Abstract
Background. Thin basement membrane nephropathy (TBMN) patients with additional inflammatory diseases and IgA nephropathy (IgAN) have not been reported before. It was unclear that if the prognosis of these patients is better or worse than patients with IgAN and TBMN, or IgAN patients with normal glomerular basement membrane (GBM). Methods. We first reported five TBMN patients with additional inflammatory diseases and IgAN: three were with rheumatoid arthritis, and two had Crohn's disease. Clinical and laboratory features were analyzed between this group (group 3), IgAN patients with normal GBM (group 1), and patients with TBMN and IgAN (group 2). Results. Significant differences were observed in serum levels of IgG, IgA, and IgM between groups 1 and 3, p < 0.001, and between groups 2 and 3, p < 0.001. Glomerular filtration rate (GFR) in group 3 was significantly lower than that of groups 1 and 2, p < 0.01, respectively. Conclusion. The prognosis of these patients is worse than patients with IgAN and TBMN or IgAN patients with normal GBM. Serum immunoglobulin levels and GFR in these patients were different from patients with IgAN and TBMN, or IgAN patients with normal GBM.
INTRODUCTION
Thin glomerular basement membranes nephropathy (TBMN) is a common glomerular abnormality encountered in up to 7% of otherwise normal individuals.[1] Many reports confirm that TBMN commonly occurs together with other glomerular diseases, such as minimal change glomerulonephritis, diabetes, membranous nephropathy, and IgA nephropathy (IgAN). The association between TBMN and IgAN was first reported in isolated clinical cases,[2,[3]] and the coexistence of the two diseases was found to be not uncommon. Although the presence of TBMN somewhat alters the clinical presentation of patients with IgAN, those alternations generally are not associated with a worse prognosis than normal basement membrane thickness.[4,[5]] Some researchers reported that the prognosis of patients with TBMN and IgAN was determined mainly by IgA deposition and the consequent activation of inflammatory mechanisms.[6]
Shaer et al.[7] reported the features of the 24 previously reported patients with inflammatory bowel disease and glomerulonephritis, and found a worse prognosis than patients with glomerulonephritis alone. There is no information available about the possible role of additional inflammatory diseases in the pathogenesis of patients with combined TBMN and IgAN. Here we reported for the first time the different clinical and laboratory features in IgAN patients with normal glomerular basement membrane (GBM), patients with TBMN and IgAN, and TBMN patients with additional inflammatory diseases and IgAN.
METHODS
Patients
IgAN was diagnosed in patients who underwent a renal biopsy in Department of Nephrology, the Second Affiliated Hospital, Nanchang University. A renal biopsy was carried out percutaneously in all patients with a 16 G Tru-cut needle. Specimens were processed for light microscopy, immunofluorescence, and electron microscopy by routine techniques. GBM thickness measurements were performed according to the Das methods.[8] Briefly, nine photomicrographs were made of peripheral capillary loops of each of two glomeruli at a final magnification of 12,000, where possible loops adjacent to grid bars were selected. The minimum distance between endothelial cell and epithelial cell plasma membranes (orthogonal intercept) was recorded in classes using a transparent measuring ruler, the measurements being made where the lines of an overlaid 4-cm grid cut the endothelium.
Diagnosis of TBMN
Systematic measurement of glomerular basement membrane thickness was made by electron microscope for width < 275 nm in men and < 265 nm in women.[9,[10]] Alport's syndrome was excluded from the diagnosis of TBMN.
The pathological diagnoses by light microscopy of all patients with IgAN in our department fell within the grades 1 through 5 of pathological damage, according to the grading system of Lee et al.[11] The main levels of Lee's grading are as follows:
grade 1: mostly normal glomeruli;
grade 2: less than half of the glomeruli show localized mesangial proliferation and sclerosis;
grade 3: diffuse mesangial proliferation and thickening with focal and segmental variation with focal interstitial edema and infiltrate occasionally present;
grade 4: marked diffuse mesangial proliferation and sclerosis with tubular atrophy and interstitial inflammation; and
grade 5: similar to grade 4 but more severe.
IgAN patients were selected randomized from Department of Nephrology, the Second Affiliated Hospital, Nanchang University, between January 2006 and January 2008. Those sporadic IgAN patients were divided into three groups:
group 1: IgAN patients with normal GBM;
group 2: patients with TBMN and IgAN; and
group 3: TBMN patients with additional inflammatory diseases and IgAN.
Group 3 included three patients with rheumatoid arthritis and two patients with Crohn's disease, as diagnosed in our Department of Nephrology.
Diagnosis of rheumatoid arthritis met the criteria of American Rheumatism Association.[12] Treatment of rheumatoid arthritis was including anti-TNFα drug infliximab or etanercept in association with methotrexate (MTX) or another disease-modifying anti-rheumatic drug (DMARD). Diagnosis of Crohn's disease was based on morphological (radiological, endoscopic or surgical findings) and pathological criteria suggesting focal, asymmetrical, transmural, or granulomatous features.[13] Treatments were with corticosteroid and 5-aminosalicylic acid (5-ASA) preparations (with or without surgery).
Statistics
The results were analyzed using students' test (mean ± SD) or chi-square calculation for enumeration data. Age of patients, blood pressure, therapies, grade of Lee's, and years of follow-up were expressed in text as mean ± SD and analyzed using one-way ANOVA. When a significant F value was found, Mann-Whitney test was used to compare different mean values. Statistical significance is set at p less than 0.05.
RESULTS
Thirty patients were selected into groups 1 and group 2, respectively. Group 3 included three patients with rheumatoid arthritis and two patients with Crohn's disease diagnosed in our Department of Nephrology between January 2006 and January 2008. Characteristics of patients in different groups (mean ± SD) are displayed in Table 1. As displayed in Table 1, there was no significant difference in sex, age, blood pressure, therapies, pathological grades, and follow-up periods in the three groups.
Table 1 Characteristics of patients in different groups (mean ± SD)
At the end of period of follow-up, clinical and laboratory data of patients in different groups were collected and demonstrated in Table 2, including serum levels of immunoglobulin, macrohematuria (blood in urine visually), hematuria, proteinuria, serum creatinine, and the glomerular filtration rate (GFR). Significant differences were observed in serum levels of IgG, IgA, and IgM between groups 1 and 3, p < 0.001, and between groups 2 and 3, p < 0.001, respectively. GFR in group 3 was significantly lower than that of groups 1 and 2, p < 0.01. There was no statistical difference in serum levels of immunoglobulin and GFR between groups 1 and 2, p > 0.05.
Table 2 Clinical and laboratory features of patients in different groups
DISCUSSION
Both IgAN and TBMN are common forms of glomerular nephropathy, and some individuals can have both IgAN and TBMN.[2,[14]] The available clinical evidence indicates that the presence of an associated glomerulopathy significantly worsens the prognosis of TBMN. This conclusion is not based on longitudinal studies but rather on the observation that patients with both TBMN and another glomerulopathy have a clinically more aggressive disease with higher levels of proteinuria, hypertension, and renal insufficiency.[5,[14],[15]] However, serum creatinine and creatinine clearance were not necessarily worse in individuals with both IgAN and TBMN.[2,[3]]
Patients with IgAN and TBMN combined with inflammatory disease have not been reported before. Here we demonstrated five patients—three with rheumatoid arthritis and two patients with Crohn's disease diagnosed in our Department of Nephrology. IgAN has been reported in association with inflammatory diseases in previous studies.[16–18] Without the remission of the inflammatory diseases, patients can develop to hematuria and renal failure. In Crohn's disease, mucosal inflammation has been shown to result in systemic absorption of antigens and bacteria,[19] which provokes an increase in IgG and IgA with the development of immune complexes.[20] Another possible mechanism for both IgAN and inflammatory bowel diseases is an underlying abnormality in T cell function, as the release of cytokines, stimulation of IgA production, and immune complexes can relate IgAN to inflammatory bowel diseases.[21,[22]] Of particular interest, the clinical and laboratory data of the patients with Crohn's disease was in parallel with treatment of the gastrointestinal disorder.
TBMN was more frequent in women and associated with a better prognosis.[9,[10],[23]] Our results indicated that the clinical and laboratory features have not significant difference between the group of IgAN patients with normal GBM and patients combined with IgAN and TBMN. Interestingly, although the observed sample in group 3 was small, a significant difference was found in serum levels of immunoglobulin (IgG, IgA, and IgM) and GFR when group 3 was compared to groups 1 or 2. This outcome was not inconsistent with the previous finding,[6] that the prognosis of patients with TBMN and IgAN was determined mainly by IgA deposition and the consequent activation of inflammatory mechanisms, though we did not routinely detect the serum levels of inflammatory factors such as interleukin-1, -2, -6, -10, TNF-α, and interferon in clinical practice.
It should also be noted that the patients brought into our study were mostly women (66%), whereas the common subgroup of IgAN patients has a majority of men. It may be caused by gender difference between different regions. To our knowledge, TBMN patients with additional inflammatory diseases and IgAN had not been reported previously. We first report that the prognosis of these patients is worse than patients with IgAN and TBMN or IgAN patients with normal GBM.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
| IgAN | IgAN + TBMN | IgAN + TBMN + ID | |
|---|---|---|---|
| (n = 30) | (n = 30) | (n = 5) | |
| Sex | |||
| Male | 10 | 10 | 2 |
| Female | 20 | 20 | 3 |
| Mean age | 32.47 ± 7.28 | 30.96 ± 7.69 | 31.13 ± 7.47 |
| Systolic blood pressure | 126 ± 19 | 125 ± 19 | 129 ± 20 |
| Diastolic blood pressure | 75 ± 14 | 75 ± 15 | 78 ± 16 |
| Therapies | |||
| Oral steroid | 9 | 9 | 2 |
| No steroid | 21 | 21 | 3 |
| Use of ACE-I or ARB | 10 | 9 | 3 |
| Grades (Lee) | |||
| 1–2 | 13 | 14 | 1 |
| 3–5 | 17 | 16 | 4 |
| Follow-up (year) | 5.13 ± 1.43 | 5.21 ± 1.58 | 5.18 ± 1.53 |
| Width of GBM† | 327 ± 31 | 232 ± 34 | 236 ± 33 |
*ID = Inflammatory disease.
†GBM = glomerular basement membrane (width: nm).
There was no significant difference in sex, age, blood pressure, therapies, pathological grades, and follow-up periods in three groups.
Abbreviations: ACE-I = angiotensin-converting enzyme inhibitor, ARB = angiotensin-2 receptor blocker.
| IgAN | IgAN + TBMN | IgAN + TBMN + ID | |
|---|---|---|---|
| (n = 30, %) | (n = 30, %) | (n = 5, %) | |
| Immunoglobulin | |||
| IgG (mg/dL) | 1243 ± 125 | 1256 ± 126 | 1387 ± 156§ |
| IgA (mg/dL) | 351 ± 32 | 353 ± 33 | 392 ± 33§ |
| IgM (mg/dL) | 134 ± 13 | 135 ± 14 | 152 ± 18§ |
| Macrohematuria | 10 (33.33) | 11 (36.67) | 3 (60) |
| Hematuria† | 16 (53.33) | 14 (46.67) | 5 (100) |
| Proteinuria | |||
| > 0.3 g/24 h | 16 (53.33) | 17 (56.67) | 5 (100) |
| >1.0 g/24 h | 6 (20) | 7 (23.33) | 5 (100) |
| >3.5 g/24 h | 2 (6.67) | 2 (6.67) | 2 (40) |
| Serum creatinine‡ | 7 (23.33) | 6 (20) | 4 (80) |
| GFR (aMDRD) | 58.4 ± 14.7 | 58.5 ± 14.8 | 33.4 ± 13.9││ |
*ID = Inflammatory disease.
†Hematuria > 100,000 RBC/mL.
‡Serum creatinine > 0.11 mmol/L.
§Group 3 versus group 1, p < 0.001; group 2 versus group 1, p > 0.05.
││Group 3 versus group 1, p < 0.01; group 2 versus group 1, p > 0.05.
Abbreviation: GFR = glomerular filtration rate, adjusted MDRD (mL/min/1.73m2). Group 1 = IgAN; group 2 = IgAN + TBMN; group 3 = IgAN + TBMN + ID.
Notes
REFERENCES
- Dische FE, Anderson VER, Keane SJ, et al. Incidence of thin membrane nephropathy: Morphometric investigation of a population sample. J Clin Pathol. 1990; 43: 457–460 [Google Scholar]
- Monga G, Mazzucco G, Roccatello D. The association of IgA glomerulonephritis and thin basement membrane disease in a hematuric patient: Light and electron microscopic and immunofluorescence investigation. Am J Kidney Dis. 1991; 18: 409–412 [Google Scholar]
- Lanteri M, Wilson D, Savige J. Clinical features in two patients with IgA glomerulonephritis and thin basement membrane disease. Nephrol Dial Transplant. 1996; 11: 791–793 [Google Scholar]
- Frasca GM, Onetti-Muda A, Renieri A. Thin basement membrane disease. J Nephrol. 2000; 13: 15–19 [Google Scholar]
- Sue YM, Huang JJ, Hsieh RY, et al. Clinical features of thin basement membrane disease and associated glomerulopathies. Nephrology (Carlton). 2004; 9: 14–18 [Google Scholar]
- Frasca GM, Soverini L, Gharavi AG, et al. Thin basement membrane disease in patients with familial IgA nephropathy. J Nephrol. 2004; 17: 778–785 [Google Scholar]
- Shaer AJ, Stewart LR, Cheek DE, Hurray D, Self SE. IgA antiglomerular basement membrane nephritis associated with Crohn's disease: A case report and review of glomerulonephritis in inflammatory bowel disease. Am J Kidney Dis. 2003; 41: 1097–1109 [Google Scholar]
- Das AK, Pickett TM, Tungekar MF. Glomerular basement membrane thickness—a comparison of two methods of measurement in patients with unexplained hematuria. Nephrol Dial Transplant. 1996; 11: 1256–1260 [Google Scholar]
- Berthoux FC, Laurent B, Koller JM, et al. Primary IgA glomerulonephritis with thin glomerular basement membrane: A peculiar pathological marker versus thin membrane nephropathy association. Contrib Nephrol. 1995; 111: 1–7 [Google Scholar]
- Berthoux FC, Laurent B, Alamartine E, Diab N. New subgroup of primary IgA nephritis with thin glomerular basement membrane (GBM): Syndrome or association. Nephrol Dial Transplant. 1996; 11: 558–559 [Google Scholar]
- Lee SMK, Rao VM, Franklin WA. IgA nephropathy: Morphologic predictors of progressive renal disease. Hum Pathol. 1982; 13: 314–322 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31: 315–324 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Witte J, Shivananda E, Lennard-Jones JE, Beltrami M, Politi P, Bonanomi A, Tsianos EV, Mouzas I, Schultz TB, Monteiro E, Clofent J, Odes S, Limonard CB, Stockbrugger RW, Russel MG. Disease outcome in inflammatory bowel disease: Mortality, morbidity, and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Scand J Gastroenterol. 2000; 35: 1272–1277 [Google Scholar]
- Cosio FG, Falkenhain ME, Sedmak DD. Association of thin glomerular basement membrane with other glomerulopathies. Kidney Int. 1994; 46: 471–474 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Savige J, Rana K, Tonna S, et al. Thin basement membrane nephropathy. Kidney Int. 2003; 64: 1169–1178 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Lopez BJM, Lafuente MP, Garcia CF, Ibarra PB, Diaz de Otazu R. Crohn's disease associated with Berger's disease. A rare complication. Rev Esp Enferm Apar Did. 1990; 78: 233–235 [Google Scholar]
- Hirsch DJ, Kailash KJ, Trillo A, Cohen AD. Acute renal failure in Crohn's disease due to IgA nephropathy. Am J Kidney Dis. 1992; 20: 189–190 [Google Scholar]
- McCallum D, Smith L, Harley F, Yiu V. IgA nephropathy and thin basement membrane disease in association with Crohn's disease. Pediatr Nephrol. 1997; 11: 637–640 [Google Scholar]
- Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastrolenterol Clin North Am. 1995; 24: 475–507 [Google Scholar]
- Delaney TA, Clay CD, Randall PI. The bowel associated dermatosis-arthritis syndrome. Aust J Dermatol. 1989; 30: 23–27 [Google Scholar]
- Kameda A, Yoshikawa N, Shiozawa S, Doi K, Nakamura H. Lymphocyte subpopulations and function in childhood IgA nephropathy. Nephron. 1991; 59: 546–551 [Google Scholar]
- Ark A, Valentijn RM, Van Es LA. The bone marrow as production site of IgA deposited in kidneys of patients with IgA nephropathy. Clin Exp Immunol. 1988; 72: 321–323 [Google Scholar]
- Deprele C, Koller JM, Alamartine E, et al. Clinical and pathological characteristics of primary IgA nephritis (IgAN) according to glomerular basement membrane (GBM) thickness: Normal vs thin. Nephrol Dial Transplant. 1998; 13: 97A [Google Scholar]