Thin Basement Membrane Nephropathy Research Articles

Inherited diseases of the glomerular basement membrane

The glomerular basement membrane (GBM) is a specialized form of basement membrane that has a major role in the maintenance of the glomerular filtration barrier. Like all basement membranes, it contains four main components: type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. Different isoforms of these large molecules are produced. These isoforms have a tissue-specific distribution; in the mature GBM, the major type IV collagen molecule is the alpha 3 alpha 4 alpha 5(IV) isoform, associated with laminin-521 (alpha 5 beta2 gamma 1), nidogen and agrin heparan sulfate proteoglycans. The importance of the GBM has been demonstrated by identification of hereditary glomerular diseases linked to structural anomalies of its components; for example, type IV collagen in Alport syndrome and familial benign hematuria, and laminin in Pierson syndrome. Type III collagen, an interstitial collagen, accumulates within the GBM of patients with the nail-patella syndrome, and abnormal deposition of fibronectin, another extracellular matrix protein, is characteristic of so-called fibronectin nephropathy. Development of animal models of these diseases has facilitated precise analysis of pathogenic mechanisms, but no specific treatments are available. Therapeutic trials in Alport syndrome nephropathy are underway, following promising preliminary results obtained in rodent and canine models of the disorder.

The significance of Goodpasture antigen in hereditary nephritis

Two types of hereditary nephritis, nonprogressive and progressive, clinically present as asymptomatic haematuria, sometimes combined with proteinuria. At the onset, in both types, light microscopic changes are minimal, immunofluorescence findings are negative, and diagnosis can be made only upon electron microscopic findings that are considered to be specific. The aim of this study was to determine the significance of Goodpasture antigen detection in diagnosis of progressive and nonprogressive hereditary nephritis in its early phase. Analysis of renal biopsy specimens was done in patients with hereditary nephritis that were followed from 1990 to 2005. Progression of renal disease was examined in 14 patients with Alport's syndrome, 10 patients with thin basement membrane disease, and 6 patients with unclassified hereditary nephritis diagnosed. For all these cases, indirect immunofluorescence study with serum from a patient with high titer of Goodpasture autoantibodies that recognize the antigenic determinants in human glomerular and tubular basement membrane was performed. In 11 out of 14 cases diagnosed as Alport's syndrome, there was negative staining with Goodpasture serum, and in 3 additional cases with Alport's syndrome, expression of Goodpasture antigen in glomerular basement membrane and thin basement membrane was highly reduced. In all 10 patients with thin basement membrane disease, immunofluorescence showed intensive, bright linear staining with Goodpasture serum along glomerular and tubular basement membrane. In 2 out of 6 patients with unclassified hereditary nephritis, Goodpasture antigen expression was very strong, in one patient it was very reduced, and in 3 patients it was negative. The results of our study show that Goodpasture antigen detection plays a very important role in differential diagnosis of progressive and nonpregressive hereditary nephritis, particularly in early phases of the disease.

Alport’s syndrome and benign familial haematuria: Light and electron microscopic studies of the kidney

Hereditary nephropathy is clinically characterized by the familial occurrence in successive generations of progressive haematuric nephritis and neural hearing loss. Hereditary nephropathy of Alport's syndrome (AS) and benign familial (recurrent) haematuria (BFH) are morphologically characterized by specific and diagnostically important thickening and splitting of lamina densa of the glomerular basement membranes. Those lesions can be recognized only by electron microscopy. Hereditary nephritis is usually present clinically with haematuria, and new mutations without a family history of haematuria. It is therefore important to differentiate hereditary nephritis from BFH and no familial haematuria. Thus, electron microscopy is essential in diagnosis of haematuria. The aim of this study was to describe, by light microscopy, constellation of renal alterations by which hereditary nephropathy can be recognized with high probability as well as to compare the diagnostic validity of the findings observed by light and electron microscopy in AS and BFH. We examined 48 renal biopsies of the patients with hereditary nephoropathies by light and electron microscopy. Tissue samples were fixed in buffered paraformaldehyde and embedded in paraffin for long-term preservation. For the electron microscopy analysis, the following fixation in 4% glutaraldehyde tissue was postfixed in 1% osmium tetroxide. Thereafter, the following dehydration procedure tissue slices were embedded in epon. Our results demonstrated that the interstitial foam cells, foetal-like glomeruli, minimal glomerular abnormalities with stain less intense in basement membranes, mild irregular mesangial widening, focal thickening of Bowman's capsule, foci of dilatation tubules, tubular ectasia and atrophy, erythrocyte tubules casts were present in hereditary nephritis. Additionally, light microscopic biopsy findings in patients with BFH were either normal or revealed minor changes (e.g. increased mesangial matrix). All biopsies were reevaluated by electron microscopy and ultrastructural findings confirmed the diagnosis of hereditary nephropathies. The findings observed by light microscopy represent an important step that leads to a definitive diagnosis of AS and BFH.The definitive diagnosis, however, depends on electron microscopy.

COL4A3/COL4A4 Mutations Link Familial Hematuria and Focal Segmental Glomerulosclerosis. Glomerular Epithelium Destruction via Basement Membrane Thinning?

The recent description of multiple gene defects in hereditary podocytopathies and in hereditary glomerular basement membrane diseases has dramatically improved the current state of our knowledge on the renal glomerular filtration barrier. Recently described mutations in collagen IV and laminin in patients with hematuria and severe nephrotic syndrome add to other experimental data supporting the hypothesis that the glomerular basement membrane (GBM) may also have a significant role in protein filtration, a function previously attributed exclusively to the podocytes. Collagen IV heterozygous mutations were thought to cause only a mild form of renal disease (thin basement membrane nephropathy—TBMN). However, data from our laboratory show that many patients who carry such mutations may later on in life develop focal and segmental glomerulosclerosis, on top of the TBMN and the microscopic hematuria, a situation that frequently progresses to chronic renal failure or even end-stage renal disease. The role of unknown modifier genes may explain the heterogeneity of symptoms in TBMN and other glomerular diseases and in particular the selected development of chronic renal failure. The molecular communication between GBM and podocytes may also be a key factor in the search for these major genetic modifiers while their understanding may improve novel drug design for glomerular diseases.

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in approximately 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

The Wages of Thin

Isolated glomerular hematuria associated with a renal biopsy finding of excessively thin glomerular basement membrane (GBM) may occur as a familial or sporadic condition. Neither of the two terms commonly used to describe these patients, benign familial hematuria or thin basement membrane disease, is entirely satisfactory. Familial hematuria is not always benign, and benign hematuria is not always familial. Basement membrane thinning is a descriptive observation, rather than a specific diagnostic finding, and it is clear that several disorders that differ at the molecular level can be associated with this abnormality.

A Novel Mutation of COL4A3 Presents a Different Contribution to Alport Syndrome and Thin Basement Membrane Nephropathy

Background: Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are heterogeneous renal hereditary diseases. Mutations of COL4A3 and COL4A4 genes were reported to be the underlying pathogenicity in both diseases. However, the mechanism of the same mutation causing totally different clinical processes and outcomes in AS and TBMN is still not clear. Subjects and Methods: Mutations of all coding exons of COL4A3 and COL4A4 were screened in a patient with autosomal recessive Alport syndrome (ARAS) of a Chinese Han consanguineous family by means of PCR and direct sequencing. Furthermore, the identified mutation was validated by restriction endonuclease AvaII in all 20 members in his family, as well as 46 patients with TBMN, 2 patients with AS from another two families, and 50 healthy controls. Results: A novel missense mutation (3725G>A, G1242D) in exon 42 of COL4A3 was identified in the proband in the homozygous form. This pathogenic mutation was demonstrated in all carriers who presented with hematuria or mild proteinuria in the heterozygous form, whereas it was not detected in others whose urinalysis was normal within the family. In addition, 10 polymorphisms, including 1 non-glycine missense variant and 9 neutral polymorphisms, were detected in COL4A3/COL4A4. Conclusion: The novel mutation (3725G>A, G1242D) of COL4A3 was the underlying pathogenic role in the homozygous form in ARAS and in the heterozygous form in TBMN within an identical family. The result provided a potentially useful clue for the functional investigation of COL4A3 in these two hereditary glomerular disorders.

Thin basement membrane nephropathy and IgA glomerulonephritis: Can they be distinguished without renal biopsy?

Thin basement membrane nephropathy (TBMN) and IgA glomerulonephritis (IgA gn) are the most common primary glomerular conditions diagnosed on renal biopsy, performed for microscopic haematuria or microscopic haematuria with proteinuria. While up to 50% of patients with IgA gn will develop chronic renal failure, most patients with TBMN enjoy an excellent prognosis. Because TBMN is estimated to occur in up to 1% of the general population, differentiation between the two conditions without resort to renal biopsy is desirable. This retrospective analysis of 248 patients diagnosed on renal biopsy as having either TBMN or IgA gn, sought to identify clinical or biochemical factors which would have enabled confident differentiation between the two conditions to be made without resort to renal biopsy. No single clinical or pathological variable adequately discriminated between the two conditions. Impaired renal function and heavy proteinuria were highly specific for IgA gn but lacked sensitivity in differentiating from TBMN. Isolated microscopic haematuria (IMH) was a more common finding in patients diagnosed with TBMN but, as a discriminator between TBMN and IgA gn, lacked sufficient specificity. However, if assumptions were made based on the differing incidence of a positive family history between IgA gn and TBMN, then specificity of >99% could be achieved. TBMN and IgA gn cannot be distinguished on the basis of clinical or pathological variables alone. However, in patients with IMH and a positive family history of either IMH or biopsy-proven TBMN, there is usually no need for renal biopsy.

Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria

Alport syndrome (ATS) and benign familial hematuria (BFH) are type IV collagen inherited disorders. Mutations in COL4A5 are generally believed to cause X-linked ATS, whereas mutations in COL4A3 and COL4A4 genes can be associated with the autosomal-recessive and -dominant type of ATS or BFH. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. This study involved screening each exon with boundary intronic sequences of COL4A3, COL4A4, and COL4A5 genes by optimized polymerase chain reaction-single-stranded conformational polymorphism analysis in 17 families with ATS and in 40 families diagnosed as having BFH. Twelve different mutations were found in the COL4A5 gene in ATS patients, comprising nine missense mutations, a splice site mutation, a mutation causing frameshift, and a nonsense mutation. One of the missense mutations (p.G624D) was present not only in one family with ATS but also in five families with suspected BFH. Three heterozygous mutations in the COL4A3 gene (two missense and one frameshift) and four heterozygous mutations in COL4A4 (two splice site, one in-frame deletion, and one missense) were identified in patients with BFH. Sixteen mutations are to the best of our knowledge new and private.

Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?

Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n=23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.

Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases

Both thin basement membrane nephropathy (TBMN) and autosomal recessive Alport syndrome result from mutations in the COL4A3 and COL4A4 genes, and this study documents further mutations and polymorphisms in these genes. Thirteen unrelated children with TBMN and five individuals with autosomal recessive Alport syndrome were examined for mutations in the 52 exons of COL4A3 and the 47 coding exons of COL4A4 using single-stranded conformation polymorphism (SSCP) analysis. Amplicons producing different electrophoretic patterns were sequenced, and mutations were defined as variants that changed an amino acid but were not present in 50 non-hematuric normals. Three further novel mutations were identified. These were IVS 22-5 T>A in the COL4A3 gene in a consanguineous family with autosomal recessive Alport syndrome, and R1677C and R1682Q in the COL4A4 gene. In addition, six novel polymorphisms (G455G, I462I, G736G and IVS 38-8 G>A in COL4A3, and L658L and A1577A in COL4A4) were demonstrated.Many different COL4A3 and COL4A4 mutations cause TBMN and autosomal recessive Alport syndrome. The identification of polymorphisms in these genes is particularly important to enable diagnostic laboratories to distinguish mutations from uncommon normal variants.

Pattern of double glomerulopathy in children

Occasional case reports have been issued on children with double glomerulopathy, involving either the coexistence of two different glomerulopathies or superimposition of a second glomerulopathy onto a first. A retrospective clinicopathological review of 294 children who had received renal biopsies resulted in 9 (3.1%) being confirmed to have double glomerulopathy. Superimposed glomerulopathy was diagnosed by a second renal biopsy in two cases, and coexistence of two glomerulopathies was confirmed by single biopsy in seven. Original glomerulopathies were those with a chronic course, such as Alport syndrome, IgA nephropathy, relapsing minimal-change nephrotic syndrome, Frasier syndrome, and thin basement membrane nephropathy. The superimposing glomerulopathies were common types in children, such as postinfectious glomerulonephritis, IgA nephropathy, and Henoch-Schönlein nephritis. Thus, the pattern of double glomerulopathy was considered to be due to the chance occurrence of two different glomerulopathies without a common pathogenesis. Acute nephritic symptoms of superimposed glomerulopathies resolved almost completely during follow-up in most cases. Double glomerulopathies are not rare in children and may occur by chance alone in most cases. The possibility of superimposed glomerulopathy should be suspected if the clinical course of a glomerulopathy changes atypically. However, the long-term influence of a superimposed glomerulopathy on renal functional deterioration remains unclear.

Useful indicators for performing renal biopsy in adult patients with isolated microscopic haematuria

Among adult patients with isolated microscopic haematuria (IMH) which is defined as persistent microscopic haematuria but without proteinura, hypertension, renal insufficiency, urinary tract infection or structural abnormality of the urinary tract, some patients have chronic glomerulonephritis (CGN), in whom early diagnosis by renal biopsy is beneficial to timely intervention. Nevertheless, a considerable number of patients with optimistic prognosis [e.g. thin basement membrane nephropathy (TBMN)] undergo invasive and needless renal biopsy. Indicators for weighing the necessity of renal biopsy would be clinically significant. To investigate the value of urinary albumin/creatinine ratio (UACR), serum IgA level, serum C3 level and serum IgA to C3 ratio in predicting the necessity of renal biopsy for adult patients with IMH, 216 patients were studied retrospectively. Patients were divided into: (CGN group, n=137), (TBMN group, n=56) and normal biopsy (normal group, n=23). Of all patients, 131 (61%) evidenced microalbuminuria (UACR=30-299 mg/g) and 85 (39%) had normoalbuminuria (UACR<30 mg/g). The mean value of UACR in CGN group was higher (96+/-17 mg/g) compared with that in TBMN (20+/-4 mg/g, p<0.01) or normal (18+/-3 mg/g, p<0.01) group. The mean values of serum IgA and serum IgA/C3 ratio in patients with IgA nephropathy (IgAN) were significantly higher than those with non-IgAN (380+/-103:217+/-99 mg/dl, p<0.01; 4.5+/-1.2 : 2.4+/-0.9, p<0.01). The odds ratio for distinguishing IgAN from non-IgAN was significantly correlated with serum IgA level and serum IgA to C3 ratio. For adult patients with IMH, UACR, serum IgA level and serum IgA to C3 ratio are non-invasive markers for predicting the necessity of renal biopsy.

Thin basement membrane nephropathy cannot be diagnosed reliably in deparaffinized, formalin-fixed tissue

In diagnostic renal pathology, electron microscopy is ideally performed on glutaraldehyde-fixed, plastic resin-embedded tissue (EM-G). When no glomeruli are present in the portion of the biopsy fixed in glutaraldehyde, formalin-fixed, paraffin-embedded tissue can be reprocessed for electron microscopy (EM-F). The usefulness of this salvage technique for the diagnosis of thin basement membrane nephropathy (TBMN) has not been studied systematically. Here we compare the glomerular basement membrane (GBM) thickness by EM-G vs EM-F in 21 renal biopsies, including TBMN (eight patients), normals (two patients), minimal change disease (MCD) (six patients) and diabetic nephropathy (DN) (five patients). There was significant reduction of the GBM thickness by EM-F compared with EM-G across all diagnostic categories in all 21 cases. The mean percentage reduction in GBM thickness was 23% for the TBMN cases, 40% for the normal/MCD cases and 34% for the DN cases. Four patients with MCD had a mean GBM thickness by EM-F that fell below the defining threshold for diagnosis of TBMN. For the TBMN cases, the 99th percentile for GBM thickness by EM-F was 194 nm, suggesting that the diagnosis of TBMN by EM-F can be excluded with confidence if the GBM thickness is above 200 nm. No clear criteria could be established to diagnose TBMN by EM-F. Renal pathologists should be aware that reprocessing of paraffin tissue for EM causes artifactual GBM thinning that precludes accurate diagnosis of TBMN.

Upregulated expression of cardiac ankyrin–repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis

Cardiac ankyrin-repeated protein (CARP) was originally identified as a protein specifically expressed in cardiomyocytes, but has recently been found to be upregulated in some muscle diseases including muscular dystrophy and myopathy, suggesting that CARP may be induced in some pathologic conditions. In this study, we immunohistochemically analyzed 69 renal biopsy samples from patients with glomerular diseases and 2 individuals with normal kidney. We found that CARP was expressed in renal podocytes at a high level in 10 of 13 cases of crescentic glomerulonephritis, 7 of 19 cases of diabetic nephropathy, and 12 of 20 cases of lupus nephritis, although it was not expressed in endocapillary glomerulonephritis, minimal change disease, thin basement membrane disease, membranous glomerulonephritis, and normal kidney. Interestingly, in lupus nephritis, CARP expression tended to be induced in cases exhibiting nephrotic syndrome, but less so in cases without nephrotic syndrome, suggesting that CARP expression is correlated with the severity of proteinuria. Furthermore, we found that CARP was not expressed in membranous glomerulonephritis but evidently expressed in most cases of membranous lupus nephritis. Although membranous glomerulonephritis and membranous lupus nephritis are sometimes morphologically indistinguishable, it is suggested that their pathologic mechanisms differ. Therefore, we propose that examination of CARP expression is useful for precise differential diagnosis of membranous glomerulonephritis and membranous lupus nephritis.

Thin Basement Membrane Nephropathy: Diffuse and Segmental Types

Diffuse thinning of the glomerular basement membrane (GBM) is the ultrastructural diagnostic criterion of thin basement membrane nephropathy (TBMN). However, there is no consensus regarding what diagnosis should be made if the attenuation is segmental. To develop a diagnostic approach to TBMN in cases with segmental GBM thinning. We compared the diagnostic sensitivities of 2 methods used for the quantitative expression of GBM width in a consecutive series of renal biopsies from 26 patients (median age, 36 years; range, 15 to 59 years) with dysmorphic hematuria (a variable degree of proteinuria in 19 patients), a thin GBM, and absence of other renal disease. The harmonic GBM width was determined from orthogonal intercepts, and the actual width in the thinnest loops was obtained by direct measurement. The GBM attenuation was categorized into diffuse or segmental types by conventional inspection. Segmental TBMN accounted for one third of the series. In neither type did the male patients have a higher harmonic mean GBM width than the female patients. Focal-global glomerulosclerosis was more common in diffuse TBMN. The laborious orthogonal intercept method proved insensitive for the verification of segmental TBMN, whereas the much simpler direct measurement technique captured all the cases. A considerable number of patients with TBMN display segmental GBM attenuation. Because the routine criterion excludes these cases from the diagnosis, we propose to define TBMN as a clinicopathologic entity of dysmorphic hematuria and a diffusely or segmentally thinned GBM confirmed by the direct measurement technique.

Occult Nephrolithiasis in Prospective Kidney Donors: A Source for Hematuria

In their report, Koushik et al. (1) identified causes for persistent, asymptomatic, microscopic hematuria in a series of 512 prospective kidney donors in Minnesota. Fourteen of these had hematuria, of whom two had a urinary tract infection, one had multiple renal arteries, one a renal cyst, two normal kidney biopsies (one with renal cysts), and eight had biopsies with varied findings. We wish to highlight another important cause for hematuria in this population: occult nephrolithiasis. In all, 192 prospective kidney donors underwent evaluation at our center between February 2002 and May 2005 that included renal imaging. Seventy-six were eventually excluded for medical or surgical reasons. Out of those excluded, eight were found to have one or more kidney stones by ultrasound (two patients) or computed tomography (CT) scan (six patients). No patient gave a previous history of hypertension, nephrolithiasis or visible hematuria. Kidney size was 11±0.7 cm, with average asymmetry 0.3 cm. Stone size varied from 1 to 7 mm in diameter with up to three in one kidney; two patients had bilateral stones. Ureteric stones, bladder stones, or renal cysts were not detected in any patient. Their age was 43±13 years, three were male, four were white, three Asian, and one Native American and BMI was 27.1±3. Their fasting and two-hour post 75 gram glucose load blood sugar levels and hemoglobin were normal, but one patient had hypercholesterolemia. All patients had a normal 24-hour urine protein excretion rate or random urine microalbumin-to-creatinine ratio, as well as a normal 24-hour urine creatinine clearance (120±21 ml/min). Although the average blood pressure was normal (124/70 mm Hg by 24-hour ambulatory BP monitoring), seven were nocturnal nondippers. Four out of these eight patients had persistent microscopic hematuria. Seven patients provided a 24-hour urine collection to evaluate for metabolic abnormalities favorable to stone formation. Three had significant hypercalciuria (9.2–16.3 mmol/d, N 0–7.5), three had hypocitraturia (0.4–1.0 mmol/d, N >1.6), two had hyperuricosuria (5.5–5.9 mmol/ d, N 2–4), and two had hyperoxaluria (508–814 μmol/d, N 190–480). Three patients had more than one metabolic abnormality. Nephrolithiasis can cause microscopic hematuria without other clinical manifestations. In one study (2), 195 of 906 subjects with asymptomatic hematuria were found to have renal calculi by ultrasound. Twenty-four of these subsequently required urological management (2). Hypercalciuria and hyperuricosuria may also cause microscopic hematuria in adults, which can resolve with appropriate therapy such as thiazides and allopurinol (3). In addition, hypercalciuria, hyperuricosuria, and nephrolithiasis are associated with thin basement membrane nephropathy, a glomerular disease (4). Although we typically decline these individuals as kidney donors, we agree with Koushik et al. that clear guidelines for managing young and healthy adults with microscopic hematuria are lacking. In summary, in addition to the list provided by Koushik et al., occult nephrolithiasis should be considered as a cause for microscopic hematuria in the prospective kidney donor population. This will enable appropriate diagnosis, counseling, referral, and management of these individuals independent of the transplantation process. G.V. Ramesh Prasad Philip A. McFarlane Division of Nephrology Department of Medicine University of Toronto Toronto, Ontario, Canada Renal Transplant Program St. Michael’s Hospital Toronto, Ontario, Canada

Analysis of renal biopsies performed in children with abnormal findings in urinary mass screening

School urinary mass screening tests are performed to make early diagnosis and provide proper treatment for chronic renal diseases. However, very few systemic analyses or studies have been reported regarding final diagnosis made on children with abnormal urinary screening results. To study the cases of renal biopsy in children detected in urinary screening. We retrospectively analysed 461 cases of renal biopsy performed on children referred to us with abnormal school urinary mass screening results who satisfied indications for renal biopsy. Pathologically abnormal findings were observed in 285 (61.8%) patients. Thin glomerular basement membrane disease was detected in 127 (27.5%) cases and IgA nephropathy in 121 (26.2%) cases. Among those 461 children, microscopic haematuria was observed in 289 (62.7%) patients, proteinuria in nine (2.0%), and both in 163 (35.4%). In addition, a statistically higher rate of pathological abnormalities on renal biopsy was noted in the group with microscopic haematuria combined with proteinuria and also in cases with more severe haematuria. School urinary mass screening has greatly contributed to diagnosing chronic renal diseases. Continuous medical observation is required when abnormal urinalysis is observed, and a more aggressive medical approach such as renal biopsy should also be performed if necessary.

Analysis of renal biopsies performed in children with abnormal findings in urinary mass screening

Abstract Background: School urinary mass screening tests are performed to make early diagnosis and provide proper treatment for chronic renal diseases. However, very few systemic analyses or studies have been reported regarding final diagnosis made on children with abnormal urinary screening results. Aim: To study the cases of renal biopsy in children detected in urinary screening. Methods: We retrospectively analysed 461 cases of renal biopsy performed on children referred to us with abnormal school urinary mass screening results who satisfied indications for renal biopsy. Results: Pathologically abnormal findings were observed in 285 (61.8%) patients. Thin glomerular basement membrane disease was detected in 127 (27.5%) cases and IgA nephropathy in 121 (26.2%) cases. Among those 461 children, microscopic haematuria was observed in 289 (62.7%) patients, proteinuria in nine (2.0%), and both in 163 (35.4%). In addition, a statistically higher rate of pathological abnormalities on renal biopsy was noted in the group with microscopic haematuria combined with proteinuria and also in cases with more severe haematuria. Conclusion: School urinary mass screening has greatly contributed to diagnosing chronic renal diseases. Continuous medical observation is required when abnormal urinalysis is observed, and a more aggressive medical approach such as renal biopsy should also be performed if necessary.

Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.