eGFR Trajectories: Beyond Measurement, Influences, and SGLT2i Effects – A Comprehensive Review of Clinical Significance and Therapeutic Implications

Abstract

Estimated glomerular filtration rate (eGFR) serves as a cornerstone in the assessment of kidney function, guiding clinical decision-making across various medical specialties. This review delves into the complexities surrounding eGFR, extending beyond mere measurement methodologies to explore the multifaceted factors influencing its values, the clinical significance of eGFR changes – particularly in the context of sodium-glucose cotransporter-2 inhibitors (SGLT2i) – and the implications of eGFR dips. A critical analysis of monitoring strategies and the often-contentious issue of medication discontinuation based on eGFR thresholds is presented. We aim to provide a comprehensive, expert-level overview that addresses current knowledge gaps and informs best practices in eGFR-guided clinical management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The accurate assessment of kidney function is paramount in clinical medicine, impacting diagnosis, prognosis, and treatment strategies across a wide spectrum of conditions. While direct measurement of glomerular filtration rate (GFR) via techniques like inulin clearance remains the gold standard, its impracticality in routine clinical settings has led to the widespread adoption of estimated GFR (eGFR). eGFR, derived from serum creatinine, cystatin C, or a combination thereof, provides a readily accessible and cost-effective surrogate for GFR. However, eGFR is not without its limitations. The inherent inaccuracies of estimation equations, coupled with the influence of various physiological and pathological factors on serum creatinine and cystatin C levels, necessitate a nuanced understanding of eGFR interpretation. This review aims to provide a comprehensive overview of eGFR, encompassing measurement methodologies, influential factors, clinical significance, and therapeutic implications, particularly in the context of SGLT2i therapy and medication discontinuation.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Methodologies for eGFR Estimation

The accuracy of eGFR is intrinsically linked to the equation employed for its calculation and the biomarkers used as input. The most common equations rely on serum creatinine, cystatin C, or both. Creatinine-based equations, such as the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, are widely used due to their simplicity and cost-effectiveness. However, creatinine generation is influenced by muscle mass, diet (particularly protein intake), and age, leading to potential inaccuracies, especially in individuals with extremes of body composition (e.g., sarcopenia, obesity) or dietary habits. The CKD-EPI equation generally outperforms the MDRD equation, particularly at higher GFR values, and is currently recommended by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [1].

Cystatin C, a low-molecular-weight protein produced by all nucleated cells, is less influenced by muscle mass and diet compared to creatinine. Cystatin C-based equations, such as the CKD-EPI cystatin C equation, offer improved accuracy in certain populations, including the elderly and those with variations in muscle mass. Combining creatinine and cystatin C in the CKD-EPI creatinine-cystatin C equation further enhances accuracy, mitigating some of the limitations associated with each individual biomarker [2].

Newer methods, such as machine learning algorithms, are being developed to improve eGFR estimation. These algorithms can incorporate a wider range of variables, including demographics, comorbidities, and other biomarkers, potentially leading to more personalized and accurate eGFR estimations. However, these methods are still under development and require further validation before widespread clinical adoption. Furthermore, the standardization of creatinine and cystatin C assays remains a challenge, impacting the comparability of eGFR values across different laboratories. Standardized assays are crucial for ensuring reliable eGFR monitoring and facilitating consistent clinical decision-making [3].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Factors Influencing eGFR Beyond Renal Disease

While eGFR serves as a key indicator of kidney function, several non-renal factors can influence its values, leading to potential misinterpretations. These factors can be broadly categorized as physiological, pathological, and pharmacological.

• Physiological factors: Age is a major determinant of eGFR, with a gradual decline occurring naturally with increasing age. This age-related decline is attributed to structural and functional changes in the kidneys, including a reduction in nephron number and glomerular sclerosis. Sex differences in muscle mass contribute to variations in creatinine generation, affecting eGFR estimations. Race is also a factor, although the inclusion of race-specific correction factors in eGFR equations remains controversial due to ethical and methodological concerns. Pregnancy induces significant physiological changes that affect eGFR, including increased renal plasma flow and glomerular filtration. These changes can lead to an apparent increase in eGFR during pregnancy [4].

• Pathological factors: Non-renal diseases, such as heart failure, liver disease, and thyroid disorders, can influence eGFR. Heart failure impairs renal perfusion, leading to a reduction in GFR. Liver disease can affect creatinine generation and clearance, impacting eGFR estimations. Thyroid disorders can alter renal hemodynamics and tubular function, influencing eGFR. Systemic inflammation, regardless of its cause, can affect both creatinine and cystatin C levels, thereby affecting eGFR [5].

• Pharmacological factors: Numerous medications can affect eGFR, either directly through renal toxicity or indirectly through hemodynamic or metabolic effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair renal prostaglandin synthesis, leading to vasoconstriction and a reduction in GFR. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can initially cause a transient decrease in eGFR due to efferent arteriolar vasodilation, but long-term use can be renoprotective. Diuretics can affect eGFR by altering intravascular volume and renal perfusion. Certain antibiotics, such as aminoglycosides and vancomycin, are nephrotoxic and can cause a significant decline in eGFR [6].

Understanding these non-renal factors is crucial for accurately interpreting eGFR values and avoiding misdiagnosis or inappropriate treatment decisions. Clinicians should consider the patient’s clinical context, including age, sex, race, comorbidities, and medications, when evaluating eGFR.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Clinical Significance of eGFR Changes and SGLT2 Inhibitors

The introduction of SGLT2i has revolutionized the management of type 2 diabetes and chronic kidney disease (CKD). These agents inhibit glucose reabsorption in the proximal tubule, leading to glycosuria and a reduction in blood glucose levels. SGLT2i also exert renoprotective effects, slowing the progression of CKD and reducing the risk of cardiovascular events in patients with diabetes and CKD [7].

SGLT2i typically induce an initial dip in eGFR, which is often observed within the first few weeks of treatment initiation. This initial dip is attributed to tubuloglomerular feedback (TGF) mechanisms. SGLT2i-induced glycosuria reduces sodium and chloride delivery to the macula densa, leading to afferent arteriolar vasodilation and a reduction in intraglomerular pressure. This mechanism can result in a transient decrease in eGFR. Importantly, this initial dip in eGFR does not necessarily indicate renal injury and is often followed by a stabilization or even an improvement in eGFR over the long term. Some studies suggest that the magnitude of the initial eGFR dip may correlate with the long-term renoprotective benefits of SGLT2i, although this remains a topic of ongoing research [8].

The long-term effects of SGLT2i on eGFR are generally favorable. Numerous clinical trials have demonstrated that SGLT2i can slow the decline in eGFR in patients with diabetes and CKD. The renoprotective effects of SGLT2i are likely mediated by a combination of mechanisms, including reduced intraglomerular pressure, improved glycemic control, reduced albuminuria, and anti-inflammatory effects [9].

However, it is crucial to monitor eGFR closely in patients receiving SGLT2i, particularly during the initial weeks of treatment. A precipitous decline in eGFR, beyond the expected initial dip, should prompt investigation for other causes of kidney injury, such as volume depletion, concurrent nephrotoxic medications, or underlying renal disease. In some cases, it may be necessary to temporarily discontinue SGLT2i if a significant decline in eGFR occurs. The definition of a “significant” decline varies, but most guidelines recommend considering discontinuation if eGFR decreases by more than 30% from baseline [10].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Implications of eGFR Dips: Distinguishing Benign from Detrimental

Differentiating between a benign and a detrimental eGFR dip requires careful clinical judgment, integrating the magnitude and timing of the decline with the patient’s overall clinical context. The initial dip associated with SGLT2i initiation, as discussed above, is generally considered benign, provided it is not excessive and is followed by stabilization or improvement. However, eGFR dips can also indicate underlying renal injury or progression of CKD [11].

• Acute Kidney Injury (AKI): A sudden and significant decline in eGFR, particularly if accompanied by other signs of AKI (e.g., oliguria, edema, electrolyte abnormalities), warrants immediate investigation and management. AKI can be caused by a variety of factors, including dehydration, infection, nephrotoxic medications, and obstruction of the urinary tract. A thorough history and physical examination, along with appropriate laboratory and imaging studies, are essential for identifying the underlying cause of AKI.

• Progression of CKD: A gradual and sustained decline in eGFR, even in the absence of overt AKI, may indicate progression of CKD. Factors that can contribute to CKD progression include uncontrolled hypertension, diabetes, proteinuria, and smoking. Aggressive management of these risk factors is crucial for slowing the progression of CKD.

• Medication-induced Nephrotoxicity: Numerous medications, as previously mentioned, can cause nephrotoxicity and a decline in eGFR. A careful review of the patient’s medication list is essential for identifying potential culprits. Discontinuation or dose adjustment of the offending medication may be necessary.

• Underlying Renal Disease: An eGFR dip may unmask previously undiagnosed underlying renal disease, such as glomerulonephritis or renovascular disease. Further evaluation, including urine analysis, renal ultrasound, or even renal biopsy, may be necessary to establish the diagnosis.

The rate of eGFR decline is also an important consideration. A rapid decline (e.g., >5 mL/min/1.73 m2 per year) is generally more concerning than a slow and gradual decline. The presence of proteinuria is another important indicator of renal damage. Significant proteinuria (e.g., urine albumin-to-creatinine ratio >300 mg/g) is associated with a higher risk of CKD progression. Furthermore, changes in blood pressure control, fluid status, and other laboratory parameters should be carefully considered in the context of an eGFR dip [12].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Monitoring Strategies and Frequency of eGFR Assessment

Regular monitoring of eGFR is essential for detecting changes in kidney function and guiding clinical decision-making. The frequency of eGFR assessment should be individualized based on the patient’s risk factors, underlying renal disease, and treatment regimen. In general, patients with CKD should have their eGFR monitored at least annually. Patients with more advanced CKD or those receiving medications that can affect kidney function may require more frequent monitoring.

• Patients with CKD: The NKF KDOQI guidelines recommend monitoring eGFR and urine albumin-to-creatinine ratio (UACR) at least annually in patients with CKD stages 1-2 (eGFR ≥60 mL/min/1.73 m2 and UACR >30 mg/g or other evidence of kidney damage) and at least twice per year in patients with CKD stages 3-5 (eGFR <60 mL/min/1.73 m2). More frequent monitoring may be necessary in patients with rapidly progressive CKD or those receiving medications that can affect kidney function [1].

• Patients with Diabetes: The American Diabetes Association (ADA) recommends monitoring eGFR and UACR at least annually in all patients with diabetes. More frequent monitoring may be necessary in patients with diabetic kidney disease or those receiving medications that can affect kidney function [13].

• Patients Receiving SGLT2i: As previously discussed, close monitoring of eGFR is particularly important in patients receiving SGLT2i, especially during the initial weeks of treatment. Most guidelines recommend monitoring eGFR within 2-4 weeks of SGLT2i initiation and periodically thereafter. The frequency of monitoring should be individualized based on the patient’s response to treatment and any changes in eGFR [10].

• Patients Receiving Nephrotoxic Medications: Patients receiving medications with known nephrotoxic potential should have their eGFR monitored regularly. The frequency of monitoring should be individualized based on the medication’s nephrotoxic potential and the patient’s risk factors for kidney injury.

In addition to eGFR, other parameters, such as blood pressure, serum electrolytes, and urine protein excretion, should be monitored regularly in patients with CKD or those at risk for kidney injury. A comprehensive assessment of these parameters provides a more complete picture of kidney function and helps guide clinical management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Medication Discontinuation Based on eGFR: Navigating the Gray Areas

The decision to discontinue medications based on eGFR thresholds is a complex and often contentious issue. While some medications are clearly contraindicated at certain eGFR levels due to increased risk of toxicity or reduced efficacy, the optimal approach for other medications is less clear [14].

• Medications Contraindicated at Low eGFR: Certain medications are known to be nephrotoxic or to accumulate to toxic levels in patients with reduced kidney function. These medications are generally contraindicated at specific eGFR levels. Examples include metformin (contraindicated at eGFR <30 mL/min/1.73 m2 in most guidelines), NSAIDs (should be avoided in patients with eGFR <60 mL/min/1.73 m2), and certain antibiotics (e.g., aminoglycosides, vancomycin) [6].

• Medications Requiring Dose Adjustment at Low eGFR: Many medications require dose adjustment in patients with reduced kidney function to avoid toxicity. The specific dose adjustments vary depending on the medication and the severity of kidney impairment. Clinicians should consult drug references and guidelines to determine appropriate dose adjustments for medications used in patients with low eGFR.

• Medications with Unclear eGFR-Based Discontinuation Thresholds: For many medications, there is no clear eGFR-based discontinuation threshold. The decision to continue or discontinue these medications should be individualized based on the patient’s clinical context, the potential benefits and risks of the medication, and the availability of alternative therapies. For example, statins are generally considered safe and effective in patients with CKD, even at low eGFR levels. However, the decision to initiate or continue statin therapy should be individualized based on the patient’s cardiovascular risk profile and the potential benefits and risks of statin therapy [15].

The decision to discontinue SGLT2i based on eGFR also warrants careful consideration. While most trials excluded patients with eGFR below a certain threshold (e.g., 30 mL/min/1.73 m2), recent evidence suggests that SGLT2i may still provide renoprotective benefits in patients with even lower eGFR levels. The 2022 KDIGO guidelines now suggest continuing SGLT2i even after dialysis is initiated, if the patient was already taking the medication prior to dialysis [16]. However, the decision to initiate SGLT2i in patients with very low eGFR should be made with caution, considering the potential risks and benefits. It is also worth considering the context of the eGFR value; a stable eGFR of 20 may be better tolerated than a rapidly declining eGFR of 40, and this may influence treatment decisions.

Shared decision-making is crucial when considering medication discontinuation based on eGFR. Patients should be informed about the potential risks and benefits of continuing or discontinuing the medication, and their preferences should be taken into account. A collaborative approach between the patient and the healthcare provider can help ensure that the best possible treatment decisions are made.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

eGFR serves as a vital tool in assessing kidney function, guiding clinical decision-making, and monitoring the impact of therapeutic interventions. However, accurate interpretation of eGFR requires a comprehensive understanding of the methodologies used for its estimation, the various factors that can influence its values, and the clinical significance of eGFR changes. SGLT2i have revolutionized the management of diabetes and CKD, but their impact on eGFR necessitates careful monitoring and individualized treatment strategies. Navigating the complexities of medication discontinuation based on eGFR thresholds requires careful clinical judgment, shared decision-making, and a commitment to providing the best possible care for patients with kidney disease.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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