The aim of this narrative review is to shed light on the correlation between metabolic-associated fatty liver disease (MAFLD) and chronic kidney disease progression (CKD). There is robust evidence from the current and recent literature that MAFLD is strongly associated with CKD incidence and progression regardless of the other confounding factors such as DM, hypertension, dyslipidemia, age, and gender. we believe that MAFLD and CKD are two important health issues, both have a global and economic burden that will continue to rise over the coming years.  Primary and secondary care physicians, particularly nephrologists should be fully aware of the impact of MAFLD on CKD patients so they can participate actively in the management plan of these patients to reduce the comorbidities and economic costs associated with it.

Methodology:

The review identified and included the most recent few studies that described the problem of interest. Recommendations are given based on our perception, interpretation, and synthesis of data from the reviewed literature.

Results:

The existence of a strong correlation between MAFLD and CKD was persistent across all the reviewed studies and articles. This correlation was independent of other traditional risk factors such as hypertension, diabetes mellitus, hyperlipidemia, gender, and age.

Conclusion:

The global prevalence of MAFLD among the general population is high reaching 30% and almost 50% of CKD patients have MAFLD. There is a strong and independent association between MAFLD and CKD incidence and progression, thus patients diagnosed with CKD should be screened for MAFLD and managed accordingly to prevent and delay CKD progression. 

Nonalcoholic fatty liver disease (NAFLD) is characterized by the presence of hepatic steatosis when no other causes for secondary hepatic fat accumulation are present. NAFLD can progress to cirrhosis. It is important to know that NAFLD is subclassified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In NAFL, hepatic steatosis is present without evidence of significant inflammation, whereas in NASH, hepatic steatosis is associated with hepatic inflammation.

The worldwide prevalence of NAFLD is 35%, In a prospective study of 400 US military personnel and their families (mean age 55 years), the prevalence of NAFLD diagnosed by ultrasound was 46%. The diagnosis of MAFLD is based on the presence of hepatic steatosis (detected by serum biomarker scores, imaging techniques or liver biopsy) and at least one of the following metabolic criteria: (a) obesity, (b) T2DM, and (c) metabolic disorders, i.e., at least two additional factors amongst increased waist circumference, hypertension, hypertriglyceridemia, low serum HDL-cholesterol levels, impaired fasting glucose, insulin resistance or subclinical inflammation. It is essential to mention that several observational studies have recently revealed and reported that the definition of MAFLD, compared with NAFLD may significantly improve the stratification of patients at higher risk of developing hepatic and extra-hepatic complications, such as CKD progression, the topic of this narrative review. Chronic kidney disease (CKD) is associated with an increased risk of morbidity and mortality, as well as with a high economic cost [18]. The prevalence of CKD worldwide is approximately 10% and it is expected that CKD might become the fifth cause of death globally in 2040. Several retrospective and prospective observational studies and systematic reviews during the last fifteen years proved the existence of a strong correlation between NAFLD and CKD progression, however the new term of MAFLD is more helpful and meaningful in stratification of CKD patients at substantial risk of progression. Several epidemiological studies and meta-analyses have demonstrated that NAFLD (detected by blood biomarkers/scores, imaging techniques, International Classification of Diseases codes or liver biopsy) is associated with an increased risk of incident CKD, independent of established CKD risk factors, diabetes, hypertension, proteinuria, and other potential confounders (20-25). The correlation between the two diseases is complex and important at the same time because both diseases are current global health issues and will continue to be a global and economic burden in the future if no serious preventive measures are put in place. 

NAFLD and Risk of CKD progression:

The meta-analysis of 13 observational longitudinal studies involving nearly 1 200 000 middle-aged individuals (28.1% with NAFLD; n=3 43 248) from different countries revealed that the long-term risk of developing CKD stage ≥3 is increased ~1.45-fold in individuals with NAFLD (Mantovani, et al. 2020). This risk increases with the severity of liver fibrosis. The table [1] demonstrates the findings of a systematic analysis of 9 studies by (Mantovani, et al. 2017)

One can conclude from this systematic analysis that Patients with NAFLD are higher risk of incident CKD than those without NAFLD (random-effects hazard ratio [HR] 1.37, 95% CI 1.20–1.53; I 2 = 33.5%). These findings are consistent with the other studies that looked at the correlation between NAFLD and CKD in the current literature.

Correlation between MALD and CKD:

The table (2) below demonstrates the association between metabolic associated nonalcoholic liver disease (MALD) and chronic kidney disease (CKD), (Mantovani, et al.2022).

We believe that the notion of metabolic associated nonalcoholic fatty liver disease (MAFLA) is clearer and more comprehensive for nephrologist, general internists, family medicine physicians, endocrinologists, and primary care physicians, when they stratify patients at high risk of developing CKD or CKD progression, albeit there is no great statistical difference between MAFLD and NAFLD in terms of CKD risk. However, several studies in the previous systematic review had shown that the risk of CKD and CKD progression is higher in the MALD group compared to NAFLD group. Thus, a holistic approach to manage this category of patients is extremely important at the level of primary and secondary care. The figure below can help and guide the concerned physicians to detect MALD as early as possible.

Pathogenesis:

The pathogenesis of MAFLD and CKD is very complex, and it is still difficult to say that MAFLD can cause CKD, though there is robust evidence about the existence of a strong correlation between the two conditions regardless of the existence of other confounding factors such as diabetes mellitus, hypertension, and proteinuria. The illustration below demonstrates how the traditional risk factors are entangled between the two diseases.

Genetic role:

The PNPLA3 rs738409 polymorphism which is associated with a predisposition to NASH has recently been shown to associate with worse kidney function, (Guangrong Dai, et al. 2019). One can extrapolate from this genetic evidence, that any patient with MAFLD is at high risk of CKD and CKD progression.

Nephrologists and MAFLD, what can be done?

Nephrologists are amongst the first line physicians who can detect MAFLD because of high rate of patient's referral and consultations as well as high rate of requesting abdominal ultrasound. However, the lack of current strong evidenced guidelines and management policy make the concise management of such patients weak. To entice the attention of nephrologists and renal medicine clinicians to this health problem, one must speak of CKD progression risk based on the CKD stages and albuminuria (KDIGO guidelines) as illustrated in the table below. The risk of CKD progression and cardiovascular disease increase as the patients GFR decreases but it is not just the GFR that determines the risk of CKD progression but also the level of albuminuria, i.e., a patient with CKD stage 1 and proteinuria A3 will have the same risk of CKD progression as a patient with CKD stage 3b without microalbuminuria. One can imagine if MAFLD status is added to the table of CKD stages and albumin to creatinine ratio how the colors of CKD progression risk would change. This suggestion can help nephrologists to stratify patients at risk of CKD progression better than before and to manage patients with MAFLD and CKD properly rather than just advising them to reduce weight because weight loss at this stage is a treatment goal and should be achieved by all available means and monitored. Patients with advanced MAFLD with liver fibrosis should be referred to hepatologist as early as possible.   

Diagnosis of MAFLD:

The diagnosis of MAFLD can be performed based on the presence of:

•  Hepatic steatosis (detected by serum biomarker scores, imaging techniques or liver biopsy) and at least one of the following metabolic criteria:
• (a) overweight/obesity,
• (b) T2DM,
• (c) metabolic dysregulation.

Non-Medical Management:

• Dietician consultation.
• Regular exercise
• Participation in weight reduction programs.

Unfortunately, there is no specific cure for MAFLD but luckily these days there are many drugs and treatment options that can help reduce weight and proteinuria at the same time and reduce the risk of renal function decline as well as reducing the risk of cardiovascular disease. Medications such as metformin, SGLT2 inhibitors, G LIKE 1 receptor agonists etc. Some authors suggest Vitamin E (800 international units per day) (level of evidence is Grade 2C).

Surgical Management:

Bariatric surgery, patients with NASH or advanced fibrosis (but without decompensated cirrhosis) for bariatric surgery if they do not meet their weight loss goals after six months of lifestyle interventions.

The main goal of either medical or surgical management is to reduce weight because early weight reduction can reverse the disease and decrease the risk of liver fibrosis as well as risk of developing CKD or CKD progression. The figure below (William N, et al. 2016) shows how weight reduction is effective.

Laboratory monitoring:

• AST AND ALT three and six months after patients with NAFLD implement lifestyle interventions for weight loss.
• AST AND ALT three and six months after patients with NAFLD implement lifestyle interventions for weight loss.
• For patients who achieve their weight loss goals and have normal serum aminotransferases, obtain a noninvasive assessment every four years.

When patients should be referred to hepatologist?

• Aminotransferases (alanine aminotransferase and aspartate aminotransferase) that remain elevated despite loss of ≥5 percent of body weight (to evaluate for other etiologies of liver disease)
• Aminotransferases (alanine aminotransferase and aspartate aminotransferase) that remain elevated despite loss of ≥5 percent of body weight (to evaluate for other etiologies of liver disease)
• Steatohepatitis on liver biopsy
• Steatohepatitis on liver biopsy

Recommendations:

• The use of the new definition MAFLD, compared to NAFLD, offers numerous advantages in clinical, epidemiological, risk stratification of CKD and research terms in the future.
• Patients diagnosed with NAFLD and at considerable risk of CKD should be managed by a multidisciplinary approach and motivated to change lifestyle and reduce weight.
• Future prospective studies involving different ethnicities to further explore the association between MAFLD, and CKD progression should be encouraged
• Based on the evidence from the current and recent literature about the strong correlation of MAFLD and CKD regardless of the existence of proteinuria, we suggest that MAFLD should be added to the KDIGO table of CKD stages and albumin to creatinine ratio to better stratify patients at risk of CKD and CVD. This can enable concerned physicians to put effective preventive measures in place.

The entanglement between MAFLD and CKD incidence and progression seems to be more than just a simple correlation as evidenced in the current literature, however more randomized controlled studies should be encouraged in the future to explore the causal relationship between them. Meanwhile it is important to set forward early management and preventive measures in patients with CKD and MAFLD to avoid rapid decline of kidney function and CKD progression.