In this analysis of the longitudinal eGFR study, in a population at high risk of renal disease and progression to ESKD, we explored the association of measures of liver function and full blood count indices with annual decline in eGFR and combined renal outcomes.
For the first outcome, the annual decline in eGFR, we report an association with low concentrations of serum albumin, haemoglobin, and high concentrations of serum bilirubin.
For the second outcome, defined as the incidence of a combined renal end point, which was the first of the following: a 30% decline in eGFR with a follow-up eGFR < 60 mL/min/1.73 m2, death from renal causes, or initiation of renal replacement therapy, we report an inverse association with concentrations of serum albumin, serum bilirubin and haemoglobin and a positive association with concentrations of GGT and ALP
Our study supports the emerging evidence that high bilirubin concentrations may be protective against decline in kidney function and poor renal outcomes. We have previously reported from the eGFR study the inverse association of log-bilirubin with UACR .Several other studies suggest a protective role of high serum bilirubin against progression of chronic kidney and poor renal outcomes and this may be related to delaying progression of fibrosis-related kidney disease [18–23]
In our study of participants with high risk of CKD, there was a statistically significant decrease in the baseline concentrations of serum ALT across categories of decreasing eGFR. However, there was no significant relationship between baseline concentration of serum ALT and the annual decline in eGFR. The inverse association of ALT with the crude hazard of renal outcomes disappeared after adjustment for other covariates. To our knowledge, there are no previous studies exploring the association of serum concentrations of ALT and AST with renal outcomes. AST was not measured in this study. However, observational studies have described lower serum concentrations of serum aminotransferases over time in adults with CKD [24, 25], with multifactorial causes postulated. The same studies have suggested that new reference ranges may need to be set for these enzymes in people with CKD although the rationale for this is not clear from the current evidence [24, 25].
Our analysis has shown a statistically significant association between increased concentrations of serum GGT and poor renal outcomes although an association with annual decline in eGFR was lacking. Other studies have also suggested that GGT is an independent predictor of mortality in patients with stage 4–5 chronic kidney disease . Some previous studies have suggested an association of serum GGT with development and progression of CKD [27–29] although some studies have suggested that in some ethnic groups this association is confounded by other factors such as body mass index, life style factors, lipids, smoking and heavy alcohol intake [28, 30]. This positive association of high baseline concentrations of GGT with poor renal outcomes may indicate that the serum levels of this enzyme can be used as a surrogate marker of risk for poor renal outcomes. The mechanism linking GGT and progression of CKD is unclear and will need to be further studied although oxidative stress and inflammation in synergy with serum ferritin have been suggested .
In this study, there was a positive association between serum ALP concentrations and increased risk of poor renal outcomes. Serum ALP concentrations increased with progression in CKD. However, this is likely to be the bone isoenzyme of the ALP (not liver) which increases with the onset and severity of renal bone disease [31–33]. Although this supports the potential use of serum ALP as predictor of poor outcomes in people with CKD [26, 32, 33], the liver isoenzyme and association with decline in eGFR and renal outcomes would need further studies.
As expected, and found in many studies, serum albumin concentrations were inversely associated with decline in eGFR and high risk of adverse renal outcomes [34–37]. Similarly, the inverse relationship between haemoglobin and decline in eGFR and poor renal outcomes is expected.
Our current study showed no association of concentrations of WBC and RBC with annual decline in eGFR and renal outcomes. The potential role of the neutrophil/lymphocyte ratio could not be assessed because these variables were not available among the data. Recent studies have demonstrated mixed results on the predictive role of WBC on decline of eGFR in the people with CKD. Some studies have showed that elevated WBC count was a strong predictor of kidney function decline , high monocyte count was significantly associated with risks of incident CKD and CKD progression to ESKD  and low WBC count was independently associated with CKD progression in the elderly . Other studies have demonstrated the potential role of the high neutrophil/lymphocyte ratio as a predictor of poor renal outcomes [7, 8]. However, in a study of inflammatory markers including hsCRP, WBC count and ferritin, hsCRP and ferritin stratified by albumin associated with RRT and rapid renal progression, but WBC count was not associated with renal outcomes . These mixed results suggest the need for further studies on this potential association of WBC with renal outcomes.
Our analysis showed no association between RBC counts and annual decline in eGFR and renal outcomes after adjusting for other covariates. In our study, we did not have data on red blood cell distribution width (RDW), a measure of the range of variation of RBC volume. The association of red blood cell count and progression of renal disease remains poorly understood. Most studies have demonstrated the shortened life span of red blood cells with progression of CKD [40–42]. Studies have also suggested the predictive value of RDW, for cardiovascular and risk of CKD and renal outcomes [43, 44]. Therefore, further studies of the association between renal outcomes and RBC counts and RDW are needed.
There were some limitations to our study. There was no data on AST, viral hepatitis, history of liver disease, which would need to be used in the adjustment for the potential role of the liver function tests (ALT, GGT, ALP, Albumin and bilirubin) in the Cox model. This will need further exploration as studies have indicated the association of liver disease with progressing of CKD [45–47]. The absence of other parameters of the FBC indices, such as the differential WBC and red RDW, meant that we were unable to corroborate the details of the association of these indices with eGFR decline and renal outcomes.
The small number of participants in the study who reached the renal outcomes potentially limited the power to detect the associations and increased the lack of precision of estimates for the associations. The median follow-up of 3.1 years was relatively short, and the ongoing long-term follow-up will provide more robust assessment of these associations.