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Thin Membrane Glomerular Disease (Thin Membrane Glomerular Dysmorphism) (TMGD)

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Nogueira M, Cartwright J Jr, Horn K, Doe N, Shappell S, Barrios R, Coroneos E, Truong LD Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation. 1: Am J Kidney Dis 2000 Apr;35(4):E15. Department of Pathology, Baylor College of Medicine, The Methodist Hospital, Houston, TX 77030, USA.

Thin basement membrane disease (TBMD) is a condition originally defined as diffuse thinning of the glomerular basement membrane (GBM) associated with hematuria in all patients. Although proteinuria has been described in up to 60% of patients with TBMD, it is almost always mild, with a 24-hour excretion mostly of less than 500 mg. We describe eight patients (four men and four women between 32 and 66 years of age) with TBMD who presented with heavy proteinuria or nephrotic syndrome. Among the seven cases with family history, hematuria was noted in five. All patients had a long history of microscopic hematuria, with episodic gross hematuria in two. Renal biopsies showed diffuse thinning of the GBM in each patient (mean between 185.3 x 29.8 nm and 232.6 x 34.5 nm versus control between 325 x 35 nm and 350 x 15 nm). Three cases showed thinning of GBM only (group I); the remaining five cases showed thinning of GBM associated with focal segmental glomerulosclerosis. All three patients of group I presented with nephrotic syndrome and normal renal function. Treatment with steroids resulted in remission of nephrotic syndrome in two, whereas nephrotic syndrome persisted in the untreated patient. Among the five patients in group II, nephrotic syndrome and normal renal function at presentation were noted in two, whereas the other three had heavy proteinuria (2.2, 2. 5, and 2.6 g/d, respectively) associated with mildly decreased renal function (serum creatinine 1.8, 1.3, and 1.5 mg/dL, respectively). At last follow-up, although the renal function was stable in all five, only the three who received steroid treatment had remission or marked improvement of proteinuria. Hematuria, however, persisted in all eight patients of both groups. Whether specific gene mutations are translated into structural changes responsible for both excessive GBM thinning and increased transcapillary permeability remains to be elucidated. Alternatively, the heavy proteinuria/nephrotic syndrome may not be related to TBMD, but rather is the manifestation of associated glomerular diseases. Follow-up, including a response to steroids, supports the latter hypothesis.

Frasca GM, Onetti-Muda A, Renieri A.: Thin glomerular basement membrane disease. J Nephrol 2000 Jan-Feb;13(1):15-9. Nephrology and Dialysis Unit, St. Orsola Hospital, Bologna, Italy. frasca@orsola-malpighi.med.unibo.it

The term thin glomerular basement membrane disease (TBMD) refers to a condition characterised by thinning of the GBM at electron microscopy examination and, clinically, by isolated hematuria, frequently occurring in other family members, with no extra-renal manifestations. Progression towards chronic renal failure (CRF), although rare, has been reported and blood pressure is high in 30-35% of cases during follow-up. TBMD is generally considered different from Alport syndrome since immunohistological investigation does not show abnormalities of type IV collagen alpha chains in the GBM, as frequently observed in Alport patients; moreover, in familial cases, the disease is transmitted as autosomal dominant trait, rarely observed in Alport syndrome. Genetic studies suggest that TBMD is a heterogeneous disease, but some cases may be related to mutations of COL4A3/COL4A4 genes, thus belonging to the spectrum of type IV collagen diseases. TBMD may arise with other glomerular diseases, most frequently IgA nephropathy, and it remains to be established whether these cases are a casual occurrence or whether a thinner than normal GBM predisposes to immune complex deposition.

Zhang Y, Zhou R, Wang S.: Thin membrane nephropathy: 27 cases. Chung Hua Nei Ko Tsa Chih 1997 Nov;36(11):736-9. Division of Nephrology, First Hospital, Beijing Medical University.

To disclose the prevalence of thin membrane nephropathy (TMN) in China and its clinical and pathological features, we prospectively studied TMN cases including 722 cases of renal biopsies in 2 years. 27 cases (male 7 cases, female 20) were diagnosed as primary glomerulonephritis. The GBM thicknesses of TMN group (n = 27) and control group (n = 32) was 207 +/- 36 nm and 382 +/- 34 nm (P < 0.01) respectively. IF of TMN was negative or trace, near normal morphology or mild mesangial proliferative glomerulo nephritis was observed by LM. A few of them had global glomerular sclerosis or single crescent formation. All TMN patients had microscopic hematuria. About one third (9/27 cases) patients with TMN presented isolated persistent microscopic hemataria, 44.4% (12/27 cases) and 22.2% (6/27 cases) patients with TMN were accompanied with mildmoderate proteinuria and heavy proteinuria (> or = 3.5 g/24 h) or nephrotic syndrome. The patients with heavy proteinuria or nephrotic syndrome had good response to corticosteroid therapy. All patients with TMN had normal renal function, only a few of them had transient hypertension. The results showed that the prognosis of TMN would be regarded as good. The familial history of 15 patients with TMN was investigated, and 47% (7/15 cases) of them had > or = two members with microscopic hematuria in their families. TMN was found in 3.7% (27/722 cases) in total renal biopsies and 11.5% (9/78 cases) in the patients with isolated microscopic hematuria. It suggests that TMN isn't a rare kidney disease in China. Careful EM is a critical method for the correct diagnosis of TMN.

Vogler C, Eliason SC, Wood EG.: Glomerular membranopathy in children with IgA nephropathy and Henoch Schonlein purpura. Pediatr Dev Pathol 1999 May-Jun;2(3):227-35. Department of Pathology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, St. Louis, MO 63104, USA.

We evaluated renal biopsies from 34 children with IgA nephropathy or Henoch Schonlein purpura to further characterize the ultrastructural features of the glomerular membranopathy that occurs in these disorders. Focal glomerular basement membrane damage was identified in 29 children and was severe in 4 of the children. Alterations included focal and segmental attenuation, splitting, duplications, and spike-like subepithelial protrusions of the lamina densa, along with saccular glomerular microaneurysms arising at the paramesangium. Those cases with extensive glomerular basement membrane lesions had either moderate or severe glomerular alterations apparent by light microscopy. Over half of the cases with glomerular membranopathy had immunohistological or ultrastructural evidence of focal peripheral glomerular capillary wall immune deposits and electron-dense deposits occurred at sites of glomerular basement membrane splitting. Despite the focal attenuation of the glomerular basement membrane, we did not identify any biopsy with findings of thin basement membrane disease. The glomerular basement membrane ultrastructural findings we describe are characteristic of IgA nephropathy and Henoch Schonlein purpura, are common in children with these disorders, and are similar to the ultrastructural alterations of the basement membrane that occur in other glomerulonephritides. These basement membrane injuries may be inflammatory cell or immune mediated but their pathogenesis requires further study.

Suh KS, Kim JO, Kang GH.: Thin glomerular basement membrane disease: light microscopic and electron microscopic studies. J Korean Med Sci 1997 Jun;12(3):234-9. Department of Pathology, Chungnam National University School of Medicine, Taejon, Korea.

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).

•Cosio FG, Falkenhain ME, Sedmak DD.: Association of thin glomerular basement membrane with other glomerulopathies. Kidney Int 1994 Aug;46(2):471-4. Department of Internal Medicine, Ohio State University, Columbus.

In the present study we assessed the prevalence of thin glomerular basement membrane (TGBM) in a large group of native kidney biopsies done for evaluation of renal disease. TGBM was present in 54 of 1078 biopsies (5%). In 12 of 54 biopsies (24%), TGBM was the only abnormality present. In the remaining biopsies TGBM was associated with other pathologic diagnoses. The overall prevalence of TGBM in this series is comparable to previous population studies. TGBM is significantly more common in patients with IgA nephropathy and mesangial proliferative glomerulonephritis. Compared to control patients, individuals with TGBM were more likely to have a history of familial hematuria (14% vs. 43%, P = 0.02). Furthermore, examination of urinary sediments in first degree relatives of patients with TGBM demonstrated microscopic hematuria in 92% of families and, in those families, hematuria was present in 47 +/- 6% of relatives. In contrast, hematuria was discovered in 38% of families of control patients, affecting 25 +/- 5% of relatives. In conclusion, the presence of TGBM in a kidney biopsy is highly predictable for the presence of familial microscopic hematuria, even in patients in whom TGBM is associated with another glomerulopathy. The present data also indicate that patients with TGBM nephropathy often have concomitant IgA nephropathy and mesangial proliferative glomerulonephritis.

McLay AL, Jackson R, Meyboom F, Jones JM.: Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach. Nephrol Dial Transplant 1992;7(3):191-9. University Department of Pathology, Glasgow Royal Infirmary, UK.

We have studied glomerular basal laminar thickness in biopsy material, using a simple technique involving 16 selected measurements per case. Twenty-nine biopsied cases of adult glomerular haematuria were examined together with 'diseased' controls represented by a variety of glomerulopathies including minimal-change disease and IgA nephropathy. 'Normal' control populations were provided by 13 patients with acute-onset renal failure of non-glomerular origin and nine patients undergoing nephrectomy. Analysis of groups determined by the presence or absence of haematuria, the degree of proteinuria and presence or absence of a diagnostically characteristic immunofluorescence pattern showed that the nine patients with haematuria and proteinuria of less than 200 mg/24 h represented a distinct subpopulation with a mean membrane thickness of 225 nm compared to the control mean of 343 nm (P less than 0.0001). All members of this subpopulation had mean values below an arbitrary cut-off value of 270 nm. Within other specific disease categories, sporadic cases had mean membrane thicknesses below this critical value, indicative of an overlap of pathologies. On short-term follow-up there is no evidence that the 'pure' thin-membrane population are subject to any deterioration in renal function. It is of further interest that eight of nine thin-membrane 'syndrome' cases were O Rh positive. This finding may provide a starting point for investigation of a specific genetic defect.

Thin Membrane Glomerular Disease (Thin Membrane Glomerular Dysmorphism) (TMGD) References:
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Nogueira M, Cartwright J Jr, Horn K, Doe N, Shappell S, Barrios R, Coroneos E, Truong LD Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation. 1: Am J Kidney Dis 2000 Apr;35(4):E15. Department of Pathology, Baylor College of Medicine, The Methodist Hospital, Houston, TX 77030, USA. Thin basement membrane disease (TBMD) is a condition originally defined as diffuse thinning of the glomerular basement membrane (GBM) associated with hematuria in all patients. Although proteinuria has been described in up to 60% of patients with TBMD, it is almost always mild, with a 24-hour excretion mostly of less than 500 mg. We describe eight patients (four men and four women between 32 and 66 years of age) with TBMD who presented with heavy proteinuria or nephrotic syndrome. Among the seven cases with family history, hematuria was noted in five. All patients had a long history of microscopic hematuria, with episodic gross hematuria in two. Renal biopsies showed diffuse thinning of the GBM in each patient (mean between 185.3 x 29.8 nm and 232.6 x 34.5 nm versus control between 325 x 35 nm and 350 x 15 nm). Three cases showed thinning of GBM only (group I); the remaining five cases showed thinning of GBM associated with focal segmental glomerulosclerosis. All three patients of group I presented with nephrotic syndrome and normal renal function. Treatment with steroids resulted in remission of nephrotic syndrome in two, whereas nephrotic syndrome persisted in the untreated patient. Among the five patients in group II, nephrotic syndrome and normal renal function at presentation were noted in two, whereas the other three had heavy proteinuria (2.2, 2. 5, and 2.6 g/d, respectively) associated with mildly decreased renal function (serum creatinine 1.8, 1.3, and 1.5 mg/dL, respectively). At last follow-up, although the renal function was stable in all five, only the three who received steroid treatment had remission or marked improvement of proteinuria. Hematuria, however, persisted in all eight patients of both groups. Whether specific gene mutations are translated into structural changes responsible for both excessive GBM thinning and increased transcapillary permeability remains to be elucidated. Alternatively, the heavy proteinuria/nephrotic syndrome may not be related to TBMD, but rather is the manifestation of associated glomerular diseases. Follow-up, including a response to steroids, supports the latter hypothesis.
Frasca GM, Onetti-Muda A, Renieri A.: Thin glomerular basement membrane disease. J Nephrol 2000 Jan-Feb;13(1):15-9. Nephrology and Dialysis Unit, St. Orsola Hospital, Bologna, Italy. frasca@orsola-malpighi.med.unibo.it The term thin glomerular basement membrane disease (TBMD) refers to a condition characterised by thinning of the GBM at electron microscopy examination and, clinically, by isolated hematuria, frequently occurring in other family members, with no extra-renal manifestations. Progression towards chronic renal failure (CRF), although rare, has been reported and blood pressure is high in 30-35% of cases during follow-up. TBMD is generally considered different from Alport syndrome since immunohistological investigation does not show abnormalities of type IV collagen alpha chains in the GBM, as frequently observed in Alport patients; moreover, in familial cases, the disease is transmitted as autosomal dominant trait, rarely observed in Alport syndrome. Genetic studies suggest that TBMD is a heterogeneous disease, but some cases may be related to mutations of COL4A3/COL4A4 genes, thus belonging to the spectrum of type IV collagen diseases. TBMD may arise with other glomerular diseases, most frequently IgA nephropathy, and it remains to be established whether these cases are a casual occurrence or whether a thinner than normal GBM predisposes to immune complex deposition.
Zhang Y, Zhou R, Wang S.: Thin membrane nephropathy: 27 cases. Chung Hua Nei Ko Tsa Chih 1997 Nov;36(11):736-9. Division of Nephrology, First Hospital, Beijing Medical University. To disclose the prevalence of thin membrane nephropathy (TMN) in China and its clinical and pathological features, we prospectively studied TMN cases including 722 cases of renal biopsies in 2 years. 27 cases (male 7 cases, female 20) were diagnosed as primary glomerulonephritis. The GBM thicknesses of TMN group (n = 27) and control group (n = 32) was 207 +/- 36 nm and 382 +/- 34 nm (P < 0.01) respectively. IF of TMN was negative or trace, near normal morphology or mild mesangial proliferative glomerulo nephritis was observed by LM. A few of them had global glomerular sclerosis or single crescent formation. All TMN patients had microscopic hematuria. About one third (9/27 cases) patients with TMN presented isolated persistent microscopic hemataria, 44.4% (12/27 cases) and 22.2% (6/27 cases) patients with TMN were accompanied with mildmoderate proteinuria and heavy proteinuria (> or = 3.5 g/24 h) or nephrotic syndrome. The patients with heavy proteinuria or nephrotic syndrome had good response to corticosteroid therapy. All patients with TMN had normal renal function, only a few of them had transient hypertension. The results showed that the prognosis of TMN would be regarded as good. The familial history of 15 patients with TMN was investigated, and 47% (7/15 cases) of them had > or = two members with microscopic hematuria in their families. TMN was found in 3.7% (27/722 cases) in total renal biopsies and 11.5% (9/78 cases) in the patients with isolated microscopic hematuria. It suggests that TMN isn't a rare kidney disease in China. Careful EM is a critical method for the correct diagnosis of TMN.
Vogler C, Eliason SC, Wood EG.: Glomerular membranopathy in children with IgA nephropathy and Henoch Schonlein purpura. Pediatr Dev Pathol 1999 May-Jun;2(3):227-35. Department of Pathology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, St. Louis, MO 63104, USA. We evaluated renal biopsies from 34 children with IgA nephropathy or Henoch Schonlein purpura to further characterize the ultrastructural features of the glomerular membranopathy that occurs in these disorders. Focal glomerular basement membrane damage was identified in 29 children and was severe in 4 of the children. Alterations included focal and segmental attenuation, splitting, duplications, and spike-like subepithelial protrusions of the lamina densa, along with saccular glomerular microaneurysms arising at the paramesangium. Those cases with extensive glomerular basement membrane lesions had either moderate or severe glomerular alterations apparent by light microscopy. Over half of the cases with glomerular membranopathy had immunohistological or ultrastructural evidence of focal peripheral glomerular capillary wall immune deposits and electron-dense deposits occurred at sites of glomerular basement membrane splitting. Despite the focal attenuation of the glomerular basement membrane, we did not identify any biopsy with findings of thin basement membrane disease. The glomerular basement membrane ultrastructural findings we describe are characteristic of IgA nephropathy and Henoch Schonlein purpura, are common in children with these disorders, and are similar to the ultrastructural alterations of the basement membrane that occur in other glomerulonephritides. These basement membrane injuries may be inflammatory cell or immune mediated but their pathogenesis requires further study.
Suh KS, Kim JO, Kang GH.: Thin glomerular basement membrane disease: light microscopic and electron microscopic studies. J Korean Med Sci 1997 Jun;12(3):234-9. Department of Pathology, Chungnam National University School of Medicine, Taejon, Korea. 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).
•Cosio FG, Falkenhain ME, Sedmak DD.: Association of thin glomerular basement membrane with other glomerulopathies. Kidney Int 1994 Aug;46(2):471-4. Department of Internal Medicine, Ohio State University, Columbus. In the present study we assessed the prevalence of thin glomerular basement membrane (TGBM) in a large group of native kidney biopsies done for evaluation of renal disease. TGBM was present in 54 of 1078 biopsies (5%). In 12 of 54 biopsies (24%), TGBM was the only abnormality present. In the remaining biopsies TGBM was associated with other pathologic diagnoses. The overall prevalence of TGBM in this series is comparable to previous population studies. TGBM is significantly more common in patients with IgA nephropathy and mesangial proliferative glomerulonephritis. Compared to control patients, individuals with TGBM were more likely to have a history of familial hematuria (14% vs. 43%, P = 0.02). Furthermore, examination of urinary sediments in first degree relatives of patients with TGBM demonstrated microscopic hematuria in 92% of families and, in those families, hematuria was present in 47 +/- 6% of relatives. In contrast, hematuria was discovered in 38% of families of control patients, affecting 25 +/- 5% of relatives. In conclusion, the presence of TGBM in a kidney biopsy is highly predictable for the presence of familial microscopic hematuria, even in patients in whom TGBM is associated with another glomerulopathy. The present data also indicate that patients with TGBM nephropathy often have concomitant IgA nephropathy and mesangial proliferative glomerulonephritis.
McLay AL, Jackson R, Meyboom F, Jones JM.: Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach. Nephrol Dial Transplant 1992;7(3):191-9. University Department of Pathology, Glasgow Royal Infirmary, UK. We have studied glomerular basal laminar thickness in biopsy material, using a simple technique involving 16 selected measurements per case. Twenty-nine biopsied cases of adult glomerular haematuria were examined together with 'diseased' controls represented by a variety of glomerulopathies including minimal-change disease and IgA nephropathy. 'Normal' control populations were provided by 13 patients with acute-onset renal failure of non-glomerular origin and nine patients undergoing nephrectomy. Analysis of groups determined by the presence or absence of haematuria, the degree of proteinuria and presence or absence of a diagnostically characteristic immunofluorescence pattern showed that the nine patients with haematuria and proteinuria of less than 200 mg/24 h represented a distinct subpopulation with a mean membrane thickness of 225 nm compared to the control mean of 343 nm (P less than 0.0001). All members of this subpopulation had mean values below an arbitrary cut-off value of 270 nm. Within other specific disease categories, sporadic cases had mean membrane thicknesses below this critical value, indicative of an overlap of pathologies. On short-term follow-up there is no evidence that the 'pure' thin-membrane population are subject to any deterioration in renal function. It is of further interest that eight of nine thin-membrane 'syndrome' cases were O Rh positive. This finding may provide a starting point for investigation of a specific genetic defect.