Lupus glomerulonephritis in 788 Chinese children: a multi-centre clinical and histopathological analysis based on 549 renal biopsies.

BACKGROUND: System lupus erythematosus (SLE) is a severe multisystem autoimmune disease. OBJECTIVE: To describe the clinical and pathological features, treatment, and renal outcome in children under 18 years with lupus nephritis (LN). METHODS: The study was undertaken by a questionnaire completed in 26 Grade 3A hospitals' paediatric renal units in China. The study comprised 788 children (619 girls, 169 boys) diagnosed with SLE by the American College of Rheumatology criteria (1997) during 2005-2010. Results of renal biopsies were classified according to the guidelines of The International Association of Nephrology and the Renal Pathology Society (2003). Guidelines by the Chinese Society of Paediatric Nephrology were applied for the diagnosis and treatment (for trial implementation) in 2010 to determine inclusion. The data included the prevalence of acute kidney injury (AKI), SLE disease activity index (SLEDAI), renal histopathology and the induction of therapy mode. RESULTS: The mean (SD) age of onset of SLE was 10.9 (2.90) years (range 1-18) and at diagnosis was 11.3 (2.9) years. The mean (SD) SLEDAI score was 13.5 (5.53). The clinical classification was as follows: about 36 (4.6%) patients had isolated haematuria, 99 (12.6%) isolated proteinuria, 60 (7.6%) isolated haematuria and proteinuria, 157 (19.9%) acute glomerulonephritis, 392 (49.7%) nephrotic syndrome, 20 (2.5%) rapidly progressive glomerulonephritis, 15 (1.9%) chronic nephritis, 2 (0.3%) tubule-interstitial damage and 7 (0.9%) subclinical LN. A total of 549 children (69.7%) underwent renal biopsy. The most frequent renal histopathological findings of LN were Class IV, followed by Class II and Class V + IV. There were no significant differences between the age groups in either renal pathological types or prognosis. In 242 (30.7%) patients, LN was complicated by AKI. Those with AKI had an older mean (SD) age at onset than the non-AKI patients [11.5 (2.8) years vs 10.7 (2.9) years, respectively, p < 0.0001] and a higher SLEDAI score [14.3 (5.8) vs 13.1 (5.4), respectively, p = 0.003]. In the induction phase, cyclophosphamide (CTX) and mycophenolate mofetil (MMF) were equally effective in the patients with the same pathological type. Follow-up records were only available for 482 (61.2%) patients, with a mean (SD) follow-up time of 21.5 (18.4) months. Six of the 35 patients who deteriorated required dialysis and seven died. CONCLUSION: In LN, AKI is a risk factor for poor outcome. Owing to different times of onset and remission, the pathological types of LN cannot be estimated by clinical manifestation alone, and therefore renal biopsy should be undertaken in all LN children with AKI. In the induction phase, there was no significant difference in efficacy between CTX and MMF. Follow-up of children with LN in China needs to be improved.

[Application of stem cell transplantation in kidney diseases].

This paper summarizes the current literature on the potential therapeutic role of stem cell transplantation for kidney injury and repair and focuses on the choice of types of stem cells, the method of transplantation, and the mechanisms of stem cell homing to injured renal tissues and its protective effects. The application of umbilical cord mesenchymal stem cells (UC-MSCs) shows wide prospects, but the approach and optimal dose of cell transplantation are under intensive investigation. Signals that regulate stem cell homing to injured renal tissues may be related to chemokines or factors released in the target site. Several studies have pointed out that paracrine and endocrine of stem cells are the most likely mechanism of action in the injured nephron. Many questions remain unanswered but stem cell-based therapy is a promising new strategy for acute and chronic kidney diseases.

Does injection of metanephric mesenchymal cells improve renal function in rats?

Chronic kidney disease (CKD) is a massive global health-care problem. Cell therapy offers a potential treatment for CKD. The aim of this study was to investigate whether the administration of a population of stem cells could be used to treat adriamycin (ADR)-induced glomerulopathy in rats, a form of CKD. We intravenously transplanted metanephric mesenchymal cells (MMCs) into rats treated with ADR. We also induced MMC differentiation in vitro using a medium derived from serum and homogenates of ADR-induced glomerulopathy rats. We detected the induction of an early epithelial phenotype (cytokeratin-18 expression) and a proximal tubule phenotype (vitamin D receptor expression) in vitro, and MMC-derived epithelial cells corresponding to the proximal tubule and glomeruli in vivo. Transplantation of MMCs after induction of glomerulopathy significantly increased the creatinine clearance rate (Ccr), a marker for glomerular filtration rate, but had no significant effect on other parameters (24-hour urinary protein excretion, serum albumin, total cholesterol). In addition, there was no significant difference in blood urea nitrogen or serum creatinine levels in rats with and without ADR administration. Our results indicate that MMCs might survive, engraft and differentiate into renal epithelia in vivo when transplanted into ADR-treated rats. However, further studies are needed to determine whether MMC transplantation improves renal function and causes renal repair in this model.

[Relationship between renal Th1/Th2 ratio and renal microvascular injury in children with Henoch-Sch-nlein purpura nephritis].

OBJECTIVE: To explore possible correlations between renal Th1/Th2 ratio and renal microvascular injury in children with Henoch-Sch-nlein purpura nephritis (HSPN). METHODS: 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. RESULTS: 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 (P<0.05). Compared with the control group, the renal microvessel density in the HSPN class II and class IIIa groups increased significantly (P<0.05), but it decreased in the HSPN class IV/V group (P<0.05). 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, P<0.01). CONCLUSIONS: The decrease of Th1/Th2 ratio in kidneys might be responsible for renal microvascular injury in children with HSPN.

[Pathological features and clinical manifestations in 313 children with nephropathy under 6].

OBJECTIVE: To explore the relationship between pathological features and clinical manifestations in children with nephropathy under 6 years old. METHODS: Renal biopsy by rapid percutaneous puncturation was performed on 313 children under 6 who were all diagnosed clinically as kidney diseases of 14 different kinds. The specimens were divided into 3 parts for microscope, electron microscope and immuno fluorescence examination respectively and processed by HE, PAS, PASM, and Masson staining. Immunofluorescence was used to detect the deposition of IgG, IgM, IgA, C3, C4, C1q, and Fb in the renal tissues. Additional examinations were done to detect HBs-Ag, HBeAg and HBcAg deposition in some cases with positive serum HBs-Ag. Altogether 290 of the specimens (290/313, 92.65%) were examined by electron microscope. RESULTS: All the renal biopsy performances were successful. The clinical manifestations comprised of persistent haematuria (32.92%, 103/313), idiopathic nephritic syndrome (26.1%, 82/313), acute nephritic syndrome (20.14%, 63/313), Henoch Schonlein purpura nephritis (8.32%, 26/313), HBV-nephritis (4.79%, 15/313), and isolated proteinuria (2.56%, 8/313). The main pathological patterns of glomerular disease were identified as mesangial proliferation (51.75%, 162/313), IgM nephropathy (8.31%,26/313), minor and minimal change (7.99%, 25/313), IgA nephropathy (7.35%, 23/313), endocapillary proliferative glomerulonephritis (5.11%, 16/313), focus segmental glomerulosclerosis (4.47%, 14/313), thin basement membrane nephropathy (4.47%, 14/313), and membrane nephropathy (4.47%, 14/313). Alport syndrome, congenital nephrotic syndrome, and thin basement membrane nephropathy can be diagnosed by electron microscope, white IgA nephropathy, IgM nephropathy and C1q nephropathy by immunopathology. CONCLUSION: Similar clinical manifestations may differ in the pathology and the clinical features of one pathological diagnosis may vary greatly. Renal biopsy is of great help to the diagnosis, treatment and the prognosis evaluation for children with nephropathy under 6. Electron microscopes also play an important role in the diagnosis of nephropathy.

[Clinicopathologic characteristics of 1,316 children with renal disease].

OBJECTIVE: To investigate the clinicopathologic characteristics of childhood renal diseases. METHODS: A retrospective analysis of 1316 renal biopsies performed over the past 20 years was performed. RESULTS: 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%). CONCLUSIONS: 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.

[Evidence-based therapy of nephrotic edema].

OBJECTIVE: To study the evidence-based therapy of edema in nephrotic syndrome by analyzing the literatures systematically. METHODS: The literatures related to the treatment of nephrotic edema were retrieved from the following: Chinese Biological Medicine Database (CBM-disk), Chinese Journals Full-text Database (CNKI, 1994-2006), Chinese Technological Periodicals Database (VIP, 1989-2006), Chinese Evidence Biological Medicine/Cochrane Central Database (CEBM/CCD), Cochrane Library Database, MEDLINE (1966-2006), EMBASE (1975-2006), MEDLARS, SCI (1985-2006) and OVID by electron and craft search with the following key words: nephrotic syndrome, edema, recalcitrant edema, refractory edema or resistant nephrotic edema, and treatment, diuretic therapy or human albumin treatment. The relevant literatures on randomized controlled trials (RCT) that met the criteria were statistically analyzed by the Coorporative network software RevMan 4.2. RESULTS: A total of 113 articles were searched (60 in Chinese and 53 in English), of which 12 were RCT. Three of the 12 articles were included for Meta analysis. Meta analysis showed that dextran-40 together with furosemide was effective for nephrotic edema. Human albumin solution could be used in nephrotic edema patients with coexistent severe hypoalbuminemia. A combination of diuretics by intravenous drip infusion was effective for diuretic-resistant nephrotic edema. CONCLUSIONS: The treatment for nephrotic edema should be individualized. The evidence of treatment of nephrotic edema has not been fully elucidated. Further multicentre, large sample, and randomized controlled trials are needed.

Assessment of mycophenolate mofetil for treatment of frequently relapsing nephrotic syndrome in children.

OBJECTIVE: To investigate the efficacy and adverse effect of mycophenolate mofetil (MMF) in the treatment of frequently relapsing nephrotic syndrome in children. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Glucocorticoid administration in steroid sensitive nephritic syndrome: a meta-analysis].

OBJECTIVE: To evaluate the benefits and toxicities of different corticosteroid regimes in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). METHODS: MEDLINE (Jan. 1963-Mar. 2007), elsevier (Jan. 1997-Aug. 2006), OVID databank (Jan. 1993-Aug. 2006), Springer databank (Jan. 1994-March 2007), the Cochrane Controlled Trials Register (Cochrane Library, Issue Feb. 2006), Cochrane Renal Group Specialised Register (Jul. 2006), EMBASE (Jan. 1980-Mar. 2007) and CNKI (Jan. 1994-Mar. 2007) etc, were searched by the terms primary nephrotic syndrome, glucocorticoid, corticosteroid, steroid, prednisone, methylprednisolone, dexamethasone and children etc for the human clinical trials about glucocorticoid (GC) administration in primary nephrotic syndrome (PNS) (aged 3 months to 18 years), controlled or semi-controlled ones, including unpublished documents from scientific meetings and theses, and similar documents listed in the references of the above documents were also included. All the studies were evaluated strictly according to Jadad Standard, and the Meta-analysis were adopted. Review manager 4.2 software was used to analyze the data. The odds ratio was calculated for the relapse rate and side effect from the initial episode to the end of follow-up between the patients treated with corticosteroids and the controls. RESULTS: Totally 12 trials with 868 subjects meeting the criteria were included in this review. A Meta-analysis of 7 trials, which compared between 2 months of prednisone and 3 months or more in the first episode, showed that longer treatment duration significantly reduced the risk of relapse at 12-24 months (RR=0.70,95% CI:0.60-0.89),without an increase of side effect. There was a negative linear relationship between the duration of treatment and risk of relapse (r2 =0.66, P=0.05). CONCLUSION: (1) Children in their first episode of SSNS should be treated for at least 3 months of GC. The therapeutic effect of patients in the primary nephrotic syndrome treated with GC for 12 weeks was prior to that for 8 weeks, compared with that in the controls. It could reduce the relapse rate of half year, the longer treatment duration in the NS patients at the first relapse was, the lower relapse risk was.(2) Compared with alternative GC administration, standard GC administration can reduce the side effects; Course more than 1 year of GC administration can reduce the 2-year relapse rate. Hence in children who relapse frequently, multicentre, well-designed experiments should be adopted.