Xiao Hj

Skin Biopsy Is a Practical Approach for the Clinical Diagnosis and Molecular Genetic Analysis of X-Linked Alport's Syndrome

A total of 209 unrelated patients of predominantly Han Chinese ethnicity and with X-linked Alports syndrome, a clinically heterogeneous hereditary nephritis, were enrolled in the present study to evaluate the ability to make a clinical diagnosis and perform molecular genetics analysis using skin biopsy. A negative or mosaic α5(IV) chain staining in the epidermal basement membrane was detected in 86.2% of male and 93.5% of female patients. COL4A5 mutations were identified in 85% of male patients with a negative α5(IV) chain staining pattern in the epidermal basement membrane. With use of skin biopsy and immunostaining, 16.4% of our patients were diagnosed before 3 years of age, and the youngest was diagnosed at 1 year of age. COL4A5 mutations were detected in 22 patients with normal epidermal basement membrane staining for the α5(IV) chain. Analysis of COL4A5 cDNA fragments from skin fibroblasts yielded a mutation detection rate of 83%, which was particularly valuable for identification of cryptic splicing mutations. Furthermore, 83% of COL4A5 mutations identified in the present study were novel. Thus, skin biopsy is a practical approach for the clinical diagnosis and molecular genetic analysis of X-linked Alports syndrome.

WT1 gene mutations in Chinese children with early onset nephrotic syndrome.

In Chinese children with steroid-resistant nephrotic syndrome (SRNS), it was reported that NPHS2 mutation was detected in 4.3%, which was lower than that in Caucasians (10–30%). However, there were no data on WT1 mutation in nephrotic syndrome (NS), especially in early-onset NS of Chinese children. Thus, a study, which enrolled 36 Chinese children with early-onset (before 3 y old) NS and steroid resistance if failing steroid therapy (early-group), was conducted. As control, 35 children with SRNS and with disease onset age after 3 y old were also analyzed (control-group). WT1 gene was examined by PCR and direct sequencing. The result showed that in the early-group 6/36 (16.7%) were detected with WT1 mutations. Further analysis according to different onset age revealed that the mutation detection rates of WT1 were 26.3% (5/19), 6.3% (1/16), and 0 (0/1) in children younger than 1 y, 1–2 y, and 2–3 y, respectively. In control-group, no WT1 (0/35) mutation was detected. WT1 mutation combined with NPHS2 variant was detected in a girl. In conclusion, WT1 mutations seemed more common in Chinese children with early-onset NS.

Value of the Oxford classification of IgA nephropathy in children with Henoch–Schönlein purpura nephritis

BackgroundThe widely used International Study of Kidney Disease in Children (ISKDC) classification for Henoch-Schönlein purpura nephritis (HSPN) does not completely correlate with the clinical presentation and long-term prognosis of this disease. Primary IgA nephropathy (IgAN) and HSPN share common features; thus, the Oxford classification of IgAN might be useful in predicting the long-term outcomes of HSPN. However, its value has not been confirmed in children with HSPN.MethodsWe selected children with HSPN diagnosed between 2003 and 2015, and reclassified their renal biopsies according to the Oxford classification scoring system. The primary outcome was impaired renal function, and remission of proteinuria and clinical remission were secondary outcomes.ResultsWe included 104 patients (58 males, 46 females) with a median age of 10 (4–17) years. Mesangial hypercellularity (M1) was strongly associated with proteinuria, and tubular atrophy/interstitial fibrosis (T1&2) and C2 (with crescents in > 25% of glomeruli) were associated with reduced estimated glomerular filtration rate (eGFR) at the time of biopsy. Patients with M1, endocapillary proliferation (E1), segmental glomerulosclerosis (S1), and crescents (C1&2) were more likely to have been treated with high-dose methylprednisolone. At univariate time-dependent analyses, S1 was strongly associated with the primary outcome (p = 0.025), whereas T1&2 was significantly negatively associated with proteinuria remission (p = 0.035) and clinical remission (p = 0.038).ConclusionsOur findings suggest that the Oxford classification is valid for children with HSPN. S and T lesions, which are ignored in the ISKDC classification, can be used to assess renal outcomes of HSPN, and such assessments are not affected by currently available treatments. The value of M, E and C lesions in predicting response to therapy and renal outcome warrants further study.

The clinical and laboratory features of Chinese Han anti-factor H autoantibody-associated hemolytic uremic syndrome

BackgroundAnti-complement factor H (CFH) autoantibody-associated hemolytic uremic syndrome (HUS) is a severe sub-type of HUS.MethodsWe assessed the clinical and renal pathological features, circulating complement levels, and genetic background of Chinese pediatric patients with this sub-type of HUS. Thirty-three consecutive patients with acute kidney injury who tested positive for serum anti-CFH autoantibodies were enrolled in this study.ResultsAll of the eight patients who underwent renal biopsies presented with changes typical of thrombotic microangiopathy, especially changes in chronic characteristics. Compared to patients in remission and normal control subjects, patients with acute disease had significantly lower plasma CFH levels and significantly higher plasma complement 3a (C3a), C5a, and terminal complement complex (SC5b-9) levels. The CFH–anti-CFH immunoglobin G (IgG) circulating immunocomplex (CFH-CIC) titers were more closely correlated with CFH plasma levels than anti-CFH IgG levels. Of the 22 patients, four (18%) were homozygous for CFHR3–1Δ and ten were heterozygous for CFHR1 or CFHR3 deletions. Most patients responded well to a combination of plasma and immunosuppressive therapies, with a remission rate of 87%. At the end of the follow-up, nine patients reached the combined end-points, including two with end-stage renal disease and seven with relapses.ConclusionPlasma C3a, C5a, and SC5b-9 levels predicted disease activity in anti-CFH autoantibody-associated HUS patients enrolled in this study. These patients responded well to plasma therapy combined with immunosuppression.

Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 and ADCK4 genes in two Chinese siblings

Hereditary nephrotic syndrome often presents with steroid-resistance and onset within the first year of life. Mutations in genes highly expressed in podocytes have been found in two thirds of these patients, especially NPHS1 and NPHS2 among at least 29 genetic causes that have been discovered. We reported two siblings with steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 (c.1339G>A, p.E447K) and ACDK4 (c.748G>C, p.D250H) genes. The siblings presented with steroid-resistant nephrotic syndrome and pathological lesions of focal segmental glomerulosclerosis (FSGS), while the elder sister also developed hypertension, renal failure and cardiac dysfunction.

LAMB2 mutation with different phenotypes in China .

BACKGROUND Mutations of the LAMB2 gene mainly cause Pierson syndrome (OMIM) #609049), characterized by congenital nephrotic syndrome (CNS) and complex ocular involvements with microcoria as the most prominent clinical feature. However, the phenotypic spectrum of LAMB2-associated disorders is broader, isolated congenital or infantile nephrotic syndrome can also be seen. The aim of this study was to explore the phenotypes of different LAMB2 mutations in China. METHODS LAMB2 mutations were analyzed in three Chinese childhood steroid-resistant nephrotic syndrome cases, two of them with ocular abnormalities. RESULTS LAMB2 mutations were confirmed in all the three cases, two presented with Pierson syndrome, while one presented with isolated infantile steroid-resistant nephrotic syndrome. CONCLUSIONS The phenotypes caused by LAMB2 mutation were variable, mainly Pierson syndrome, as well as isolated nephrotic syndrome without ocular involvement. Mutational analysis of LAMB2 should be considered in all steroid-resistant nephrotic syndrome patients, with or without any ocular abnormalities.
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Mutations in TTC21B cause different phenotypes in two childhood cases in China

The TTC21B gene is now known as causative of nephronophthisis‐related ciliopathies (NPHP‐RC). We reported two Chinese paediatric cases with end‐stage renal disease and other phenotypes caused by the TTC21B gene mutations.

The ratio of urinary α1-microglobulin to microalbumin can be used as a diagnostic criterion for tubuloproteinuria

Low-molecular-weight proteinuria is one of the characteristic clinical manifestations of renal tubular and interstitial diseases. Low-molecular-weight proteinuria is defined as excessive urinary loss of α1-microglobulin, β2-microglobulin, or other low-molecular-weight plasma proteins. The current study examined the ratio of urinary α1-microglobulin to microalbumin in 24 Chinese pediatric patients with renal tubular and interstitial diseases, including 10 patients with Dent disease, 2 patients with Lowe syndrome, 6 patients with acute tubulointerstitial nephritis (ATIN), 4 patients with acute tubulointerstitial nephritis with uveitis syndrome (TINU), and 2 patients with nephronophthisis (NPHP). Patients with steroid-sensitive nephrotic syndrome, IgA nephropathy, Henoch-Schonlein purpura nephritis, or lupus nephritis served as control groups. In all of the patients with tubular and interstitial disease, urinary α1-microglobin increased 10-300-fold above the upper limit of the normal range, the ratio of urinary α1-microglobulin to microalbumin was greater than 1, and the percentage of low-molecular-weight plasma proteins (LMWP) in urine was greater than 50% according to urine protein electrophoresis. There was close correlation between the ratio of urinary α1-microglobulin to microalbumin and the percentage of LMWP in urine according to urine protein electrophoresis (r = 0.797, p = 0.000). We suggested firstly that the ratio of urinary α1-microglobulin to microalbumin, greater than 1, can be used as a diagnostic criterion for tubuloproteinuria.

Dent disease: Same CLCN5 mutation but different phenotypes in two brothers in China

Dent disease is an X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life, caused by mutations in CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes, respectively. It presents mainly with hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis and progressive renal failure. We report here the same CLCN5 mutation but different phenotypes in two Chinese brothers, and speculate on the possible reasons for the variability of the genotype-phenotype correlations.

Diagnosis and treatment of Dent disease in 10 Chinese boys.

Dent disease is a rare X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life. Dent disease is clinically characterized by the presence of low molecular weight proteinuria (LMWP), hypercalciuria, medullary nephrocalcinosis, nephrolithiasis, and progressive renal failure. The clinical features, diagnosis, and treatment of Dent disease were examined in 10 Chinese boys. All 10 childhood cases of Dent disease in China presented with tubular proteinuria in the nephrotic range and hypercalciuria. The ratio of α1-microglobulinuria to microalbuminuria, if close to or above 1, can be used as a diagnostic criterion for tubuloproteinuria. Lotensin was ineffective at treating proteinuria while dihydrochlorothiazide reduced urine calcium excretion.