缬沙坦联合小剂量氢氯噻嗪对老年原发性高血压病患者血压控制的临床研究

目的:探讨缬沙坦联合小剂量氢氯噻嗪对老年原发性高血压病患者血压的影响.方法:选择我院2007年4月～2009年4月原发性高血压患者84例,以上患者随机分为两组,缬沙坦联合小剂量氢氯噻嗪组和缬沙坦组.同时选择我院健康体检者40例,作为健康对照组.缬沙坦联合小剂量氢氟噻嗪组采用缬沙坦联合小剂量氢氯噻嗪口服治疗.缬沙坦组口服缬沙坦治疗.两组患者均治疗12周.治疗前后测定两组患者的收缩压(SBP)和舒张压(DBP).结果:缬沙坦联合小剂量氢氯噻嗪组和缬沙坦组患者的血压低于对照组(P＜0.05);两组治疗后的血压显著低于治疗前(P＜0.05);缬沙坦联合小剂量氢氯噻嗪组治疗后血压与缬沙坦组比较,差异有统计学意义,P＜0.05.结论:缬沙坦联合小剂量氢氯噻嗪对老年高血压病患者血压的控制优于单用缬沙坦.     

缬沙坦联合氢氯噻嗪治疗高血压心脏病的疗效观察

目的:探讨缬沙坦联合氢氯噻嗪治疗高血压心脏病的临床疗效。方法:随机将医院收治入院的96例高血压心脏病患者随机分为观察组和对照组,每组48例,观察组给予缬沙坦50mg/天+氢氯噻嗪6.5mg/天口服,若无效将氢氯噻嗪增至13mg/天,对照组给予缬沙坦50mg/天口服,若无效将缬沙坦100mg/天,服药16周后测量患者收缩压(SBP),舒张压(DBP),心电图,心动超声及左室肥厚(LVH)指标的改善情况。结果:观察组的总有效率为93.75%,对照组的总有效率为68.75%,两组间比较差异有统计学意义(P<0.05),观察组和对照组的SBP,DBP,左室高电压,LVH指标较治疗前均有所降低,差异有统计学意义(P<0.05),观察组降低的幅度较对照组的明显(P<0.05)。结论:缬沙坦联合氢氯噻嗪治疗高血压心脏病疗效确切,能有效改善心功能,不良反应小,对高血压心脏病的临床治疗有重要意义。     

氨氯地平联合氢氯噻嗪治疗老年高血压患者疗效分析

目的观察氨氯地平联合氢氯噻嗪在治疗老年高血压患者中的临床疗效,评价其安全性和有效性。方法将92例确诊原发性高血压的老年患者随机分为两组,每组46例,观察组给予氨氯地平5mg/d,氢氯噻嗪12.5mg/d;对照组只给予给予氨氯地平5mg/d,8周为1个疗程。结果治疗后,两组血压均较治疗前明显降低（P〈0.01）;观察组和对照组总有效率分别为为93.5%（43/46）和82.6%（38/46）,两组间差异明显（P〈0.05）;观察组和对照组药物相关不良反应发生率分别为2.8%（1/46）和13.1%（6/46）,差异有统计学意义（P〈0.05）。结论氨氯地平联合氢氯噻嗪治疗老年人高血压患者副作用少、有效率高,安全性高,是一种值得推荐的老年高血压治疗方案。     

新辅助化疗联合胃癌根治术治疗老年进展期胃癌患者的疗效分析

目的探讨新辅助化疗联合胃癌根治术治疗老年进展期胃癌患者的安全性和有效性。方法回顾性分析2012年1月至2020年10月于华中科技大学同济医学院附属协和医院接受新辅助化疗的148例进展期胃癌患者的临床资料, 分为中青年组(111例)和老年组(37例), 比较其临床病理和预后。结果两组在新辅助化疗所致的贫血(χ2=0.235, P=0.628)、白细胞减少(χ2=0.613, P=0.434)、中性粒细胞减少(χ2=0.011, P=0.918)及血小板减少(χ2=0.253, P=0.615)等血液学并发症和恶心(χ2=0.092, P=0.762)、呕吐(χ2=0.166, P=0.683)、腹泻(χ2=0.015, P=0.902)及黏膜炎(χ2=0.199, P=0.766)等非血液学并发症发生率方面差异均无统计学意义。老年组与中青年组在手术时间(t=0.270, P=0.604)、术中出血量(t=1.140, P=0.250)和R0切除率(χ2=0.105, P=0.750)方面差异均无统计学意义。中青年组与老年组术后并发症发生率分别为25.2%、37.8%, 差异无统计学意义(...     

骨肉瘤中miR-194的表达水平及其与临床病理参数的关系

目的探讨骨肉瘤中miR-194的表达水平及其与临床病理参数的关系。方法应用荧光定量实时PCR分析68例冻存的骨肉瘤组织及其对应的癌旁组织标本中miR-194的表达水平,并分析其与临床病理参数及患者预后的关系。结果与癌旁组织相比,骨肉瘤组织中miR-194的表达显著降低(t=8.408,P<0.001)。随着临床分期的增加,miR-194表达水平逐渐降低,miR-194表达下调与临床分期有关(χ2=15.859,P=0.001)。软组织浸润患者miR-194表达水平显著低于无软组织浸润患者(χ2=21.580,P<0.001)。与无转移患者相比,转移患者miR-194表达水平显著降低(χ2=14.071,P<0.001)。miR-194高表达组中位生存时间为30.40个月,累积生存率为81.48%(22/27);而低表达组中位生存时间为23.71个月,累积生存率为58.54%(24/41);两组比较差异有统计学意义(χ2=4.138,P=0.042)。结论骨肉瘤患者组织中miR-194表达水平明显降低,与临床分期、软组织浸润、肿瘤转移等临床病理特征有关,其低表达与患者预后不良密切相关。     

无抗凝血液滤过用于不同原因高危出血倾向患者的研究

目的:研究不同原因的高危出血倾向患者在实施无抗凝连续性静脉-静脉血液滤过(continuous veno-venous hemofiltration,CVVH)时,滤器使用寿命和溶质清除效果的差异。方法:按照高危出血倾向的不同原因,将无抗凝CVVH治疗的118例次患者分为低凝组(n=58)和出血组(n=60),比较CVVH治疗前后两组间血ΔScr、ΔBUN和滤器使用寿命的差异。结果:出血组滤器使用寿命(17.5±11.2)h,低于低凝组(35.8±15.8)h,差异具有统计学意义。滤器使用寿命12 h的比例在低凝组、出血组分别是72.4%、38.3%,滤器使用寿命24 h的比例在低凝组、出血组分别是43.1%、16.7%,其差异均具有统计学意义。出血组ΔScr(74.5±32.2)μmol/L、ΔBUN(7.0±2.8)mmol/L,低于低凝组(167.0±100.5)μmol/L、(11.1±4.9)mmol/L,其差异均具有统计学意义。结论:无抗凝CVVH可应用于因凝血功能障碍或血小板减少导致的高危出血倾向患者,不建议用于活动性出血或外科术后的高危出血倾向患者。     

进展期胃上部癌患者行近端胃切除的预后分析

目的比较进展期胃上部癌患者行近端胃切除术(PG)和全胃切除术(TG)的预后差异。方法本研究纳入2011年1月至2016年12月期间确诊为胃癌并在哈尔滨医科大学附属肿瘤医院因胃上部癌接受胃癌根治术的363例患者, 根据手术方式分为TG组(178例)和PG组(185例)。结果与PG组相比, TG组患者的肿瘤直径>4 cm、大体类型为BorrmannⅢ型、术后病理分期为Ⅲ期的比例更高, 差异均有统计学意义(χ2=9.687P=0.002;χ2=24.897, P=0.001;χ2=6.257, P=0.044)。PG组和TG组的5年总体生存率分别为64.3%(95%CI:45.1%～50.5%)和60.6%(95%CI:41.3%～47.6%), 差异无统计学意义(P=0.297)。倾向性评分匹配后再次比较发现两组间5年总体生存率差异无统计学意义(P=0.876)。经化疗亚组分析发现, TG组与PG组生存情况差异无统计学意义(P=0.309)。结论进展期胃上部癌患者行PG与TG的预后无差异。     

厄贝沙坦氢氯噻嗪片对血压晨峰及左心室质量相关参数的影响

目的观察厄贝沙坦氢氯噻嗪片对中老年原发性高血压患者血压晨峰（MBPS）及左心室质量（LVM）相关参数的影响。方法选择120例轻中度原发性高血压患者,口服厄贝沙坦氢氯噻嗪片150mg／12.5mg,4-8周不达标者剂量加倍,治疗12个月,应用动态血压监测（ABPM）评价治疗前后MBPS的变化,应用超声心动图评价LVM相关参数的变化。结果（1）经厄贝沙坦氢氯噻嗪片治疗后,MBPS（＋）的患者减少,MBPs（-）的患者增多,与治疗前比较差异有统计学意义（P〈0.01）。（2）治疗后MBPS（＋）患者晨峰程度较治疗前明显降低[收缩压（SBP）差值（16.1±1.8）mmHg（1mmHg=0.133kPa）比（29.4±2.8）mmHg,舒张压（DBP）差值（10.2±2.3）mmHg比（21.2±2.2）mmHg,P〈0.01],而MBPS（-）患者晨峰程度较治疗前无明显下降[SBP差值（11.2±2.4）mmHg比（10.1±1.2）mmHg,DBP差值（5.9±1.9）mmHg比（6.8±3.2）mmHg]。（3）MBPs（＋）和MBPS（-）患者治疗后LVM相关参数较治疗前均明显减小,且MBPs（＋）患者治疗后左心室后壁厚度、LVM、LVM指数与MBPS（-）患者治疗后比较差异有统计学意义（P〈0.05）。结论厄贝沙坦氢氯噻嗪片能有效遏制MBPS的发生,降低晨峰程度,并能逆转左心室肥厚。     

子宫肌瘤剔除术后切口感染相关因素及心理干预研究

目的研究子宫肌瘤剔除术后切口感染相关因素及对患者进行心理干预的作用。方法将2015年1月至2016年10月于本院接受手术治疗的180例子宫肌瘤患者纳入调查,根据患者手术后切口是否有感染,将手术患者分成未感染组(126例)和感染组(54例)。对两组患者体质、性别、年龄、术前服用的抗菌药物、手术所用时间、手术中的操作、手术切口情况及患者并发症等进行统计分析。结果感染组60岁以上患者较未感染组多(χ~2=5.68、P=0.02),该组患者体质良好率较未感染组低(χ~2=7.65、P=0.01),差异有统计学意义;而两组患者平均体重(t=1.95、P=0.71)、血红蛋白(t=0.18、P=0.92)水平和有盆腔手术史患者(χ~2=0.53,P=0.06)均无统计学意义。感染组患者在合并附件手术(χ~2=0.85、P=0.04)和轻度盆腔粘连(χ~2=0.28、P=0.03)程度较未感染组高,差异均具有统计学意义。两组患者的后壁肌间肌瘤比率(χ~2=0.12、P=0.76)、最大肌瘤直径(t=1.36、P=0.82)、术中肌瘤个数(t=1.75、P=0.69)和术中出血量(t=1.58、P=0.75)差异均无统计学意义。结论患者自身的身体素质、手术切口的长度、服用抗菌药物、手术时间的长度及有无并发症等是影响患者切口感染的主要因素。     

全胸腔镜肺癌根治术淋巴结清扫的探讨

目的探讨全胸腔镜下肺叶切除治疗临床Ⅰ期非小细胞肺癌淋巴结清扫的安全性和可行性。方法 2006年1月～2008年12月,160例临床Ⅰ期非小细胞肺癌接受全腔镜下肺叶切除术、纵隔淋巴结清扫,采用不撑开肋骨三孔法,并与同期247例接受常规开放手术的Ⅰ期非小细胞肺癌进行比较。结果胸腔镜组淋巴结清扫组数(2.4±1.5)组与开胸组(2.6±1.6)组无显著差异(t=1.262,P=0.208),胸腔镜组清扫淋巴结(9.8±6.2)枚,与开胸组(9.9±5.9)枚无统计学差异(t=-0.160,P=0.873)。开胸组并发症发生率11.7%(29/247)和围手术期死亡率2.8%(7/247)与胸腔镜组并发症发生率9.4%(15/160)和围手术期死亡率0.6%(1/160)无显著差异(χ2=0.564,P=0.453;χ2=1.446,P=0.229)。胸腔镜组生存情况优于开胸组(χ2=5.373,P=0.020)。结论全胸腔镜肺叶切除术治疗临床Ⅰ期非小细胞肺癌在技术上是安全可行的,其淋巴结清扫可达到开放手术的范围,远期疗效不亚于开放手术。     

Calcium polystyrene sulfonate in treating hyperkalemia patients with chronic kidney disease: a multi-center clinical study

Objective To evaluate the efficacy and safety of calcium polystyrene sulfonate in treating hyperkalemia patients with chronic kidney disease. Methods A single-arm, open, multi- center, phase Ⅳ clinical trial was carried out. Ninety-eight patients were enrolled in 11 centers from September 5, 2011 to June 21, 2012. The patients took calcium polystyrene sulfonate 15 g/d for one week. Total 5 visits were on 0, 2, 4, 8 and 14 days respectively. Results One day after treatment, potassium levels decreased rapidly from (5.85±0.26) mmol/L to (5.16±0.51) mmol/L (P＜0.01) and average value dropped to normal range. Three days after treatment, serum potassium levels decreased to (4.88±0.58) mmol/L(P＜0.01). After one week of treatment, serum potassium levels decreased to (4.67±0.57) mmol/L (P＜0.01). A week after the withdrawal, potassium levels were (4.96±0.66) mmol/L (P＜0.01). Serum potassium levels in all visits during the treatment and after discontinuation of calcium polystyrene sulfonate were all significantly decreased comparing to the baseline level (all P＜0.01). At the same time, serum levels of sodium, phosphorus, calcium showed no significant changes during the treatment. Constipation (9.2% ) was the commonest side effect. There was no treatment-related serious adverse effect. Conclusions This single-arm, open, multi-center clinical study shows that calcium polystyrene sulfonate is effective and safe in treating hyperkalemia due to chronic kidney disease.     

他克莫司与霉酚酸酯治疗儿童难治性IgA肾病的疗效比较

目的比较他克莫司(tacrolimus,TAC)与霉酚酸酯(mycophenolate mofetil,MMF)在难治性IgA肾病(IgA nephropathy,IgAN)患儿的临床疗效。方法难治性IgAN的诊断定义为:在联合肾素-血管紧张素系统(RAS)阻断剂及糖皮质激素序贯治疗后,仍表现为大量蛋白尿(≥50 mg·kg-1·d-1)。遵循病例对照匹配方法,回顾性选取2012年1月1日至2016年12月31日在东部战区总医院行肾活检确诊为难治性IgAN的患儿76例,根据治疗方案将患儿分为TAC组(38例)和MMF组(38例),比较两组24 h尿蛋白量(24hUP)、血清白蛋白(Alb)、血清肌酐(Scr)、血清尿酸(UA)、血糖(Glu)、不良反应发生情况以及疗效等。结果两组患者间年龄、性别比、血压、估算肾小球滤过率(eGFR)、24hUP、尿红细胞计数(U-RBC)、Scr、Alb、BUN、天门冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、Glu及病理牛津分型、加用免疫抑制剂前行大剂量甲泼尼龙冲击治疗比例差异均无统计学意义(均P>0.05),两组患者具有可比性。用药3个月起,两组患儿24hUP均较基线值明显降低,差异有统计学意义(均P<0.05),且在3、6、12个月时TAC组24hUP均显著低于MMF组(均P<0.05)。TAC组Alb在用药1个月后即较基线值明显升高(P<0.05),而MMF组在用药3个月后明显升高(P<0.05),其中TAC组Alb在1、3、6个月时均高于MMF组(均P<0.05),在12个月时两组Alb差异无统计学意义。TAC组的总有效率、完全缓解率及无效率自用药3个月起与MMF组差异均有统计学意义(均P<0.05),但随访期间部分缓解率、随访时点复发率及累计复发率两组间差异无统计学意义(均P>0.05)。其中TAC组在6个月时达到最大有效率(94.7%),而MMF组在12个月时达到最大有效率(68.4%),差异有统计学意义(χ2=8.756,P=0.003)。两组不良反应发生率比较差异无统计学意义(15.8%比21.1%,χ2=0.350,P=0.554)。但TAC组在治疗3个月时血糖高于MMF组,差异有统计学意义[5.02(4.72,5.22)mmol/L比4.42(4.19,5.07)mmol/L,Z=-2.745,P=0.006]。结论TAC与MMF治疗难治性IgAN均取得良好的治疗效果,但TAC组更快达到缓解水平,且缓解率更高。     

Analysis of predictive factors for the decline of residual renal function in new peritoneal dialysis patients

Objective To prospectively evaluate the risk factors for the decline of residual renal function (RRF) in new peritoneal dialysis (PD) patients. Methods A total of 84 new PD patients in our PD center were included in this study. Clinical comprehensive assessment were made, and regression models was established to analyze the relationship between the decline of RRF and clinical indicators, which included the rate of peritonitis, systolic pressure, diastolic pressure, urine volume, 24 h urinary protein, serum albumin, C-reactive protein(CRP), history of diabetes mellitus, and the use of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) drugs, cardiac functional grading, sodium and water retention and biochemical indicators. The primary outcome was defined as two consecutive urine volume ≤100 ml/24 h. Results The mean follow-up time was (11.7± 1.1) months, primary outcome occurred in 20 patients, accounting for 23.8%, and their average period progressed to the primary outcome was (10.5±2.0) months. The 20 patients had higher ultrafiltration volume [(551.6±328.2) ml vs（294.1±288.0) ml, P=0.001], higher systolic blood pressure [(145.2±16.5) mmHg vs (136.0±13.8) mmHg, P=0.016], worse cardiac functional grading [(1.7±0.8) vs (1.3±0.4), P=0.000], more serious water-sodium retention [(1.0±0.7) vs (0.6±0.5), P=0.012], higher peritonitis rates (35.0% vs 4.7% ,P=0.000), lower Kt/V [(1.7 ± 0.4) vs (2.0 ± 0.3), P=0.003], lower hemoglobin levels [(89.0±14.9) g/L vs (99.5±17.8) g/L, P=0.020], higher C - reactive protein levels [(19.4±34.4) mg/L vs(8.7±12.6) mg/L, P=0.017], higher Scr levels [(1 004.6±291.1) μmol/L vs (753.1± 254.3) μmol/L, P=0.000], lower serum calcium levels[(1.86±0.1) mmol/L vs (2.02±0.2) mmol/L, P=0.000], higher serum phosphorus [(2.1±0.6) mmol/L vs (1.6±0.4）mmol/L, P=0.001] and higher calcium phosphorus product [(3.8±1.1) mmol2/L2 vs (3.1±0.8) mmol2/L2, P=0.010] as compared with those of the patients without the primary outcome. Based on the results of multivariable Cox regression analysis, ultrafiltration volume, cardiac functional grading, peritonitis, Kt/V and serum phosphorus level contributed to the decline of RRF significantly. Conclusion The higher Kt/V in PD patients plays a protective role, the higher ultrafiltration volume, the worse heart function, the more peritonitis rate and higher serum phosphorus predict more rapid declination of RRF.     

Survival of analysis of older patients with external iliac vein tunneled cuffed catheters on maintenance hemodialysis

Objective To investigate the survival of older patients with iliac vein tunneled cuffed catheters on maintenance hemodialysis. Methods A total of 70 older patients with external iliac vein tunneled cuffed catheters on maintenace hemodialysis were included in this study, there were 94 patients with internal jugular vein tunneled cuffed catheters as control group. The baseline anthropometric and 1aboratory parameters were measured. The catheter dysfunction and catheter related complications were documented. Results There were lower survival rate and catheter survival in the external iliac vein group compared with internal jugular vein group（χ2=13.714, P＜0.01;χ2=13.093, P＜0.01）. Compared with internal jugular vein group, there was lower rate of catheter infection in external iliac vein group(χ2=9.416, P＜0.01); In addition, there were higher rate of cardiovascular disease(CVD) events and catheter dysfunction among patients in external iliac vein group (χ2=7.492, P＜0.01;χ2=5.912, P＜0.05). Furthermore, the incidence of catheter dysfunction and cardiovascular disease events were the independent risk factors of mortality for older patients with iliac vein tunneled cuffed catheters on maintenance hemodialysis by Cox regression model. Conclusions Patients with iliac vein tunneled cuffed catheters have a shorter survival time. Those with catheter dysfunction or cardiovascular disease events are in higher risk of mortality．     

血浆凝血因子VIII水平与IgA肾病患者临床病理改变及预后的关系

目的探讨血浆凝血因子VIII(factor VIII,FVIII)水平与IgA肾病(IgAN)患者临床参数及预后的关系。方法收集2016年1月至2016年12月中南大学湘雅二医院确诊的IgAN患者的临床资料。按照时间依赖的受试者工作特征曲线(ROC)得出的血浆FVIII预测IgAN预后的临界值,将患者分为高FVIII组(FVIII>140.50%)和低FVIII组(FVIII≤140.50%),比较两组患者肾活检时基线临床参数的差异。以估算肾小球滤过率(eGFR)下降≥30%或进入终末期肾脏病(ESRD)为终点事件,采用Kaplan-Meier生存曲线及Cox回归方程法分析血浆FVIII水平对IgAN患者预后的影响。结果共93例IgAN患者纳入本研究,中位随访时间为35.15(33.77,36.76)个月,12例(12.90%)患者发生终点事件。高FVIII组患者年龄、血肌酐、尿素氮、血三酰甘油、血总胆固醇、血浆纤维蛋白原、D-二聚体、24 h尿蛋白量、蛋白C、蛋白S和eGFR下降速率高于低FVIII组(均P<0.05);eGFR、血白蛋白、中位随访时间低于低FVIII组(均P<0.05)。Kaplan-Meier生存分析结果显示,与低FVIII组比较,高FVIII组患者肾脏累积生存率降低(χ2=5.635,P=0.018)。在校正收缩压、eGFR、尿蛋白、肾小管萎缩/间质纤维化程度等因素后,多因素Cox回归分析结果显示,高血浆FVIII水平是IgAN患者肾脏预后不良的独立危险因素(HR=4.147,95%CI 1.055~16.308,P=0.042)。结论血浆FVIII水平与IgAN患者临床指标及预后相关,高血浆FVIII水平是IgAN患者肾脏预后不良的独立危险因素。     

Association of metabolic syndrome and chronic kidney disease among Uygur adults in Moyu country in Xinjiang Uygur Autonomous Region

Objective To examine the effects of different compositions of metabolic syndrome[Overweight and (or) obesity, hyperglycemia, hypertension, dyslipidemia] on chronic kidney disease. Methods A total of 1552 health data were collected from the survey of chronic kidney diseases among Uygur adults in Moyu country in Xinjiang Uygur Autonomous Region and the relationship between metabolic syndrome and chronic kidney disease was analyzed by using SPSS 15.0 software package. Results Before and after adjusting of age and gender, the prevalence of metabolic syndrome was 14.18% and 14.45% (95% CI 14.30%-14.60%). The prevalence of albuminuria (7.27% vs 3.83%,χ2=5.42, P=0.02), reduced estimated glomerular filtration rate (9.55% vs 3.45%,χ2=16.96, P=0.00) and chronic kidney disease(13.64% vs 6.76%,χ2=12.52, P =0.00) increased in residents diagnosed as metabolic syndrome than those without metabolic syndrome. The prevalence of chronic kidney disease increased with the increasing number of metabolic syndrome elements. Conclusions The prevalence of chronic kidney disease is associated with the accumulation of metabolic syndrome compositions. Early intervention on metabolic risk factors may reduce the risk of chronic kidney disease.     

Gitelman's syndrome (familial hypokalemia-hypomagnesemia)

Gitelman's syndrome (GS) is a heritable renal disorder characterized by hypomagnesemia, hypokalemia and hypocalciuria, and distinct from Bartter's syndrome (BS). As compared to those with BS, patients with GS present at an older age, and they have a milder clinical picture, normal or slightly decreased concentrating ability, reduced urinary excretion of calcium, and permanently decreased serum magnesium level. GS is caused by defective NaCl transport in the distal convoluted tubule, and linked to the gene encoding the thiazide sensitive Na-Cl-cotransporter located on chromosome 16q. Patients with BS, on the other hand, have mutations in the transporters in the thick ascending loop of Henle (NKCC2, ROMK, and C1C-Kb). Treatment of GS consists of magnesium salt replacement. Long term prognosis in terms of maintaining growth, preserving renal function and life expectancy is excellent.     

A novel mutation in the chloride channel gene,CLCNKB, as a cause of Gitelman and Bartter syndromes

BACKGROUND: Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary hypokalemic tubulopathies with distinct phenotypic features. GS has been considered a genetically homogeneous disorder caused by mutation in the gene encoding the NaCl cotransporter (TSC) of the distal convoluted tubule. In contrast, BS is caused by mutations in the genes encoding either the Na-K-2Cl cotransporter (NKCC2), the K+ channel (ROMK) or the Cl- channel (ClC-Kb) of the thick ascending limb. The purpose of this study was to examine the clinical, biochemical and genetic characteristics of a very large inbred Bedouin kindred in Northern Israel with hereditary hypokalemic tubulopathy. METHODS: Twelve family members affected with hypokalemic tubulopathy, as well as 26 close relatives were clinically and biochemically evaluated. All study participants underwent genetic linkage analysis. Mutation analysis was performed in affected individuals. RESULTS: Evaluation of affected family members (age range 3 to 36 years) revealed phenotypic features of both GS and classic Bartter syndrome (CBS). Features typical of GS included late age of presentation (>15 years) in 7 patients (58%), normal growth in 9 (75%), hypomagnesemia (SMg <0.7mmol/L) in 5 (42%), hypermagnesiuria (FEMg>5%) in 6 (50%) and hypocalciuria (urinary calcium/creatinine mmol/mmol <0.15) in 5 (42%). Features typical of CBS included early age of presentation (<1 year) in 3 (25%), polyuria/dehydration in 4 (33%), growth retardation in 3 (25%), hypercalciuria (urinary calcium/creatinine mmol/mmoverline>0.55) in 4 (33%) and nephrolithiasis in 1 (8%). Linkage analysis in affected patients excluded the TSC gene, SLC12A3, as the mutated gene, but demonstrated linkage to the Cl- channel gene, CLCNKB, on chromosome 1p36. Mutation analysis by direct sequencing revealed a novel homozygous missense mutation, arginine 438 to histidine (R438H), in exon 13 of CLCNKB in all patients. A restriction fragment length polymorphism (RFLP) analysis has been developed to aid in genotyping of family members. CONCLUSIONS: Our findings demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS phenotypes, in a kindred with the CLCNKB R438H mutation. We conclude that GS can be caused by a mutation in a gene other than SLC12A3. The exact role of the CLCNKB R438H mutation in the pathogenesis of the electrolyte and mineral abnormalities in GS and CBS remains to be established.     

Modulation of renal calcium handling by 11 beta-hydroxysteroid dehydrogenase type 2

Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11 beta HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THF+5 alpha THF)/THE as a parameter of 11 beta HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THF+5 alpha THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 +/- 10/7 versus 115/73 +/- 8/6 mmHg; P < 0.001 for systolic; P < 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 +/- 0.05 to 1.18 +/- 0.04 mmol/L (P < 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 +/- 3.6 to 31.9 +/- 3.1 micromol/L GFR (P < 0.01). Fractional calcium excretion increased from 2.4 +/- 0.3 to 2.7 +/- 0.3% (P < 0.01) and was negatively correlated to the fractional sodium excretion during GA (R = -0.35; P < 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R = 0.66; P < 0.0001). Inhibition of 11 beta HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.     

Ca2+Mg3+-ATPase activity in erythrocyte membranes in hypercalciuric nephrolithiasic patients

SUMMARY: Ca²⁺Mg²⁺ATPase is an enzyme involved in calcium transport across biological membranes. In order to determine its possible role in the pathogenesis of calcium nephrolithiasis, we assessed Ca²⁺Mg²⁺-ATPase activity in erythrocyte membranes from 18 hypercalciuric (HC) nephrolithiasic patients (nine with absorptive hypercalciuria (AHC), nine with renal hypercalciuria (RHC)) and eight normocalciuric healthy controls (C). Participants took no medication for at least 3 months before the study and remained on a diet containing approximately 25 mmol of calcium per day for 14 days. Pump activity was measured in calmodulin-free red blood cell membranes and expressed in umol of phosphate released per mg of membrane protein per h. There were statistically significant differences in pump activity between groups (1.43±0.07; 1.93±0.1; 1.65±0.06; C, AHC, RHC, respectively, P < 0.005 (three groups) and P < 0.02 AHC versus RHC. Enzyme activity was positively correlated with 24-h urinary calcium excretion (r = 0.64, P < 0.01) in HC patients; no such relationship was found in C. In conclusion, erythrocyte membrane Ca²⁺Mg²⁺ATPase activity is increased in HC. Differences in enzyme activity between AHC and RHC may reflect different degrees of a single generalized epithelial calcium transport disturbance.