The objectives of this systematic literature review were to evaluate the risk of CV morbidity, CV mortality and all-cause mortality in patients with CKD at each eGFR and albuminuria stage (according to KDIGO categorisations ), and to quantify the cost and healthcare resource utilisation implications associated with the management of CV morbidity in CKD in both US and UK settings. In total, 29 studies reported on the risk of adverse clinical outcomes based on the combined relationship between eGFR and albuminuria stage as per KDIGO categorisation.
In 2012, KDIGO published guidelines on the evaluation and management of CKD . Earlier KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines  focused on eGFR alone to categorise CKD and quantify patient risk and did not account for variations in albuminuria. KDIGO 2012 highlighted the importance of albuminuria to aid in the identification of higher-risk patients and recommended the measurement of urinary protein alongside eGFR to better evaluate CKD. Of the 29 studies included in this review, 10 were published from 2013 onwards. Of those, only six reported eGFR and albuminuria as per KDIGO categorisation, and indicates that further research is required to ensure that risk of adverse outcomes at each CKD and albuminuria stage can be accurately evaluated.
Across all outcomes, risk increased with eGFR decline and increased further with the worsening of albuminuria; even at the same level of renal function, worsening of albuminuria could increase the risk of CV morbidity, CV mortality or all-cause mortality by over fourfold. An increase in the risk of adverse outcomes was apparent even in patients with early-stage CKD. Patients with stage 2 CKD with normoalbuminuria had up to 36% increases in the risk of adverse clinical outcomes, increasing up to threefold for those with stage 2 CKD and macroalbuminuria; the risk increased 12-fold in patients with stage 5 CKD and macroalbuminuria.
The additional costs and bed day provision associated with the management of CV morbidity in patients with CKD are substantial in the UK, but are significantly higher in the USA. These differences are likely driven by the greater cost of healthcare in the USA compared with the UK and reflect differences in per capita costs of healthcare between the two countries [US$4018 (£2989) per person in the UK in 2017 vs. US$10,398 (£7736) per person in the USA] .
Whilst micro- and macroalbuminuria (at any CKD stage) are less prevalent than normoalbuminuria in the overall CKD population—13% and 24% of all patients with CKD in the USA and UK respectively—the cost and healthcare resource burden associated with the management of CKD-related CV morbidity in these patients is significant compared to those with normoalbuminuria. At a patient level, the additional costs and bed days associated with managing a patient with macroalbuminuria are four to eight times greater than for a patient with normoalbuminuria at the same CKD stage. At a population level, 42% and 66% of estimated additional costs and bed days in the USA and UK respectively that are required to manage CV morbidity in patients with CKD are consumed by those with micro- or macroalbuminuria.
Given this substantial increase in cost and healthcare resource utilisation associated with the management of CV morbidity in micro- and macroalbuminuria and in latter-stage CKD, it should be a priority of healthcare providers to avoid patients reaching macroalbuminuria and advanced stage CKD through early identification of the disease and proactive management—especially in patients with more rapidly advancing disease—to slow CKD and albuminuria progression. Any reduction in the number of patients reaching latter-stage CKD has the potential to alleviate the burden of CV morbidity and its impact on healthcare resources.
Studies included in this systematic review were conducted across a broad population of patients with CKD, with approximately one-third conducted in higher-risk patient cohorts, including patients with diabetes, hypertension, prior MI or stroke, amongst others. Risks of all-cause mortality based on worsening eGFR in the subgroups of patients with baseline comorbidity tended to be higher than across the entire cohort, with patients with diabetes at highest risk. Therefore, it would be prudent for healthcare providers to both prioritise CKD screening in patients with comorbidities to ensure early identification of CKD, and ensure optimal management of CKD in those already diagnosed to slow progression and thus reduce the already elevated risk of morbidity and early mortality in those with more advanced disease.
The major strength of this systematic literature review is the applicability of the findings across a wide CKD population. Approximately one third of the studies included were conducted in higher-risk patient cohorts and the remaining were based on general population cohorts, many of which included patients with significant comorbidity. However, this study is not without limitations. There was significant heterogeneity in the categorisation of eGFR and albuminuria across studies and many did not align with KDIGO categories, preventing their inclusion in the overall analysis. There is also potential for publication bias to impact the generalisability of the results; if fewer studies with non-significant outcomes are published, it could result in an overestimation of the level of risk associated with more advanced CKD. Whilst the funnel plot of included studies indicated the potential presence of publication bias, this is thought to be primarily as a result of the inclusion of large observational studies, and the clinical demographics of the CKD population rather than the presence of significant publication bias, as high-risk patients, such as those with stage 5 CKD, make up a comparatively small proportion of the overall CKD population. This conclusion was supported by consistency in results between the random- and fixed-effects meta-analysis and also the sensitivity analysis which excluded studies with fewer than 10,000 patients. There is also the potential that these findings are confounded as a result of significant differences in patient characteristics (including comorbidities such as type 2 diabetes, heart failure etc.) between different KDIGO categorisations; however, many of the included studies adjusted results for relevant patient characteristics and there is a well-established causal relationship between renal impairment and the incidence of adverse clinical outcomes in patients with CKD.
In addition, this analysis has only addressed risk at absolute eGFR/albuminuria stages, whereas risk is also linked to the rate of eGFR decline/albuminuria rise. Future research could explore the risk of adverse clinical outcomes based on the rate of CKD progression and delve deeper into the role that comorbidities such as diabetes or heart failure play in the risk of adverse clinical outcomes. Furthermore, the economic analysis in this manuscript focused only on the additional costs and bed days associated with the management of CV morbidity associated with CKD; there are further costs (e.g. monitoring and treatment costs) that also need to be considered when evaluating the full economic burden of CKD. Additionally, costs associated with CV morbidity in the USA setting were derived in a population of patients with type 2 diabetes rather than CKD; however, costs represent the per-event cost associated with the incidence of CV events and as such costs are likely to be representative of other comorbid populations.
Lastly, the quality of our analysis is limited by the availability of source data to inform our cost and bed day estimations. During this analysis, we noted significant differences in the prevalence of stage 2 CKD with normoalbuminuria in US and UK (75% vs. 33% respectively) CKD populations, likely due to the availability of data rather than significant differences in clinical practice and the diagnosis of early-stage CKD. Indeed, epidemiological data to inform US estimates was sourced from the US Renal Data System  which includes both diagnosed and potentially undiagnosed patients with CKD. Given our outcome of interest was CV morbidity and CV events will happen in both diagnosed and undiagnosed patients, the US Renal Data System data are relevant; however, these differences between US and UK data indicate that the true number of patients with earlier-stage CKD in the UK may be underestimated.
Safe and effective therapies to slow the rate to CKD progression are essential to reduce the cost and healthcare resource burden of CV morbidity in CKD. Treatment options to delay CKD progression have previously been limited to renin–angiotensin–aldosterone system inhibitors, despite considerable residual risk of disease progression. However, following the observation that sodium–glucose co-transporter 2 (SGLT2) inhibitors demonstrated a reduced risk of CV and renal events in patients with type 2 diabetes [23,24,25], this class of drug is now being studied in CKD populations. Dapagliflozin has recently been evaluated in patients with and without type 2 diabetes in the DAPA-CKD study . Dapagliflozin was associated with reductions in the risk of kidney failure, CV mortality, or hospitalisation for heart failure, and prolonged survival in patients with CKD with or without type 2 diabetes , potentially signalling a new class of therapy for patients with CKD, regardless of diabetes status.
In conclusion, the results of this systematic review and meta-analysis demonstrate that CKD (with or without albuminuria) is associated with poor patient outcomes even from an early stage. The risks increased with more advanced disease and the highest risk of CV morbidity, CV mortality and all-cause mortality was observed consistently in patients with stage 5 CKD with macroalbuminuria. The additional costs and bed days associated with management of the associated CV morbidity in patients with CKD are substantial and increase with disease severity. Early diagnosis and proactive management of CKD is important to be able to slow CKD progression, and reduce the risk of adverse clinical outcomes in patients with CKD. More effective management of the disease may result in a reduced healthcare, societal and patient burden of CKD.