Cheng Xue

Effects of endothelial nitric oxide synthase gene on end stage renal disease progression in autosomal dominant polycystic kidney disease

To investigate whether endothelial nitric oxide synthase (eNOS) gene associate with the progression of autosomal dominant polycystic kidney disease (ADPKD).

Long-Term Treatment with Mammalian Target of Rapamycin Inhibitor Does Not Benefit Patients with Autosomal Dominant Polycystic Kidney Disease: A Meta-Analysis

Background: The role of the mammalian target of rapamycin (mTOR) inhibition in the treatment of autosomal dominant polycystic kidney disease (ADPKD) remains unclear. This meta-analysis included all randomized controlled trials (RCTs) that used mTOR inhibitors (TORIs) to halt the progression of ADPKD. Methods: Databases including MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant trials. RCTs of TORI treatment in patients with ADPKD were included. Effects on the primary outcome [total kidney volume (TKV)] and secondary outcomes [changes in cyst volume (CV) and parenchymal volume (PV), glomerular filtration rate (GFR), proteinuria, and adverse events] were analyzed. Results: The results of 5 RCTs, which included 619 patients, were analyzed. TORIs did not significantly reduce TKV [mean difference (WMD) -90.01 ml, 95% CI -235.49 to 55.47, p = 0.23; I2 = 0%; p for heterogeneity = 0.67]. CV decreased after TORI treatment (WMD -15.08 ml, 95% CI -17.82 to -12.34, p < 0.00001), and PV did not change (WMD -0.55 ml, 95% CI -64.55 to 63.45, p = 0.99). There was no significant difference in GFR between the TORI-treated and control groups (WMD 4.94 ml/min, 95% CI -0.81 to 10.68, p = 0.09). Proteinuria was significantly higher in the TORI-treated group than in the control group (standard mean difference 0.27, 95% CI 0.09-0.44, p = 0.002). Conclusion: Long-term treatment with TORIs does not benefit patients with ADPKD.

Fibroblast Growth Factor 23 Predicts All-Cause Mortality in a Dose-Response Fashion in Pre-Dialysis Patients with Chronic Kidney Disease

Background: Quantitative dose-response associations between fibroblast growth factor 23 (FGF23) and risks of mortality, cardiovascular disease (CVD), and renal events in chronic kidney disease (CKD) are not known. This study aimed to summarize and quantify the predictive effects of FGF23 among the pre-dialysis CKD stages 1-5 population. Methods: Data sources included PubMed, EMBASE, and Web of Science. Prospective cohort studies assessing the associations between FGF23 and all-cause mortality, CVD, and renal events in CKD patients were selected. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. The composite higher or the highest level in FGF23 categories of each study was considered the high level. The reference level was regarded as the low level in the overall analysis. The restricted cubic spline model was used to estimate dose-response associations. Results: Fifteen prospective cohort studies centered around 15,355 subjects were analyzed. A high FGF23 level was associated with increased risks of all-cause mortality (RR 1.46, 95% CI 1.38-1.55, p < 0.001), CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001), and renal events (RR 1.31, 95% CI 1.07-1.59, p = 0.008), respectively. There was a positive, nonlinear, dose-response relationship between FGF23 and all-cause mortality. The reference level in dose-response analysis was defined as 51 RU/mL of c-terminal FGF23. We then calculated RRs for increments of 20 RU/mL, which was associated with increased risks of mortality (RR 1.04, 95% CI 1.00-1.07, p = 0.038), CVD (RR 1.02, p < 0.001), and renal events (RR 1.01, p < 0.001), respectively. Conclusions: There may be positive dose-response predictive effects of FGF23 on all-cause mortality, CVD, and renal events in patients with CKD.

4 G/4 G polymorphism of plasminogen activator inhibitor-1 gene increases the risk of diabetic nephropathy

Abstract Diabetic nephropathy (DN) has become the most common pathogenesis of end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of DN. A meta-analysis was conducted to investigate the association between 4 G/5 G variants in the PAI-1 gene and DN susceptibility. Databases including Pubmed, EMBASE, ISI, etc., were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. Ten studies involving 1366 cases and 1888 controls were included. Significant association between 4 G/4 G variant and DN risk was observed (OR 1.26, 95% CI 1.08–1.48, p = 0.004) in overall populations by the recessive model. 4 G allele was also associated with the risk of DN than the 5 G allele (OR 1.15, 95% CI 1.04–1.27, p = 0.008). In the subgroup analysis performed by the ethnicity, 4 G/4 G polymorphism was significantly associated with DN risk than 4 G/5 G + 5 G/5 G in East Asians (OR 1.42, 95% CI 1.03–1.96; p = 0.03), but not in Caucasians. In the stratified analysis by types of DM, the results showed significant association between 4 G/4 G variant and DN in Type-2 DM (OR 1.42, 95% CI 1.03–1.96, p = 0.03). In conclusion, 4 G/4 G phenotype of PAI-1 gene may be associated with DN risk. Additional larger studies should be conducted in future analyses.

Apolipoprotein E Gene Variants on the Risk of End Stage Renal Disease

Objective End-stage renal disease (ESRD) is a severe health concern over the world. Associations between apolipoprotein E (apoE) gene polymorphisms and the risk of ESRD remained inconclusive. This study aimed to investigate the association between apoE gene polymorphisms and ESRD susceptibility. Methods Databases including PubMed, Embase, Web of Science and the Cochrane Library were searched to find relevant studies. Meta-analysis method was used synthesize the eligible studies. Results Sixteen pertinent case-control studies which included 3510 cases and 13924 controls were analyzed. A significant association was found between ε2 allele and the ESRD risk (odds ratio (OR) = 1.30, 95% confidence interval (CI) 1.15–1.46, P < 0.0001; I 2 = 18%, P for heterogeneity = 0.24). The ε2ε3, ε2ε4, ε3ε3, ε3ε4, ε4ε4, ε3 and ε4 were not associated with the susceptibility of ESRD. In the subgroup analysis by ethnicity, there was a statistically significant association between ε2ε3 or ε2 allele and ESRD risk in East Asians (OR = 1.66, 95% CI 1.31–2.10, P < 0.0001; OR = 1.62, 95% CI 1.31–2.01, P < 0.0001, respectively), but not in Caucasians. E2 carriers had higher plasma apoE (mean difference = 16.24 mg/L, 95% CI 7.76-24.73, P = 0.0002) than the (ε3 + ε4) carriers in patients with ESRD. The publication bias was not significant. Conclusion The ε2 allele of apoE gene might increase the risk of ESRD. E2 carriers expressed higher level of plasma apoE in patients with ESRD. More well-designed studies are needed to confirm these associations in the future.

The Clinical Manifestation and Management of Autosomal Dominant Polycystic Kidney Disease in China.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic hereditary kidney disease characterized by progressive enlargement of renal cysts. The incidence is 1-2‰ worldwide. Mutations in two genes (PKD1 and PKD2) cause ADPKD. Currently, there is no pharmaceutical treatment available for ADPKD patients in China. Summary: This review focused on advances in clinical manifestation, gene diagnosis, risk factors, and management of ADPKD in China. There is an age-dependent increase in total kidney volume (TKV) and decrease in renal function in Chinese ADPKD patients. ADPKD is more severe in males than in females. Great progress has been made in molecular diagnosis in the last two decades. Nephrologists found many novel PKD mutations in Chinese ADPKD patients early through polymerase chain reaction, and then through liquid chromatography in 2000s, and recently through next-generation sequencing. Major predictive factors for ADPKD progression are age, PKD genotype, sex, estimated glomerular filtration rate (eGFR), and TKV. With respect to the management of ADPKD, inhibitors targeting mTOR and cAMP are the focus of clinical trials. Triptolide has been used to treat ADPKD patients in clinical trials in China. Triptolide significantly protected eGFR of ADPKD patients compared with placebo. Key Messages: ADPKD affects about 1.5 million people in China. An additional PKD gene besides PKD1 and PKD2 was not found in the Chinese. The prevalence of intracranial aneurysm in Chinese ADPKD patients was 12.4%. The predictive factors for eGFR decrease in Chinese ADPKD patients are TKV, proteinuria, history of hypertension, and age. The treatment strategies in clinical trials for ADPKD patients in China are similar to those in the West except for triptolide. Facts from East and West: (1) ADPKD is diagnosed globally by ultrasound detection of kidney enlargement and presence of cysts. Recent analyses of variants of the PKD1 and PKD2 genes by next-generation sequencing in Chinese and Western ADPKD patients might lead to the development of reliable genetic tests. (2) Besides lifestyle changes (low-salt diet, sufficient fluid intake, and no smoking), blood pressure control is the primary nonspecific treatment recommended by Kidney Disease - Improving Global Outcomes (KDIGO) for ADPKD patients. How low the blood pressure target should be and what the means of achieving it are remain open questions depending on the severity of chronic kidney disease and the age of the patients. In a recent Chinese study, diagnostic needle aspiration and laparoscopic unroofing surgery successfully improved infection, pain, and hypertension. Peritoneal dialysis was found to be a feasible treatment for most Chinese ADPKD patients with end-stage renal disease. In most Western centers, patients without contraindication are selected for peritoneal dialysis. Kidney transplantation with concurrent bilateral nephrectomy was successful in relieving hypertension and infection in Chinese ADPKD patients. In Western countries, sequential surgical intervention with kidney transplantation after nephrectomy, or the other way round, is preferred in order to reduce risks. (3) The vasopressin 2 receptor antagonist tolvaptan was approved in Europe, Canada, Japan, and Korea to slow down progression of kidney disease in ADPKD patients. Tolvaptan is not yet approved in the USA or in China. mTOR pathway-targeting drugs are currently under evaluation: mTOR inhibitors could slow down the increase in total kidney volume in a cohort of Western and Japanese ADPKD patients. Western studies as well as an ongoing study in China failed to show benefit from rapamycin. A study performed in Italy indicates protective effects of the somatostatin analog octreotide in ADPKD patients. Western and Chinese studies revealed a potential beneficial effect of triptolide, the active substance of the traditional Chinese medicine Tripterygium wilfordii (Lei Gong Teng) to prevent worsening in ADPKD patients.

Amputation of the first metatarsophalangeal joint due to a giant gouty tophi: A case report

Rationale: The first metatarsophalangeal joint (MTP1) is the most frequent site of gouty tophi. We report an unusual case with a giant skin-perforating tophi. This is the first case of gouty tophi at MTP1 which accepts surgical debulking and amputation. Patient Concerns: A 42-year-old man presented with a seven-year history of gout and a giant tophi at MTP1. The patient was referred to hospital due to persistent pain and ulcerations on the surface of the left MTP1. This rounded, giant, swelling, tophaceous tophi severely interfered with his normal walking. Diagnoses: The patient was diagnosed with gouty arthritis seven years ago, and did not receive regular anti-gout treatments. Outcomes: Biochemical examination showed he had raised serum uric acid (SUA, 11.92 mg/dl) and creatinine (258 &mgr;mol/l). There was a severe joint destruction of MTP1 by X-ray examination. We controlled the skin infection by sulbenicillin. He was given febuxostat to reduce SUA. After 3 months of treatment, SUA fell to 6.8 mg/dl. Then we performed surgical debulking of MTP1 and amputation of hallux. Surgical operations obviously relieved the pain, and improved the function of his left foot. The visual closure after amputation was good. Conclusion: Surgical amputation of the gout lesion at MTP1 maximized the function, and reduced the pain of this patient. In the case of giant tophi with severe gouty arthritis or skin infections, surgical decisions need to weigh gains and losses carefully.

Saikosaponin-d inhibits proliferation by up-regulating autophagy via the CaMKKβ–AMPK–mTOR pathway in ADPKD cells

Autosomal dominant polycystic kidney disease (ADPKD) is a common heritable human disease. Recently, the role of repressed autophagy in ADPKD has drawn increasing attention. Here, we investigate the mechanism underlying the effect of Saikosaponin-d (SSd), a sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA) inhibitor. We show that SSd suppresses proliferation in ADPKD cells by up-regulating autophagy. We found that treatment with SSd results in the accumulation of intracellular calcium, which in turn activates the CaMKKβ–AMPK signalling cascade, inhibits mTOR signalling and induces autophagy. Conversely, we also found that treatment with an autophagy inhibitor (3-methyladenine), AMPK inhibitor (Compound C), CaMKKβ inhibitor (STO-609) and intracellular calcium chelator (BAPTA/AM) could reduce autophagy puncta formation mediated by SSd. Our results demonstrated that SSd induces autophagy through the CaMKKβ–AMPK–mTOR signalling pathway in ADPKD cells, indicating that SSd might be a potential therapy for ADPKD and that SERCA might be a new target for ADPKD treatment.

Dialysis modality and mortality in polycystic kidney disease: Dialysis modality and mortality in PKD

Introduction: Identifying the appropriate modality between hemodialysis (HD) and peritoneal dialysis (PD) is an unresolved issue in polycystic kidney disease (PKD) patients. This study aims to illustrate whether the mortality and survival are different among individuals receiving HD comparing PD.

Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial

Introduction Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ). Methods and analysis This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4–8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5–25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a months fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18–80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90). Ethics and dissemination BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal. Trial registration number NCT02646397.