangial locations, as in type II mesangiocapillary glomerulonephritis. In one of the latter cases dense deposits were intermixed with aggregates of amorphous fibrillar material indistinguishable from amyloid. In two cases involving IgA kappa chain deposition the histologic and ultrastructural appearance was that of mesangial glomerulonephritis. Considerable heterogeneity was found in the clinical features of the patient population. Specific clinical or serologic parameters for this disease could not be identified. Only one patient had an associated lymphoplasmacytic disorder. After follow-up periods ranging from six months to 17 years, all of the patients were alive, including four who had progressed to end-stage renal disease and required dialysis. Two of the latter patients underwent successful renal transplantation; one had been alive for five years and the other for three months without evidence of recurrence of the renal disease at the last follow-up examination.     

轻链肾病的病理学特点

目的 探讨轻链肾病(1ight chain nephropathy,LCN)的病理学特点及其诊断方法。方法 对7例LCN进行了系统的光镜、免疫荧光及透射电镜检查,并进行轻链蛋白(κ、λ)的免疫荧光和免疫电镜标记。结果 7例的光镜表现不一,3例系膜结节状硬化性肾小球病,1例系膜轻至中度增生;其余3例为管型肾病,肾小球病变轻微。免疫荧光检查：7例均可见单一品种的轻链蛋白在肾小球系膜区团块状,及肾小球基底膜、肾小管基底膜和小血管壁呈线性沉积。透射电镜检查可见肾小球系膜区和基底膜内侧、肾小管基底膜外侧及小血管壁的颗粒状电子致密物沉积。免疫电镜标记显示,肾小球基底膜内侧和系膜区、肾小管基底膜外侧及小血管壁的颗粒状沉积物均可被单一品种轻链蛋白(5例κ,2例λ)标记。结论 典型的LCN呈系膜结节状硬化性肾小球病,电镜观察到LCN的特征性超微结构改变具有诊断意义,结合轻链蛋白(κ、λ)的免疫荧光或免疫电镜检查可进一步确诊,尤其对光镜病变不明显的LCN更有意义。     

Differential expression of laminin isoforms in diabetic nephropathy and other renal diseases

Laminin a non-collagenous glycoprotein is a major component of the renal glomerular basement membrane and mesangium. Thus far eleven distinct chains have been described, permutations of which make up 15 laminin isoforms. Laminin molecules interact with cells and other matrix molecules during organ development and differentiation. We studied the distribution of laminin isoforms in patients with type 1 diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis and IgA nephropathy/ Henoch-Sch?nlein purpura. Immunofluorescence microscopic studies with laminin-chain-specific antibodies to the α1, α2, α5, β1, β2 and γ1 chains detected α2, β1 and γ1 chain expression in the normal mesangium and α5, β2 and γ1 in normal glomerular basement membrane. Significantly, constituents of the glomerular basement membrane, α5, β2 and γ1 chains were overexpressed in kidneys with diabetic nephropathy. Initially the constituents of the mesangium increased commensurate with the degree of mesangial expansion and degree of diabetic nephropathy. Reduction in α2 chain intensity was observed with severe mesangial expansion and in the areas of nodular glomerulosclerosis. In addition, with late disease aberrant expression of α2 and β2 chains was observed in the mesangium. Glomerular basement membrane in renal disease overexpressed molecules normally present in that location. In summary, the alterations in basement membrane composition in various renal diseases seem to not only reflect the balance between synthesis and degradation of normal basement membrane constituents, but also their aberrant expression.     

Immunoelectron microscopic studies of immune complex deposits and basement membrane components in IgA nephropathy

The relationship between the immune complex deposits of mesangial IgA nephropathy and the basement membrane components, type IV collagen and fibronectin, has been investigated by an indirect immunogold technique in four cases of mesangial IgA disease. Using paraformaldehyde-fixed, Lowicryl K4M resin-embedded kidney, IgA, IgM and C3 were localized in the mesangial electron-dense deposits with 10 and 20 nm gold-labelled secondary antibodies. In the same glomeruli, type IV collagen and fibronectin were rarely present within the electron-dense deposits, although both were distributed throughout the remainder of the mesangial matrix with the exception of the subepithelial regions. These two components were also present within the glomerular basement membrane and localized mainly on the endothelial aspect. A similar distribution of the basement membrane components was seen in a control kidney processed in the same way. This technique gives reproducible results and has demonstrated for the first time the relationship between the mesangial immune complex deposits of mesangial IgA nephropathy and the basement membrane components of the matrix in which they are found.     

膜性肾病合并IgA肾病的临床病理特点

目的探讨膜性肾病合并IgA肾病的临床病理特点。方法回顾性研究北京大学第一医院肾内科和北京大学肾脏病研究所1998年1月—2006年4月问的肾活检病例9572例,对11例膜性肾病合并IgA肾病的临床病理特点进行分析,结合免疫电镜标记方法,对其病理诊断及发病机制进行探讨。结果11例患者以中年为发病高峰,平均年龄39．9岁,女性多于男性（男：女为1：2．9）,临床表现为蛋白尿,其中7例（63．6％）出现肾病综合征水平的蛋白尿,7例（63．6％）合并镜下血尿,肾功能均正常,除外了肝炎病毒感染、系统性红斑狼疮等继发性疾病。光镜下可见肾小球基底膜空泡变性和增厚,系膜细胞和基质轻度增生,2例可见少数肾小球伴有新月体形成。免疫荧光检查见IgG和c3颗粒样沿肾小球毛细血管壁沉积;IgA团块状在肾小球系膜区沉积。电镜检查可见肾小球上皮细胞下多数块状电子致密物沉积,系膜区可见团块状电子致密物沉积。免疫电镜标记结果显示,IgG定位于肾小球上皮细胞下的电子致密物,IgA定位于肾小球系膜区的电子致密物。结论膜性肾病合并IgA肾病兼具有膜性肾病和IgA肾病的临床病理特点,其发生过程可能为各自独立发生的两种疾病的叠加所致。     

Kappa light chain nephropathy

Summary Percutaneous renal biopsies from 4 patients with clinically unsuspected kappa light chain nephropathy were studied using light, immunofluorescence, and electron microscopy. The diagnosis in each case was established by demonstrating monoclonal kappa light chain deposits in basement membranes and basement membrane-like structures of glomeruli, tubules, and blood vessels by immunofluorescence microscopy. Characteristic electron dense deposits occurred in every case but the intensity and distribution of electron densitites did not correlate with the immunofluorescence findings. When light chain aggregation occurred, as evidenced by the distribution of electron dense deposits, it was proportional to the amount of basement membrane-like material as if these immunoglobulins had a particular affinity for structures chemically related to basement membranes. Although active tubulointerstitial lesions were prominent in all biopsies, there was considerable variation in glomerular pathology with only 1 case exhibiting the typical nodular glomerulosclerosis. Correlation of the light, immunofluorescence, and electron microscopic findings in these cases suggests that the pathogenesis of kappa light chain nephropathy is related to light chain nephrotoxicity directed to basement membrane-like structures with subsequent alterations in hemodynamics and structural renal damage.     

ACE inhibitors and diabetic nephropathy: clinical and experimental findings

Summary Apart from near normal metabolic control, early treatment of an increase in blood pressure in diabetic patients with nephropathy, is one of the most important therapeutic methods to prevent further progression of this complication. Long-term studies, recently published, suggest that ACE inhibitors have a beneficial effect on albuminuria and progression of nephropathy, irrespective of their hemodynamic effects. However, the mechanism by which ACE inhibitors exert these positive effects on glomerular pathology is still unclear. Several non-hemodynamic factors have been identified as being involved in the pathogenesis of diabetic nephropathy: (a) changes in the composition of glomerular basement membrane due to a changed metabolism of the proteins which make up this structure; consequences are an impairment of the filtration properties, onset of proteinuria as well as thickening of basement membrane; (b) Mesangial expansion due to an overproduction of mesangial matrix and deposition of proteins as well as (c) impairment of mesangial clearance function; consequences are development of glomerulosclerosis and reduction of filtration surface. It is known that the renin-angiotensin-system is stimulated in diabetic patients with nephropathy and that angiotensin II influences the synthesis of glomerular and mesangial proteins as well as the function of mesangial cells. Hypothetically, these points could explain the beneficial effects of ACE-inhibitors on the progression of diabetic nephropathy.     

Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy

Summary Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capilleries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra- and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focuse on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucose-induced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of extracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.Abbreviations HSPG heparan sulfate proteoglycan - GBM glomerular basement membrane - ECM extracellular matrix - AGE advanced glucosylation end products - TNF tumor necrosis factor - bFGF basic fibroblast growth factor     

Immunohistochemical study of the membrane attack complex of complement in IgA nephropathy

Summary The localization of the membrane attack complex of complement (MAC) was examined in the normal human kidneys and in biopsy specimens from patients with primary IgA nephropathy by immunofluorescent and immunoelectron microscopies. Immunofluorescent staining for MAC was significantly more intense than in the normal kidneys, and was observed in the mesangium and occasionally along the glomerular capillary walls of 22 of 30 patients with IgA nephropathy. By dualstaining, the MAC deposits were generally concordant with the deposits of IgA, C3, C5 and C9, or of IgG, when present. C1_q or C4 was infrequently observed in the glomeruli. Immunoelectron microscopy revealed various staining patterns of glomerular MAC deposition; homogeneous fine-granular staining beneath the glomerular basement membrane (GBM) in the paramesangial zone, patchy staining within the mesangial electron dense deposits (EDD), and ring-shaped or ribbon-like staining, associated with the striated membrane structures (SMS), in the matrix of the mesangium, GBM and tubular basement membrane (TBM). This study suggests that the terminal complement system is activated, mainly by an alternative complement pathway mechanism, in the mesangium of IgA nephropathy, and is associated with the paramesangial lesion and EDD. MAC deposition in glomerular SMS may also result from in situ activation rather than trapping from the circulation. There was little correlation between glomerular MAC deposition and proteinuria or renal histology of patients with IgA nephropathy.     

Glomerular capillary aneurysms in light-chain nephropathy. An ultrastructural proposal of pathogenesis.

The occurrence of glomerular capillary aneurysms in light-chain nephropathy and a morphologic pattern of development as determined by electron microscopy are described. Renal biopsies from 4 patients with nodular glomerulopathy were evaluated. Light-chain deposition in mesangium and capillary walls was associated with monocyte accumulation in capillaries. Loss of endothelial cell lining and disruption of mesangial anchoring points of basement membranes ensued, resulting in aneurysmal dilatation of the capillaries. The walls collapsed, and the aneurysms healed as a result of mesangial interposition, a process which, in combination with enlarging nodules, led to thickening and collapse of the walls and narrowing of the lumens. This study, in conjunction with review of photographs from previously published reports, indicates that glomerular aneurysms are a common feature of nodular light-chain glomerulopathy. It also emphasizes additional light-microscopic similarities between this glomerulopathy and nodular diabetic glomerulosclerosis.     

Frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma

The frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy was determined in a necropsy study of 57 patients with myeloma. The diagnosis of light chain deposition nephropathy was established by immunofluorescence microscopic examination of kidney tissue demonstrating linear deposits of a single light chain isotype along tubular and other renal basement membranes, and by electron microscopy, which showed the characteristic granular nature of the deposits. In this study, 3 patients (5%) had kappa light chain deposition nephropathy, 6 (11%) had renal amyloidosis, and 18 (32%) had Bence Jones cast nephropathy. The data indicate that light chain deposition nephropathy is a rare complication of multiple myeloma.     

Henoch-Schönlein anaphylactoid purpura nephropathy: Electron microscopic lesions mimicking acute poststreptococcal nephritis

The clinical, laboratory, and histologic features of a patient with Henoch-Schönlein syndrome are presented. The skin biopsy examination showed “leucocytoclastic vasculitis”. Kidney tissue demonstrated deposits of IgG, IgA, C3, and fibrinogen-fibrin by fluorescence microscopy in the mesangium and the peripheral glomerular basement membrane in a granular-nodular pattern. These correlated well with areas of mesangial hyperplasia and polymorphonuclear leucocyte infiltration seen by light and electron microscopy. Several well delineated, variably sized, subepithelial electron dense deposits flanked by polymorphonuclear leucocytes adherent to the glomerular basement membrane were seen in two of the four glomeruli examined by electron microscopy.The significance of these findings is discussed. A detailed ultrastructural evaluation of patients with Henoch-Schönlein nephropathy may yield information about the frequency of subepithelial deposits and perhaps may help to clarify the pathogenesis of this syndrome.     

Proliferative glomerulonephritis with discrete deposition of monoclonal immunoglobulin γ1 CH2 heavy chain and κ light chain: A new variant of monoclonal immunoglobulin deposition disease

A 45‐year‐old man presented with moderate proteinuria and hematuria. A renal biopsy showed mesangial/endocapillary proliferative glomerulonephritis, linear deposition of monoclonal immunoglobulin γ1 C_H2 heavy chain along glomerular and tubular basement membranes (GBMs and TBMs), granular deposition of κ light chain within the mesangial area, and continuous linear deposits of finely granular electron‐dense materials along GBMs and TBMs. Dual immunostaining showed essentially discrete glomerular localization of γ1 C_H2 heavy chain and κ light chain. Monoclonal protein was not detected in urine and serum. A bone marrow aspiration showed no abnormalities. Steroid therapy led to the improvement of proteinuria and hematuria. We would classify this case as a new variant of monoclonal immunoglobulin deposition disease, light chain/heavy chain deposition disease. In contrast with light and heavy chain deposition disease, the remarkable characteristics of this variant are separate deposition of monoclonal heavy chain and light chain, deposition of largely deleted γ heavy chain lacking the C_H1 domain, and good response to steroid therapy.     

Ultrastructure of kidney from three patients with HBeAg-associated nephropathy with special reference to virus-like particles in the glomerular tufts

The biopsied kidneys from three patients with hepatitis Be antigen (HBeAg)-associated nephropathy were observed by light microscopy, immunohistochemistry and electron microscopy. By an indirect technique utilizing horseradish peroxidase-conjugated antisera, HBeAg was found to be deposited in a diffuse granular fashion along the glomerular capillary wall. No deposition of hepatitis Bs or hepatitis Bc antigen was detected. The three cases were diagnosed as HBeAg-associated nephropathy. Ultrastructurally, there were finely granular electron-dense deposits in the subendothelial area, basement membrane, mesangial area and subepithelial area of the glomerular tufts. In all three cases, virus-like particles between 30 and 70 nm in diameter were also found in such areas of the glomerular tufts, and rarely in the glomerular capillary lumen and space of Bowman. They occasionally formed clusters in the phagosomes of mesangial cells. In addition, tubulo-reticular structures were noted in the cytoplasm of endothelial cells in the glomerular capillaries. The presence of HBeAg both in the serum and in the kidney and of virus-like particles in the glomerular tufts suggests that HBeAg is causally related to the development of HBeAg-associated nephropathy.     

The immunochemical characterization of the light chains in the mesangial IgA deposits in IgA nephropathy

The immunochemical characterization of the light chains of the mesangial immunoglobulin A (IgA) deposits were studied in 45 patients with IgA nephropathy. Kappa and lambda light chains were detected with direct immunofluorescence (IF) method, using monospecific rabbit anti-human anti-kappa and anti-lambda anti-sera. The glomeruli of 42 renal biopsies studied were strongly positive for lambda light chain, while only 25 specimens were positive for kappa light chain. Sixty-five percent of the biopsies showed a predominance of lambda light chain IF staining in the mesangial deposits. This IF pattern is unique as compared with similar studies on renal biopsies from patients with systemic lupus erythematosus, idiopathic membranous nephropathy, and normal postmortem renal tissue. The results indicate that mesangial IgA deposits in IgA nephropathy consist mainly of IgA with lambda light chains despite the fact that the normal ratio of kappa to lambda light-chain-containing immunoglobulin in human serum is two to one.     

IgM nephropathy in adults: incidence and correlation with electron microscopic features

IgM nephropathy is characterised on light microscopy (LM) by variable features of normal glomeruli to mesangial hypercellularity; and immunofluorescence (IF) deposits of LgM. Our aim was to study the incidence of IgM nephropathy in adults with primary glomerular disease, with correlation to electron microscopy (EM) features. All adults presenting with proteinuria glomerular hematuria underwent renal biopsy. We excluded patients with systemic diseases and post-infectious glomerulonephritis. All the specimens were evaluated by LM, IF and EM. Our series had 146 cases. Of the 42 cases diagnosed on LM as minimal change disease, mesangial deposition of IgM was present in 11 cases. In addition there were seven cases of mesangioproliferative glomerulonephritis with mesangial IgM deposition. Thus, there were a total of 18 cases of IgM nephropathy (12.3%). Only six of these 18 cases showed typical electron dense deposits in the mesangium on EM. We feel that IgM nephropathy is probably a separate pathological entity, comprising 12.3% of all adults with primary chronic glomerulopathy. Electron dense deposits are seen in only about a third of these cases.     

ULTRASTRUCTURE OF KIDNEY FROM THREE PATIENTS WITH HBeAg-ASSOCIATED NEPHROPATHY WITH SPECIAL REFERENCE TO VIRUS-LIKE PARTICLES IN THE GLOMERULAR TUFTS

The biopsied kidneys from three patients with hepatitis Be antigen (HBeAg)-associated nephropathy were observed by light microscopy, immunohistochemistry and electron microscopy. By an indirect technique utilizing horseradish peroxidase-conjugated antisera, HBeAg was found to be deposited in a diffuse granular fashion along the glomerular capillary wall. No deposition of hepatitis Bs or hepatitis Be antigen was detected. The three cases were diagnosed as HBeAg-associated nephropathy. Ultrastructurally, there were finely granular electron-dense deposits in the subendothelial area, basement membrane, mesangial area and subepithelial area of the glomerular tufts. In all three cases, virus-like particles between 30 and 70 nm in diameter were also found in such areas of the glomerular tufts, and rarely in the glomerular capillary lumen and space of Bowman. They occasionally formed clusters in the phagosomes of mesangial cells. In addition, tubulo-reticular structures were noted in the cytoplasm of endothelial cells in the glomerular capillaries. The presence of HBeAg both in the serum and in the kidney and of virus-like particles in the glomerular tufts suggests that HBeAg is causally related to the development of HBeAg-associated nephropathy.     

Glomerular electron-dense deposits in childhood IgA nephropathy

Summary An electron-microscopic study of the glomeruli was made on 154 children with IgA nephropathy and no evidence of systemic disease, in whom immunofluorescence microscopy had shown diffuse mesangial deposition of IgA. Mesangial deposits were observed in all but eight children. Subepithelial deposits were observed in 40 children and were almost always accompanied by both mesangial and subendothelial deposits. Subepithelial deposits were significantly associated with more severe clinical presentations, a worse outcome and more severe light microscopic glomerular changes. These observations support the concept that IgA nephropathy is an immune complex disease.