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Objective: To explore clinical and genetic features of persistent asymptomatic microscopic hematuria in children. Methods: A retrospective case analysis of 135 individuals admitted to Xi 'an Children's Hospital with persistent asymptomatic microscopic haematuria between January 2016 to December 2023 was conducted. The demographic characteristics, kidney pathology and gene results of 135 individuals were analyzed. One hundred and thirty-five individuals were divided into 2 groups (positive group and negative group) according to family history of glomerulogenic hematuria in first-degree relatives. The differences of hematuria remission, proteinuria and gene variation were compared between the 2 groups. Two independent sample t test, Wilcoxon rank sum test, Pearson Chi-square, Yates' corrected Chi-squared test or Fisher exact test were used for comparison between groups. Results: All 135 children, with 48 males and 87 females, were 8.5 (6.5, 9.5) years old at first presentation. Kidney biopsy was performed in 73 cases (54.1%). Kidney pathology showed mild lesions in 41 cases (56.2%), thin basement membrane disease (TBMD) in 24 cases (32.9%), typical pathological features of Alport syndrome in 5 cases (6.8%), and other manifestations in 3 cases (4.1%). The positive group comprised 52 individuals, whereas the negative group consisted of 83 individuals. The positive group demonstrated a higher susceptibility in proteinuria and gene variation, while the negative group exhibited a greater rate of hematuria remission (χ2=5.00, 5.27, 8.52, all P<0.05). Whole exome sequencing was performed in 80 individuals and 18 individuals (22.5%) had a pathogenic or likely pathogenic variant in COL4A3-5. COL4A5 was the most common gene afected, accounting for 11 cases. The 135 individuals were followed up for 4.2 (2.9, 5.1) years, of which 31 cases (22.9%) had complete hematuria remission at 2.1 (1.4, 2.7) years. Up to March 2024, there were also 7 individuals (5.2%) with varying degrees of proteinuria, and 3 individuals (2.2%) with proteinuria progressed to chronic kidney insufficiency. Conclusions: The most common kidney pathological types in children with persistent asymptomatic microscopic hematuria are minor lesions and TBMD. Children with microscopic hematuria whose first-degree relatives have a family history of hematuria are more likely to have proteinuria and gene variants. COL4A3-5 genetic screening could be considered a priority in these children.

Although infiltrating macrophages found in renal biopsy specimens have been accepted as a useful marker for evaluating the activity of IgA nephropathy (IgAN), it is difficult to perform renal biopsies repeatedly, especially in children. To establish a more convenient and noninvasive method for estimating the degree of macrophage infiltration we examined the number of macrophages in urinary sediments. Ten ml of morning urine were collected from 30 children with IgAN, 10 with thin basement membrane disease (TBMD), 8 with idiopathic renal hemorrhage (IRH) which was defined as nonglomerular hematuria due to nutcracker phenomenon revealed on ultrasonography, and 10 healthy children as controls. Ten of the 30 children with IgAN were treated with combination therapy comprising prednisolone, warfarin and dipyridamole and urine samples were collected weekly during the period of treatment. Two microl of the urine sediment were smeared on glass slides, dried and stained with a monoclonal antibody to human macrophages (anti-CD68, PG-M1) followed by a FITC-conjugated secondary antibody. After staining with propidium iodide (PI), the cells were examined by fluorescence microscopy with cells stained with both FITC and PI being counted as macrophages. In addition, anti-CD68 staining was used to quantify macrophage infiltration in renal biopsies from the same group of IgAN patients. The number of urine macrophages in children with IgAN was significantly higher than in children with TBMD and IRH as well as the control group (p < 0.01), whereas that was similar among TBMD, IRH and healthy children. In IgAN, there was a significant correlation between urine macrophage number and the activity index (p < 0.01), proteinuria (p < 0.01) and urine WBC count (p < 0.01). In addition, there was also a significant correlation between urine macrophage number and glomerular (p < 0.05) as well as interstitial macrophage infiltration (p < 0.01). In children with IgAN who received combination therapy, urine macrophage number decreased significantly (p < 0.01) in the 1st week of treatment whilst the degree of proteinuria decreased significantly (p < 0.01) in the 4th week. Urinary macrophage number may represent a noninvasive and straightforward estimate of the pathological activity evident in renal biopsy specimens, and may also be a more sensitive indicator than proteinuria of the therapeutic effect of interventional treatments in childhood IgAN.

Loin pain-hematuria syndrome associated with thin glomerular basement membrane disease and hemorrhage into renal tubules

Differential diagnosis between X-linked Alport syndrome and thin basement membrane nephropathy

JO N 2871 A previously well, 52-year-old woman presented after one week of headache, nausea and difficulty speaking. She had a history of hypertension treated with metoprolol and painless microscopic hematuria. There was no family history of hematuria or renal disease. Renal ultrasound and cystoscopy were normal, and a renal biopsy one year before presentation showed thin glomerular basement membrane nephropathy (TBMN, Fig. 1C). Examination revealed an expressive dysphasia and a right homonymous hemianopia. Blood pressure was 140/76; there were no overt clinical features suggestive of a connective tissue disorder. MRI and MR angiography showed a Nicholas J. Cutfield John L. Wilson L. Jonathan Zwi Barry J. Snow

Background: Microscopic hematuria without proteinuria is a common clinical finding in cases of immunoglobulin A (IgA) nephropathy and of thin basement membrane nephropathy. Liver-type fatty acid-binding protein (L-FABP) is expressed in renal proximal tubules and is reported to be a useful marker of the progression of chronic glomerulonephritis. Aim: To assess urinary L-FABP levels for differential diagnosis in patients with microscopic hematuria but without proteinuria. Methods: This was a multi-center retrospective study. Thirty adult patients who underwent renal biopsy for microscopic hematuria and 20 healthy adult volunteers were included in this study. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay and compared, particularly between those diagnosed with IgA nephropathy and those diagnosed with thin basement membrane nephropathy. Results: Twelve (40%) patients had IgA nephropathy, 6 (20%) had thin basement membrane nephropathy and 12 (40%) had normal biopsy findings. The urinary L-FABP level was significantly higher in patients with IgA nephropathy (38.4 ± 26.8 µg/g Cr) than in healthy subjects (5.8 ± 4.0 µg/g Cr) (p < 0.01); however, the level in patients with thin basement membrane nephropathy or normal biopsy results was comparable to that in healthy subjects. Follow-up data were available for 11 of the 12 patients with IgA nephropathy who initially had no proteinuria. After 24 months, 4 of the 11 were found to have proteinuria, and the urinary L-FABP level had increased from 40.6 ± 30.5 µg/g Cr to 58.8 ± 40.5 µg/g Cr (p < 0.01). Conclusions: Our data suggest that the urinary L-FABP level can be used to discriminate between IgA nephropathy and thin basement membrane nephropathy in patients with microscopic hematuria.

To clarify the incidence of thin basement membrane disease (TMD) among the patients with idiopathic asymptomatic hematuria and/or proteinuria, in 217 serious renal biopsies (children 85, adults 132) were studied with clinical and morphometric analysis. TMD used is defined as follows: 1) Glomerulus in minor abnormalities; 2) GBM less than or equal to 200 nm in width, with more than 20% in total glomerular capillary surface; 3) Absence of significant immunoglobulins or complement components. Out of 217 patients 93% had either IgA nephropathy (55%), normal glomeruli (21%) or TMD (17%). TMD consisted of 22% in children and 14% in adults. Remained 15 consisted of non-IgA mesangial proliferative glomerulonephritis (6 cases), incomplete foot process disease (5), membranous nephropathy (2), membranoproliferative glomerulonephritis (1), and unclassified (1). Patients with TMD were found mostly (71%) in younger age less than 20 years old. Out of the patients with TMD, 38% had renal abnormality in the family history, but remainders were sporadic. The common urinary abnormality in TMD was microscopic hematuria occasionally with mild proteinuria (95%), while proteinuria only was rare (5%). Outcome of TMD was favorable prognosis with normal renal function. TMD was histologically divided into 2 groups; diffuse type (GBM thinning was more than 50% in the capillary surface) (19 cases; 51%), and focal type (it was less than 50%) (18 cases; 49%). The incidence of those family history was 64% and 15%, respectively (p less than 0.05). It was concluded that TMD was a popular disorder in patients with asymptomatic hematuria and/or proteinuria and it may expect 17% in incidence.

Thin basement membrane nephropathy is recognized by a diffusely thin glomerular basement membrane (GBM) ultrastructurally. In contrast to Alport syndrome (AS), there is no GBM thickening, lamellation, or granular inclusions. Morphologically, there is overlap between thin basement membrane nephropathy and AS in female patients in whom there might be only thin GBM and no pathognomonic findings of AS. To determine if the use of antibodies to collagen IV is helpful in making the distinction between thin basement membrane nephropathy and AS in female patients with primarily thin GBMs. We examined renal biopsies from 9 adult female patients with thin GBMs for the presence of alpha1, alpha3, alpha4, and alpha5 chains of type IV collagen by immunofluorescence. In 2 patients with segmental GBM staining, no suggestion for AS was found on physical examination or in their family history. In the remaining 7 patients with normal GBM staining, 4 had family members with end-stage renal disease of unknown etiology, raising the suspicion of X-linked or autosomal-recessive AS. Three patients were presumed to have thin basement membrane nephropathy. Segmental GBM staining for alpha3, alpha4, and alpha5 chains of type IV collagen raises the suspicion of AS in the presence of adequate controls and other supporting evidence. Normal GBM staining for alpha3, alpha4, and alpha5 chains of type IV collagen, however, does not exclude AS.

Objective: In order to learn the serum level of galactose-deficient IgA1 (GdIgA1), IgG antibody to galactose-deficient IgA1(GdIgA1-IgG) and the clinical role of them in IgA nephropathy(IgAN) children. Method: We compared blood levels of GdIgA1, GdIgA1-IgG in 33 children with IgAN, 38 children with other renal disease (including focal segmental glomerular nephritis, minimal change disease, Alport syndrome and thin basement membrane nephropathy) as disease controls, 35 healthy children as normal controls with enzyme-linked immunosorbent assay(ELISA). Twenty-four-hour urine protein content and Lee's pathological classification were collected in IgAN cases. The difference among the three groups were examined by analysis of variance. The specificity and sensitivity of GdIgA1, GdIgA1-IgG to IgA nephropathy were evaluated by ROC curve.The correlations were analyzed by correlation analysis among GdIgA1, GdIgA1-IgG and urine protein content and pathological classification . All statistical analyses were performed by SPSS 18.0. P value of <0.05 was considered statistically significant. Result: The levels of GdIgA1 and GdIgA1-IgG significantly elevated in children with IgAN compared to disease controls and normal controls. GdIgA1(mg/L): 1.728±0.456, 1.123±0.461, 1.410±0.905 (F=15.04, P<0.001); GdIgA1-IgG(g/L): 1.299±0.499, 1.111±0.549, 0.628±0.142 (F=76.96, P<0.001). Area under the curve of ROC of GdIgA1 between IgAN and normal controls was 0.765, with specificity 0.943 and sensitivity 0.697, while the area under the curve of GdIgA1-IgG was 0.969, with specificity 0.971 and sensitivity 0.939.The blood level of GdIgA1-IgG was mildly correlated with both 24-hour urine protein(r=0.364, ) and renal pathological grading(r=0.392) in children with IgAN. Conclusion: The levels of GdIgA1 and GdIgA1-IgG significantly elevated in children with IgAN compared to disease controls and normal controls. GdIgA1-IgG had higher sensitivity in distinguishing IgAN from normal controls, GdIgA1-IgG was mildly correlated with 24-hour urine protein volume and pathological grading in children with IgAN.

Statistical Prediction in Pathological Types of Chronic Kidney Disease.

Thin basement membrane nephropathy (TBMN) is a disorder characterized by ultrastructural abnormalities of the glomerular basement membrane (GBM), representing a spectrum of genetic and clinical phenotypes ranging from benign hematuria to proteinuria and chronic kidney disease. Recent studies have shown that a significant percentage of patients who initially present with hematuria later develop proteinuria and worsening renal function. We retrospectively analyzed records of patients diagnosed with TBMN, including their clinical, laboratory, and histological features, in Slovenia from 2015 to 2020. TBMN was the main diagnosis at kidney biopsy in 34 (65%) of 52 included patients, while in 18 patients (35%) TBMN was diagnosed in addition to other renal diseases. In the isolated TBMN group, 29 of 34 patients had glomerulosclerosis (global, global and segmental, segmental only) accompanied by interstitial fibrosis/tubular atrophy of varying degrees. 13 patients with isolated TBMN had signs of advanced chronic kidney disease at the time of diagnosis, with estimated glomerular filtration rate < 60 mL/min/1.73m2. 29 patients had proteinuria, which exceeded 3 g/day in 4 patients. TBMN represents a proportion of patients with focal segmental glomerulosclerosis (FSGS) that have often been classified in the past as etiologically indeterminate FSGS. Ultrastructural examination showing diffuse thinning of the GBM is crucial for the TBMN diagnosis. TBMN was the main diagnosis of kidney biopsy in 2/3 of our patients, while it was accompanied by other renal diseases in 1/3. Up to 1/3 of patients with isolated TBMN had evidence of advanced chronic kidney disease at the time of diagnosis.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease, accounting for approximately 5% of kidney failure worldwide. While Alport syndrome (AS) is an inherited progressive disease that typically presents with microhematuria in childhood and subsequently progresses to hematuria, proteinuria, and progressive renal impairment. The coexistence of ADPKD and AS is rare. Here, we present a case of a child with ADPKD and AS who presented with bilateral renal cysts and hematuria. Furthermore, we described the clinical and genetic characteristics of the present case and summarized the above features of previously reported cases. A 4-year-old boy had persistent microscopic hematuria and intermittent gross hematuria for 1year. During routine examinations, microscopic hematuria (++), bilateral renal cysts, and high-frequency hearing loss were discovered. Furthermore, His mother had microscopic hematuria and was later diagnosed with ADPKD. A pathogenic variant was found in COL4A5 through genetic testing, while a variant of undermined significance (VUS) was discovered in PKD1. These clinical and genetic findings are consistent with the diagnosis of ADPKD and AS co-occurring. Enalapril was administered. A 2-year follow-up revealed that the patient had continuous microscopic hematuria and normal range renal function. We also reviewed four cases of ADPKD and AS coexisting. Moreover, hematuria and decreased renal function were the most common clinical features. They all had a positive family history. This disease has a poor prognosis, with three cases progressing to kidney failure. ADPKD and AS are often associated with hematuria, renal cysts, and decreased renal function. Comprehensive clinical information and early genetic testing is critical for diagnosis, prognostic stratification, and initiating targeted therapies to delay progression.

Immunoglobulin A (IgA) nephropathy is the most common glomerular disease, and it often manifests as persistent microscopic hematuria or gross hematuria. Fabry disease and Alport syndrome are hereditary diseases caused by mutation of genes, and these diseases are rare in China. At present, patients can be diagnosed with IgA nephropathy by clinical manifestations and laboratory examinations, but there is still controversy about the simultaneous diagnosis of Alport syndrome and Fabry disease in patients with IgA nephropathy. The present case was a 17-year-old girl with hematuria and proteinuria who underwent a renal biopsy. Light microscopy and immunofluorescence showed that IgA was deposited in the mesangium. Under electron microscopy, zebra bodies with a lamellated structure were detected. A gene test showed a COL4A3 gene mutation. The patient was administered prednisone 40 mg once a day and dispersible tablets of mycophenolate mofetil 0.75 g two times a day. The patient’s condition showed a trend of remission. The findings in our case emphasize the importance of renal biopsy and gene detection in hereditary kidney disease, especially for Fabry disease and its rare coexistence with Alport syndrome.

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.

Autosomal recessive Alport’s syndrome and benign familial hematuria are collagen type IV diseases