CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease

Abstract

The increasing global prevalence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has prompted research efforts to tackle the growing epidemic of diabetic kidney disease (DKD; also known as diabetic nephropathy). The limited success of much of this research might in part be due to the fact that not all patients diagnosed with DKD have renal dysfunction as a consequence of their diabetes mellitus. Patients who present with CKD and diabetes mellitus (type 1 or type 2) can have true DKD (wherein CKD is a direct consequence of their diabetes status), nondiabetic kidney disease (NDKD) coincident with diabetes mellitus, or a combination of both DKD and NDKD. Preclinical studies using models that more accurately mimic these three entities might improve the ability of animal models to predict clinical trial outcomes. Moreover, improved insights into the pathomechanisms that are shared by these entities — including sodium–glucose cotransporter 2 (SGLT2) and renin–angiotensin system-driven glomerular hyperfiltration and tubular hyper-reabsorption — as well as those that are unique to individual entities might lead to the identification of new treatment targets. Acknowledging that the clinical entity of CKD plus diabetes mellitus encompasses NDKD as well as DKD could help solve some of the urgent unmet medical needs of patients affected by these conditions.

Key points

  • Cardiovascular mortality and progression to end-stage renal disease are the two major unmet medical needs in patients with chronic kidney disease (CKD) plus diabetes mellitus.

  • In patients with diabetes mellitus, primary prevention of kidney disease, regardless of aetiology (diabetic kidney disease (DKD; also known as diabetic nephropathy)) or nondiabetic kidney disease (NDKD)), is essential and includes appropriate control of glucose, blood pressure, and body weight and avoidance of nephrotoxic drugs.

  • The clinical entity CKD plus diabetes encompasses DKD and NDKD or a combination of the two; diagnosis of these entities by kidney biopsy is important for disease management and research.

  • Biopsy studies show that NDKD is common in patients with type 2 diabetes mellitus (T2DM); as most patients with T2DM entering clinical diabetes trials do not undergo kidney biopsy, the pathophysiology underlying their kidney disease remains uncertain.

  • A disconnect exists between animal models used in preclinical studies of DKD and clinical studies with regard to differences in age, obesity status, renal function at onset, and use of co-medications; this disconnect might contribute to the poor predictability of animal studies for clinical trial outcomes.

  • Findings from clinical trials suggest that hyperfiltration driven by the sodium–glucose cotransporter 2 and the renin–angiotensin system is a common upstream mechanism that drives kidney disease in both DKD and NDKD in the context of diabetes mellitus.

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Fig. 1: Histopathological characteristics of DKD and NDKD at different stages of CKD.
Fig. 2: Causes of CKD in patients with diabetes mellitus and the pathophysiology of DKD.
Fig. 3: Haemodynamic and mechanic consequences of diabetes mellitus in DKD and NDKD.
Fig. 4: Nephron loss and compensatory nephromegaly of remnant nephrons and kidney size in DKD versus NDKD.
Fig. 5: Pathways of podocyte damage in diabetes mellitus.
Fig. 6: Hierarchy of pathomechanisms and temporal associations of diabetes mellitus and NDKD.

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Acknowledgements

H.-J.A. is supported by the Deutsche Forschungsgemeinschaft (DFG; AN372/24-1) and the European Union (EU)’s Research and Innovation programmes (under grant agreements Horizon 2020 and NEPHSTROM No. 634086). T.B.H. is supported by the DFG (CRC1140, CRC 992), by the Federal Ministry of Education and Research (BMBF; 01GM1518C; Germany), by the European Research Council grant 616891, and by the Horizon 2020 Innovative Medicines Initiative 2 consortium BEAt-DKD (Biomarker Enterprise to Attack DKD). M.S. was supported by BMBF grant 01GM1518A and a Fritz Thyssen Grant (10.16.2.026MN). The views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out.

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H.-J.A. has received consultancy fees from Roche, Bayer, Janssen, and Boehringer and lecture fees from Amgen and Fresenius. B.I., T.B.H., and M.S. declare no competing interests.

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Glossary

Diabetic kidney disease

(DKD). Also known as diabetic nephropathy. Often defined as a clinical syndrome of albuminuria in patients with diabetes mellitus but more accurately defined as a distinct histopathological pattern of kidney injury, characterized by arteriolar hyalinosis and nodular glomerulosclerosis, induced by hyperglycaemia.

Sodium–glucose cotransporter 2

(SGLT2). A transporter expressed in the S2 segment of the (convoluted) proximal tubule that reabsorbs freely filtered glucose and cotransports sodium.

GLP1 analogue

Glucagon-like peptide 1 analogues are incretin mimetics that reduce meal-related hyperglycaemia and have a low risk of causing hypoglycaemia. Liraglutide reduced cardiovascular and renal end points in patients with type 2 diabetes mellitus.

Kidney hypertrophy

A diffuse nephron hypertrophy that increases the size of the kidney.

Tubuloglomerular feedback

An autoregulatory mechanism of glomerular perfusion that maintains a submaximal single-nephron glomerular filtration rate (SNGFR) and responds to changes in intravascular fluid volume. Hyperglycaemia deactivates tubuloglomerular feedback and leads to a persistent increase in SNGFR.

Glomerular hyperfiltration

The consequence of an increase in single-nephron glomerular filtration rate due to impaired autoregulation of glomerular haemodynamics or a reduction in the nephron number:body mass ratio.

Glomerular hypertension

The increased pressure gradient across the glomerular filtration barrier that occurs, for example, when glomerular hyperfiltration is not associated with a respective increase in filtration surface.

Sterile inflammation

Non-infectious causes of inflammation such as those that occur in autoinflammatory or autoimmune disorders upon trauma or toxic tissue injury.

Spiegelmer

L-Ribonucleic acid aptamers that mirror structures of natural RNA oligonucleotides, protecting them from enzymatic degradation. Spiegelmers can bind and neutralize small proteins.

Danger-associated molecular patterns

(DAMPs). Natural cellular components, often released by dying cells, that induce inflammation via specific pattern recognition receptors of the innate immune system.

Adipokines

Cytokines secreted by the adipose tissue, including leptin, adiponectin, and apelin.

Nephron hypertrophy

The increased dimensions of nephrons, usually as a consequence of glomerular hypertension and hyperfiltration.

Total GFR

In poorly controlled diabetes, the total glomerular filtration rate (GFR) is close to maximal GFR.

Nephron number

A critical parameter for kidney function. The number of nephrons multiplied by single-nephron glomerular filtration rate (GFR) equals the total GFR.

Kimmelstiel–Wilson lesions

A lesion characterized by nodular glomerulosclerosis that is commonly found in biopsy samples from patients with diabetes mellitus.

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Anders, H., Huber, T.B., Isermann, B. et al. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol 14, 361–377 (2018). https://doi.org/10.1038/s41581-018-0001-y

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