Novel Mutations of COL4A5 Identified in Chinese Families with X-Linked Alport Syndrome and Literature Review.

Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the COL4A5 gene. This study explored novel deletion and missense mutations in COL4A5 responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs∗11) in exon 7 of COL4A5. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 µmol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the COL4A5 gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried COL4A5 deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%, P = 0.041). This study identified two novel COL4A5 mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the COL4A5 gene, and presented findings that are significant for the screening and genetic diagnosis of AS.

A Variant in the NEDD4L Gene Associates With Hypertension in Chronic Kidney Disease in the Southeastern Han Chinese Population.

BACKGROUND: "Neuronal precursor cell expressed developmentally down-regulated 4-like" (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS: We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using quantitative polymerase chain reaction. RESULTS: For rs4149601, significant differences in genotype frequencies in an additive model (GG vs. GA vs. AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension, and ambulatory systolic hypertension (P = 0.038, 0.005, and 0.006, respectively). In a recessive model (GG + GA vs. AA), the frequency of the AA genotype of rs4149601 in the hypertension groups was all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared with the GG + GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension, and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS: The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.

High serum IgA/C3 ratio better predicts a diagnosis of IgA nephropathy among primary glomerular nephropathy patients with proteinuria ≤ 1 g/d: an observational cross-sectional study.

BACKGROUND: The serum immunoglobulin A (IgA)/C3 ratio is considered to be an effective predictor of IgA nephropathy (IgAN). This study sought to explore the diagnostic value of the IgA/C3 ratio in IgAN among primary glomerular nephropathy patients in China. METHODS: We recruited 1095 biopsy-diagnosed primary glomerular nephropathy patients, including 757 IgAN patients and 338 non-IgAN patients. Patient demographics, serum immunological indices, and other clinical examinations were measured. IgAN cases were propensity score matched (PSM) to non-IgAN cases on the logit of the propensity score using nearest neighbor matching in a 1:1 fashion, with a caliper of 0.02 with no replacements, according to age, gender, BMI, proteinuria level, and estimated glomerular filtration rate (eGFR). RESULTS: We found that in both the full cohort and PSM cohort, the IgA/C3 ratio in the IgAN group was significantly higher than that of the non-IgAN group. The same results were also obtained with stratification by different levels of proteinuria and renal function. In the PSM cohort, there was no difference in IgA/C3 ratio in patients with IgAN between different proteinuria groups and different chronic kidney disease (CKD) groups. The area under the ROC curve (AUROC) of the IgA/C3 ratio in distinguishing IgAN among primary glomerular disease was 0.767 in the full cohort, and 0.734 in the PSM cohort. The highest AUROC of the IgA/C3 ratio was in the ≤1 g/d proteinuria group (0.801 in the full cohort, and 0.803 in the PSM cohort); however, there was no difference between all CKD groups. Meanwhile, the diagnostic accordance rate for the diagnosis of IgAN among all patients with an IgA/C3 ratio > 3.5304 was as high as 92.02% in the full cohort. IgAN was independently correlated with IgA/C3 ratio in the full cohort by multivariate logistic regression analysis. CONCLUSIONS: The present study provides clear evidence that the IgA/C3 ratio is an effective predictor of IgA diagnosis, especially in patients with proteinuria ≤1 g/d. In order to study the effectiveness of this biomarker, and to determine a standardized cut-off value, additional multicenter large-scale studies are needed.

Clonal evolution in a chronic neutrophilic leukemia patient.

Objectives and importance: Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R); these mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Clinical presentation: We present a male patient who presented peripheral blood leukocytosis. On the basis of his morphological appearances and molecular findings he was determined to have a diagnosis of chronic neutrophilic leukemia. At a follow-up at 7 months, in addition to the CSF3R c.2373G > A (p.W791*) truncated mutation, another CSF3R mutation appeared as c.1853C > T(p.T618I). Discussion and conclusion: We present the first patient with a diagnosis of chronic neutrophilic leukemia with a c.2373G > A (p.W791*) truncated mutation of CSF3R. These findings elucidate a novel paradigm of CNL pathogenesis and explain how mutations drive the development of the disease. The order of acquisition of CSF3R mutations relative to mutations in epigenetic modifiers and the spliceosome have been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL.

Syndrome of uremic encephalopathy and bilateral basal ganglia lesions in non-diabetic hemodialysis patient: a case report.

BACKGROUND: Uremic encephalopathy (UE), a toxic metabolic encephalopathy, is an uncommon complication resulting from endogenous uremic toxins in patients with severe renal failure. UE syndrome can range from mild inattention to coma. The imaging findings of UE include cortical or subcortical involvement, basal ganglia involvement and white matter involvement. The basal ganglia type is uncommon, although previous cases have reported that Asian patients with diabetes mellitus (DM) are usually affected. CASE PRESENTATION: A 32 year-old woman with a history of non-diabetic hemodialysis for 3 years suffered from severe involuntary movement, and brain magnetic resonance imaging showed symmetrical T2-weighted imaging (T2WI) and T2/fluid-attenuated inversion recovery (T2FLAIR) hyperintense nonhemorrhagic lesions in the bilateral basal ganglia. She was diagnosed with UE as syndrome of bilateral basal ganglia lesions, due to a combined effect of uremic toxins and hyperthyroidism. After treatment with high frequency and high flux dialysis, hyperbaric oxygen therapy and declining parathyroid hormone, the patient achieved complete remission with normal body movement and was discharged. CONCLUSION: UE with basal ganglia involvement is uncommon, although generally seen in Asian patients with DM. Our case reported a hemodialysis patient that had non-diabetic UE with typical bilateral basal ganglia lesions, presenting with involuntary movement.

Prevalence, determinants, and clinical significance of masked hypertension and white-coat hypertension in patients with chronic kidney disease.

BACKGROUND: Masked hypertension and white-coat hypertension have been studied among the general population and in hypertensive patients. However, little insight is available on masked and white-coat hypertension among patients with chronic kidney disease (CKD). METHODS: We recruited 1322 CKD patients admitted to our hospital division. Patients were divided into four groups: normotension; white-coat hypertension (WCHT); masked hypertension (MHT); sustained hypertension. Multivariable logistic regression analyses were used to evaluate the correlation between WCHT, MHT and renal/cardiovascular parameters. RESULTS: The prevalence of WCHT and MHT was 10.21% and 16.11%, respectively. Patients with WCHT and MHT had more severe target-organ damage (TOD) than patients with normotension, but had less severe TOD than patients with sustained hypertension. MHT correlated with impaired renal function and left-ventricular hypertrophy, whereas WCHT was associated with abnormal carotid intima media thickness. Age, body mass index, clinic and 24-h systolic blood pressure correlated with MHT, whereas clinic, 24-h diastolic blood pressure and night-time systolic blood pressure was associated with WCHT. CONCLUSIONS: Prevalence of WCHT and MHT was 10.21% and 16.11%, respectively. WCHT and MHT show a close relationship with TOD in CKD patients.

High prevalence of isolated nocturnal hypertension in Chinese patients with chronic kidney disease.

BACKGROUND: Isolated nocturnal hypertension (INH) has been studied among the general population and hypertensive patients. However, little insight is available on the prevalence of INH and its role in target-organ damage among patients with chronic kidney disease (CKD). METHODS AND RESULTS: We recruited 1282 CKD patients admitted to our hospital division. Patients were divided into 4 groups: INH; isolated daytime hypertension; day-night sustained; and ambulatory normotension. Multiple linear regression analyses were used to evaluate the correlation between INH and renal/cardiovascular parameters. A total of 262 (20.44%) CKD patients had isolated nocturnal hypertension and 651 (50.78%) had day-night sustained hypertension, whereas only 350 (27.30%) patients showed normotension and 19 (1.48%) had isolated daytime hypertension. Multivariate logistic regression analysis showed that INH was associated mainly with age, estimated glomerular filtration rate, clinic diastolic blood pressure, and that INH was determined only by age, estimated glomerular filtration rate, and clinic diastolic blood pressure. The prevalence of impaired renal function, left ventricular hypertrophy, and carotid intima-media thickness in patients with INH were higher than in normotensive patients (P<0.05), whereas impaired renal function and left ventricular hypertrophy in these patients were lower than patients in the day-night sustained hypertension group (P<0.05). INH was correlated with estimated glomerular filtration rate, left ventricular mass index, and carotid intima-media thickness according to multiple linear regression analyses. CONCLUSIONS: The prevalence of INH in CKD patients was high, and INH was correlated with target-organ damage in CKD patients.

Nocturnal Hypertension Correlates Better With Target Organ Damage in Patients With Chronic Kidney Disease than a Nondipping Pattern.

Both nocturnal hypertension and nondipping pattern are associated with target organ damages (TODs); however, no data exist with respect to Chinese patients with chronic kidney disease (CKD). The authors recruited 1322 patients with CKD admitted to our hospital division and referred with data in this cross-sectional study. Patients with nocturnal systolic hypertension had a lower estimated glomerular filtration rate (eGFR) and higher left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) compared with patients with normal nocturnal systolic blood pressure (SPB; all, P<.001), while patients in the dipper and nondipper groups had similar levels of eGFR, LVMI, and cIMT when the patients had a similar nocturnal SBP. Factorial-designed analysis of variance indicated that the main effect of nocturnal SBP was significant for all TOD differences (all, P<.001), but no significance existed with respect to the main effect of the dipper pattern and an interaction between the two factors (all, P>.05). Nocturnal systolic hypertension, rather than nondipping pattern, was an independent risk factor for TOD in CKD patients. Nocturnal hypertension, rather than a nondipping pattern, was better associated with TOD in CKD patients.

Disparate assessment of clinic blood pressure and ambulatory blood pressure in differently aged patients with chronic kidney disease.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is recommended to assess hypertensive status in patients with chronic kidney disease (CKD). However, the difference in blood pressure (BP) based on clinic and ambulatory monitoring in CKD patients of different ages is not known. METHODS: We recruited 1116 CKD patients admitted to our hospital division and referred with data in this cross-sectional study. Patients were divided into three groups: young, middle age and old. Inter-method agreement between clinic BP and ABPM in different age groups was assessed using the Kappa (κ) coefficient. Linear and logistic regression analyses were used to evaluate renal and cardiovascular parameters. RESULTS: κ coefficient for inter-method agreement between clinic BP and ABP in patients from young, middle-age and old groups was 0.472 (p<0.001), 0.335 (p<0.001) and 0.102 (p=0.086), respectively. Age was the main factor determining the difference in clinic BP and ABP by multiple linear regression analyses. Prevalence of masked hypertension in older patients was higher than that in young and middle-age patients (p<0.001), and age was associated with the onset of masked hypertension. Age and ABP were independently correlated with estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI), whereas age and clinic BP were associated with carotid intima media thickness (cIMT) by linear and logistic regression analyses. CONCLUSIONS: We have provided evidence of disparate assessment of the diagnosis and correlation with TOD from clinic BP and ABP in untreated, different-aged, CKD patients. Good-quality, long-term, large longitudinal trials are needed to validate the role of ABPM for Chinese CKD patients.

The ambulatory arterial stiffness index and target-organ damage in Chinese patients with chronic kidney disease.

BACKGROUND: The ambulatory arterial stiffness index (AASI) can be used to predict cardiovascular morbidity and mortality in hypertensive patients. However, data on AASI in Chinese patients with chronic kidney disease (CKD) is not available. METHODS: This cross-sectional study enrolled 583 CKD patients. Univariate and multivariate analyses were used to evaluate the relationship between AASI and renal function and parameters of cardiovascular injury. RESULTS: Patients with a higher AASI had a higher systolic blood pressure, a lower estimated glomerular filtration rate (eGFR), a higher serum cystatin C, a higher left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT). Univariate analyses showed that AASI was positively correlated with serum cystatin C (r=0.296, P < 0.001), serum creatinine (r=0.182, P < 0.001), and LVMI (r = 0.205, P < 0.001) and negatively correlated with the eGFR (r = -0.200, P < 0.001). Multivariate analyses revealed that serum cystatin C, eGFR, serum creatinine and LVMI were independently correlated with AASI. CONCLUSIONS: These data suggest that AASI was closely correlated with renal function and parameters of cardiovascular injury in Chinese CKD patients. Good quality, long-term, large longitudinal trials to validate the role of AASI in clinical practice for Chinese CKD patients.

[Characteristics of fusion gene and immunophenotype in MLL gene rearrangement positive childhood acute lymphoblastic leukemia].

The study was aimed to investigate the fusion gene transcript and immunophenotypic characteristics of the mixed linage leukemia (MLL)-rearranged positive childhood acute lymphoblastic leukemia (ALL). The incidence of MLL rearrangement in 601 cases of ALL patients was detected by the multiple-nested polymerase chain reaction (PCR); the subtypes and features of the fusion gene transcript were analyzed by PCR products sequencing; the immunophenotypic characteristics at diagnosis were compared between the 22 MLL rearrangement positive of ALL patient, 30 negative control which selected randomly from the patients whose fusion gene could not be detected in the same term and 43 pro-B-ALL patients. The results showed that the incidence of MLL positive ALL was 3.66%, constituted 29.9% of the pro-B-ALL. The MLL rearrangement positive 20 B-ALL patients were all CD10 negative; the number of patients who carried CD13, CD33 and CD34 was lower than that of pro-B-ALL who had no fusion gene, whereas the expression of CD20, CD22, CD2, CD5, CD7 showed no difference. 4 kind partner genes of MLL-AF4, AF9, AF10 and ENL were detected. The fusion loci of MLL gene were mainly located at the exon 6, 7, 8 and many kind of fusion loci of MLL may exist in one patient; whereas its partner gene fusion loci were relatively single. A transcript contains a random insert sequence existed in a transcript of one MLL-AF10+ patient. It is concluded that though incidence of MLL rearrangement is low, but it has a variety of fusion transcripts, the ALL patients has unique biological characteristics at immunophenotype and fusion transcript.

[Immunophenotypic characteristics of children with acute lymphoblastic leukemia carrying TEL-AML1 fusion gene].

To investigate the immunological and other clinical characteristics in TEL/AML1+ childhood B-acute lymphoblastic leukemia (B-ALL), immunophenotyping was performed with three-color flow cytometry, and the expression of TEL-AML1 fusion gene was detected with nested RT-PCR. Diagnosis was made according to FAB and MIC criteria. The results showed that (1) among 119 children with B-ALL, 22 (18.5%) were TEL-AML1 positive and classified as L2 morphological subtype. In TEL-AML1+ group, positive rate and score of PAS, which were 65% and 121 respectively, were all higher than that of TEL-AML1- group (P < 0.05); (2) compared with TEL-AML1- group, no significant difference was found in age, gender, white cell count and blasts count in peripheral blood of TEL-AML1+; (3) in TEL-AML1+ group, 21 out of 22 (95.5%) were common ALL, as compared with TEL-AML1- group, the positive rate of CD13 was higher (59.1%, 13/22) and the positive rate of CD20 was lower (22.7%, 5/22) than that in TEL-AML1- group, respectively (P < 0.05), and the mean fluorescence index of CD10 and HLA-DR significantly increased to 92.80 and 53.61, respectively (P < 0.05). It is concluded that TEL-AML1 rearrangement is a frequent molecular abnormality in childhood ALL. Leukemic blasts with this anomaly have special immunophenotypic characteristics. These characteristics may be useful in detection of minimal residual leukemia.

[Expression of transporter associated with antigen processing (TAP) in childhood acute leukemia and its clinical significance].

BACKGROUND & OBJECTIVE: Transporter associated with antigen processing(TAP) participates in immune surveillance, so it is probably relevant to carcinogenesis. Investigation of expression of TAP and its clinical significance in childhood acute leukemia will be helpful to clarify pathogenesis and to develop immunotherapy strategy. METHODS: RT-PCR analysis was used to detect the expression of TAP1 and TAP2 in leukemia cells from bone marrow in 34 inpatients with primary acute lymphoblastic leukemia (ALL), 15 inpatients with relapsed ALL, 20 inpatients with acute medullary leukemia (AML), and 20 surgical inpatients without systematic disorders as control. And then,the absorbance (A) values of expanded bands were measured by digital imaging analyzer and relative A values were worked out based on A value of GAPDH (positive inside control). RESULTS: The relative A values of TAP1(0.448+/-0.167 and 0.169+/-0.021,respectively) and TAP2(0.196+/-0.180 and 0.112+/-0.020, respectively) in primary ALL group and relapsed ALL group were lower than those in control group (P< 0.01). The A values of LMP2, LMP7, and PA28alpha (991.4+/-532.7, 686.3+/-663.8, and 2022.3+/-1622.3, respectively) in relapsed ALL group were lower than those in control group (P less than 0.01,0.01 and 0.05, respectively). The A value of LMP2 in relapsed group was lower than that in control (P< 0.01). The A values of LMP7 for the cases with no remission and relapse were both lower than that for the cases with constant complete remission in primary ALL group (P< 0.01). The relative A value of TAP2 in AML group was lower than that in control group (P< 0.05). The relative A value of TAP1 in relapsed ALL group was lower than that in primary ALL group (P< 0.05). In primary ALL group, the relative A value of TAP1 (0.215+/-0.159) for cases with relapse (6/34 cases) was lower than that (0.462+/-0.189) for those with constant complete remission (24/34 cases) (P< 0.05). CONCLUSION: There exists decreased expression of TAP in both childhood ALL and AML, which probably contributes to the escape of leukemia cells from immune surveillance. Decreased expression of TAP1 subunit is probably related to the relapse of ALL.