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Background Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive renal insufficiency and defective cellular immunity. Podocytic infolding glomerulopathy (PIG) is a newly proposed disease entity characterized by microspheres or microtubular structures associated with podocytes infolding into the glomerular basement membrane (GBM) on electron microscopy (EM). Case presentation A 4-year-old boy was admitted to our ward due to proteinuria and edema lasting 1 month. He had a short trunk and demonstrated subtle dysmorphology, with a triangular shape, a broad nasal bridge and a bulbous nasal tip. The laboratory findings were as follows: lymphocytes, 0.5 × 109/L; urine protein, 3.67 g/d; albumin, 9.8 g/L; and cholesterol, 11.72 mmol/L. Skeletal X rays showed small iliac wings, small ossification centers of the capital femoral epiphyses, shallow dysplastic acetabular fossae and mildly flattened vertebrae. The specimen for light microscopy (LM) suggested focal segmental glomerulosclerosis (FSGS). EM revealed a focal thickness of the GBM with some cytoplasmic processes of podocyte infolding into the GBM. Gene sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (c.2141 + 5G > A; c.2528 + 1G > A) that were inherited from his parents. Finally, we established the diagnosis of SIOD and treated him with diuretics and angiotensin-converting enzyme inhibitors (ACEIs). Conclusion The pathogenic mechanism of PIG has not been clarified. Further studies are required to understand whether gene mutations, especially those related to podocytes, contribute to the pathogenesis of podocytic infolding.

Approximately 20% of children with idiopathic nephrotic syndrome do not respond to steroid therapy. More than 30 genes have been identified as disease-causing genes for the steroid-resistant nephrotic syndrome (SRNS). Few reports were from the Chinese population. The coding regions of genes commonly associated with SRNS were analyzed to characterize the gene mutation spectrum in children with SRNS in central China. The first phase study involved 38 children with five genes (NPHS1, NPHS2, PLCE1, WT1, and TRPC6) by Sanger sequencing. The second phase study involved 33 children with 17 genes by next generation DNA sequencing (NGS. 22 new patients, and 11 patients from first phase study but without positive findings). Overall deleterious or putatively deleterious gene variants were identified in 19 patients (31.7%), including four NPHS1 variants among five patients and three PLCE1 variants among four other patients. Variants in COL4A3, COL4A4, or COL4A5 were found in six patients. Eight novel variants were identified, including two in NPHS1, two in PLCE1, one in NPHS2, LAMB2, COL4A3, and COL4A4, respectively. 55.6% of the children with variants failed to respond to immunosuppressive agent therapy, while the resistance rate in children without variants was 44.4%. Our results show that screening for deleterious variants in some common genes in children clinically suspected with SRNS might be helpful for disease diagnosis as well as prediction of treatment efficacy and prognosis.

Tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome (SRNS), but its clinical application in China is still limited. We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS. In this prospective non-randomized, non-controlled study, Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus (0.1 mg/kg/day) and low-dose prednisone (0.25–0.50 mg/kg/day). We compared the overall remission rate (ORR) and adverse events in the follow-up period with this therapeutic regimen. A total of 76 children were enrolled into the study with an average follow-up period of 18 ± 6 months (maximum 36 months). ORR achieved by the first, third, and sixth months was 94.7%, 94.7%, and 96.0%, respectively. All patients who attained an initial tacrolimus trough concentration (FK506C0) > 6 ng/mL (60.3%) achieved remission. The relative risk of relapse at FK506C0

Focal segmental glomerulosclerosis (FSGS) is a pathological lesion rather than a disease, with a diverse etiology. FSGS may result from genetic and non-genetic factors. FSGS is considered a podocyte disease due to the fact that in the majority of patients with proven-FSGS, the lesion results from defects in the podocyte structure or function. However, FSGS does not result exclusively from podocyte-associated genes, however also from other genes including collagen IV-associated genes. Patients who carry the collagen type IVA3 chain (COL4A3) or COL4A4 mutations usually exhibit Alport Syndrome (AS), thin basement membrane neuropathy or familial hematuria (FH). Previous studies revealed that long-time persistent microscopic hematuria may lead to FSGS. A case of a family is presented here where affected individuals exhibited FH with FSGS-proven, or chronic kidney disease. Renal biopsies were unhelpful and failed to demonstrate glomerular or basement membrane defects consistent with an inherited glomerulopathy, and therefore a possible underlying genetic cause for a unifying diagnosis was pursued. Genomic DNA of the siblings affected by FH with biopsy-proven FSGS was analyzed, and their father was screened for 18 gene mutations associated with FSGS [nephrin, podocin, CD2 associated protein, phospholipase C ε, actinin α 4, transient receptor potential cation channel subfamily C member 6, inverted formin, FH2 and WH2 domain containing, Wilms tumor 1, LIM homeobox transcription factor 1 β, laminin subunit β 2, laminin subunit β 3, galactosida α, integrin subunit β 4, scavenger receptor class B member 2, coenzyme Q2, decaprenyl diphosphate synthase subunit 2, mitochondrially encoded tRNA leucine 1 (UUA/G; TRNL1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1] using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology. Then whole exome sequencing (WES) was performed in the two probands to ascertain whether there were other known or unknown gene mutations that segregated with the disease. Using mass array technology, a TRNL1 missense homozygous mutation (m. 3290T>C) was identified in the probands diagnosed with FH and manifested as FSGS on biopsy. In addition, a COL4A4 missense mutation c. 4195A>T (p. M1399L) in heterozygous pattern was identified using WES. None of these variants were detected in their father. In the present study, a mutation in TRNL1 (m. 3290T>C) was identified, which was the first reported variant associated with FSGS. The COL4A4 (c. 4195A>T) may co-segregate with FSGS. Screening for COL4A mutations in familial FSGS patients is suggested in the present study. Genetic investigations of families with similar clinical phenotypes should be a priority for nephrologists. The combination of mass array technology and WES may improve the detection rate of genetic mutation with a high level of accuracy.

Hepatitis B virus-associated glomerulonephritis (HBV-GN) is recognized as one of the major secondary nephropathies in HBV high-risk areas. To determine possible differences in the expression of HBV immune markers in tissues, we retrospectively examined HBV immune markers in the serum, renal tissues, and liver tissues in 132 HBV-GN children.All 132 patients had biopsy-proven HBV-GN including the presence of positive HBV antigens in the kidney. Serum-HBV immune markers were tested by an enzyme-linked immunosorbent assay. Renal and liver biopsies were done in 26 patients. All renal tissues were examined for HBV immune markers by immunofluorescence, and liver tissues were examined by immunohistochemistry.Among the 132 patients, all showed varying degrees of kidney injury. Serum hepatitis B envelope antigen (HBeAg) was positive in 80 patients and negative in 52 patients. The positivity rate of Hepatitis B core antigen in renal tissue was statistically higher in serum HBeAg (-) than in serum HBeAg (+) patients (96.2% vs. 55.0%). Furthermore, there was no relationship between the presence of hepatitis B surface antigen and HBcAg in liver and renal tissue.HBV markers are not consistently present in serum, renal tissues, and liver tissues in children with HBV-GN.

To investigate the urinary neutrophil gelatinase-associated lipocalin (NGAL) concentration in children with idiopathic nephrotic syndrome (INS) and its clinical significance.Thirty-four children newly diagnosed with INS received oral prednisone for 4 weeks. Patients whose urinary protein did not become negative were classified as steroid-resistant nephrotic syndrome (SRNS) group, while those whose urinary protein did become negative were classified as steroid-sensitive nephrotic syndrome (SSNS) group. Morning midstream urine specimens were collected from all patients before use of prednisone and after 1, 2, 3, and 4 weeks of treatment with prednisone. Enzyme-linked immunosorbent assay was used to measure the urinary NGAL concentration. Meanwhile, urinary creatinine (Cr) concentration was measured, and urinary NGAL concentration in a single urine collection was adjusted according to the urinary Cr excretion. The two groups were compared in terms of urinary NGAL/Cr ratio.Compared with the SRNS group, the SSNS group had significantly decreased urinary NGAL/Cr ratios after 3 and 4 weeks of prednisone treatment (P0.05). Compared with the SRNS group, the SSNS group had a significantly decreased urinary β2-MG/Cr ratio after 4 weeks of prednisone treatment (P0.05). In both groups, urinary NGAL/Cr ratio was positively correlated with urinary protein/Cr ratio (r = 0.510, P0.01). The results of ROC curve analysis showed when diagnostic cut-off point of urinary NGAL/Cr was 0.043 by 3 weeks after treatment, sensitivity and specificity achieved 100% and 79.2% respectively.Urinary NGAL/Cr ratio remains high in children with SRNS, while this ratio decreases gradually during prednisone treatment in children with SSNS, and it falls ahead of urinary β2-MG/Cr ratio. These results suggest that dynamic monitoring of urinary NGAL/Cr ratio is useful for early judgment of response to prednisone in patients with INS.

To explore possible correlations between renal Th1/Th2 ratio and renal microvascular injury in children with Henoch-Sch-nlein purpura nephritis (HSPN).Thirty-two children with HSPN were enrolled. They were classified into four groups by renal pathology: HSPN class II (n=8), HSPN class IIIa (n=7), HSPN class IIIb (n=10) and HSPN class IV/V (n=7). Five patients undergoing nephrectomy due to trauma were used as the controls. INFγ, IL-4 and CD34 in the renal tissues were measured by immunohistochemical analysis. INFγ was used as a marker of Th1, IL-4 was used as a marker of Th2 and CD34 was used as a marker of microvessel. The renal microvessel density was evaluated according to the Weidner standard. The relationships among the local Th1/Th2 ratio, renal pathological grade, microvessel score and microvessel density were studied.Immunohistochemical analysis showed a lower expression of INFγ and a higher expression of IL-4 in the HSPN groups than in the control group. The local Th1/Th2 ratio in the HSPN groups decreased and correlated significantly with the renal pathological grade. There were significant differences among four HSPN subgroups (P0.05). Compared with the control group, the renal microvessel density in the HSPN class II and class IIIa groups increased significantly (P0.05), but it decreased in the HSPN class IV/V group (P0.05). The renal microvessel scores in the HSPN class IIIa, class IIIb and class IV/V groups increased significantly compared with those in the control and the HSPN classⅡ. The increased renal microvessel scores were associated with more severe renal pathological changes. A negative correlation was found between the local Th1/Th2 ratio and the microvessel density in kidneys (r=-0.921, P0.01).The decrease of Th1/Th2 ratio in kidneys might be responsible for renal microvascular injury in children with HSPN.

To investigate the role of leukotrienes (LTs) in the progress of children's Henoch-Schoenlein purpura (HSP) nephritis (HSPN), and to provide an experimental basis for clinical application of leukotrienes antagonists in treatment of HSPN.The serum and urine samples were collected from 34 patients with HSPN 18 of them received renal biopsy, 27 cases with HSP and 16 healthy children as control. The level of LTB4 in the serum and urine was tested by enzyme-linked immunosorbent assay (ELISA) and LTE4 in urine in each group by enzyme immunoassay (EIA). The extent of expression of LTC4 synthase was detected by indirect immune fluorescence (IIF) in the renal tissue of 18 HSPN cases who received renal needle biopsy. Meanwhile, 3 cases with thin basement membrane nephropathy (TBMN) and 4 cases with simple hematuria were enrolled as controls. The results of pathological examination of the 4 cases with simple hematuria was normal by light microscope or electron microscope. At the same time, total urine protein in 24 hours was determined in 24 HSPN patients.(1) The level of serum and urinary LTB4 in the children with HSPN was (1164.33 +/- 300.28) ng/L and (841.19 +/- 115.23) ng/L, respectively. The level of serum and urinary LTB4 in those with HSP was (559.60 +/- 180.23) ng/L and (574.42 +/- 101.17) ng/L, respectively. The level of serum and urinary LTB4 in the control group was (211.95 +/- 67.72) ng/L and (227.33 +/- 76.12) ng/L, respectively. There was significant difference in the LTB4 level between HSPN group and HSP group (P0.01) while there was statistically significant difference in the LTB4 level between HSPN group and control group (P0.01). The urinary LTE4 was (1252.31 +/- 251.62) ng/L, (805.93 +/- 185.52) ng/L and (149.51 +/- 33.66) ng/L for HSPN group, HSP group and control group, respectively, and the differences were significant (P0.01). (2) The increase of serum and urinary LTB4 and urinary LTE4 was closely relative to the severity of histopathological changes. (3) Serum and urinary LTB4, urinary LTE4 increased in parallel to the enhancement of urine protein in HSPN patients (P0.01 or P0.05). (4) Markedly significant difference of LTC4 synthase by IIF existed between HSPN groups and control group.LTs can promote the progress of children's HSPN. There is a close relationship between LTs expression in renal tissues, the pathological severity of HSPN and proteinuria.

To investigate the efficacy and adverse effect of mycophenolate mofetil (MMF) in the treatment of frequently relapsing nephrotic syndrome in children.The study population consisted of 37 children (24 simple nephrotic syndrome and 13 nephritis-type syndrome) suffering from frequently relapsing nephrotic syndrome. Patients received 20-30 mg/(kg d) of MMF in conjunction with 1 mg/(kg d) prednisone for 3-6 months.Out of 24 patients suffered from simple nephrotic syndrome, 17 patients (70.8%) with complete relief, 4 patients (16.7%) with partial relief and 3 patients (12.5%) with non-relief, whereas out of 13 patients suffered from nephritis-type syndrome 6 patients (46.2%) with complete relief, 3 patients (23.1%) with partial relief and 4 patients (30.7%) with non-relief. Eight patients with Minimal Change Disease (MCD) achieved complete relief. Of 23 patients with Mesangial Proliferative Glomerulonephritis (MsPGN) or Membranoproliferative Glomerulonephritis (MPGN), complete relief was observed in 17 patients (73.9%), partial relief in 4 patients (17.4%) and non-relief in 2 patients.These Results suggest that MMF has better efficacy against simple renal disease than against nephritis-type syndrome, and MMF may be more suitable for the treatment of frequently relapsing nephrotic syndrome characterized by proliferative lesions.

To investigate the clinicopathologic characteristics of childhood renal diseases.A retrospective analysis of 1316 renal biopsies performed over the past 20 years was performed.Of the 1316 patients, 383 (29.09% ) were diagnosed as nephrotic syndrome, 291 (22.00%) as acute nephritis syndrome, 224 (17.21%) as isolated hematuria, 209(15.87%) as purpura nephritis, and 96 (7.30% ) as hepatitis B virus-associated nephritis . Mesangial proliferation was the most common pathological change (756 cases; 57.45%), followed by IgA nephropathy (113 cases; 8.59%), endothelial capillary proliferation(112 cases; 8.51%), membranous nephropathy (66 cases; 5.02%), and various minor and minimal changes (59 cases; 4.48%). Alport syndrome, congenital nephrotic syndrome, thin basement membrane nephropathy, fibrillary glomerulopathy disease, and Fabry disease were confirmed by electronic microscopy. IgA, IgM and C1q nephropathy were definitely diagnosed using immune histochemistry or immunofluorescent. A diagnosis of primary glomerular disease was made in 69.53% of the cases (915 cases); secondary glomerular disease was noted in 26.14% (344 cases). Of the 915 cases of primary glomerular disease, 375 (41.0%) had nephrotic syndrome. Secondary glomerular disease due to purura nephritis was common (209/344; 60.8%).Primiary glomerular disease predominates in children. Nephrotic syndrome is the most common clinical diagnosis. Mesangial proliferation is the most common pathological patterns in children with renal disease.

To study the roles of IL-4, IL-5 and IgE in childhood cough variant asthma (CVA).The IL-4 and IL-5 levels in peripheral blood mononuclear cell (PBMC) and the serum IgE levels were determined using ELISA in children with CVA in the acute stage (n=21) and in the convalesce stage (n=9). The samples from 30 children with acute bronchial asthma and from 30 healthy children were used as controls.The levels of PBMC IL-4 (91.57 +/- 12.19 ng/L) and IL-5 (13.28 +/- 0.31 ng/mL) in children with CVA in the acute stage were significantly higher than those in the convalesce stage (74.68 +/- 11.54 ng/L, 6.53 +/- 0.28 ng/mL) and also higher than those in the healthy controls (70.32 +/- 18.16 ng/L, 5.29 +/- 0.36 ng/mL) (P0.01). The levels of serum IgE in children with CVA in the acute stage (279.6 +/- 41.3 KU /L) were strikingly higher than those in the convalesce stage (153.8 +/- 37.5 KU/L) (P0.01). The levels of serum IgE in children with CVA either in the acute stage or in the convalesce stage were significantly higher than those in healthy controls (90.6 +/- 44.8 KU /L) (P0.01). There were no significant differences in the levels of IL-4, IL-5 and IgE between children with acute CVA and acute asthma.A combined determination of PBMC IL-4 and IL-5 and serum IgE may be valuable for the diagnosis and the outcome evaluation of CVA. IL-4 and IL-5 may play a role in the pathogenesis of CVA. It is speculated that CVA may have similar pathogenesis to bronchial asthma since acute CVA patients have similar IL-4, IL-5 and IgE levels to children with acute bronchial asthma.

To investigate the difference of Pax2 and P53 expressions in children with primary nephritic syndrome (PNS) and the effect of Pax2 on glucocorsteroid (GC)-resistance.Renal Pax2 and P53 expressions in children with PNS (40 patients) were detected by immunohistochemistry. A semiquantitative score was used to evaluate the injury degree of the glomeruli and the tubulointerstitium, and correlation analysis was done among Pax2, P53 and pathologic score.Pax2 and P53 expressions were not found in the control group. Pax2 expression of renal tubule epithelia exsisted in children with PNS and there was weak or no expression of Pax2 in the podocytes. Pax2 expressions in the proximal tubule and the distal tubule in the GC-resistant group were more intense than those in the GC-intensive group (P0.01). The more the Pax2 expression in the tubule, the more abnormal structure such as dilation and atrophy. Pax2 expression in the tubule epithelia was positively correlated with pathologic score of tubulointerstitium (P0.01). There was no P53 expression in the GC-intensive group, but there exsisted P53 expression in parts of the patients from the GC-resistant group, mainly distributing in the renal tubular epithelia. P53 expression was positively correlated with P53 expression and the pathologic score of tubulointerstitium (P0.01).Over-expression of Pax2 in the renal tubule epithelia may improve P53 expression to a certain degree, which may aggravate the lesion of the renal tubule. It may be one of the mechanisms resulting in GC-resistant in children with PNS.

Glucocorticoid (GC) is the first therapeutic choice of primary nephrotic syndrome (PNS). The response to GC treatment is an important indicator for the outcome of PNS children. Children with GC-resistant PNS present with incomplete or no response to GC, and may herald the progression to end-stage renal failure. However, the detailed mechanism of GC-resistance or GC-sensitive effect in these PNS children has not been clearly elucidated. The previous study by the authors indicated that there was increased expression of GR beta in PBMCs in GC-resistant children with PNS, and the over expression of GR beta resulted in GC resistance via influencing the ability of GR alpha nuclear translocation. To elucidate the relationship between GR beta expression in renal and in PBMCs and the effect of glucocorticoid on glucocorticoid-resistance children with PNS, the expression of GR alpha and GR beta in renal tissue and in PBMCs were detected by immunohistochemistry.Forty children with PNS were divided into two groups, GC-resistant group(20) and GC-sensitive group(20), the expression of GR alpha and GR beta in renal intrinsic cells and in PBMCs were measured with the immunohistochemistry technique. A semiquantitative score was used to evaluate the injury degree of the glomeruli and tubulointerstitium.Compared with GC-sensitive group, the glomerular pathologic scores (6.91 +/- 1.98) and renal tubular pathologic scores (7.12 +/- 1.62) in GC- resistant group were significantly different (P0.01, respectively). GR alpha expressions of renal tissue and PBMCs were higher in the control group (58.3 +/- 2.6, 59.1 +/- 7.2) than those in the GC-sensitive group (40.2 +/- 7.2 and 36.6 +/- 5.1, P0.01, respectively) and GC-resistant group (35.0 +/- 8.2 and 36.4 +/- 6.6, P0.01, respectively). GR beta expressions of renal tissue and PBMCs were higher in the GC-resistant group (13.8 +/- 3.0 and 12.1 +/- 4.1) and in the GC-sensitive group (6.5 +/- 1.9 and 5.9 +/- 1.0) than that in control group (2.3 +/- 0.4 and 3.2 +/- 1.1, P0.01, respectively). GR beta expressions in renal tissue and PBMCs were higher in the GC-resistant group than that in the GC-sensitive group (P0.01). Compared with control group, GR beta expressions in PBMCs and in renal tissue were lower than those in mild renal lesion group (5.4 +/- 2.8, 6.46 +/- 2.50), midmedium renal lesion group (8.7 +/- 2.4 and 11.4 +/- 3.7) and (17.1 +/- 0.4 and 18.7 +/- 0.7) in severe renal lesion group (F = 5.8, 15.6, P0.01, respectively). GR beta expression of PBMCs had a positive correlation with GR beta expression of renal intrinsic cells (r = 0.651, P0.01). GR beta expressions by PBMCs and renal intrinsic cells were positively correlated with renal pathologic scores (r = 0.579 and 0.623, P0.01, respectively).GC-resistant children with PNS were related to the increased GR beta expression in PBMCs and renal intrinsic cells. There was no correlation between the GR alpha expressions in PBMCs and in renal intrinsic cells. Increased GR beta expression might decrease the effect of GC via inhibiting the activity of GR alpha.