Changing Paradigm for Reducing Proteinuria and Slowing Renal Insufficiency in People with Diabetic Kidney Disease

INTRODUCTION Chronic kidney disease (CKD) in the context of diabetes, commonly referred to as diabetic kidney disease (DKD), remains a significant global public health challenge. The presence and progression of proteinuria, or albuminuria, serve not only as key indicators of renal damage but also as contributors to further injury. Conventionally, proteinuria reduction has been considered primarily a surrogate marker for renoprotection. However, recent developments indicate that early, aggressive, and multimechanistic interventions targeting proteinuria and its underlying pathogenic drivers represent a new paradigm. In this editorial, we will examine the evolution of this paradigm, which is shifting from a narrow focus on glycemic and blood pressure control to a comprehensive, multitargeted, and precision medicine approach that addresses hemodynamics, metabolism, inflammation, tubular injury, and fibrosis, all with the objective of slowing CKD progression in patients with DKD. THE LEGACY VIEW: PROTEINURIA AS MARKER AND MEDIATOR Proteinuria is both a key marker and a mediator of kidney damage. Its presence indicates glomerular injury and contributes to the progression of CKD. Studies such as the REIN trial[1] have shown that higher baseline proteinuria predicts a more rapid decline in kidney function. Analyses of 11 trials confirm that reducing proteinuria improves renal outcomes, regardless of the underlying cause or treatment.[2,3] Increases in proteinuria are never linked to better outcomes.[2] These findings have shifted clinical focus to proteinuria not only as a prognostic marker but also as a central therapeutic target for slowing CKD progression. Elevated urinary protein excretion reflects glomerular damage and is associated with faster decline in estimated glomerular filtration rate (eGFR) and progression to end-stage kidney disease (ESKD). Evidence shows that proteinuria actively contributes to further renal injury through mechanisms such as glomerular hyperfiltration, podocyte stress and loss, tubular overload, and interstitial inflammation and fibrosis.[3] This dual role as both marker and mediator supports targeting proteinuria reduction as a key therapeutic strategy. In DKD, the classic paradigm was: optimize glycemia, blood pressure, control lipids, lifestyle change; over time reduce albuminuria and thereby slowing CKD progression. However, in clinical practice, many patients experience disease progression despite receiving these standard-of-care treatments. This observation prompts consideration of whether the current management paradigm has reached its maximum efficacy and highlights the need to identify strategies to further improve patient outcomes. KEY PILLARS OF THE NEW PARADIGM Hemodynamic modulation beyond renin–angiotensin–aldosterone system (RAAS) RAAS blockade with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers remains the cornerstone of therapy in DKD. Reductions in proteinuria and slower decline in eGFR served as the basis for earlier clinical trials. The new paradigm refines hemodynamic modulation. Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce intraglomerular hypertension by decreasing tubular sodium reabsorption and modulating tubuloglomerular feedback. This process results in afferent arteriolar constriction and reduced glomerular stress. Clinical trials such as CREDENCE[4] and DAPA-CKD[5] demonstrated significant improvements in renal outcomes. Therefore, combining SGLT2 inhibition with RAAS blockade constitutes a major integrated hemodynamic strategy. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) such as finerenone target mineralocorticoid receptor-mediated hemodynamic and nonhemodynamic effects, including sodium reabsorption, fibrosis, and inflammation. The combination of RAAS blockade, SGLT2 inhibitors, and MRAs provides a robust, evidence-based foundation for reducing proteinuria.[6] Metabolic and glucorenal protection Hyperglycemia remains a primary driver of DKD development and progression. However, intensive glycemic control alone is often insufficient to prevent progression once albuminuria is present. The current paradigm emphasizes early and sustained glycemic control as part of a broader, multifaceted strategy rather than the sole focus. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only improve glycemic control and promote weight loss but may also provide direct renal protection through anti-inflammatory effects and reduction of albuminuria. For example, the FLOW trial of semaglutide reported renal outcome benefits.[7] Thus, metabolic modulation is an essential pillar of the new therapeutic approach. Anti-inflammatory and antifibrotic strategies A significant advancement in the paradigm is the recognition that persistent proteinuria and hyperfiltration trigger inflammation, oxidative stress, tubular injury, interstitial fibrosis, and ultimately nephron loss. Much of the irreversible damage in CKD results from tubulointerstitial injury rather than glomerular lesions alone.[3] Therefore, reducing proteinuria should be complemented by therapies targeting the downstream consequences of protein overload. These include: Targeting mineralocorticoid receptor overactivation (through finerenone), which reduces inflammation and fibrosis[6] Exploring endothelin-1 (ET-1) receptor antagonists (e.g., atrasentan), which showed proteinuria reduction in DKD (albeit with cardiovascular concerns) and are illustrative that nonhemodynamic pathways matter[6] Investigating tubular cell protection, modulation of autophagy and ferroptosis, epigenetic interventions (emerging research), which may impact proteinuria indirectly by preserving nephron integrity.[8] Early intervention and combination therapy A major shift in the new paradigm is the timing and combination of therapies. Historically, interventions were escalated in a stepwise manner, beginning with RAAS blockade, followed by the addition of SGLT2 inhibitors and other agents as needed. The new approach advocates for early use of multiple agents, to achieve greater proteinuria reduction, improved renal outcomes, and potentially alter the trajectory of CKD progression.[9] A network meta-analysis cited in Zhang et al.[8] demonstrated that combining SGLT2 inhibitors, GLP-1 RAs, and nonsteroidal MRAs reduced CKD progression by approximately 58% (Hazard Ratio [HR]: 0.42; 95% confidence interval: 0.31–0.56) in modeled projections compared with RAAS monotherapy. Although real-world data on full triple therapy are still emerging, these findings support the shift toward early combination therapy. In clinical practice, this paradigm suggests that for patients with type 2 diabetes mellitus (T2DM) and albuminuria, RAAS blockade, SGLT2 inhibitors, and possibly MRAs should be initiated earlier, with close monitoring of residual albuminuria and prompt adjustment of therapy as needed. Precision medicine and biomarkers of residual risk The new paradigm also emphasizes identifying residual risk beyond standard clinical markers. Some patients with controlled glycemia and blood pressure continue to experience disease progression, indicating the presence of unrecognized pathogenic processes. Research into biomarkers such as tubular injury markers, inflammatory signatures, genetic and epigenetic markers, and exosomes is gaining momentum.[8] Tailoring therapy based on these biomarkers –for example, by selecting anti-inflammatory or antifibrotic therapies for patients with a high inflammatory biomarker burden – is increasingly being considered. Although emerging biomarkers such as neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), urinary proteomic panels, and exosome-derived signatures hold promise for earlier detection and more precise risk stratification, their widespread clinical application is currently constrained by limited assay availability, high cost, and the absence of robust, prospective validation in a large, diverse DKD population.[10] At present, these biomarkers should therefore be regarded as investigational tools that complement, but do not replace, established markers such as albuminuria and eGFR in routine clinical practice. This paradigm also supports more rigorous monitoring of albuminuria or proteinuria, not simply as an optional measure but as a guide for therapy intensification. If residual albuminuria remains above 300 mg/g despite first-line therapy, earlier escalation of treatment is recommended. DKD manifests phenotypic heterogeneity, with nonproteinuric DKD representing a clinically important but underaddressed form comprising 20%–40% of cases, particularly in type 2 diabetes. Unlike classical proteinuric DKD, this phenotype features progressive eGFR decline without significant albuminuria (300 mg/g) and CKD (eGFR 300 mg/g and eGFR decline) for these therapies may maximize benefit. Advocacy for access and generic options remains vital. LOOKING AHEAD: FUTURE DIRECTIONS The emerging paradigm suggests several promising avenues for future research: Biomarker development and residual risk stratification: Identifying patients who remain at high risk despite optimal standard care, such as those with persistent albuminuria or elevated inflammatory and fibrotic biomarkers, will facilitate individualized therapy and enable early treatment intensification Novel therapeutic pathways: Agents that target ferroptosis, tubular epithelial injury, exosome-mediated intercellular signaling, epigenetic modification, and complement activation are currently in development Precision combination trials: Future clinical trials may tailor therapy according to mechanistic phenotypes Implementation science and global equity: Applying this paradigm in real-world settings, particularly in low- and middle-income countries, will require redesigning healthcare systems, conducting cost-effectiveness modeling, improving access to medications, and enhancing patient education Long-term outcome data and real-world evidence: Although albuminuria reduction serves as an intermediate endpoint, comprehensive long-term data on ESKD, dialysis initiation, cardiovascular mortality, and the cost-effectiveness of early combination therapy remain essential. CONCLUSION The management of proteinuria in DKD and the progression of CKD are undergoing significant transformation. A more comprehensive paradigm is emerging that integrates hemodynamic modulation (RAAS system inhibitors, SGLT2 inhibitors, and MRAs), metabolic and glucorenal strategies (GLP-1 RAs), and anti-inflammatory or antifibrotic interventions. These approaches are increasingly applied early, often in combination, tailored to individual risk profiles, and guided by proteinuria and other biomarkers. Within this framework, proteinuria is recognized not only as a marker but also as a modifiable therapeutic target, with its reduction established as a primary objective. For clinicians, this shift necessitates reconsideration of the timing and intensity of therapeutic initiation in patients with T2DM and albuminuria. It requires adopting multiagent strategies, actively monitoring albuminuria, and individualizing therapy rather than relying on standard care until failure. Successful implementation of this paradigm has the potential to be transformative, resulting in slower CKD progression, fewer patients requiring dialysis or transplantation, reduced cardiovascular burden, and improved quality of life for millions.