Thin basement membrane nephropathy as a cause of recurrent haematuria in childhood

A survey of 69 children presenting with recurrent or persistent haematuria and submitted to percutaneous renal biopsy at this hospital over a 17-year period, was performed to establish the incidence of thin basement membrane nephropathy (TBMN). A diagnosis of primary glomerular disease was established in 44 (IgA nephropathy in 16, Alport's syndrome in 13 and other varieties of glomerulonephritis in 15). Of the remaining 25 patients in whom light microscopical and immunochemical examination revealed no abnormalities, material for electron microscopy was available in 11. In eight of these (five of whom had a family history), TBMN was diagnosed on the basis of ultrastructural morphometric evaluation of glomerular basement membrane thickness. Assuming a similar proportion of the remaining 14 patients with renal biopsy specimens normal by light microscopy had TBMN, the probable frequency of this abnormality in the whole series would be 26%, very similar to that of IgA nephropathy. In the eight TBMN patients the mean glomerular basement membrane thickness ranged between 181 and 236 nm, whilst in 'control' biopsies from children with 'minimal change' nephrotic syndrome or IgA nephropathy, the mean thickness ranged between 242 and 333 nm.     

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).     

Basement membrane nephropathy: a new classification for Alport's syndrome and asymptomatic hematuria based on ultrastructural findings

Renal biopsy specimens from 19 patients with asymptomatic hematuria, normal glomeruli on light microscopic examination, and negative immunofluorescence were studied to characterize the ultrastructural changes of the glomerular basement membrane. Three groups of patients were identified. Four patients (group 1) had type I basement membrane nephropathy, characterized by marked thickening and lamellation of the basement membrane in a pattern resembling that of Alport's syndrome. Seven patients (group 2) had type II basement membrane nephropathy, which was characterized by extensive attenuation of the basement membrane with only occasional small areas of lamellation or fragmentation. Eight patients (group 3) had moderate variability in basement membrane thickness with no other structural alterations. The authors propose that this pathologic classification be used in patients with asymptomatic hematuria as a basis for long-term clinical investigations, in hopes of distinguishing the natural history of each group.     

Thin Glomerular Basement Membranes in Patients with Hematuria and Minimal Change Disease

A detailed morphometric analysis of glomerular basement membrane (GBM) thickness was carried out on biopsies from 16 patients exhibiting normal histology and unremarkable immunofluorescence. Eleven of these patients presented with proteinuria, 8 in the nephrotic syndrome range, while 5 had hematuria as well. The remaining 5 patients presented with hematuria only. Eight patients had an initial diagnosis of minimal change disease, 4 were diagnosed as thin-membrane nephropathy, 2 had Alport syndrome, and the remaining 2 had hypertensive nephropathy. Quantitative morphometric analysis of GBM identified 3 subsets of patients. The first subset consisted of 6 patients: 5 adults, with an average GBM width of 361+/- 34 nm, and 1 child. The second subset included 8 patients with thin GBMs and a mean thickness of 253+/- 15 nm. The last subset comprised 2 patients with Alport syndrome showing marked variability in GBM thickness. This study has confirmed the presence of thin GBMs in hematurics, but has also revealed GBM thinning in 50% of patients with a diagnosis of minimal change disease.     

Chronic hereditary nephritis. A clinicopathologic study of 23 new kindreds and review of the literature.

Thirty-three patients with chronic hereditary nephritis, obtained from 23 unrelated families, were evaluated with respect to clinicopathologic features. Renal tissue was examined by light microscopy in 25 cases, immunofluorescence in 19 cases, and electron microscopy in 16 cases. The light microscopic findings varied, and foam cells were present in only four cases. Immunofluorescence was negative in all but four cases, and in these the immunomicroscopic pattern was compatible with the findings of end stage glomeruli and hyaline arteriolar sclerosis. Although electron microscopy uniformly showed marked thinning or splitting of the glomerular basement membrane, parallel splitting of the glomerular basement membrane with interposition of electron dense granular particles was seen in only eight cases. Association of glomerular basement membrane splitting with granular particles was observed in four of six patients with IgA nephropathy, in two patients with benign familial hematuria, and in a normal kidney donor. Eleven patients, seven men and four women, had chronic renal failure requiring dialysis. Of five patients who received renal allografts, three are alive, with post-transplant survival ranging from 24 to 70 months. The other two died of septicemia.     

Renal diseases associated with hematuria in children and adolescents: a brief tutorial

The detection of microscopic hematuria in a child's urine prompts evaluation for renal and urinary bladder causes. Microscopic hematuria identified during a routine physical examination by the pediatrician is much more common than macroscopic hematuria. Persistent microscopic hematuria is particularly worrisome and may require a percutaneous needle core kidney biopsy to determine whether the etiology is secondary to glomerular disease, tubulointerstitial disease, urinary tract infection, urinary tract structural abnormalities, medications, or toxins. This paper reviews the epidemiology, pathologic features, pathogenesis, treatment, and outcome of familial hematuria (Alport syndrome [hereditary nephritis]), thin basement membrane nephropathy), IgA nephropathy, Henoch-Sch?nlein purpura, and acute postinfectious glomerulonephritis.     

Isolate diffuse thickening of glomerular capillary basement membrane: a renal lesion in prediabetes?

A total of 23 patients with proteinuria and isolated ultrastructural diffuse thickening of the glomerular capillary basement membrane were studied, focusing on the possibility of diabetes mellitus, morphometry of the capillary basement membrane, and the comparison with three other groups of patients. These included 14 patients with minimal change nephropathy (MCN), 45 patients with type II diabetes arbitrarily divided into 11 early and 34 late diabetic patients, defined, respectively, as less than 3 and over 5 years history, and 13 patients biopsied for transient mild proteinuria or hematuria, with no evidence of renal disease on follow-up were used as controls. The level of proteinuria and prevalence of hematuria were similar in patients with isolated thick basement membrane and with diabetes. Diabetic retinopathy was present in 10% of early diabetes, 69% of late diabetes, but not in isolated thick basement membrane. Kimmelstiel-Wilson nodules were seen in late diabetes, and not in other patients. Hyaline arteriosclerosis was more common in late diabetes than in early diabetes or isolated thick basement membrane. The basement membrane thickness was similar between controls (371+/-17 nm) and MCN (345+/-16 nm), between patients with isolated thick basement membrane (482+/-69 nm) and early diabetes (457+/-64 nm), but significantly thicker in isolated thick basement membrane as compared to controls and MCN. In patients with isolated thick basement membrane, the basement membrane thickness was not correlated with age, smoking, body weight, hyaline arteriosclerosis, and hypertension. However, blood tests for diabetes were positive in 20% of patients at biopsy, in 44% at 6 months and 70% at 24 months follow-up, while seven patients showed no evidence of diabetes on follow-up. Patients with proteinuria and isolated thick glomerular basement membrane must be differentiated from MCN for therapeutic implications, and specifically managed for its strong association with prediabetes or early diabetes.     

Idiopathic linear glomerular IgA deposition

Linear deposition of IgA immunoglobulin was found along the glomerular basement membrane in two patients with normal renal function and no pulmonary abnormalities. One patient had recurrent gross hematuria and a mild focal proliferative glomerulonephritis without deposits on electron microscopy; the second patient had a renal cell carcinoma. This observation of linear IgA antibody deposition in the absence of Goodpasture's syndrome or diabetes mellitus extends the spectrum of diseases associated with glomerular basement membrane-IgA deposition.     

The ultrastructural characteristics of minor glomerular abnormalities]

Among 1168 patients in whom clinical data and light microscopic, immunofluorescence and electron microscopic findings of renal biopsies were available, 329 had minor glomerular abnormalities. These 329 cases included 38 with glomerular minimal change (MC), 32 with glomerular minor lesion, 143 with mild mesangioproliferative GN, 14 with mild mesangioproliferative IgM nephropathy, 4 with C1q nephropathy, 37 with IgA nephropathy, 12 with Henoch-Sch?nlein purpura GN, 17 with lupus nephritis, 16 with early stage membranous nephropathy (eMN), 4 with Alport's syndrome (ALS), 7 with thin basement membrane nephropathy (TMN) and 5 with nonglomerular haematuria. Their histologic appearances were nearly normal, and immunofluorescence was negative or mild positive. But electron microscopic appearances were diagnostic. Electron microscopy is the only diagnostic method for MC, ALS, TMN and eMN.     

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。     

Glomerular basement membrane abnormalities associated with apparently idiopathic hematuria: ultrastructural morphometric analysis

In a recent review of 480 renal biopsies, 41 cases were identified in which glomerular basement membrane (GBM) ultrastructural abnormalities were the major lesion. All of the patients had hematuria. None had evidence of immune-mediated glomerulonephritis. Positive family histories of renal disease were present in the majority of cases, and one case of Alport's syndrome was included. Subjectively, the GBM changes were variable but nearly always included membrane thinning. For objective characterization of this glomerular abnormality, a detailed morphometric study of GBM thickness was undertaken: 12 of these patients (study group) were compared with seven patients (control subjects) with subjectively normal glomeruli who underwent biopsy for reasons other than nonsurgical hematuria but who were also thought to have normal glomerular ultrastructure. The seven control subjects had a mean GBM thickness of 394 nm (SD, 19; range, 356 to 432 nm). Of the 12 study group patients, 11 had mean GBM thicknesses significantly different from control values (nine had mean GBM thinning: range, 235 to 327 nm; two had thickening: means, 440 and 469 nm). In the remaining case (Alport's syndrome) the overall mean was normal, but an abnormal distribution of very thin and very thick GBM regions was seen. Of the four apparently normal hematuric patients, significant mean GBM thinning (326 to 347 nm) was demonstrated in three, with an excess of thin GBM in the fourth case, although the mean thickness was normal. Thus, measurable abnormalities were defined in all of the cases of hematuria examined. The GBM measurements confirmed the subjective impression of membrane abnormality, usually attenuation, as the principal finding in this group of hematuric patients. Furthermore, morphometric analysis may reveal subtle changes of GBM thickness missed by subjective assessment.     

Glomerular alterations in idiopathic haematuria--ultrastructural and morphometric analysis.

Re-evaluation of kidney biopsies has been done along with morphometric analysis of glomerular basement membrane thickness (G.B.M.) in 41 cases of idiopathic haematuria, in whom the initial routine light, immunofluorescent and electron microscopic examination had not shown any significant alterations. Extreme attenuation of G.B.M. (mean thickness of 2581 +/- 488 A) had been found in thirty one patients in contrast to mean GBM thickness of 4295 +/- 470 A found in control group. Absence of any history of familial haematuria in these patients distinguished them from hereditary nephropathies and hence categorized under the term thin basement membrane nephropathy. Follow up of these patients for upto 8 years had shown persistence of symptoms without further deterioration of renal function as well as morphology.     

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.     

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.     

IgA nephropathy. Correlation of clinical and histologic features

The clinical and histologic features of 81 patients with IgA nephropathy were analyzed. Azotemia was present in 32 per cent of the patients, proteinuria was present in 88 per cent, and gross or microscopic hematuria was present in all of the patients tested. The median age of histologic diagnosis was 27 years. The median age at onset of clinical signs was 20 years. There was no increased incidence in any HLA-A or -B antigen within the patient population over our control population. All patients had glomerular mesangial IgA deposition (by definition) greater than or equal to IgG or IgM. Histologic changes were quantitated and ranged from normal to necrotizing and/or crescentic glomerulonephritis. Many patients (48 per cent) had mild or moderate generalized glomerlular hypercellularity. Nonparametric statistical analysis showed strong correlations among patient age at histologic diagnosis, creatinine, proteinuria, global glomerular sclerosis, and interstital fibrosis. Our analysis suggests that IgA nephropathy is an indolent disease generally beginning in childhood. It is a cause of renal insufficiency in a significant number of patients. Interpretation of this series and other reported studies suggests that most cases of IgA nephropathy in the United States are best considered idiopathic but that hereditary and secondary forms may exist.     

Immunoelectron microscopy of IgA nephropathy

The distribution of IgA, IgG, IgM, C3, and albumin in kidney biopsy specimens from 11 children and adults with recurrent gross and microscopic hematuria and IgA nephropathy and 7 control specimens were evaluated by the direct peroxidase-labeled antibody method and electron microscopy. Granular masses of reaction product (RP), representing IgA, IgG, IgM, and C3, were observed within the mesangial matrix of glomeruli from all patients with IgA nephropathy. Occasional smaller masses of IgA-RP and C3-RP were noted along the peripheral glomerular capillary loops, the tubular basement membranes, and within the interstitial matrix of some patients. Large amounts of IgA-RP and C3-RP were present within the walls of small renal arterioles of several patients. These observations support the concept that immune-complex deposits are involved in the pathogenesis of IgA nephropathy and suggest that vascular deposits may have a more important role in the progression of the disease in some patients.     

Thin basement membrane syndrome in adults.

Eight (two men, six women) cases of adult thin basement membrane syndrome were studied to clarify the clinicopathological characteristics of the disease. The average age at the time of biopsy was 40 years. All the patients had persistent microscopic haematuria, normal renal function, and normal blood pressure, with the exception of one who was hypotensive. Most of them had persistent or transient proteinuria. Renal symptoms were found in four families, although no relative had Alport's syndrome. Renal biopsy findings observed by light and immunofluorescence microscopy did not indicate any important abnormalities, but extensive diffuse thinning of the glomerular basement membrane, ranging from 153 to 213 nm, was a constant finding by electron microscopy. All the patients retained stable renal function at the time of final follow up, indicating a benign prognosis of the syndrome.     

Thin basement membranes in minimally abnormal glomeruli

The light microscopic, immunofluorescence, and electron microscopic appearances of renal biopsy specimens were reviewed and correlated with the clinical and laboratory findings in 61 patients in whom the findings were initially considered to be either normal or to show only minor non-specific abnormalities. In all cases this reassessment included quantitative measurement of glomerular basement membrane thickness by an orthogonal intercept technique. On the basis of the indication for biopsy, patients were classified into three groups: those with haematuria (group I, n = 41); those with a minor degree of proteinuria (group II, n = 16); and those without any urinary abnormality but in whom possible renal disease as a result of systemic disease was suspected (group III, n = 6). About half of the patients with haematuria had significantly thinner glomerular basement membranes than those in the other two groups, irrespective of the variable selected for assessment, and in three this was confirmed in follow up biopsy specimens. Follow up for up to eight years showed that in patients either with or without thin basement membranes haematuria commonly persisted, but the long term outlook in all three groups was otherwise good and no patient developed impaired renal function.     

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.