Diabetic kidney disease (DKD), also known as diabetic nephropathy, is the most common cause of end-stage kidney disease in patients in developed countries (1,2). Approximately 20-30% of patients with diabetes develop DKD in their lifetime (1,3). DKD is common in both patients with type 1 and type 2 diabetes mellitus, but it is more common in those with type 2 diabetes (4). CKD in diabetes is diagnosed through the same means as patients without diabetes and is measured by evaluating a patient’s kidney function, usually consisting of albumin-to-creatinine ratio and glomerular filtration rate (GFR). Patients are diagnosed with DKD after three months of experiencing reduced kidney function or kidney damage in the presence of diabetes (5). Once diagnosed, DKD is a chronic condition that worsens over many years, leading to eventual end-stage kidney disease. (1,2). Therefore, it is important to understand the development and progression of this disease.

Hyperglycemia is the main factor that initiates progression toward kidney disease in patients with diabetes. Other factors that contribute to this progression include insulin resistance, hyperinsulinemia, and concurrent hypertension (4). Prolonged hyperglycemia can begin damaging the kidney through altering tissues and direct damage from glucose metabolism products (6,7). Hyperglycemia triggers the accumulation of advanced glycation end products (AGEs) that can cause cell injury through both receptor and non-receptor mediated pathways (6,7). AGEs decrease nitric oxide (NO) bioavailability, increasing oxidative stress. AGE receptor activation can cause the activation of both reactive oxygen species (ROS), that triggers pancreatic beta cell apoptosis, and nuclear factor kappa B (NFKB), a transcription factor that is the stimuli for several harmful intracellular and extracellular products. Through these pathways, many unfavorable processes take place, including cell growth and hypertrophy, inflammation, angiogenesis, endothelial dysfunction, and extracellular matrix (ECM) production. Outside of the cell, ECM production leads to collagen crosslinking that decreases tissue compliance and causes tissue damage.

Glucose metabolism products can activate several pathways including the polyly, hexosamine, and protein kinase C (PKC) pathways. These pathways lead to increased oxidative stress, increased connective tissue growth factor (CTGF), and decreased matrix metalloproteinases (MMP), an extracellular matrix component. These hyperglycemia-mediated, metabolic pathways can then lead to cell damage, cell and vascular dysfunction, and negative cellular environments, such as inflammation and tissue fibrosis (6,8). Inflammation and tissue fibrosis are seen as causes of diabetic nephropathy and may lead to CKD progression through macrophage pathways or secondary kidney injury (6). While macrophages are attracted to the kidney, endothelial cell dysfunction and damage leads to the production of adhesion molecules of the cell surface that allows transendothelial movement of macrophages. Injury to kidney cells, such as podocytes, mesangial cells, and tubular cells stimulates the secretion of chemokines that allows intrarenal macrophage movement. Macrophages are activated into proinflammatory M1 through ROS, angiotensin II, and mineralocorticoid receptor (MR) activation. These activated macrophages can cause damage while also releasing profibrotic cytokines that cause cell proliferation and ECM expansion, leading to tissue fibrosis. Transforming growth factor beta-1 (TGFB1), which importantly contributes to mesangial cell hypertrophy and extracellular matrix accumulation (diabetic glomerulosclerosis), can also increase CTGF and decrease MMPs, forming another pathway to fibrosis of cells. Inflammation and fibrosis may also lead to CKD progression by contributing to acute kidney injury (AKI).

Hemodynamic factors can also lead to the progression of DKD (6). One such factor that may occur early on in patients with diabetes is hyperfiltration, which is the increase in the glomerular filtration rate of a single nephron due to the increase in glomerular capillary pressure. There are many factors in a patient with diabetes that may cause this intraglomerular hypertension characterized by a disproportionate reduction in afferent versus efferent renal arteriolar resistance as a result of multiple circulating vasoactive factors. Also contributing is the upregulation of the sodium glucose cotransporters, SGLT1 and SGLT2, which reduce sodium chloride delivery to the macula densa and decrease afferent arteriolar tone further. Other contributors to the development of DKD, specifically in regard to nephropathy, are growth factors such as vascular endothelial growth factor (VEGF). VEGF leads to vascular proliferation and increased endothelial permeability within the kidney that will damage nephrons over time.

Nephrons, the functional units of the kidney, can be damaged and lose their functionality in the progression of DKD (9). As the kidney experiences a decrease in functioning nephrons, along with a decreased GFR, the kidney will initiate compensatory effects in an attempt to normalize filtering and excretion. Compensatory kidney effects can lead to hyperfunction of remaining nephrons. One result of these compensatory pathways is an increase in single nephron glomerular filtration rate (SNGFR). The kidney can also experience glomerular hypertrophy and an increase in glomerular capillary pressure, creating a state of hypertension within the kidney that furthers damage over time. As nephron damage continues due to these compensatory effects, patients will experience further decline in kidney function and progression of their CKD.

The damage to the kidneys can manifest in several ways. There are several possible signs of kidney disease in patients with diabetes both in the early and late stages (10). The earliest sign of kidney disease in diabetes is increased albumin excretion in the urine which may be later associated with development of frank proteinuria, weight gain, ankle swelling, increased frequency of urination at night, and an increased blood pressure. Therefore, it is important for patients with diabetes to have their blood, urine, and blood pressure checked regularly to monitor for these signs. Late signs of kidney disease in diabetes include increased blood urea nitrogen (BUN) and creatinine levels. Patients may experience anemia, muscle cramps, itching, increased fatigue, nausea, vomiting, and a loss of appetite. In addition to these indicators, pathology, if available, reveals the histological damage due to DKD including glomerular lesions, tubular atrophy, and interstitial fibrosis (1,8). Glomerular lesions can take a few years to develop in patients with either type 1 or type 2 diabetes (1). The severity of these lesions correlates with decreased kidney function, including decreased GFR and albuminuria.

Many pathways contribute to kidney damage and dysfunction in diabetic kidney disease; therefore, it is important to monitor the development of DKD and vigorously manage glycemic control in patients with diabetes. Those living with diabetes can work to prevent DKD through glycemic control and healthy lifestyle. It is important for patients with both diabetes and CKD to avoid hyperglycemia and lifestyle factors, such as smoking, increased alcohol consumption, unhealthy eating, and lack of exercise, which can worsen their diabetes and increase their risk of CKD progression.

References:

1. Caramori ML, Rossing P. Diabetic Kidney Disease. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; August 3, 2022.
2. Varghese RT, Jialal I. Diabetic Nephropathy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 25, 2022.
3. Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: diabetic nephropathy. Am J Kidney Dis. 2015;66(5):e37-e38. doi:10.1053/j.ajkd.2015.08.010
4. Thomas MC, Brownlee M, Susztak K, et al. Diabetic kidney disease. Nat Rev Dis Primers. 2015;1:15018. Published 2015 Jul 30. doi:10.1038/nrdp.2015.18
5. Pavkov ME, Collins AJ, Coresh J, Nelson RG. Kidney Disease in Diabetes. In: Cowie CC, Casagrande SS, Menke A, et al., eds. Diabetes in America. 3rd ed. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); August 2018.
6. Agarwal R. Pathogenesis of Diabetic Nephropathy. In: Chronic Kidney Disease and Type 2 Diabetes. Arlington (VA): American Diabetes Association; June 2021.2-7.
7. Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol. 2011;1(3):1175-1232. doi:10.1002/cphy.c100049
8. Tervaert TW, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556-563. doi:10.1681/ASN.2010010010
9. Fattah H, Layton A, Vallon V. How Do Kidneys Adapt to a Deficit or Loss in Nephron Number?. Physiology (Bethesda). 2019;34(3):189-197. doi:10.1152/physiol.00052.2018
10. Diabetes – A Major Risk Factor for Kidney Disease. National Kidney Foundation. www.kidney.org/atoz/content/diabetes. Accessed June 29, 2023.

GMO-000824  Rev A  09/2023