
Clinico-pathological characteristics and outcomes in adult patients with thin basement membrane nephropathy
Wang Shaofan, Zhang Wen, Xu Feng, Cheng Zhen, Chen Xin, Wang Qingwen
Clinico-pathological characteristics and outcomes in adult patients with thin basement membrane nephropathy
Objective To investigate the clinico-pathological characteristics and outcomes of adult patients with thin basement membrane nephropathy (TBMN). Methods Patients with biopsy-proven TBMN in National Clinical Research Center of Kidney Diseases, Jinling Hospital during Jan 1, 2008 to Dec 31, 2017 were collected. The clinico-pathological characteristics, prognosis, the influencing factors of proteinuria and renal chronic lesions were retrospectively analyzed. Results Among 135 adult patients included, 116 cases (85.9%) were female, and 19 cases were males. The age was (40.56±10.30) years old. There were 30 cases (22.2%) with hypertension and 32 cases (23.7%) with overweight or obesity. Proteinuria was found in 41 patients (30.4%) with (0.65±0.19) g/24 h of urine protein, and microscopic hematuria was found in all 135 patients. Serum creatinine was normal in all patients. Glomerulosclerosis was observed in 102 cases (75.6%), in which 51 cases (37.8%) had glomerulosclerosis>10%. There were 79 cases (58.5%) with mild chronic tubulointerstitial lesions, and 53 patients (39.3%) with vascular hyalinosis. The proportions of proteinuria, chronic tubular interstitial lesion and renal vascular lesion in patients with overweight/obesity and/or hypertension were higher than those without complications (all P<0.05). Multivariate logistic regression results showed that overweight/obesity (OR=7.550, 95%CI 2.091-27.257, P=0.002) and hypertension (OR=4.424, 95%CI 1.091-17.935, P=0.037) were independent influencing factors for proteinuria, while proteinuria was the independent influencing factor for chronic tubular interstitial lesion (OR=3.151, 95%CI 1.046-9.491, P=0.041). Four patients were lost to follow-up, and the median follow-up time of the remaining patients was 64.0(24.0, 96.5) months. At the end of the follow-up, urine protein increased in 10 patients (7.4%) and estimated glomerular filtration rate decreased in 3 patients (2.2%). The above 13 cases were all complicated with overweight/obesity and 4 cases with hypertension. The urine test and renal function in the remaining 118 patients didn't change significantly from baseline. Conclusions The incidences of proteinuria and renal chronic lesion are high in adult TBMN patients. Overweight/obesity and hypertension may cause a poor prognosis, and TBMN patients without metabolic abnormalities probably have good prognosis, but need long-term follow-up.
Glomerular basement membrane / Pathology, clinical / Prognosis / Thin basement membrane nephropathy / Type Ⅳ collagen {{custom_keyword}} /
表1 薄基底膜肾小球病患者的临床病理特征(n=135) |
项目 | 数值 |
---|---|
男/女(例) | 19/116 |
年龄(岁, | 40.56±10.30 |
病程[月,M(P25,P75)] | 24(8,60) |
血尿家族史[例(%)] | 63(46.7) |
高血压[例(%)] | 30(22.2) |
超重/肥胖[例(%)] | 32(23.7) |
尿沉渣红细胞计数[万/ml,M(P25,P75)] | 105(35,200) |
尿蛋白量(g/24 h, | 0.33±0.24 |
蛋白尿[例(%)] | 41(30.4) |
血清肌酐(μmol/L, | 56.58±11.49 |
尿NAG酶[U/g·Cr,M(P25,P75)] | 8.80(5.65,14.65) |
尿RBP[mg/L,M(P25,P75)] | 0.2(0.1,0.4) |
肾小球球性硬化比例[%,M(P25,P75)] | 6.3(2.2,13.6) |
球性硬化>10%[例(%)] | 51(37.8) |
肾小管间质病变[例(%)] | 79(58.5) |
肾血管病变[例(%)] | 53(39.3) |
注:NAG:尿N-乙酰-β-D-氨基葡萄糖苷酶;RBP:尿视黄醇结合蛋白 |
表2 薄基底膜肾小球病患者蛋白尿的影响因素(Logistic回归分析,n=135) |
影响因素 | 单因素 | 多因素 | ||
---|---|---|---|---|
OR(95%CI) | P值 | OR(95%CI) | P值 | |
年龄(岁) | 1.021(0.985~1.059) | 0.253 | ||
病程(月) | 1.000(0.995~1.005) | 0.951 | ||
超重/肥胖(有/无) | 15.176(5.844~39.415) | <0.001 | 7.550(2.091~27.257) | 0.002 |
高血压(有/无) | 11.287(4.371~29.145) | <0.001 | 4.424(1.091~17.935) | 0.037 |
超重/肥胖伴高血压(有/无) | 29.440(6.343~136.641) | <0.001 | 1.041(0.102~10.575) | 0.973 |
肾小球硬化>10%(有/无) | 3.028(1.413~6.490) | 0.004 | 1.828(0.655~5.100) | 0.249 |
肾小管间质慢性病变(有/无) | 6.629(2.548~17.245) | <0.001 | 2.399(0.739~7.784) | 0.145 |
表3 薄基底膜肾小球病患者肾小球慢性病变(肾小球球性硬化>10%)的影响因素(Logistic回归分析,n=135) |
影响因素 | 单因素 | 多因素 | ||
---|---|---|---|---|
OR(95%CI) | P值 | OR(95%CI) | P值 | |
年龄(岁) | 1.036(1.000~1.074) | 0.048 | 1.035(0.996~1.075) | 0.080 |
病程(月) | 1.001(0.997~1.006) | 0.571 | ||
高血压(有/无) | 2.370(1.027~5.470) | 0.043 | 0.578(0.133~2.523) | 0.466 |
超重/肥胖(有/无) | 2.219(0.988~4.982) | 0.053 | 0.655(0.174~2.470) | 0.532 |
超重/肥胖伴高血压(有/无) | 3.398(1.220~9.466) | 0.019 | 3.855(0.479~30.991) | 0.205 |
蛋白尿(有/无) | 3.028(1.413~6.490) | 0.004 | 2.569(0.980~6.734) | 0.055 |
肾血管病变(有/无) | 2.000(0.973~4.110) | 0.059 | 1.700(0.771~3.749) | 0.188 |
表4 薄基底膜肾小球病患者肾小管间质慢性病变的影响因素(Logistic回归分析,n=135) |
影响因素 | 单因素 | 多因素 | ||
---|---|---|---|---|
OR(95%CI) | P值 | OR(95%CI) | P值 | |
年龄(岁) | 1.050(1.013~1.088) | 0.008 | 1.040(0.999~1.082) | 0.056 |
病程(月) | 1.002(0.997~1.007) | 0.469 | ||
高血压(有/无) | 8.667(2.472~30.379) | 0.001 | 2.496(0.452~13.775) | 0.294 |
超重/肥胖(有/无) | 7.137(2.337~21.800) | 0.001 | 2.321(0.547~9.856) | 0.254 |
超重/肥胖伴高血压(有/无) | 15.081(1.943~117.051) | 0.009 | 1.283(0.067~24.658) | 0.869 |
蛋白尿(有/无) | 6.629(2.548~17.245) | <0.001 | 3.151(1.046~9.491) | 0.041 |
肾血管病变(有/无) | 2.533(1.211~5.299) | 0.014 | 1.666(0.712~3.899) | 0.239 |
表5 合并超重/肥胖和(或)高血压患者与无合并症患者肾脏损害比较 |
项目 | 有合并症(n=44) | 无合并症(n=91) | 统计值(t/Z/χ2) | P值 |
---|---|---|---|---|
年龄(岁, | 43.5±9.6 | 39.1±10.3 | 5.578 | 0.020 |
尿蛋白量(g/24 h, | 0.49±0.26 | 0.26±0.19 | 36.190 | <0.001 |
蛋白尿[例(%)] | 29(65.9) | 12(13.2) | 38.986 | <0.001 |
NAG[U/g·Cr,M(P25,P75)] | 12.00(6.90,17.50) | 7.40(4.95,12.15) | -1.783 | 0.075 |
RBP[mg/L,M(P25,P75)] | 0.21(0.14,0.40) | 0.15(0.10,0.39) | -0.669 | 0.792 |
血清肌酐(μmol/L, | 59.2±12.4 | 55.7±11.5 | 2.608 | 0.109 |
肾小球硬化比例[%,M(P25,P75)] | 8.00(3.15,16.38) | 5.90(0,11.10) | -1.409 | 0.159 |
肾小球硬化>10%[例(%)] | 20(45.5) | 31(34.1) | 1.637 | 0.201 |
肾小管间质慢性病变[例(%)] | 38(86.4) | 42(46.2) | 19.863 | <0.001 |
肾血管病变[例(%)] | 15(34.1) | 10(11.0) | 10.490 | 0.001 |
注:NAG:尿N-乙酰-β-D-氨基葡萄糖苷酶;RBP:尿视黄醇结合蛋白 |
[1] |
Familial benign hematuria (FBH) is a common autosomal dominant disorder characterized by the presence of persistent or recurrent hematuria. The clinical and pathologic features of this syndrome resemble those of early Alport syndrome (AS), and for this reason a common molecular defect has been proposed. The COL4A3/4 genes seem to be involved in both autosomal AS and FBH. This study involves a linkage analysis for the COL4A3/4 loci and a search for mutations within these genes in 11 biopsy-proven FBH families. Haplotype analysis showed that linkage to the COL4A3/4 locus could not be excluded in eight of nine families. One family was not linked to this locus; however, it included three affected women who could be X-linked AS carriers. Two families were too small to perform linkage analysis. COL4A3 and COL4A4 mutation screening disclosed six new pathogenic mutations, two in the COL4A3 gene (G985V and G1015E) and four in the COL4A4 gene (3222insA, IVS23-1G>C, 31del11, and G960R). It is the first time that mutations within the COL4A3 gene are described in families with FBH. This study clearly demonstrates the main role of the COL4A4 and COL4A3 genes in the pathogenesis of FBH.
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[2] |
Thin basement membrane nephropathy (TBMN) is a glomerular disorder characterized clinically by isolated hematuria and pathologically by diffuse thinning of the glomerular basement membrane (GBM) on ultrastructural examination. The pathologic diagnosis of TBMN is problematic, in part because of the wide range of GBM thicknesses in the normal population. GBM thickness varies with age, sex, and the different methods of tissue preparation and measurement. In addition, there are no standardized diagnostic criteria defining the degree or extent of GBM thinning required for the diagnosis of TBMN. GBM thinning is often seen in other glomerulopathies, where it may represent an overlap with TBMN or may be secondary to GBM damage and remodeling. Importantly, TBMN must be differentiated from the GBM thinning seen in some renal biopsy specimens from boys and female heterozygotes with X-linked Alport syndrome because of the very different prognoses of these two conditions.
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[3] |
Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria >500 mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.
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[4] |
Thin basement membrane nephropathy (TBMN) is a common, lifelong condition affecting the kidneys that is characterized by microscopic glomerular hematuria, minimal or no proteinuria, and normal renal function. It often is discovered incidentally, and usually has an excellent prognosis. Many cases are familial and show autosomal-dominant inheritance. The defining characteristic is a glomerular basement membrane (GBM) that is thinned to about half its normal thickness on ultrastructural examination of the renal biopsy specimen. However, occasionally patients with TBMN develop marked proteinuria or renal impairment. It is unclear whether individuals with TBMN and impaired renal function represent part of the spectrum of TBMN associated with heterozygous COL4A3 or COL4A4 mutations, or if their disease is caused by mutations of other genes, or whether it is caused by a second coexistent renal lesion or is misdiagnosed Alport syndrome.
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[5] |
Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease.In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction.All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis.Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.
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[6] |
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[7] |
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[8] |
Background: Thin basement membrane disease (TBMD) occurs in 5–11% of renal biopsy series, and can be associated with other glomerulopathies (GNs). Data on the prevalence, clinical features, and prognosis of TBMD with other GNs are limited.
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[9] |
Thin glomerular basement membrane (GBM) nephropathy, also called familial benign hematuria, is characterized by chronic hematuria and uniform thinning of the lamina densa of the glomerular basement membrane. It generally holds an excellent renal prognosis. Alport syndrome in early stages can also show attenuation of the GBM; conversely, renal insufficiency has been reported in familial benign hematuria. To discern early Alport syndrome from thin GBM nephropathy, we carried out a prospective epidemiological study in which 19 normotensive and non-azotemic adult patients with chronic microscopic (18 of 19) and macroscopic (1 of 19) hematuria and biopsy-proven thin GBM nephropathy were followed for a median of 12 years (range 9 to 15 years). Renal biopsies of thin GBM patients at entry showed an increased incidence of focal global glomerulosclerosis when compared to disease controls as IgA nephropathy (P = 0.047) and normal renal tissue (P = 0.0075). All renal biopsies showed the presence of the Goodpasture antigen when tested immunohistochemically. Presence of Alport syndrome was excluded clinically as none of the patients had complaints of hearing loss or abnormalities by audiography and ophthalmology. At the end of follow-up, the incidence of hypertension in thin GBM nephropathy (35%) exceeded that of healthy clinical controls (P = 0.048), and one hypertensive patient developed mild renal failure. In the normotensive patients, the glomerular filtration rate at follow-up as measured by inulin clearance was reduced in three out of seven; these were over 50 years of age. Although no family members were known to have renal disease at inclusion, within four families six elderly first degree relatives had developed unexplained renal insufficiency at the end of follow-up. Thus, thin GBM nephropathy predisposes to premature glomerular obsolescence, leading in time to increased incidences of hypertension and late onset renal insufficiency.
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[10] |
To chart the epidemiology of primary glomerular disease by means of a prospective regional study in the southern part of The Netherlands.Experienced renal technicians collected renal biopsies, blood, and 24-hour urine samples at the bed site in each of the participating hospitals. The material was processed and analyzed at the University Hospital Maastricht. Analysis included light microscopy, immunohistochemistry, and electron microscopy of the biopsies as well as serologic and chemical analysis.Primary IgA nephropathy (IgAN), membranous glomerulopathy, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and thin basement membrane nephropathy (TBMN) are the most common primary glomerular diseases in this order of sequence. Our data show the clinical and histologic phenotype of TBMN to be diverse: the vast majority of TBMN has chronic microscopic hematuria, frequently associated with hypertension in late middle age; about 15% of TBMN has in addition substantial proteinuria which is associated in the majority of cases with the lesions of focal segmental glomerulosclerosis (FSGS). In 5% of TBMN a nephrotic syndrome is observed, occasionally associated with FSGS tip lesions.These results support the notion that TBMN is a disease of genetic heterogeneity; it is not a benign renal condition in a substantial number of patients, particularly those in late middle age.
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[11] |
Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for <5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear.
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[12] |
Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown.Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation.Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic.This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.
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[13] |
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[14] |
Alport syndrome (AS) is an hereditary disease of basement membrane collagen. It is mainly transmitted as a dominant X-linked trait and caused by mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen. However, autosomal recessive AS due to mutations in the COL4A3 or COL4A4 genes could represent up to 15% of AS. Using the immunofluorescence technique, we analyzed the distribution of the different chains of type IV collagen in renal (12 specimens) and skin (4 specimens) basement membranes of 12 AS patients belonging to 11 unrelated kindreds in which autosomal recessive inheritance had been demonstrated (3 kindreds) or was suggested by clinical and genealogic data (8 kindreds). The renal and skin distribution was normal in one patient with COL4A4 mutations. A peculiar pattern of distribution of the alpha 3-alpha 5(IV) chains was observed in the other patients. It was characterized the co-absence of the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains in the glomerular basement membrane, and the presence of the alpha 5(IV) chain in a series of extraglomerular basement membranes including capsular, collecting ducts and epidermal basement membranes, a combination never observed in X-linked AS. This immunohistochemical pattern is correlated with the specific distribution of the alpha 3-alpha 5 chains of type IV collagen chains within extraglomerular basement membranes. It could be a useful marker for the identification of autosomal recessive AS.
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[15] |
The process of glomerular filtration of plasma fluid has been known for over 160 years and the measurement of the rate of its formation (glomerular filtration rate, GFR) has been possible for over 80 years. Studies conducted in the 1930's to the 1950's clearly established that GFR declines, perhaps inexorably, with normal ageing, usually beginning after 30-40 years of age. The rate of decline may accelerate after age 50-60 years. This decline appears to be a part of the normal physiologic process of cellular and organ senescence and is associated with structural changes in the kidneys. In the last decade a new paradigm has been introduced in which the true or measured GFR is estimated (eGFR) by formulas based on serum creatinine levels and in which these estimates are applied to the diagnoses of chronic kidney disease (CKD) in the general population. These criteria for diagnosis of CKD include an absolute threshold for eGFR, unadjusted for the effects of age on the normal values for eGFR. A consequence of these criteria has been to overstate the frequency of CKD in the general population and to generate many "false positive" diagnoses of CKD. This paper discusses the known effects of ageing on GFR and the consequences of using a classification system for defining CKD that does not take into account the normal decline of GFR with ageing.
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[16] |
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[17] |
Metabolic syndrome (MetS) is a risk factor for the development of diabetes and cardiovascular disease, and recently was linked to incident chronic kidney disease (CKD). The purpose of this study is to examine whether MetS is associated with CKD progression in Japanese at a single center. Outcome variables were a decrease in estimated glomerular filtration rate (eGFR) of 50 % or 25 ml/min/1.73 m(2), end-stage renal disease (ESRD), death, or a composite outcome of all three. There were 213 subjects in the analysis, 40.4 % of whom met the criteria for MetS. The group of subjects with MetS had higher urinary albumin-to-creatinine (UACR) levels. Survival curves stratified by MetS status showed early separation of the curves and a significantly higher survival rate in the group without MetS (P = 0.0086). Comparisons with normoalbuminuria and microalbuminuria showed that macroalbuminuria was equally associated with predicted composite outcome (GFR, ESRD, or death) both in the presence and absence of MetS. Multivariate analyses for all covariates showed that eGFR (hazard ratio (HR) 8.286, 95 % confidence interval (CI) 2.360-28.044, P = 0.0012) and the UACR (HR 2.338, 95 % CI 1.442-3.861, P = 0.0005) at baseline were independently associated with the composite outcomes. The results show that MetS was associated with albuminuria in a cohort of Japanese CKD patients, and both MetS and albuminuria were independently associated with CKD progression.
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[18] |
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[19] |
Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.
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