<Emphasis Type="Italic">MDR-1</Emphasis> gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children

The study was aimed at investigating the association between MDR-1 genetic polymorphisms [C1236T, G2677T(A), C3435T] and parameters describing the clinical course and treatment response of childhood steroid-responsive nephrotic syndrome (SRNS). Three MDR-1 genetic markers were analyzed in 108 children diagnosed with SRNS and in 135 healthy controls with neither allergic nor renal disease. All subjects were genotyped by PCR-restriction fragment length polymorphism (RFLP) analysis, and an EM algorithm-based analysis was utilized to estimate haplotype frequencies. As expected, there was no difference in genotypic and allelic distribution between and among SRNS patients and healthy children. However, all individual polymorphisms were strongly associated with time to response to initial prednisone therapy. The frequencies of the mutated alleles were higher in late responders (time to remission: >7 days) to oral prednisone (0.53, 0.52,0.66) than in early responders (time to remission: <7 days; 0.24, 0.19, 0.32), with all p values <0.001 for positions 1236, 2677 and 3435, respectively). Odds ratios (ORs) reflecting the strength of the associations were as follows: 6.79 (95% CI:1.96– 23.54) for 1236 T/T, 13.7 (95% CI:2.78–67) for 2677 T/T and 9.92 (95% CI: 3.01–32.71) for 3435 T/T as compared to the respective-wild type homozygotes. The TTT haplotype was similarly found to be significantly associated with late oral steroid response (0.49 vs. 0.19, p=0.0003). Variants 1236T, 2677TA and 3435T identify patients that respond slower to oral prednisone. Although the functional properties of the substitutions investigated here are still to be determined, our findings may be a small step toward the optimization of immunosuppressive therapy in SRNS children.     

Association of the macrophage migration inhibitory factor −173*C allele with childhood nephrotic syndrome

Macrophage migration inflammatory factor (MIF) is a proinflammatory cytokine with a unique role as the physiologic counterregulator of the immunosuppressive effects of glucocorticoids. MIF has been implicated in the pathogenesis of glomerular inflammation. The MIF promoter contains a G/C polymorphism that is functionally relevant, with the C allele being associated with higher MIF production and linked to susceptibility to inflammatory diseases. We genotyped the MIF −173 polymorphism in 257 children with idiopathic nephrotic syndrome (INS) and 355 controls. Frequency of carriers of the high-producer MIF −173*C allele was higher in patients with INS (31.7%) than in controls (22.0%) [odds ratio (OR) 1.67, p = 0.006] The MIF −173 C allele was more frequent in steroid-resistant patients (43.5%) compared with steroid responders (22.8%) (OR 2.61, p = 0.0005). This difference was particularly evident in focal segmental glomerulosclerosis patients (OR 14.0, p = 0.002). No association with response to cyclosporin A was found. Carriers of the MIF −173*C allele had a significantly higher probability of end-stage renal disease (ESRD) compared with G/G homozygous patients within 5 years from onset (log rank 5.11 p = 0.024). These results underscore the role of MIF in INS disease progression and in the response to glucocorticoid treatment and suggest that screening of MIF genotype at disease onset may identify patients requiring a more aggressive therapeutic approach. Marina Vivarelli and Leila Emma D’Urbano contributed equally to the work.     

Glucocorticoid receptors expression and histopathological types in children with nephrotic syndrome

Background: Some children with idiopathic nephrotic syndrome (NS) patients fail to respond even when given high dose of steroid. The aim of this study was to assess the GCR expression on the T lymphocytes of children with NS and its relation to the response to steroid and to histopathological type. Methods: Forty-six pediatric patients with idiopathic NS and 20 age and sex matched apparently healthy children as controls were included. Flow cytometry was employed to determine the percentage of CD3+/GCR+ cells which then correlated with pattern of steroid response. Renal biopsy was done for steroid-dependent and steroid-resistant cases for determination of the underlying histopathological type. Results: The mean percentage of T lymphocyte expression of GCRs (CD3+/GCR) was significantly higher in early steroid responders than in late responders and was slightly lower than the controls. There was a significantly lower GCRs expression in steroid-resistant patients in comparison to early responders, late responders and controls. Renal biopsy showed that most cases of late responders were of the focal segmental glomerulosclerosis (FSGS) type. The mean percentage of lymphocyte expression of GCRs was significantly higher in patients with minimal change disease (MCD) compared to patients with FSGS. Conclusion: Evaluation of the expression of intracellular GCRs in T lymphocytes at time of diagnosis of NS can predict the response to steroid therapy and can help in determination of the outcome of NS patients regarding future relapses.     

Tuberculosis in childhood nephrotic syndrome in India

We studied the prevalence, clinical features, and impact of tuberculosis (TB) on children with nephrotic syndrome (NS). Of the 300 children with NS, 28 (9.3%) were diagnosed as having TB. This occurred following the initiation of immunosuppressive therapy in 27 children, and in 1 child it preceded the onset of NS. Pulmonary involvement was the commonest (22/28), followed by tubercular lymphadenitis (2/28), meningitis (2/28), and occult TB (2/28). Of the various diagnostic criteria, history of previous cough, fever, or exposure to a case of TB (23/28) and chest skiagram (21/28) were the most useful. The occurrence of TB did not induce a relapse or affect the subsequent response to steroid therapy (as is often seen with other infections) or have a deleterious effect on renal function. Patients who received higher doses of steroids (frequent relapsers, steroid dependent, initial non-responders, and subsequent non-responders) had a significantly higher prevalence of TB (19/148) than those who received lower doses (infrequent relapsers 8/151) (P = 0.04). We thus found TB to be an important complication of children with NS in our country. The conventional diagnostic tests, such as Mantoux and acid-fast bacilli isolation, are often unhelpful in these children, and a high index of suspicion is required, especially in children who require frequent courses of steroid therapy. Received March 11, 1996; received in revised form February 27, 1997; accepted March 4, 1997     

Idiopathic membranous nephropathy in children

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.     

Genetic polymorphisms influence the steroid treatment of children with idiopathic nephrotic syndrome

Background

Idiopathic nephrotic syndrome (INS) is the most frequent type of nephrotic syndrome that occurs in children. Its response to treatment with steroids varies. The aim of this study was to analyze the correlation between steroid metabolism-related genes and the response to steroid treatment.

Methods

The patient cohort comprised 74 children with INS, of whom were 58 steroid-sensitive (SS) cases and 16 steroid-resistant (SR) cases. The genetic polymorphisms analyzed were those of the CYP3A5 gene (A6986G) and ABCB1 gene (C1236T, G2677T/A, and C3435T), and the polymorphisms between SS and SR children were compared.

Results

C1236T in ABCB1 was associated with steroid resistance in INS children [odds ratio (OR) 2.65, 95?% confidence interval (CI) 1.01–6.94; p?=?0.042] The frequency of the T allele was significantly higher in SR subjects than in SS subjects (0.81 vs. 0.62, respectively). A6986G in CYP3A5 showed a trend of association, but this association did not reach statistical significance (OR 2.63, 95?% CI 0.94–7.37; p?=?0.059). No significant correlation was found between treatment response and G2677T/A or C3435T in ABCB1.

Conclusions

Our results indicate that among our pediatric patients with INS the C1236T polymorphism in the ABCB1 gene was associated with steroid resistance, while the A6986G polymorphism in the CYP3A5 gene showed a trend of association, but did not reach statistical significance, requiring further analysis.     

Response to prednisone in relation to <Emphasis Type="Italic">NR3C1</Emphasis> intron B polymorphisms in childhood nephrotic syndrome

The variation in time required to obtain cessation of proteinuria in children with nephrotic syndrome (NS) represents one aspect of the variations shown by these children in response to glucocorticoid (GC) treatment. Polymorphism of the GC receptor gene (NR3C1) has been postulated as one factor that would partially explain differences in both the clinical presentation and the reaction to treatment in GC-treated diseases. We genotyped 118 children diagnosed with NS who initially responded to oral GC treatment [steroid-responsive nephrotic syndrome (SRNS) group] and 136 healthy children for three intron B single nucleotide polymorphisms of NR3C1, namely Bcl I (C/G), rs33389 (C/T) and rs33388 (A/T). In the SRNS group, we performed a three-marker haplotype analysis of NR3C1 in relation to the response to prednisone, represented as time to proteinuria resolution (TPR) as categorical and ordinal variable. Results: The distribution of individual polymorphisms and three-marker haplotypes was similar in healthy children and SRNS patients (all p values >0.05). The GTA haplotype was associated with a higher GC sensitivity, as determined by TPR, and was found to be more prevalent in early (response 7 days) prednisone responders (27.7 vs. 14.5%, hap-score = -2.22, p = 0.05 adjusted for biopsy results). These results are in agreement with those reported earlier on an association of intron B haplotypes with GC sensitivity. The distribution of GC polymorphisms among the residents of north-eastern Poland was also determined.     

ACE gene insertion/deletion polymorphism in childhood idiopathic nephrotic syndrome

The aim of this study was to determine the distribution of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, and its effects on clinical, laboratory, histological findings, treatment responses and progression to end-stage renal disease in childhood idiopathic nephrotic syndrome (NS). 227 children diagnosed with idiopathic NS were included in the study. Eighty-three of patients were steroid resistant and 77 of patients were focal segmental glomerulosclerosis. The control group was consisted of 287 unrelated healthy adult volunteers. ACE gene I/D polymorphism were analyzed by using PCR based method. In the entire group of children with NS, the frequencies of the II, ID, and DD genotypes of ACE gene were 13.7%, 38.3% and 48%, respectively. D allele frequency was higher in NS group than control group (0.67 vs. 0.56, p=0.001). Percentage of frequent relapser patients was found more frequently in ID or DD genotype (38.7%) than II genotype (15%) when only steroid sensitive patients were evaluated (p=0.045). The D-allele frequency was 0.65, 0.69 and 0.68 respectively in focal segmental glomerulosclerosis, biopsy proven minimal change and entire minimal change group (p>0.05) and 0.69 and 0.64 respectively in steroid sensitive and resistant groups (p>0.05). D allele frequency was not significantly different in patients with or without end-stage renal disease (0.64 vs. 0.67 respectively, p>0.005) when 115 patients who were at least five year follow-up were evaluated. The D allele frequency was higher in NS patients than healthy controls and DD or ID genotype was related with frequent relapses. ACE gene I/D polymorphism was not important in laboratory and histological findings and progression of the disease in children with NS.     

IgG subclass/IgM ratio and response to therapy in focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is relatively steroid resistant and no clinical or histological marker can predict the response to therapy. To investigate the role of serum immunoglobulin subclass/IgM in predicting the response to therapy in FSGS, serum concentrations of total IgG, IgG subclasses, and the ratio of serum IgG subclasses to total IgG (% IgG subclass) were measured in 27 children during the acute nephrotic state. Prednisolone, cyclophosphamide, and Persantine (dipyridamole) were given for 12 weeks. We divided the patients into good responders or poor responders according to clinical response. The clinical and nephrotic status were similar in both groups. Fourteen patients were good responders with higher serum IgG1/IgM than that of non-responders (4.00±0.67 vs. 1.61±0.20, P<0.05). There was no significant difference in IgG2/IgM between these two groups. These results suggest that higher serum IgG1/IgM ratios may be associated with a better clinical response. These changes may reflect dysregulation of immunoglobulin class switching in patients with FSGS. Received December 15, 1997; received in revised form and accepted June 1, 1998     

HLA-DR7 predicts the response to alkylating agents in steroid-sensitive nephrotic syndrome

There is a lack of reliable predictors of the response to alkylating agents in children with idiopathic nephrotic syndrome (NS). HLA-DR7 is strongly associated with the frequency of relapses in steroid-sensitive NS before cytostatic therapy. We therefore examined retrospectively the time to the first relapse and the incidence of subsequent relapses in 54 HLA-typed children with frequently relapsing NS, after treatment with cyclophosphamide (n = 49) or chlorambucil (n = 5) for 8 or 12 weeks; 38 patients were HLA-DR7 positive and 16 negative with 80% in both groups being steroid dependent. HLA typing was performed using serological or DNA typing methods. Renal biopsy showed minimal glomerular changes. A lower proportion of HLA-DR7 positive than negative patients remained in remission after 3 years (36% vs. 81%, P<0.02) and 5 years (36% vs. 72%, P<0.03). In the first 3 years after cytostatic therapy the mean number of prednisone-treated relapses was 1.3/patient per year in HLA-DR7-positive patients compared with 0.4 in negative patients (P<0.025). There was no statistically significant difference in the proportion of relapse-free patients with and without steroid dependency. The HLA status predicts the response of NS patients to alkylating agents better than the rate of previous relapses. Received September 19, 1995; received in revised form and accepted April 16, 1996     

Do current recommendations for kidney biopsy in nephrotic syndrome need modifications?

The current recommendations of kidney biopsy in childhood idiopathic nephrotic syndrome (CINS) were put forward to minimize unnecessary kidney biopsies in underlying minimal change disease (MCD). However, there remains a diversity of opinion about the criteria for biopsying children with idiopathic nephrotic syndrome. This study was conducted to prospectively study their usefulness in avoiding biopsies in MCD and to evaluate further modifications for minimizing biopsies in CINS. Of 400 consecutive CINS patients, 222 patients were subjected to kidney biopsy according to the current recommendations. The histopathology spectrum of these selectively biopsied children revealed focal segmental glomerulosclerosis (FSGS) in 39%, MCD in 34.2%, membranoproliferative glomerulonephritis (MPGN) in 16.2%, mesangioproliferative glomerulonephritis (MesPGN) in 7.6%, membranous nephropathy (MN) in 1.8%, and diffuse mesangial sclerosis (DMS) in 0.9%. We observed that despite the current recommendations and efforts to minimize biopsy, 34% of children had MCD on histopathology. Two or more clinical (hematuria and hypertension) or biochemical (renal insufficiency) parameters were present in all children with MPGN. Low C3 was present only in children with MPGN. All the steroid responders were found to have MCD, FSGS, or MesPGN on biopsy. Cyclophosphamide response correlated better with steroid responsiveness (P=0.02) than with histo- pathology (P=0.80) in MCD, FSGS, and MesPGN. Based on these observations, we suggest some modifications in current recommendations for kidney biopsy to minimize biopsying children with MCD. These are (1) biopsies in children (age 1–16 years) should be restricted (a) to a subgroup with two or more clinical and biochemical parameters and (b) in steroid non-responders, (2) the decision to administer cyclophosphamide should be based on steroid response pattern without requiring a prior routine biopsy. Received: 16 July 1999 / Revised: 20 November 2001 / Accepted: 24 November 2001     

High incidence of initial and late steroid resistance in childhood nephrotic syndrome

BACKGROUND: Conventional wisdom states that greater than 80% of children with nephrotic syndrome (NS) respond to steroid treatment, remain steroid-sensitive during subsequent relapses, and consequently have a favorable long-term prognosis. In contrast, steroid resistance is believed to be associated with a high risk of developing chronic renal failure. Recent reports suggest that the histologic pattern of NS in children may be changing, but whether the change is accompanied by a parallel change in steroid sensitivity is unknown. METHODS: Initial and subsequent steroid responsiveness was evaluated in all children aged 1 to 18 years who presented with newly diagnosed NS to the 2 pediatric nephrology referral centers in southeastern Louisiana between 1994 and 2003. NS was defined as presence of edema, heavy proteinuria, and serum albumin concentration below 2.5 g/dL. Steroid sensitivity (SS) was defined as total resolution of proteinuria and edema, and partial response to steroids (PR) was defined as loss of edema with continuing proteinuria. RESULTS: There were 210 new cases of NS. Forty-one patients (20%) had immune complex glomerulonephritis. Six patients were excluded because of incomplete data availability. Of the remaining 163 patients, 115 (71%) were SS and 23 (14%) achieved PR during the initial 4 weeks of treatment; 25 (15%) were steroid-resistant (SR). Follow-up data were available for 91 of the 115 initially SS patients; 19 subsequently became steroid-resistant. Thus, at least 45% of the patients with new-onset NS did not have typical childhood steroid-responsive NS. Initial steroid resistance was more likely in African American children and in children with older age at onset (11.5 vs. 4.6 years). Development of steroid resistance after initial SS was associated with shorter interval to the first relapse (2.2 vs. 5.4 months) and having the first relapse during the initial steroid treatment. CONCLUSION: Compared to previous reports, our results show a higher incidence of initial and subsequent steroid resistance, characteristics not consistent with typical minimal change NS with a benign prognosis. The results suggest that in the current era, NS in children may not be as benign as indicated by earlier studies.     

Metabolomics Signature for Non-Responders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients: The Newfoundland Osteoarthritis Study

Although total joint replacement (TJR) surgery is considered as the most effective treatment for advanced osteoarthritis (OA) patients, up to one-third of patients reported unfavorable long-term post-operative pain outcomes. We aimed to identify metabolic biomarkers to predict non-responders to TJR using a metabolomics approach. TJR patients were recruited and followed-up at least 1-year post-surgery; TJR outcomes were assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Targeted metabolomic profiling was performed on plasma samples collected pre-surgery and pairwise metabolite ratios, as proxies for enzymatic reactions, were calculated. Association tests were performed between each metabolite ratio and non-responders. The metabolome-wide significance was defined as p < 2 × 10⁻⁵. A total of 461 TJR patients due to primary OA were included in the analysis. Fifteen percent of patients were classified as pain non-responders; 16% were classified as function non-responders. Lower baseline WOMAC pain and function scores were significantly associated with pain and function non-responders, respectively (both p < 0.03). Two metabolite ratios were significantly associated with pain non-responders; acetylcarnitine (C2) to phosphatidylcholine acyl-alkyl C40:1 (PC ae C40:1) was five times higher in pain non-responders whereas phosphatidylcholine diacyl C36:4 (PC aa C36:4) to isoleucine was twenty one times lower in pain non-responders than responders (all p ≤ 1.93 × 10⁻⁵). One metabolite ratio, glutamine to isoleucine, was significantly lower in function non-responders than responders (eight times lower; p = 1.08 × 10⁻⁵). Three metabolite ratios (C2 to PC ae C40:1, PC aa C36:4, and glutamine to isoleucine) related to inflammation and muscle breakdown could be considered as novel plasma markers for predicting non-responders to TJR and warrant further investigation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:793-802, 2020     

Multidrug-Resistance 1 Gene Single-Nucleotide Polymorphisms Do Not Influence Long-Term Graft Survival After Kidney Transplantation

Background

The single-nucleotide polymorphisms (SNPs) of the Multidrug resistance 1 (MDR1) gene have been associated with changes in the pharmacokinetics of cyclosporine (CsA) and tacrolimus (FK506). Our aim was investigate the influence of MDR1 SNPs on long-term graft survival in a population of kidney transplant recipients.

Methods

We retrospectively analyzed 154 patients; they were genotyped for the SNPs C1236T, G2677T/A, and C3435T and evaluated for the influence of those 3 SNPs on CsA or FK506 pharmacokinetics and on long-term graft survival.

Results

Thirty-one patients were wild-type for C1236T, G2677T/A, and C3435T polymorphisms (group A), 76 patients had ≥1 heterozygous mutations (group B), and 47 patients had ≥1 homozygous mutations (group C). CsA-receiving patients in group C needed a significantly higher oral dose than patients in groups B and A (P = .02). No differences in FK506 trough level nor in oral dose taken were observed in FK506-receiving patients. Kaplan-Meier analysis did not show survival differences in the 3 groups, and Cox proportional hazards model confirmed that the MDR1 SNPs did not represent a risk for graft loss.

Conclusions

Pretransplantation determination of MDR1 SNPs may be helpful to optimize the starting dose of CsA but can not predict long-term graft survival.     

霉酚酸酯药代动力学与多重耐药基因1多态性的相关性研究

目的 研究肾移植受者术后早期霉酚酸酯(MMF)的药代动力学与人类多重耐药基因1(MDRI)多态性的相关性.方法 选择初次肾移植的汉族受者28例,肾移植术后2周时,于口服MMF之前及服药后0.5、1、1.5、2、4、6、8、10、12 h共10个时间点分别采集外周血,以高效液相色谱(HPLC)法测定全血霉酚酸酯(MMF)的活性成分霉酚酸(MPA)的浓度,直接观察其峰值浓度(Cmax)和达峰时间(Tmax).应用Winnolin 3.1软件计算MPA 0～12 h药物时间一浓度曲线下面积(AUC)和平均滞留时间(MRT).同时从外周血提取基因组DNA,应用多聚酶链反应-限制性片断长度多态性(PCR-RFLP)测定MDR1第12、21、26号外显子C1236 T、G2677 T/A、C3435 T单核苷酸多态性(SNP).比较3个SNP位点的不同基因型、单倍型间MMF药代动力学参数的差异;比较MPA高暴露组(MPA AUC≥60 mg·h-1·L-1)与MPA低暴露组(MPA AUC＜60 mg·h-1·L-1)间MDR1多态性差异.结果 MDR1第12、21、26号外显子SNP位点突变型纯合子基因型(1236 TT、2677 TT/AA、3435 TT)频率分别为0.368、0.184和0.211.1236 TT基因型受者MPA AUC水平显著高于1236 cc/CT受者,分别为(65.36±11.51)mg·h-1·L-1和(53.33±13.77)mg·h-1·L-1(P=0.032).MPA高暴露组第12号外显子SNP位点上,TT基因型频率显著高于低暴露组,分别为66.7%和15.8%(P=0.013,OR=2.526);T等位基因频率有高于低暴露组的趋势,分别为83.3%和53.3%(P=0.072).结论 具有MDR1第12号外显子TT等位基因的受者,肾移植早期MPA AUC显著高于同一位点其他基因型受者,是MPA高暴露的危险个体.     

Focal and segmental glomerulosclerosis in children: a longitudinal assessment

Recent data suggest that the histologic finding of focal and segmental glomerulosclerosis (FSGS) is increasing among children. There are, however, limited longitudinal pediatric data on prevalence, demographics, and steroid responsiveness in FSGS. We identified 201 consecutive nephrotic children diagnosed between 1977 and 2002 with 2 years follow-up; 51% had undergone renal biopsy due to steroid sequelae or resistance; 48 children with FSGS were diagnosed. Compared with non-FSGS children, FSGS children were older at diagnosis (6.9 years vs 4.4 years, P < 0.02), more likely girls (54% vs 28%, P < 0.02), Black or Hispanic (42% vs 16%, P < 0.001), and the FSGS was more likely to be steroid resistant (73% vs 10%, P < 0.001). To assess for longitudinal differences, we grouped children by presentation: pre-1985, between 1985 and 1995, and post-1995. There was no difference in proportion of children biopsied or diagnosed with FSGS during each interval. Among FSGS children, there was no difference in racial or gender composition in each period, but there was a difference in age at diagnosis (2.6 vs 5.7 vs 8.5 years; P = 0.01), also observed in the non-FSGS children (2.2 vs 3.9 vs 4.9 years; P = 0.02). In contradistinction to non-FSGS children, there was a marked increase in steroid resistance with FSGS (43% vs 62% vs 86%; P = 0.03).     

Spectrum of infections in Indian children with nephrotic syndrome

We conducted a retrospective analysis of infections in 154 children (114 boys, 40 girls) with nephrotic syndrome who satisfied the International Study of Kidney Disease in Children criteria. Their mean age at onset of symptoms was 6.2 years (range 6 months to 16 years) and the mean duration of follow-up was 32 months (range 6–55 months). One or more infectious complications were observed in 59 of the 154 children (38%), with urinary tract infection being the commonest (13.7%), followed by pulmonary tuberculosis (10.4%), peritonitis (9.1%), skin infections (5.2%), upper respiratory infections (5.2%), lower respiratory tract infections (3.9%) and pyomeningitis (0.6%). There were 3 deaths, the mortality in 2 patients being attributable to infections. There was no significant difference between children who developed infection and those who didn't in terms of age of onset, sex, duration of disease, serum creatinine, blood urea nitrogen and 24-h proteinuria. However, the children who developed infectious complications had significantly higher serum cholesterol levels (P<0.01) and lower serum albumin levels (P<0.02). The frequency of infections was higher inchildren who were frequent relapsers, steroid dependent and subsequent non-responders (28/60) compared with infrequent relapsers and initial non-responders (29/94).     

Clinical and immunological results of corneal allograft rejection

Of 111 episodes of graft rejection in 66 patients, 62 responded to therapy with graft clearing (responders); 49 did not (non-responders). Both groups were of similar age, sex, and etiology; both had a similar rate of glaucoma and a similar rate of previous grafting. In responders the graft reaction was shorter in duration (2.2 vs. 5.6 wks. p less than 0.005), and it was necessary to increase the number of glaucoma medications more often in non-responders compared to responders (41% vs. 19%, p less than 0.02). The interval from surgery to reaction was similar in responders and non-responders (18.2 vs. 13.3 mos., p greater than 0.1). An epithelial rejection line was present in 11% of responders, but was not present in non-responders (p less than 0.05). Lymphocytotoxic antibody development correlated with rejection in 16 of 64 episodes. Patients who responded to treatment were more frequently asymptomatic (p less than 0.05) or were treated earlier following the onset of symptoms compared to non-responders (p less than 0.0001).     

Impact of interlead distance on immediate and mid-term response to cardiac resynchronization therapy

Abstract

Objectives. It is currently recommended that the left ventricular (LV) lead be placed at the posterolateral or lateral wall of heart during cardiac resynchronization therapy (CRT). The aim of our study is to evaluate the influence of interlead distance on immediate and mid-term response to CRT with altered right ventricular (RV) pacing site. Design. A total of 35 consecutive patients underwent CRT for standard indications. RV pacing site was altered from RV outflow tract (RVOT) to RV apex (RVA) in the course of implantation, permitting assessment of a “poorer response” and a “better response” site based on intraprocedural aortic velocity time integral (aVTI). LV–RV interlead distances were compared between these sites during operation. We also made a comparison of the interlead distances between responders and non-responders 6 months after CRT. Results. In the process of CRT implantation, the better response site showed significantly larger interlead distance (16.5 ± 4.4 cm vs.12.4 ± 5.6 cm, p = 0.001) as well as its vertical component (9.8 ± 4.8 cm vs. 4.3 ± 2.8 mm, p = 0.001) on lateral fluoroscopy view as compared with the poorer response site. Furthermore, RVA proved more likely to be the “better response” site than RVOT (91% vs. 9%, p = 0.001). At 6-month -up, responders demonstrated larger direct interlead distance (18.1 ± 4.5 cm vs. 14.8 ± 3.5 cm, p = 0.011) and horizontal interlead distance (14.1 ± 6.6 cm vs. 8.3 ± 6.1 cm, p = 0.004) on the lateral radiograph in comparison with non-responders with great significance. Conclusions. Larger interlead distance on lateral fluoroscopy view is associated with more favorable immediate and mid-term response to CRT. Use of these findings may help to maximize the benefit derived from CRT.