Liver Stiffness, Albuminuria And Chronic Kidney Disease in Patients With NAFLD: A Systematic Review And Meta-Analysis Ⅱ
Jun 28, 2024
3. Results
3.1. Search Results
From a total of 526 articles identified by literature research, 365 were screened after duplicates were removed. Of these, 347 were excluded by reading the title and abstract based on the previously provided criteria. We examined the full text of the remaining 18 studies. After excluding articles with a different design (n = 1) or that did not report the outcome of interest (n = 10), a final number of seven included studies were analyzed and assessed for quality. A PRISMA flow diagram of the study selection is shown in Figure 1.
Figure 1. Flow diagram of study selectio
3.2. Features ofthe Included Articles
The main characteristics of the included studies are reported in Table 1. All wereobservational cross-sectional studies and most of them were performed on patients withT2D followed at university clinics. Overall, they included 7736 individuals with an agerange of 42 to 69 years. Three studies were carried out in Asia (India and China), threein Europe (ltaly and Croatia) and one in the US. The prevalence of T2D ranged from 20%to 100% and most studies included overweight or obese participants (mean BMl range27.4-34.0 kg/m?). All studies included a similar number of men and women (proportion of men range: 47-66%).Four studies used a single cut-off to define significant fibrosis, while the remainingthree used different cut-offs for the M and XL Fibroscan probes. Five studies reportedCKD (as a composite of increased UACR and reduced eGFR) as an outcome, two reportedincreased UACR and one reported both.
NEW HERBS FOR CHRONIC KIDNEY DISEASE (CKD)
As shown in Table 1, six studies were considered at low risk of bias (receiving eightstars), and one was considered at medium risk (seven stars), thus indicating an overall lowto medium risk of bias.
3.3. Association between Liver Stifness and Kidney Outcomes
As shown in Figure 2, the pooled OR for prevalent CKD in patients with significantliver fibrosis (n = 5 studies) was 2.49 (95% CI 1.89-3.29; test for overall effect z = 6.475p<0.001) when pooling adjusted effect estimates. The test for heterogeneity was notsignificant (12=0%, Cochrane'sQ= 3.29, degrees of freedom (df)= 4, p= 0.510). No studysuggested a decreased risk of prevalent CKD in patients with significant fibrosis.
Figure 2. Forest plot and pooled estimates on the effect of increased liver stiffness by vibrationcontrolled transient elastography (VCTE) on the odds of chronic kidney disease (CKD). CKD wasdefined as a urinary albumin to creatinine ratio >30 mg/g, an estimated glomerular filtrationrate < 60 mL/min/1.73 m? or both. Abbreviations: NAFLD, nonalcoholic fatty liver disease; ORodds ratio; Cl, confidence interval.
As shown in Figure 3, the pooled OR for prevalent increased UACR in patients withsignificant liver fibrosis (n = 3 studies) was 1. 98 (95% CI 1.29-3.05: test for overall effectz = 3.113, p = 0.002) when pooling adjusted effect estimates. The test for heterogeneity was notsignificant (1?=46.5%,Cochran's Q= 3.74, degrees of freedom (df) =2,p = 0.154). No studysuggested a decreased risk of prevalent albuminuria in patients with significant fibrosis.
3.4. Sensitivity Analyses and Riskof Publication Bias
Changes in the overall effect size following omission ofone study each time and recalculating the pooled effect estimate on the remaining studies are shown in Supplementary Table S3Given the low number of included studies for each outcome, subgroup analyses werenot performed. Visual inspection of the funnel plot could not exclude the possibility ofpublication bias (Supplementary Figure S1). As recommended by the Cochrane collabora.tion, tests for funnel plot asymmetry were not performed as they can be considered usefumeasures only when there are at least 10 studies included in the meta-analysis, becausewhen there are fewer studies the power of the tests is too low to distinguish chance fromreal asymmetry [20].
4. Discussion
The results of the present study expand those of previous meta-analyses focusing on the association between NAFLD and incident CKD. The most recent, by Mantovani et al., which included 13 longitudinal studies, found that patients with NAFLD (diagnosed by different modalities including elevated liver enzymes, blood-based biomarkers, imaging methods and ICD-9/10 codes) had a higher risk of developing CKD (defined as an eGFR < 60 mL/min/1.73 m2 ) even after adjustment for several confounders [11]. The authors identified four studies reporting the effect of the severity of NAFLD on kidney outcomes, but since the definition of NAFLD severity was heterogeneous (based on either gamma glytamyl-transpeptidase levels, non-invasive fibrosis score or liver biopsy) no pooling of results in a meta-analysis was performed. In the present study, we focused on VCTE as the single non-invasive method included to estimate the degree of fibrosis. This was done to provide a summary of studies employing the same technique and enabled us to avoid the presence of significant heterogeneity.
It is well known that the term NAFLD comprises a large spectrum of histologic changes going from simple steatosis to advanced fibrosis and cirrhosis and that the degree of liver fibrosis represents the strongest predictor of liver-related outcomes. Current screening strategies therefore aim at identifying patients with ≥F2 fibrosis. While no international consensus exists on how to perform the screening, strategies employing VCTE or a combination of non-invasive serum-based scores (such as Fibrosis-4 or the NAFLD fibrosis score) and VCTE seem to provide the best compromise between sensitivity and risk of misclassification [27]. In this context, wider application of VCTE as a screening techniques in primary care and diabetes clinics might not only enable the identification of patients at higher risk of liver-related outcomes, but also recognize individuals that are prone to develop albuminuria and CKD, recognized risk factors for end-stage renal disease.
From a pathophysiological standpoint, several mechanisms might account for the role of liver fibrosis (and therefore stiffness) as a potential driver of albuminuria and CKD. It has been shown that NAFLD and its progression towards fibrosis are accompanied by upregulation of pro-fibrogenic cytokines (such as fibroblast growth factor-21 and transforming growth factor-β) which might act on the kidney, as well as by a low-grade inflammation and pro-thrombotic milieu [28]. Genetics might also play a role. Recent studies showed that a common polymorphism in the gene encoding the patatin-like phospholipase domaincontaining protein (PNPLA3), which is strongly associated with NAFLD and progression toward fibrosis [29], seems to predispose to the development of CKD, forming a potential link between the two conditions [30]. It should also be stressed that both NAFLD and CKD represent two important risk factors for CVD, and patients with these conditions should be carefully screened for asymptomatic cardiovascular complications.
The current meta-analysis has several limitations that deserve to be acknowledged. First, given the observational nature of the included studies, it is not possible to definitely prove a causality link between the exposure and the outcome. Second, while most studies adjusted for several potential confounders including age, BMI, presence of diabetes, hypertension, use of anti-albuminuric drugs (as shown in Table 1), the possibility of residual confounding by unmeasured factors cannot be excluded. Moreover, it was not possible to combine models that accounted for the exact same variables.
Third, interpretation of our results demands cautiousness, given the cross-sectional nature of the included studies. Nonetheless, while reverse causality cannot be excluded, it is unlikely that albuminuria or CKD are involved in the pathogenesis of liver fibrosis, while the opposite cause–effect direction is suggested by previous data [31]. Future studies using a prospective design are needed to provide further evidence on the topic. Fourth, none of the included studies used a gold-standard technique, such as liver biopsy or magnetic resonance spectroscopy, to diagnose NAFLD. In fact, while these two techniques are more reliable than liver ultrasound or VCTE itself through the CAP values (which were used in the included studies), they are expensive and time consuming, making them unsuitable for large scale population studies or use in clinical practice. Moreover, liver biopsy is an invasive technique with possible (although rare) life-threatening complications, raising ethical concerns related to its use in apparently healthy subjects [12].
Our analysis also has some important strengths. It incorporates data from studies performed in Asia, Europe and the US including a representative pool of patients with NAFLD from the general population or followed at diabetes clinics. Moreover, the large number of both exposed individuals and patients with the outcome of interest yields high statistical power to quantify the association between liver stiffness and renal dysfunction,without significant heterogeneity
5. Conclusions
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/biom12010105/s1, Figure S1: Funnel plot of selected studies for the primary outcome describing the relationship between effect size and standard error on the log scale. The vertical line represents the pooled effect size and the dashed lines represent the pseudo 95% confidence intervals, Table S1: Focused search strategy in MEDLINE database, Table S2: PRISMA checklist, Table S3: Sensitivity analysis of selected studies. Each row shows the recalculated pooled OR of remaining studies by omitting studies listed in the left column one at a time. Author Contributions: S.C. and G.P. designed the study, wrote, reviewed and edited the manuscript. S.C. researched and analysed data. C.B. and R.T. reviewed the manuscript. S.C. is the guarantor of this work. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The dataset used for this meta-analysis is available from the corresponding author upon reasonable request. Conflicts of Interest: The authors declare no conflict of interest.
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