Hypertension in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) has been shown to be associated with a greater than 50 percent incidence of hypertension prior to deterioration in renal function as assessed by glomerular filtration rate. The present study provides evidence for increased cardiac pre-load, as assessed by plasma atrial natriuretic factor (ANF) and cardiac index, in hypertensive as compared to normotensive ADPKD. The hypertensive ADPKD patients exhibited an increased renal vascular resistance as compared to the normotensive patients in spite of comparable glomerular filtration rates. It is hypothesized that the renal involvement of hypertensive ADPKD patients causes an impaired renal response to the observed increase in cardiac index, and also may release a venoconstrictor (such as angiotensin) which contributes to the enhanced cardiac pre-load and thus the hypertension.     

The response of GFR to amino acids differs between autosomal dominant polycystic kidney disease (ADPKD) and glomerular disease.

We compared the glomerular filtration rate (GFR) response to amino acids in patients with glomerular disease and polycystic kidney disease. The GFR response to infusion of amino acids (75 g/12 h), of dopamine (2 micrograms/kg per min), or their combination was evaluated in nine healthy probands and in patients with two types of renal diseases at various degrees of renal function: 15 patients with ADPKD and 11 patients with glomerular disease (IgA glomerulonephritis or diabetic nephropathy). Steady-state inulin infusion technique was used. In healthy subjects amino acids increased median C(in) in response to amino acids was not found in glomerular disease. In contrast in most ADPKD patients median C(in) increased after amino acids (+6.0 ml/min; range -4 to +68), (P less than 0.05). The response to amino acids was not modified by dopamine. The results demonstrate that amino acid-induced acute changes of glomerular filtration differ in polycystic kidney disease compared with glomerular disease. These observations may have implications with respect to mechanisms of progression.     

Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate

Fibroblast growth factor 23 (FGF23) and parathyroid hormone blood levels rise following progressive loss of renal function. Here we measured parameters of phosphate metabolism in 100 patients with autosomal dominant polycystic kidney disease (ADPKD) in stage 1 or 2 of chronic kidney disease, 20 patients with non-diabetic chronic kidney disease, and 26 with type 2 diabetes. Twenty healthy volunteers served as controls. The mean levels of FGF23 were significantly (4-fold) higher in ADPKD compared to non-diabetic and diabetic patients, and healthy volunteers. Mean serum phosphate levels were significantly lower in ADPKD patients compared to non-diabetic and diabetic patients, and the healthy volunteers. The prevalence of hypophosphatemia was 38, 25, 27, and 5% in ADPKD, non-diabetic and diabetic patients, and healthy volunteers, respectively. The tubular maximum of phosphate reabsorption per glomerular filtration rate was lowest in ADPKD patients with a significantly high positive correlation with serum phosphate levels. Estimated glomerular filtration rates were approximately 100 ml/min per 1.73 m2 in all groups and parathyroid hormone and vitamin D metabolite levels were in the normal range. Thus, FGF23 was substantially elevated in ADPKD patients compared to other CKD patients matched for glomerular filtration rate, and was associated with increased renal phosphate excretion. The mechanism for this anomaly will require further study.     

Renal and cardiac effects of antihypertensive treatment with ramipril vs metoprolol in autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension is a common complication in autosomal dominant polycystic kidney disease (ADPKD). This prospective randomized double-blind study was performed to compare the renal and cardiac effects of the ACE inhibitor ramipril and the beta-blocker metoprolol as first line therapy in ADPKD patients with hypertension. METHODS: Forty-six hypertensive ADPKD patients were randomized to either ramipril (n = 23) or metoprolol (n = 23). Twenty-four hour (24-h) ambulatory blood pressure (BP), glomerular filtration rate (GFR) as calculated by the Cockcroft and Gault formula, urinary albumin excretion (albumin/creatinine ratio), and left ventricular mass index (LVMI) were established at baseline and at yearly intervals. The total follow-up was 3 years. Baseline characteristics were similar in both groups. RESULTS: Mean arterial pressure (MAP) decreased significantly in both the ramipril and the metoprolol group (-8 +/- 2 and -6 +/- 2 mmHg; both P < 0.01). There was a significant decline in renal function during follow-up which was similar in patients treated with ramipril or metoprolol (-2.5 +/- 0.7 vs -2.9 +/- 0.8 ml/min/year; P = NS). After the 3 years follow-up, no differences in GFR, LVMI and urinary albumin excretion were observed between the ramipril and the metoprolol group (80.7 +/- 10.7 vs 78.0 +/- 7.6 ml/min, 102.6 +/- 6.8 vs 100.3 +/- 5.4 g/m(2); and 42.6 +/- 12.3 vs 70.3 +/- 32.5 mg/g, respectively; all P = NS). A post-hoc analysis evaluating the effects of BP control, revealed that LVMI increased in patients with standard BP control while it remained stable in patients with rigorous BP control with a significant difference in LVMI between the groups after 3 years of follow-up (110.5 +/- 6.3 vs 90.9 +/- 4.7 g/m(2); P = 0.017). Also, by the end of the study albuminuria was lower in patients with rigorous vs standard BP control (23.5 +/- 6.7 vs 94.8 +/- 35.4 mg/g; P = 0.05). CONCLUSIONS: In our study population of hypertensive ADPKD patients, no differences in renal function, urinary albumin excretion and LVMI were detected between those treated with ramipril or metoprolol, respectively, during a 3 years follow-up. Rigorous BP control prevented an increase in LVMI and reduced urinary albumin excretion, suggesting a crucial role of BP control for slowing progression of cardiac and renal organ damage in ADPKD.     

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. METHODS: Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. RESULTS: Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. CONCLUSION: MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.     

Effect of dilazep dihydrochloride on urinary albumin excretion in patients with autosomal dominant polycystic kidney disease

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 +/- 52 to 46 +/- 26 microg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.     

Serum cystatin C as an index of renal function in kidney transplant patients

Management of renal transplant patients requires periodic measurement of renal function, which is usually assessed by measuring the glomerular filtration rate (GFR). The most commonly used marker for GFR is serum creatinine, although muscle wasting and tubular secretion may lead to overestimation of the actual GFR. Serum concentrations of the low-molecular-weight proteins, cystatin C and beta(2)-microglobulin (B(2)M), may afford useful markers to determine a reduced GFR. We investigated whether these molecules provide reliable indicators of renal function in 75 renal transplant patients. Cystatin C and B(2)M correlated significantly with creatinine (r =.648, P <.05 and r =.578, P <.05, respectively). Inverse serum creatinine was superior to inverse cystatin C and inverse B(2)M when renal function equations were used (r =.95, P <.05, according to MDRD; r =.87, P <.05, according to Cockroft-Gault). Receiver operating characteristic (ROC) analysis was performed to quantitate the accuracy of the different markers to detect reduced GFR using a cutoff value of 70 mL/min. No significant difference between the areas under the ROC curves comparing cystatin C and B(2)M was observed; however, serum creatinine demonstrated a significantly greater value than cystatin C (.981 vs.724, P =.001). We conclude that serum creatinine is a more efficacious marker than serum cystatin C to assess renal function.     

The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomal-dominant polycystic kidney disease

BACKGROUND: Hypertension in autosomal-dominant polycystic kidney disease (ADPKD) patients is associated with more rapid progression of renal disease and a high incidence of left ventricular hypertrophy (LVH). The present study was undertaken to examine the role of parental hypertension in the occurrence of hypertension in 475 ADPKD offspring. METHODS: Adult subjects participating in an ongoing study of the natural history of ADPKD were included in the analysis if they were diagnosed with ADPKD, had a known affected parent, and knew the hypertensive status of both parents. RESULTS: When the affected parent was hypertensive, the ADPKD male (82% versus 62%, P < 0.05) and female (61% versus 37%, P < 0.005) offspring had a significantly higher frequency of hypertension than when the ADPKD-affected parent was normotensive. The median age of diagnosis of hypertension was also significantly earlier in both male (33 years versus 40 years, P < 0.05) and female (38 years versus 50 years, P < 0.05) ADPKD patients when their affected parents were hypertensive as compared with normotensive. These effects of hypertension in the affected parent on hypertension in the ADPKD offspring were independent of age, renal volume, and renal function in the offspring. Hypertension in unaffected parents also increased the frequency of hypertension in the ADPKD female (69% versus 53%, P < 0.01), but not male (89% versus 77%, NS) subjects. CONCLUSION: The results indicate that parental hypertension influences the frequency of hypertension in ADPKD patients.     

胱抑素C对评价慢性肾脏病患者代谢指标的应用价值

目的 研究胱抑素C对慢性肾脏病患者代谢指标及心脏疾病患病率的评价作用.方法 制作慢性肾脏病患者估算肾小球滤过率、血清肌酐、胱抑素C分别与血红蛋白、血钾、碳酸氢根、血磷散点图,并行直线回归相关分析.使用完全随机设计的单因素ANOVA分析胱抑素C与慢性肾脏病患者心脏疾病关系.结果 胱抑素C在评价慢性肾脏病患者贫血程度、高钾血症、高磷血症中的作用优于估算肾小球滤过率及血清肌酐.胱抑素C及血清肌酐在评价慢性肾脏病患者代谢性酸中毒的作用优于估算肾小球滤过率.胱抑素C水平高低与慢性肾脏病患者的心脏疾病的患病率成正相关(P＜0.05).结论 通过估算肾小球滤过率和血清肌酐,胱抑素C在评价慢性肾脏病患者代谢指标方面及评估患者心脏疾病患病率方面存在优势.     

Urinary angiotensinogen,related factors and clinical implications in normotensive autosomal dominant polycystic kidney disease patients

Background: Although several lines of evidence suggest that renin angiotensin system (RAS) proteins are synthesized by cyst epithelium and dilated tubules, role of intrarenal RAS in the progression of otozomal dominant polycystic kidney disease (ADPKD) is not well known. We aimed to study the levels and clinical correlations of urinary angiotensinogen (UAGT) in normotensive ADPKD patients compared with age- and sex-matched healthy subjects. Methods: The study included 20 normotensive ADPKD patients (F/M: 11/9) and 20 age and sex matched healthy controls (F/M: 9/11). Diagnosis of ADPKD was made based on Ravine criteria. Twenty-four hours ambulatory blood pressure monitoring (ABPM) was performed. Serum concentrations of creatinine, Na, K, uric acid, and urinary concentrations of Na, K, uric acid, creatinine, protein and albumin were measured. UAGT were measured via commercially available ELISA kit. Results: ADPKD patients had higher urinary albumin:creatinine ratio (UAIb/UCrea) than healthy controls (p?r?=?0.785, p?=?0.01), and UAIb/UCrea (r?=?0.681, p?=?0.01) in normotensive ADPKD patients. Conclusion: This pilot study demonstrates that UAGT levels tend to be elevated and are correlated with proteinuria and albuminuria in normotensive ADPKD patients during relatively early stages of the disease.     

Evaluation of urine biomarkers of kidney injury in polycystic kidney disease

Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of autosomal dominant polycystic kidney disease (ADPKD). Here we evaluated the effect of these processes on the expression of Lcn2 (NGAL) and interleukin (IL)-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated, which resulted in early- or adult-onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples collected from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4/year and the mean decline in eGFR 2.4?ml/min/year. The trend of increased mean urine NGAL and IL-18 over 3 years was statistically significant; however, there was no association between tertiles of IL-18 or quartiles of NGAL and change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion is mildly and stably elevated in ADPKD, but does not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.     

The relationship between renal volume and renal function in autosomal dominant polycystic kidney disease

Background  

In patients with autosomal dominant polycystic kidney disease (ADPKD), renal cysts grow exponentially. Since remaining renal parenchyma has a capacity to compensate for the loss of glomerular filtration, the glomerular filtration rate (GFR) may be sustained until the disease progresses. The purpose of this study was to determine if renal volumetric indices and clinical parameters are associated with renal function in Japanese patients with ADPKD.     

Cystatin C: efficacy as screening test for reduced glomerular filtration rate

Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.     

JAK2-STAT3 pathway regulates the expression of complement factor B in autosomal dominant polycystic kidney disease

Objective To investigate the role of JAK2-STAT3 pathway in the expression of complement factor B (CFB) in autosomal dominant polycystic kidney disease (ADPKD). Methods Renal tissue samples of patients with ADPKD after nephrectomy were collected. Normal renal tissue samples as control were taken from patients after radical nephrectomy. Renal tissue samples of Han: SPRD Cy/+ rats (ADPKD model) and wild-type Han: SPRD +/+ rats were also collected at 4, 8, 16 week. Han:SPRD Cy/+ rat renal tubular epithelial cells (16 w) were primarily cultured in vitro, then stimulated with the JAK2 inhibitor (WP1066) and STAT3 inhibitor (pyrimethamine) for 24 h respectively. Western blotting was used to detect the expression of p-JAK2, JAK2, p-STAT3, STAT3, CFB protein. Results Compared with control group, the protein expressions of p-JAK2, p-STAT3, STAT3, CFB significantly increased in the renal tissue of ADPKD patients (all P＜0.05). The protein expressions of p-JAK2, JAK2, p-STAT3, STAT3 and CFB also significantly increased in the renal tissue of Cy/+ rats compared with wild-type rats (all P＜0.01). When the Cy/+ renal tubular epithelial cells were treated with WP1066, the expressions of p-JAK2, p-STAT3, CFB were suppressed (P＜0.05) and the degree of inhibition was correlated with the WP1066 dose. Pyrimethamine inhibited the protein expressions of p-STAT3 and CFB in the tubular epithelial cells of Cy/+ rats (all P＜0.05) and the degree of inhibition was correlated with the pyrimethamine dose. Conclusions The JAK2-STAT3 pathway is abnormally activated in ADPKD and increases the protein expression of CFB. CFB protein level is correlated with the progress of ADPKD, suggesting that it may take part in the growth and development of ADPKD vesicles.     

常染色体显性多囊肾病患者动脉形态学、力学与部分功能性参数研究

目的 应用超声技术检测肾功能正常不同血压的常染色体显性多囊肾病(ADPKD)患者肱动脉与颈动脉形态学、力学与功能性部分参数，探讨ADPKD患者是否早期即存在心血管病危险因素。 方法 应用高频超声分别探测ADPKD高血压、ADPKD正常血压、原发性高血压及正常对照4组人群的肱动脉内皮依赖性舒张功能、颈动脉内中膜厚度(IMT)及颈动脉扩张性。 结果 (1) ADPKD高血压组反应性充血后肱动脉内径变化显著小于原发性高血压组和ADPKD正常血压组，而ADPKD正常血压组显著小于正常对照。(2) ADPKD高血压组和原发性高血压组IMT均显著高于ADPKD正常血压组和正常对照，而ADPKD正常血压组IMT也显著高于正常对照组。(3)ADPKD高血压组、原发性高血压组与ADPKD正常血压组、正常对照组比较，横断面扩张性(CD)和弹性模量增值(Einc)差异有统计学意义，而ADPKD正常血压组与正常对照组间差异也有统计学意义。 结论 肾功能正常的ADPKD高血压和正常血压患者存在显著的内皮功能受损、IMT增加和颈动脉扩张性降低，提示ADPKD早期就可能发生动脉粥样硬化。     

Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease

BACKGROUND: Left ventricular diastolic dysfunction has been shown in patients with autosomal-dominant polycystic kidney disease (ADPKD). However, there is no study evaluating right ventricular functions in these patients. METHODS: In the present study, diastolic functions of both ventricles in normotensive and hypertensive ADPKD patients with well-preserved renal function were investigated. Fifteen hypertensive and 16 normotensive patients with ADPKD with well-preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Conventional left and right ventricular echocardiographic measurements were performed in all subjects. Left and right ventricular functions were investigated both by myocardial performance index (MPI) [calculated by dividing the sum of isovolumic contraction time and isovolumic relaxation time (IVRT) by ejection time] and by tissue Doppler imaging (TDI). RESULTS: Left ventricular deceleration time and IVRT were significantly prolonged in hypertensive patients with ADPKD compared with patients with essential hypertension and even in normotensive patients with ADPKD compared with healthy subjects. Left and right MPIs were significantly higher in patients with ADPKD compared with healthy subjects, showing systolic and diastolic dysfunction. Moreover, by using TDI, the peak early diastolic mitral annular velocity (Em) to peak late diastolic mitral annular velocity (Am) ratio and the peak early diastolic tricuspid annular velocity (Et) to peak late diastolic tricuspid annular velocity (At) ratio were decreased in patients with ADPKD, suggesting biventricular diastolic dysfunction. CONCLUSION: Both hypertensive and normotensive patients with ADPKD show significant biventricular diastolic dysfunction, suggesting cardiac involvement very early in the course of ADPKD.     

Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease

BACKGROUND: The fluid filling renal cysts in human polycystic kidneys is secreted chiefly by the tubular epithelium lining the cysts via secondary chloride transport. Inhibiting this process by somatostatin therapy should induce shrinking of renal cysts. METHODS: In this randomized, cross-over, placebo-controlled trial we compared the risk/benefit profile of 6-month treatment with long-acting somatostatin (octreotide-LAR, 40 mg intramuscularly every 28 days) or placebo in autosomal-dominant polycystic kidney disease (ADPKD) patients with mild-to-moderate renal insufficiency and no evidence of other kidney disease. Volumes of kidney structures were evaluated by a two-slice computed tomography (CT) scanner; while glomerular filtration rate (GFR) was estimated by iohexol plasma clearance. RESULTS: One patient on somatostatin and one on placebo were prematurely withdrawn because of nonsymptomatic, reversible colelithiasis and asthenia, respectively. In the remaining 12 patients somatostatin was well tolerated. Kidney volume increased by 71 +/- 107 mL (P < 0.05) on somatostatin and by 162 +/- 114 mL (P < 0.01) on placebo. The percent increase was significantly lower on somatostatin (2.2 +/- 3.7% vs. 5.9 +/- 5.4%) (P < 0.05). Cystic volume tended to increase less on somatostatin than on placebo (3.0 +/- 6.5% vs. 5.6 +/- 5.8%). The "parenchymal" volume nonsignificantly increased by 2.5 +/- 8.4% on placebo and slightly decreased by 4.4 +/- 8.9% on somatostatin. The GFR did not change significantly during both treatment periods. CONCLUSION: In ADPKD patients, 6-month somatostatin therapy is safe and may slow renal volume expansion. This may reflect an inhibited growth in particular of smallest cysts beyond the detection threshold of CT scan evaluation. Whether this effect may prove renoprotective in the long term should be tested in additional trials of longer duration.     

Expression of secreted frizzled related protein 4 and effect of induced-apoptosis in autosomal dominant polycystic kidney disease

Objective To evaluate the expression of secreted frizzled related protein 4 (sFRP4) in autosomal dominant polycystic kidney disease(ADPKD) and the effect of sFRP4 induced apoptosis in ADPKD. Methods (1)Serological method: serum samples of 12 healthy people and 20 ADPKD patients were collected and the levels of sFRP4 in serum were detected by ELSIA assay. (2)Tissue experiments: normal renal tissue was collected from radical nephrectomy for renal carcinoma; polycystic renal tissues were taken from ADPKD patients. The expression of sFRP4 in renal tissues was observed by immunohistochemistry; Real-time PCR was used to explore the mRNA level of sFRP4 and caspase-3; TUNEL method was applied to observe the apoptosis cells existing in ADPKD. (3)studies in vitro: HEK-293T cells were transfected with PcDNA6 and Flag. sFRP4.PcDNA6 respectively, after which Western blotting was performed to detect the expression of caspase-3 protein and flow cytometry was performed to estimate cell apoptosis rate. Results (1)ELISA results showed serum concentrations of sFRP4 in ADPKD were markedly higher than normal control (P＜0.05). (2)Compared with normal renal tissues, the sFRP4 expression was dramatically increased in ADPKD and mainly distributed in the cytoplasm of renal tubular epithelial cells. (3)Real-time PCR showed the expression of sFRP4 and Caspase-3 mRNA in ADPKD were up-regulated comparing with those in normal control (P＜0.05). (4)TUNEL assays revealed that elevated apoptosis appeared in tubular epithelial cells of ADPKD. (5)The level of caspase-3 protein and apoptosis rate were significantly increased after over-expressed sFRP4 in HEK-293T cells (all P＜0.05). Conclusions The expression of sFRP4 is strikingly up-regulated in ADPKD. In addition, abnormal apoptosis of tubular epithelial cells exists in ADPKD and over-expressed sFRP4 can induce apoptosis of HEK-293T cells. This phenomenon may be attributed to the elevated sFRP4.     

成人微小病变肾病综合征发生急性肾损伤的相关影响因素分析

目的探讨成人微小病变肾病综合征发生急性肾损伤( AKI)的相关影响因素。 方法回顾性分析2002年1月1日至2015年12月31日在解放军总医院病理诊断为微小病变肾病,临床表现为首发肾病综合征的成年患者。记录其横断面临床及病理指标,并将其分为AKI组及非AKI组进行比较。用单因素及多元Logistic回归分析与AKI发生相关的影响因素。并对AKI相关的各影响因素进行交互作用检验。 结果共纳入403例患者,男女比例为1∶1.13,肾活检时平均年龄为(39.5 ± 15.1)岁,其中118(29.3%)例发生了AKI。AKI组与非AKI组相比,年龄、性别、尿蛋白定量、血清白蛋白、血肌酐、血尿素氮、估算的肾小球率过滤、肾小管萎缩、肾间质病变差异均有统计学意义(P<0.05)。单因素Logistic回归分析显示高龄、男性、尿蛋白定量多、肾小管萎缩、肾间质水肿、间质纤维化及炎细胞浸润、高血压是成人微小病变肾病发生AKI的危险因素。交互作用检验表明血清白蛋白对AKI的作用受到肾间质纤维化的显著影响(P＝0.0 050),且在调整年龄分组、性别、高血压、尿蛋白定量、肾小管萎缩、肾间质水肿、肾间质炎细胞浸润混杂因素后,其交互作用仍显著(P＝0.0 263)。从多元Logistic回归分析可见,在无肾间质纤维化的人群中,血清白蛋白水平的升高是AKI的独立保护因素(调整后的OR 0.8,95%CI 0.7～ 0.9,P<0.001)。在有肾间质纤维化人群中,血清白蛋白的升高对AKI肾脏的保护作用不显著(调整后的OR 1.0,95%CI 0.9～1.0,P＝0.0 278)。 结论高龄、男性、尿蛋白定量多、肾小管萎缩、肾间质水肿、间质纤维化及炎细胞浸润、高血压是成人微小病变肾病综合征发生AKI的危险因素。血清白蛋白升高对AKI的保护作用受到肾间质纤维化的影响。     

Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease.

BACKGROUND: In animal models, HMG-CoA reductase inhibitors were able to improve renal function and endothelium-dependent vascular reactivity. In various experimental renal diseases, including autosomal dominant polycystic kidney disease (ADPKD), HMG-CoA reductase inhibitors improved the rate of decline in renal function. We studied the effect of simvastatin on ADPKD patients. METHODS: In a double-blind cross-over study, 10 normocholesterolaemic ADPKD patients were treated in random order for 4 weeks with 40 mg simvastatin or placebo daily. After each treatment period, we investigated the effect of simvastatin on renal blood flow and endothelium-dependent vascular reactivity. These periods were separated by a 4-week wash-out period. RESULTS: After treatment with simvastatin, glomerular filtration rate (GFR) significantly increased from 124+/-4 ml/min to 132+/-6 ml/min (P<0.05). Simultaneously, effective renal plasma flow (ERPF) increased significantly from 494+/-30 ml/min to 619+/-67 ml/min after simvastatin treatment (P<0.05). These renal effects were accompanied by a significantly enhanced vasodilator response to acetylcholine in the forearm after simvastatin treatment. Total serum cholesterol levels were significantly reduced after treatment with simvastatin, from 4.24+/-0.32 to 3.17+/-0.22 mmol/l (P<0.001). CONCLUSION: We concluded that simvastatin treatment can ameliorate renal function in ADPKD patients, by increasing renal plasma flow, possibly via improvement of endothelial function. Long-term clinical trials with HMG-CoA reductase inhibitors are needed to confirm these results and to establish a chronic inhibiting effect of HMG-CoA reductase inhibitors on the progression towards end-stage renal disease in ADPKD patients.