Abstract

Introduction

Chronic kidney disease (CKD), which may lead to chronic renal failure, is characterized by a gradual loss in renal function over a period of months to years. This loss in renal function is defined by a persistent reduction in the glomerular filtration rate (GFR) or functional or structural abnormalities of kidneys on biopsy, urinalysis, or imaging (¹1. Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol 2011; 54: 1020-1029, doi: 10.1016/j.jhep.2010.11.007.
https://doi.org/10.1016/j.jhep.2010.11.0... ). The GFR plays a crucial role in CKD and is used to classify the disease into five stages according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines: >90 mL/min per 1.73 m² (stage 1), 60-89 mL/min per 1.73 m² (stage 2), 30-59 mL/min per 1.73 m² (stage 3), 15-29 mL/min per 1.73 m² (stage 4), and <15 mL/min per 1.73 m² (stage 5, or end-stage renal disease) (²2. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379: 165-180, doi: 10.1016/S0140-6736(11)60178-5.
https://doi.org/10.1016/S0140-6736(11)60... ,³3. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80: 17-28, doi: 10.1038/ki.2010.483.
https://doi.org/10.1038/ki.2010.483... ). Increasing morbidity, high expense, and poor outcomes of CKD have caused it to become a well-known health threat (⁴4. Levey AS, Schoolwerth AC, Burrows NR, Williams DE, Stith KR, McClellan W. Comprehensive public health strategies for preventing the development, progression, and complications of CKD: report of an expert panel convened by the Centers for Disease Control and Prevention. Am J Kidney Dis 2009; 53: 522-535, doi: 10.1053/j.ajkd.2008.11.019.
https://doi.org/10.1053/j.ajkd.2008.11.0... ). The prevalence of CKD is >200 cases per 1 million people per year, and nearly 400 cases are diagnosed each year in the US and Taiwan (²2. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379: 165-180, doi: 10.1016/S0140-6736(11)60178-5.
https://doi.org/10.1016/S0140-6736(11)60... ). The risk factors for CKD include age, hypotension, cardiac dysfunction, diabetes mellitus, obesity, atherosclerosis, and nephrotoxic drugs (⁵5. Otero A, de Francisco A, Gayoso P, Garcia F. Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia 2010; 30: 78-86, doi: 10.3265/Nefrologia.pre2009.Dic.5732.
https://doi.org/10.3265/Nefrologia.pre20... ,⁶6. Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009; 119: 1785-1794, doi: 10.1161/CIRCULATIONAHA.108.827972.
https://doi.org/10.1161/CIRCULATIONAHA.1... ). Risk factors for end-stage renal disease include hypotension, age, daily proteinuria, a history of chronic renal insufficiency, a family history of kidney disease, obesity, hyperuricemia, diabetes mellitus, and heroin abuse (⁷7. Abbasi MA, Chertow GM, Hall YN. End-stage renal disease. BMJ Clin Evid 2010; 2010.). With respect to treatment of CKD, stages 1 to 4 require broad management principles such as blood pressure control and treatment of the primary disease, and stage 5 CKD usually requires renal replacement treatment (including dialysis), and transplantation is recommended when the renal function is insufficient to maintain health (⁸8. Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 572-586, doi: 10.1038/ki.2011.223.
https://doi.org/10.1038/ki.2011.223... ,⁹9. Chertow GM, Levin NW, Beck GJ, Depner TA, Eggers PW, Gassman JJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010; 363: 2287-2300, doi: 10.1056/NEJMoa1001593.
https://doi.org/10.1056/NEJMoa1001593... ).

Hemodialysis (HD) utilizes countercurrent flow to achieve extracorporeal removal of waste products from blood, including urea, creatinine, and free water, when the kidneys are in a state of failure (¹⁰10. Goswami S, Bhowmick S, Majumdar A, Sikdar S, CN S, Chatterjee TK. Appropriateness and efficacy of the use of erythropoietin in hemodialysis patients in an Eastern Indian population. History 2014; 17: 15-22.). Dialyzers are a part of the filter equipment used in HD; their hollow fiber walls are made of a semipermeable membrane. High-flux HD (HFHD) and low-flux HD (LFHD) are distinguished based on the pore size and fiber area (http://www.google.com.proxy.its.virginia.edu/patents/US20110009), which allows effective removal of uremic toxins and fluids. HD procedures are routinely patient-specific and involve a detailed prescription by a nephrologist, including frequency, length of each treatment, flow rates of the blood and dialysis solution, and dialyzer size (¹¹11. Eloot S, Ledebo I, Ward RA. Extracorporeal removal of uremic toxins: can we still do better? Semin Nephrol 2014; 34: 209-227, doi: 10.1016/j.semnephrol.2014.02.011.
https://doi.org/10.1016/j.semnephrol.201... ). Complications associated with HD include chest pain, low blood pressure, fatigue, nausea, leg cramps, and headache (¹²12. VReddenna L, Basha SA, Reddy KSK. Dialysis treatment: A comprehensive description. Int J 2014; 3: 1-13.). Contrasting opinions exist among experts regarding the procedure, with multiple studies confirming the benefits of HFHD in treating CKD (⁸8. Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 572-586, doi: 10.1038/ki.2011.223.
https://doi.org/10.1038/ki.2011.223... ,¹³13. Asci G, Tz H, Ozkahya M, Duman S, Demirci MS, Cirit M, et al. The impact of membrane permeability and dialysate purity on cardiovascular outcomes. J Am Soc Nephrol 2013; 24: 1014-1023, doi: 10.1681/ASN.2012090908.
https://doi.org/10.1681/ASN.2012090908... ) and other studies questioning its benefits (¹⁴14. Schneider A, Drechsler C, Krane V, Krieter DH, Scharnagl H, Schneider MP, et al. The effect of high-flux hemodialysis on hemoglobin concentrations in patients with CKD: results of the MINOXIS study. Clin J Am Soc Nephrol 2012; 7: 52-59, doi: 10.2215/CJN.02710311.
https://doi.org/10.2215/CJN.02710311... ,¹⁵15. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol 2009; 20: 645-654, doi: 10.1681/ASN.2008060590.
https://doi.org/10.1681/ASN.2008060590... ). To resolve this issue, we conducted the present meta-analysis to investigate the prognostic effect of HFHD in patients with CKD.

Material and Methods

Data sources and key words

Computerized bibliographic databases were searched to identify relevant studies on the prognostic effect of HFHD in patients with CKD, without restrictions on data collection. The following databases were searched: PubMed, Springerlink, Wiley, EBSCO, Ovid, Web of Science, Wanfang database, China National Knowledge Infrastructure (CNKI), and the Weipu Journal Database. The following combination of free words and key words was applied in our rigorous search strategy: “high flux hemodialysis” or “high-flux hemodialysis” or “high permeable hemodialysis” or “HFHD.” Furthermore, manual searches were applied to identify additional potentially relevant articles.

Inclusion and exclusion criteria

Published studies eligible for enrollment in the current meta-analysis were required to fulfill the following selection criteria: 1) research type: case-control studies comparing the prognostic effects of HFHD and LFHD in patients with CKD; 2) research objective: all patients with CKD were treated by HD; and 3) end outcomes: the all-cause death rate among patients with CKD and the cardiovascular death rate. Studies were excluded if 1) they had incomplete data; 2) they were published repeatedly; or 3) the diagnostic criteria were unclear.

Data extraction and quality assessment

Two reviewers independently extracted data from all enrolled studies using a standardized data-extraction form and reached an agreement on all items after discussion. The following information was collected: surname of first author, time of publication, country, ethnicity, language, disease, age, gender, sample size, follow-up time and study design. The quality of enrolled studies was independently evaluated by two reviewers based on the Critical Appraisal Skills Programme (CASP) criteria (http://www.casp-uk.net/). The CASP criteria are scored based on the following 12 aspects: Does the study address a clearly focused issue (CASP01)? Was the recruited cohort selected in an acceptable way (CASP02)? Was the exposure accurately measured to minimize bias (CASP03)? Was the outcome accurately measured to minimize bias (CASP04)? Have the authors identified all important confounding factors (CASP05)? Was the follow-up of subjects complete enough (CASP06)? What are the results of the study (CASP07)? How precise are the results (CASP08)? Are the results believable (CASP09)? Can the results be applied to the local population (CASP10)? Do the results of the study fit with other available evidence (CASP11)? What are the implications of this study for practice (CASP12)?

Statistical analysis

Comprehensive meta-analysis 2.0 (CMA 2.0; https://www.meta-analysis.com/downloads/Meta-Analysis-Manual.pdf) was applied in our meta-analysis. The prognostic effects of HFHD and LFHD in patients with CKD were evaluated by odds ratios (ORs) and their 95% confidence intervals (95%CIs) under a fixed-effects or random-effects model. The significance of pooled standardized mean differences was detected by the Z-test. Cochran’s Q-statistic (P<0.05 was considered significant) and the I² test (0%, no heterogeneity; 100%, maximal heterogeneity) were also applied to reflect the heterogeneity among studies (¹⁶16. Jackson D, White IR, Riley RD. Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 2012; 31: 3805-3820, doi: 10.1002/sim.5453.
https://doi.org/10.1002/sim.5453... ). A random-effects model was used if there was evidence of significant heterogeneity (P<0.05 or I² test exhibited >50%); otherwise, a fixed-effects model was applied (¹⁷17. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005; 28: 123-137, doi: 10.1002/gepi.20048.
https://doi.org/10.1002/gepi.20048... ). The potential source of heterogeneity was assessed by univariate and multivariate meta-regression analysis, and Monte Carlo simulation was conducted for reexamination (¹⁶16. Jackson D, White IR, Riley RD. Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 2012; 31: 3805-3820, doi: 10.1002/sim.5453.
https://doi.org/10.1002/sim.5453... ,¹⁸18. Huizenga HM, Visser I, Dolan CV. Testing overall and moderator effects in random effects meta-regression. Br J Math Stat Psychol 2011; 64: 1-19, doi: 10.1348/000711010X522687.
https://doi.org/10.1348/000711010X522687... ,¹⁹19. Ferrenberg AM, Swendsen RH. New Monte Carlo technique for studying phase transitions. Phys Rev Lett 1988; 61: 2635-2638, doi: 10.1103/PhysRevLett.61.2635.
https://doi.org/10.1103/PhysRevLett.61.2... ). Sensitivity analysis was conducted by deleting each enrolled study to estimate the effect of a single study on the overall results. A funnel plot, the classic fail-safe N method, and the Egger test were implemented to assess whether publication bias existed and thus further confirm the original result (²⁰20. Wikstrom EA, Naik S, Lodha N, Cauraugh JH. Balance capabilities after lateral ankle trauma and intervention: a meta-analysis. Med Sci Sports Exerc 2009; 41: 1287-1295, doi: 10.1249/MSS.0b013e318196cbc6.
https://doi.org/10.1249/MSS.0b013e318196... ,²¹21. Zintzaras E, Ioannidis JP. HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics 2005; 21: 3672-3673, doi: 10.1093/bioinformatics/bti536.
https://doi.org/10.1093/bioinformatics/b... ). All tests were two-sided, and a P value of <0.05 was considered to be statistically significant.

Results

Baseline characteristics

Based on our rigorous criteria, we retrieved 227 studies through both electronic database and manual searching. The retrieved studies were carefully screened to exclude duplicates (n=20), letters, reviews, and meta-analyses (n=6); non-human studies (n=25); and studies not related to HD (n=42). The full texts of the remaining studies (n=134) were reviewed, and additional studies were excluded if they were not relevant to HFHD (n=37) or LFHD (n=41) or lacked data related to mortality (n=44). After the remaining 12 trials were further assessed, eight eligible cohort studies performed from 2002 to 2013 were finally selected for the present meta-analysis. The selected studies involved 4967 patients with CKD (2416 in the HFHD group, 2551 in the LFHD group) (¹³13. Asci G, Tz H, Ozkahya M, Duman S, Demirci MS, Cirit M, et al. The impact of membrane permeability and dialysate purity on cardiovascular outcomes. J Am Soc Nephrol 2013; 24: 1014-1023, doi: 10.1681/ASN.2012090908.
https://doi.org/10.1681/ASN.2012090908... ¹⁵15. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol 2009; 20: 645-654, doi: 10.1681/ASN.2008060590.
https://doi.org/10.1681/ASN.2008060590... ²²22. Santoro A, Mancini E, Bolzani R, Boggi R, Cagnoli L, Francioso A, et al. The effect of on-line high-flux hemofiltration versus low-flux hemodialysis on mortality in chronic kidney failure: a small randomized controlled trial. Am J Kidney Dis 2008; 52: 507-518, doi: 10.1053/j.ajkd.2008.05.011.
https://doi.org/10.1053/j.ajkd.2008.05.0... ²³23. Krane V, Krieter DH, Olschewski M, Marz W, Mann JF, Ritz E, et al. Dialyzer membrane characteristics and outcome of patients with type 2 diabetes on maintenance hemodialysis. Am J Kidney Dis 2007; 49: 267-275, doi: 10.1053/j.ajkd.2006.11.026.
https://doi.org/10.1053/j.ajkd.2006.11.0... ²⁴24. Gotz AK, Boger CA, Popal M, Banas B, Kramer BK. Effect of membrane flux and dialyzer biocompatibility on survival in end-stage diabetic nephropathy. Nephron Clin Pract 2008; 109: c154-c160, doi: 10.1159/000145459.
https://doi.org/10.1159/000145459... ²⁵25. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002; 347: 2010-2019, doi: 10.1056/NEJMoa021583.
https://doi.org/10.1056/NEJMoa021583... ²⁶26. Chauveau P, Nguyen H, Combe C, Chene G, Azar R, Cano N, et al. Dialyzer membrane permeability and survival in hemodialysis patients. Am J Kidney Dis 2005; 45: 565-571, doi: 10.1053/j.ajkd.2004.11.014.
https://doi.org/10.1053/j.ajkd.2004.11.0... ). All eight studies involved Caucasians; two were from the US, one was from the UK, one was from Belgium, one was from Sweden, two were from Germany, and one was from France. The sample size of all enrolled studies ranged from 64 to 1846. The baseline characteristics of the eight studies are shown in Table 1.

Pooled outcome of meta-analysis

The influence of HFHD and LFHD on the all-cause death rate among patients with CKD was reported by all eight enrolled studies. A random-effects model was applied because of the presence of heterogeneity among studies (I²=73.594%, P<0.001). The results of our meta-analysis showed that the all-cause death rate in the HFHD group was evidently lower than that in the LFHD group (OR=0.704, 95%CI=0.533-0.929, P=0.013) (Figure 1A).

Four studies reported the influence of HFHD and LFHD on the cardiovascular death rate among patients with CKD. A fixed-effects model was applied because of the absence of heterogeneity among studies (I²=13.328%, P=0.326). The results of our meta-analysis showed that the cardiovascular death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.731, 95%CI=0.616-0.866, P<0.001) (Figure 1B).

Subgroup analysis based on the follow-up demonstrated that the all-cause death rate in the HFHD group was evidently lower than that in the LFHD group within a follow-up of <3 years (OR=0.510, 95%CI=0.351-0.741, P<0.001); however, the difference in the all-cause death rate between the HFHD and LFHD group exhibited no statistical significance with a follow-up of ≥3 years (OR=0.755, 95%CI=0.553-1.030, P=0.076) (Figure 2A). A subgroup analysis based on sample size clarified that the all-cause death rate in the HFHD group was evidently lower than that in the LFHD group (n≥500) (OR=0.643, 95%CI=0.461-0.898, P=0.010), but the difference in the all-cause death rate between the HFHD and LFHD groups showed no statistical significance (n<500) (OR=0.808, 95%CI=0.484-1.350, P=0.416) (Figure 2B).

Sensitivity analysis and publication bias

The result of the sensitivity analysis showed that none of the enrolled studies had a significant effect on the pooled standardized mean differences for the influence of HFHD and LFHD to the all-cause death rate and cardiovascular death rate in patients with CKD (Figure 3). The symmetrical funnel plots suggested that there was no publication bias in the enrolled studies, and the Egger linear regression analysis and classic fail-safe N method further confirmed the lack of publication bias (all P>0.05) (Figure 4). Univariate and multivariate meta-regression analysis showed that the publication year, country, and sample size were not potential sources of heterogeneity or crucial factors influencing the overall effect size (all P>0.05) (Figure 5, Table 2).

Discussion

We performed a systematic meta-analysis to investigate the prognostic effect of HFHD and LFHD in patients with CKD. The main results of our meta-analysis revealed that the all-cause death rate and cardiovascular death rate in the HFHD group were remarkably lower than those in the LFHD group, suggesting that HFHD can be implemented as the first-line therapy choice in patients with CKD. In renal failure, the kidneys fail to filter the blood from water. Such failure can be caused by many factors including drug overdoses, crush syndrome, uncontrolled hypertension, long-term diabetes, and genetic predisposition such as that caused by APOL1 mutation (²⁷27. Kes P, Basic-Jukic N, Ljutic D, Brunetta-Gavranic B. [The role of arterial hypertension in developement of chronic renal failure]. Acta Med Croatica 2011; 65 (Suppl 3): 78-84.,²⁸28. Bostrom MA, Freedman BI. The spectrum of MYH9-associated nephropathy. Clin J Am Soc Nephrol 2010; 5: 1107-1113, doi: 10.2215/CJN.08721209.
https://doi.org/10.2215/CJN.08721209... ). CKD, a growing public health problem, is commonly characterized by albuminuria and/or a reduced GFR, which plays a crucial role in evaluating renal function (²⁹29. Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010; 268: 456-467, doi: 10.1111/j.1365-2796.2010.02269.x.
https://doi.org/10.1111/j.1365-2796.2010... ). HD is the most common treatment for CKD and efficiently cleans the blood outside the body in an artificial kidney using a dialysis machine (³⁰30. Bergbom J. Home dialysis: how could the dialysis treatment be optimized in order to minimize the affect to the patients lives? 2013.). HFHD is an extracorporeal blood cleansing process that is mainly useful in eliminating or clearing small-molecular-weight solutes similar to creatinine and urea, for which diffusive mass transfer is swift (³¹31. Attaluri AC, Huang Z, Belwalkar A, Van Geertruyden W, Gao D, Misiolek W. Evaluation of nano-porous alumina membranes for hemodialysis application. ASAIO J 2009; 55: 217-223, doi: 10.1097/MAT.0b013e3181949924.
https://doi.org/10.1097/MAT.0b013e318194... ). HFHD is performed using a high-flux biocompatible dialyzer and can minimize inflammation and oxidative stress and improve the survival rate and quality of life of patients with CKD (³²32. Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, et al. Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study. Nephrol Dial Transplant 2013; 28: 192-202, doi: 10.1093/ndt/gfs407.
https://doi.org/10.1093/ndt/gfs407... ³³33. Cerda J, Ronco C. Modalities of continuous renal replacement therapy: technical and clinical considerations. Semin Dial 2009; 22: 114-122, doi: 10.1111/j.1525-139X.2008.00549.x.
https://doi.org/10.1111/j.1525-139X.2008... ³⁴34. Himmelfarb J. Oxidative stress in hemodialysis. Contrib Nephrol 2008; 161: 132-137, doi: 10.1159/000130658.
https://doi.org/10.1159/000130658... ). HFHD involves the use of dialyzer membranes with notable porosity to larger molecules ([beta-2 microglobulin (β2-M)] clearance of >20 mL/min) following an increase in the ultrafiltration coefficient to >15 mL/mmHg per hour, which has better biocompatibility and an amelioration in middle-to-large molecule clearance with subsequent reduction in the residual uremic milieu (³⁵35. Schiffl H. High-flux dialyzers, backfiltration, and dialysis fluid quality. Semin Dial 2011; 24: 1-4, doi: 10.1111/j.1525-139X.2010.00786.x.
https://doi.org/10.1111/j.1525-139X.2010... ). β2-M, the non-polymorphic chain, is found on the surface of all nucleated cells with a normal synthesis rate of 2 to 4 mg/kg per day, which varies inversely with the GFR (³⁶36. Mumtaz A, Anees M, Bilal M, Ibrahim M. Beta-2 microglobulin levels in hemodialysis patients. Saudi J Kidney Dis Transpl 2010; 21: 701-706.). Filtered by the glomerulus, β2-M is also decreased by HFHD treatment, and this is beneficial to patients in delaying amyloid-related arthropathy (³⁷37. Okuno S, Ishimura E, Kohno K, Fujino-Katoh Y, Maeno Y, Yamakawa T, et al. Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients. Nephrol Dial Transplant 2009; 24: 571-577, doi: 10.1093/ndt/gfn521.
https://doi.org/10.1093/ndt/gfn521... ,³⁸38. Palmer SC, Rabindranath KS, Craig JC, Roderick PJ, Locatelli F, Strippoli GF. High-flux versus low-flux membranes for end-stage kidney disease. Cochrane Database Syst Rev 2012; 9: CD005016, doi: 10.1002/14651858.CD005016.pub2.
https://doi.org/10.1002/14651858.CD00501... ). In accordance with our main results, Cheung et al. also found that the serum β2-M level was significantly lower with utilization of HF dialyzers than with LF dialyzers because of the presence of 12,000-Da molecules, which LF dialyzers cannot clear (³⁹39. Cheung AK, Greene T, Leypoldt JK, Yan G, Allon M, Delmez J, et al. Association between serum 2-microglobulin level and infectious mortality in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3: 69-77, doi: 10.2215/CJN.02340607.
https://doi.org/10.2215/CJN.02340607... ). Patients with lipid metabolism disorders undergoing HD also exhibited improvement in their symptoms following HFHD treatment. Such treatment is also associated with decreased complications of cardiovascular diseases (⁴⁰40. de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 2009; 302: 1782-1789, doi: 10.1001/jama.2009.1488.
https://doi.org/10.1001/jama.2009.1488... ).

The subgroup analysis based on follow-up revealed that the all-cause death rate in the HFHD group was significantly lower than that in the LFHD group within a follow-up of <3 years, and the difference in the all-cause death rate between the HFHD and LFHD groups was not statistically significant within a follow-up of ≥3 years. A subgroup analysis based on sample size showed that the all-cause death rate in the HFHD group was lower than that in the LFHD group, but the difference in the all-cause death rate between the HFHD and LFHD groups was not statistically significant.

Potential limitations of this study should be taken into consideration. First and foremost, only Caucasian patients were analyzed; this might have contributed to selection bias. Another important limitation was that language bias might have been present because all studies were published only in the English language. Additionally, the absence of data on end outcomes may have resulted in questionable validity of our results. Finally, the enrolled studies did not provide detailed data on clinical subtypes; thus, further investigation of subtypes by subgroup analysis could not be performed.

In summary, our meta-analysis provides strong evidence that HFHD can decrease the all-cause death rate and cardiovascular death rate in patients with CKD, and HFHD can be implemented as a first-line therapy choice for CKD. However, future studies with larger populations, diverse ethnicities, and better study designs are required for a comprehensive analysis of the benefits of HFHD in patients with CKD.

References

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