Non-Proteinuric Diabetic Kidney Disease: The Flip Side of the Story

More than a decade ago, as a new nephrologist in town, I approached diabetic kidney disease (DKD) with the assumption that proteinuria, especially albuminuria (>30 mg/g Cr or urine albumin >30 mg/day), was the earliest and essential biomarker for its diagnosis(1). In the absence of proteinuria, I would confidently exclude DKD, guided by the prevailing understanding at the time. However, I was unaware of the broader narrative surrounding this complex condition. Over time, with a growing body of evidence challenging this long-held belief, I came to realize the existence of a non-proteinuric variant of DKD (NP-DKD)—a form of the disease characterized by reduced glomerular filtration rates (GFR) and structural kidney damage, but without significant proteinuria ( eGFR< 60 ml/min and UACR <30 mg/g Cr) (2). 

Worldwide, diabetes mellitus affects 1 in 10 adults, and 40% of them develop DKD (3). Approximately 30-50% of patients with DKD progress to ESRD, and over half experience some form of cardiovascular disease, including coronary artery disease, stroke, and heart failure (4). The traditional view of DKD is believed to follow a five-stage progression model: starting with glomerular hyperfiltration, advancing to microalbuminuria ( >30 mg/g Cr), then macroalbuminuria ( >300 mg/g Cr), followed by a gradual decline in GFR and ultimately progressing to ESRD (5). In this model, albuminuria precedes the decrease in GFR and is associated with an increased risk of ESRD and cardiovascular mortality. The presence of albumin in the urine increases the risk of chronic kidney disease (CKD) progression as reabsorption of filtered albumin in the proximal tubule activates reactive oxygen species and the production of pro-inflammatory cytokines, endothelin-1, and TGF-β, ultimately driving tubulointerstitial fibrosis, atrophy, and renal function decline, so often seen in patients with diabetic nephropathy (6). Histologically, albuminuria (proteinuria) is usually associated with glomerular disease, as manifested by glomerular basement membrane thickening, mesangial expansion, hyalinosis, and nodular glomerulosclerosis on kidney biopsy (called diabetic glomerulopathy or diabetic nephropathy). 

On the flip side, 20-40% of patients with diabetes have NP-DKD, with a prevalence of around 20% in patients with T1DM and up to 40% in T2DM. Recent data from the Third National Health and Nutrition Examination Survey (NHANES III) have indicated that the prevalence of DKD is rising despite the decreasing prevalence of albuminuria. These opposite trends in the two most important manifestations of DKD argue against the traditional view of CKD in DKD and suggest that GFR decline may occur irrespective of albuminuria. Patients with NP-DKD tend to be more commonly females, the older age group, non-smokers, and those with a known relatively shorter duration of diabetes (7).. Aggressive use of RAAS blockade and SGLT2 inhibitors has mitigated proteinuria but has contributed to the increased prevalence of NP-DKD. Besides, patients with NP-DKD tend to have better BP control, lower HbA1C levels, and better lipid profiles.  Interestingly, stigmata of microvascular disease, like retinopathy and neuropathy, are less common in this phenotype than in the proteinuric DKD (P-DKD). Although kidney biopsies are less commonly performed in this subgroup, histological studies have shown a higher prevalence of tubulointerstitial fibrosis, atrophy, and vascular lesions like arteriosclerosis and arteriolar hyalinosis in this cohort, suggesting a different underlying pathophysiology (Table 1). In fact, varying glomerular lesions are seen in less than 20% of biopsies in patients with NP-DKD compared to >50% in patients with proteinuric DKD. These findings suggest that renal impairment in NP-DKD is not caused by hyperglycemia or microangiopathy, but aging, arteriosclerosis, and macroangiopathy are more likely to contribute to NP-DKD. Superimposed factors such as hypertensive nephrosclerosis, episodes of acute kidney injury, and concomitant additional renal disease have all been suggested to explain the underlying pathophysiology for this subtype of DKD (6).

Characteristics	Proteinuric DKD	Nonproteinuric DKD
Sex	Predominantly males	Predominantly females
Age	Young	Old
HbA1C correlation	Yes	No
Metabolic Profile	Poor	Good
BP control	Sub optimal	Somewhat optimal
Biopsy features	Predominantly glomerular lesions	Predominantly tubulointerstitial and vascular lesions
Retinopathy	>50%	<20%
CV disease	High	High
ESRD progression	Very high	High
Treatment strategies	RAAS inhibitors, SGLT-2 inhibitors, MRAs, GLP-1 agonists	RAAS blockers?SGLT-2 inhibitors?GLP-1 agonists

Table 1. Differentiating features between proteinuric and nonproteinuric diabetic kidney disease

On the flip side, 20-40% of patients with diabetes have NP-DKD, with a prevalence of around 20% in patients with T1DM and up to 40% in T2DM. Recent data from the Third National Health and Nutrition Examination Survey (NHANES III) have indicated that the prevalence of DKD is rising despite the decreasing prevalence of albuminuria. These opposite trends in the two most important manifestations of DKD argue against the traditional view of CKD in DKD and suggest that GFR decline may occur irrespective of albuminuria. Patients with NP-DKD tend to be more commonly females, the older age group, non-smokers, and those with a known relatively shorter duration of diabetes (7). Aggressive use of RAAS blockade and SGLT2 inhibitors has mitigated proteinuria but has contributed to the increased prevalence of NP-DKD. Besides, patients with NP-DKD tend to have better BP control, lower HbA1C levels, and better lipid profiles.  Interestingly, stigmata of microvascular disease, like retinopathy and neuropathy, are less common in this phenotype than in the proteinuric DKD (P-DKD). Although kidney biopsies are less commonly performed in this subgroup, histological studies have shown a higher prevalence of tubulointerstitial fibrosis, atrophy, and vascular lesions like arteriosclerosis and arteriolar hyalinosis in this cohort, suggesting a different underlying pathophysiology. In fact, varying glomerular lesions are seen in less than 20% of biopsies in patients with NP-DKD compared to >50% in patients with proteinuric DKD. These findings suggest that renal impairment in NP-DKD is not caused by hyperglycemia or microangiopathy, but aging, arteriosclerosis, and macroangiopathy are more likely to contribute to NP-DKD. Superimposed factors such as hypertensive nephrosclerosis, episodes of acute kidney injury, and concomitant additional renal disease have all been suggested to explain the underlying pathophysiology for this subtype of DKD(6).

While the GFR decline in patients with NP-DKD is lower than in patients with P-DKD (2-3% vs. 5-6% per year), the risk of cardiovascular and all-cause mortality is comparable to P-DKD with preserved GFR, suggesting that macrovascular complications may be more common in this subset of patients than adverse renal outcomes (8). Recent advances in treating P-DKD have markedly improved outcomes, particularly in reducing albuminuria. SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (e.g., finerenone), and GLP-1 receptor agonists have demonstrated significant antiproteinuric and cardioprotective effects. However, while these agents slow disease progression, therapies that directly preserve or restore GFR remain limited. Current strategies, including risk factor modification, mitigate damage rather than reverse it, and a subset of patients continues to progress despite optimal therapy. This underscores the need for novel treatments targeting tubulointerstitial fibrosis and inflammation and the development of better biomarkers to identify high-risk individuals earlier and personalize intervention.

NP-CKD represents the flip side of the DKD story that is often overlooked. While reducing proteinuria remains central to slowing DKD progression and improving cardiovascular outcomes, patients with NP-DKD progress to ESRD through distinct, proteinuria-independent mechanisms. This highlights a critical gap—current therapies may be less effective in NP-DKD, and targeted research is urgently needed to uncover specific pathways and develop treatments that address this phenotype to halt CKD progression.

References:

1. Diabetes Control, and Complications Trial/Epidemiology of Diabetes Interventions, and Complications (DCCT/EDIC) Research Group. Renal Outcomes in Patients with Type 1 Diabetes and Macroalbuminuria. J. Am. Soc. Nephrol.

2. Yadav, R. K.; Sangha, S.; S Kumar, A.; Bagchi, S.; Mahajan, S.; Bhowmik, D.; Agarwal, S. K. Pos-364 to Study the Clinical Phenotype of Non - Proteinuric Kidney Disease in Type 2 Diabetic Patients. Kidney Int. Rep. 2021, 6 (4), S158.

3. Diabetes now affects one in 10 adults worldwide. International Diabetes Federation. https://idf.org/news/diabetes-now-affects-one-in-10-adults-worldwide/ (accessed 2025-04-06).

4. Scilletta, S.; Di Marco, M.; Miano, N.; Filippello, A.; Di Mauro, S.; Scamporrino, A.; Musmeci, M.; Coppolino, G.; Di Giacomo Barbagallo, F.; Bosco, G.; Scicali, R.; Piro, S.; Purrello, F.; Di Pino, A. Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk. Biomolecules 2023, 13 (5), 752.

5. Yamanouchi, M.; Furuichi, K.; Hoshino, J.; Ubara, Y.; Wada, T. Nonproteinuric Diabetic Kidney Disease. Clin. Exp. Nephrol. 2020, 24 (7), 573–581.

6. D’Marco, L.; Guerra-Torres, X.; Viejo, I.; Lopez-Romero, L.; Yugueros, A.; Bermídez, V. Non-Albuminuric Diabetic Kidney Disease Phenotype: Beyond Albuminuria. touchREV. Endocrinol. 2022, 18 (2), 102–105.

7. Shi, S.; Ni, L.; Gao, L.; Wu, X. Comparison of Nonalbuminuric and Albuminuric Diabetic Kidney Disease among Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Front. Endocrinol. (Lausanne) 2022, 13, 871272.

8. Jin, Q.; Luk, A. O.; Lau, E. S. H.; Tam, C. H. T.; Ozaki, R.; Lim, C. K. P.; Wu, H.; Jiang, G.; Chow, E. Y. K.; Ng, J. K.; Kong, A. P. S.; Fan, B.; Lee, K. F.; Siu, S. C.; Hui, G.; Tsang, C. C.; Lau, K. P.; Leung, J. Y.; Tsang, M.-W.; Kam, G.; Lau, I. T.; Li, J. K.; Yeung, V. T.; Lau, E.; Lo, S.; Fung, S.; Cheng, Y. L.; Chow, C. C.; Huang, Y.; Lan, H.-Y.; Szeto, C. C.; So, W. Y.; Chan, J. C. N.; Ma, R. C. W.; Hong Kong Diabetes Biobank Study Group. Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings from the Hong Kong Diabetes Biobank. Am. J. Kidney Dis. 2022, 80 (2), 196-206.e1.