Diabetes and Kidney Disease: The Perfect Storm

Diabetic kidney disease (DKD) imposes a tremendous medical, economic, and societal burden. It is reported to occur in around 40% of people with diabetes in the US, although estimates vary considerably. There are 37.3 million people in the US who live with diabetes, meaning DKD has a very high prevalence.

The mortality rate for patients with DKD is approximately twice that of people with diabetes without kidney disease or people with non-diabetic chronic kidney disease. Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) and kidney failure, followed by hypertension. Either HT or CKD can permanently compromise kidney function, but together they constitute a “perfect storm” that further increases the risks of progressive DKD, kidney failure, and a diminished average lifespan.

While this article focuses on the links between DM and DKD, In addition to hypertension, other frequently contributing risk factors such as unhealthy lipid levels, obesity, and smoking, must also be considered in efforts to prevent or minimize the progression of DKD. This is particularly important given the poorer outcomes for patients with DKD when compared to those with non-diabetic CKD.

What is chronic kidney disease (CKD)?

A diagnosis of CKD requires an abnormal level of overall kidney function (glomerular filtration rate or GFR) or the presence of a blood protein (albumin) in the urine (also referred to as albuminuria or proteinuria) for at least 3 months. In the case of diabetes, these are the most common signs of early kidney injury.

These abnormalities arise from damage to the hundreds of thousands of microscopic kidney filtration units (nephrons). Each nephron contains a glomerulus and an attached tubule. Within the ball-shaped glomerulus are tiny blood vessels through which blood flows and undergoes filtration to separate water, waste products, and other small molecules from the blood cells. This solution then flows through tubules that selectively return minerals, electrolytes, and water to the blood, while allowing unnecessary fluid and waste products to be excreted into the urine.

When nephrons are damaged in diabetic CKD, kidney blood flow, filtration, and excretion are compromised. As a result, there is decreased capacity for waste product elimination, body fluid regulation, and loss of proteins (principally albumin) in the urine due to the damaged filter. Urine albumin content is a frequently measured indicator of protein leakage. The continuous leakage of even modest amounts of albumin may be an early sign of kidney injury.

Since the early stages of DKD are usually asymptomatic and slowly progressive, monitoring for DKD is commonly done by measuring albuminuria and detecting a decreased GFR. People with diabetes should have regular monitoring of urine protein levels and overall kidney function to assess for DKD.

What are the direct effects of diabetes on the kidney?

At least 40% of people with diabetes develop DKD. The presence or absence of DKD has a significant impact on patient survival. Compared to people with diabetes and without DKD, the 10-year mortality rate for those with DKD increases at least fourfold. Many complex and interrelated disturbances of metabolic processes leading to hypertension also can contribute to chronic kidney injury. Nonetheless, the direct or indirect consequences of chronically elevated blood sugar (hyperglycemia) play the primary role.

In general, hyperglycemia disrupts the structure and function of the walls of arteries, big and small. It also is associated with low-grade inflammation and blood vessel narrowing and occlusion. The net effect is the disruption of the body’s ability to regulate blood flow, including flow through the kidney glomeruli, diminishing the efficiency of kidney filtration.

Chronic hyperglycemia also affects kidney tubular structure and function, resulting in a diminished capacity to excrete waste products and regulate water and mineral balance.

With increasing numbers of irreversibly injured kidney nephrons, there are increased stresses and accompanying injury to the remaining functional nephrons (hyperfiltration). Over time, this leads to further nephron loss and a vicious cycle that can eventually result in kidney failure.

The progression of DKD and the presence of several other risk factors, if detected early, can often be stabilized or slowed. Note that hyperglycemia also triggers injuries to systemic arteries, leading to increased risks of atherosclerosis, cardiovascular disease, stroke, and impaired vision or blindness (diabetic retinopathy) among others.

Can DKD be prevented or controlled?

There are several measures that should be implemented to prevent or control the progression of DKD. Overall, the general recommendations for the management of CKD apply to DKD. It is essential to closely monitor kidney function and the rate of albumin excretion for early detection.

Conventional treatments for CKD that include lifestyle changes, diet modifications, and blood pressure control, along with blood sugar normalization, can be effective treatments for diabetic hyperglycemia. Estimates vary, but the consistent control of blood sugar (HbA1c), alone, can increase patient survival by years. However, this approach reduces but does not eliminate, the risks of DKD and the other potential complications of diabetes. From a medication standpoint, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are often used to treat elevated blood pressure in diabetics, both to control hypertension and diminish stressors that adversely affect nephron function and survival. Although these medications are beneficial, they are incompletely effective in controlling chronic CKD. This has led to research to identify other medications that may be used alone, or in combination with, ACE-Is or ARBs.

Recently, several newer classes of medications have generated considerable interest for the treatment of diabetic chronic kidney disease.

Endothelin A receptor antagonists

Selective endothelin A receptor antagonists (SERA) block the actions of endothelin-1. Endothelin-1 has multiple effects that include blood vessel constriction, inflammation, and tissue fibrosis. These are among the factors that contribute to progressive chronic kidney disease. Hyperglycemia induces endothelin-1. Experimental studies have convincingly shown that some SERAs can decrease proteinuria and slow the progression of DKD. Human trials are in their early stages and preliminary results are favorable. SERAs can cause kidney water and sodium retention, which cause or worsen congestive heart failure.

Sodium/glucose co-transporter 2 (SGLT-2) inhibitors

SGLT-2 inhibitors (e.g. Dapagliflozin [Farxiga]) are glucose-lowering drugs that also have additional beneficial properties in DKD. These include improvement and possible stabilization of kidney function (GFR) and reduction of hyperfiltration that, in itself, causes ongoing injury to the kidney nephrons. Clinical studies of SGLT-2 inhibitors have generally demonstrated slower progression of DKD and resulted in fewer patients requiring dialysis and/or kidney transplantation.

Glucagon-like peptide-1 receptor agonists (GLP-1ra)

GLP-1ra is another glucose-lowering class that can be used in patients at any stage of DKD. It also can prevent or diminish high levels of albuminuria and slows the decline of overall kidney function. These are indicators of stabilization or improvement of ongoing kidney injury. Additional benefits include weight reduction and cardiovascular protection.

Key takeaways

DKD occurs in at least 40% of patients with diabetes mellitus.

Early signs of DKD are abnormal amounts of albumin in the urine or tests that indicate diminished kidney function.

If unchecked, diabetic kidney disease can progress, and patients may require dialysis and/or kidney transplantation. In the US, DKD is the leading cause of end-stage kidney disease resulting in dialysis and/or kidney transplantation. Patient mortality is also significantly affected.

There are multiple processes in people with diabetes that result in kidney injury; the majority, but not all, of these are linked to poor control of glucose levels (hyperglycemia). Elevated levels of blood glucose cause numerous metabolic and cellular abnormalities that are not limited to the kidney.

Several potentially modifiable factors that can diminish the degree of DKD include the basic management principles for chronic kidney disease. It is particularly important to strictly control elevated glucose levels and hypertension, maintain a healthy weight, and quit smoking.

Recent studies have shown some glucose-lowering drugs have demonstrated properties that can slow the progression of DKD. The drug classes include sodium/glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1ra). These are often used in combination with angiotensin-converting enzyme inhibitors or receptor blockers. Selective endothelin A receptor antagonists (SERA) also can blunt hyperglycemia-associated inflammation and injury to kidney nephrons.

Resources:

Afkarian M, Sachs MC, Kestenbaum B. et al. Kidney Disease and Increased Mortality Risk in Type 2 Diabetes. 2013; JASN 24 (2): 302-308

Centers for Disease Control (CDC) Diabetes/Chronic kidney disease

CDC National Diabetes Statistics Report (2020)

Hiddo J, Heerspink L, de Zeeuw D. Endothelin Receptor Antagonists for Kidney Protection: Lessons from the SONAR Trial. 2022; CJASN 17 (6) 908-910.

Hussain S, Jamali MC, Habib A. Diabetic kidney disease: an overview of prevalence, and biomarkers. 2020; Clinical Epidemiology and Global health.

Kalra S, Kaira B. Counselling Patients for GLP-1 Analogue Therapy: Comparing GLP-1 Analogue with Insulin Counselling

National Kidney Foundation Preventing Diabetic Kidney Disease: 10 Answers to Questions

National Kidney Foundation Hot Topics: SGLT2 Inhibitors and Kidney Disease GLP

Tachkov K, Mitov K, Koleva Y, et al. Life expectancy and survival analysis of patients with diabetes compared to the non-diabetic population in Bulgaria. 2020; PLoS One: 15(5)

Wen CP, Chang CH, Tsai MK, et al. Diabetes with early kidney involvement may shorten life expectancy by 16 years. 2017; Kidney International 92: 388-396

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