What is diabetic nephropathy

Diabetic Nephropathy (DN) is a renal complication of type 1 and 2 diabetes. It must be differentiated from Diabetes Associated Renal Disease (DARD), which refers to Chronic Kidney Disease (CKD) attributed to Diabetes itself.

In diabetes, CKD is defined as the loss of renal function that reaches an estimated Glomerular Filtration Rate (eGFR) – 60 ml/min/1.73m2 (a figure above which we speak of Renal Insufficiency) and/or the presence of persistent Albuminuria (albumin in urine) (Albumin/creatinine ratio – 30 mg/g or albuminuria – 30 mg/24 h). However, Diabetic Nephropathy is reserved for those patients with diabetes who present histologically confirmed lesion of diabetic disease by Renal Biopsy.

The most common cause of renal disease in patients with diabetes is diabetic nephropathy (DN). Over the years, the condition slowly damages the kidneys’ filtration system, thus affecting their ability to eliminate wastes and excess fluid from the body.

Kidney Disease can progress to Renal Insufficiency which, as it progresses, can reach an advanced stage to the point of needing Dialysis and Renal Transplantation.

What is the diagnosis?

Early diagnosis of DKD is crucial and aims to prevent its progression and reduce the associated complications.

It is important to diagnose and screen all diabetic patients (type 1 and type 2) to determine the presence of diabetic kidney disease, as well as to maintain periodic medical check-ups.

Screening consists in the determination of Urinary Excretion of Albumin (EUA) with the albumin/creatinine ratio in isolated urine and serum Creatinine (Crp), together with the estimated Glomerular Filtration (eGFR).

Why does it occur?

  1. Elevated glucose levels exert their toxic effects inside the cells:

The presence of a situation of chronic hyperglycemia conditions the development and progression of Diabetes Associated Renal Disease (DARD).

Over time, poorly controlled diabetes damages blood vessels and other cells in the kidneys that filter wastes from the blood. Functional and structural changes occur in the kidney, which can lead to kidney damage and high blood pressure.

In addition, high blood pressure can cause even more kidney damage by increasing pressure on the kidneys’ delicate filtration system.

  1. Advanced glycation products (AGEs):

Hyperglycemia and increased intracellular glucose result in the activation of metabolic and enzymatic pathways that influence the formation of advanced glycation products (AGEs), which interact with other factors to produce tissue damage.

Advanced glycosylation is a process where the binding of sugars to different molecules such as proteins of the cell basement membrane and extracellular matrix occurs.

  1. The participation of oxidative stress:

The high metabolic activity of the kidney determines the generation of a significant amount of oxidizing molecules (Free Radicals). To eliminate them, the organism has an antioxidant defense system made up of enzymatic and non-enzymatic elements. Oxidative stress, a situation in which there is an excess of these highly reactive molecules with oxidative capacity, has been related to important deleterious actions at the renal level.

Hyperglycemia can induce oxidative stress, both through enzymatic and non-enzymatic pathways. All renal structures are susceptible to oxidative damage.

Intervention aimed at reducing oxidative stress has been postulated as a therapeutic strategy in DN. Likewise, from a non-pharmacological point of view, weight reduction and sodium intake restriction have been recommended as useful strategies. In relation to pharmacological strategies, various antioxidants have been used to assess their potential benefit as renoprotective agents.

  1. Growth factors and inflammatory phenomena:

The relationship between inflammation and DM complications is a topic of great interest, there being currently evidence of their close interrelationship.

Several studies have highlighted the role of inflammation and tissue repair phenomena in the pathogenesis of renal diseases. In this sense, the microvascular complications present in diabetes constitute a paradigm of the damaging action of growth factors and numerous inflammatory cytokines.

  1. The crucial role of the Renin-Angiotensin-Aldosterone System (RAS) in the genesis and progression of renal damage in diabetic patients:

The RAS is central to the mechanisms involved in renal and vascular damage. In addition, this system controls blood pressure (BP) and water-electrolyte balance through coordinated actions on the heart, blood vessels and kidneys.

Angiotensin II, the main effector of the RAS, exerts its vasoconstrictor effect predominantly on the efferent arterioles of the glomerulus, causing an increase in glomerular capillary pressure and, as a consequence, a greater ultrafiltration of plasma proteins that will contribute to proteinuria, an important phenomenon in the appearance and progression of renal damage.

Angiotensin II also contributes directly to the progression of renal disease through non-hemodynamic effects, since it acts as a true cytokine favoring inflammation, cell growth and fibrosis.

From the hemodynamic point of view, one of the main objectives to prevent the development and progression of nephropathy, as well as to reduce cardiovascular risk, is strict control of blood pressure (BP less than 130/80 mmHg).

In this context, RAS blockers offer differential therapeutic benefits on renal and cardiovascular risk that are not totally dependent on their effect on BP, making them first-line antihypertensive and antiproteinuric drugs in the treatment of patients with DN.

To optimize this antiproteinuric and renoprotective effect, titration to a dose capable of reducing proteinuria or the use of a combination of ACE inhibitors and ARBs is necessary.

  1. Increased knowledge of genetic susceptibility factors is growing and provides insight into interindividual variability in the development and progression of ND:

To date, it is not possible to predict which patients will develop ND. We know that only a percentage of diabetic patients will develop this complication, and that, moreover, despite the same therapeutic strategy, some will have a good response to treatment, while others will remain stable or progress to renal failure. All this suggests the existence of genetic factors related to the development and progression of DN, as well as to the response to treatment.

In addition, there are a number of risk factors that increase the likelihood of kidney damage.

What are the risk factors?

Factors that can increase the risk of Diabetic Nephropathy are:

  • High blood glucose (hyperglycemia).
  • Uncontrolled high blood pressure (hypertension).
  • Smoking.
  • High blood cholesterol level.
  • Obesity.
  • Family history of diabetes and kidney disease.

What symptoms can alert us?

In the early stages of diabetic nephropathy, it is quite possible that no signs or symptoms will be detected. In later stages, symptoms may include:

  • Worsening blood pressure control.
  • Protein in the urine.
  • Swelling of feet, ankles, hands or eyes (fluid accumulation edema).
  • Increased need to urinate more frequently.
  • Decreased need for insulin or diabetes medications.
  • Confusion or difficulty concentrating.
  • Shortness of breath.
  • loss of appetite
  • Nausea and vomiting.
  • constant itching
  • Fatigue.

Can we prevent the onset of diabetic nephropathy?

In order to prevent the onset of Diabetic Nephropathy (DN), slow its progression and reduce or avoid cardiovascular complications, we need:

  • Keep regular medical appointments for diabetes management: Keep annual medical appointments (or more frequent appointments if recommended by your health care team) to check your diabetes control and to identify diabetic nephropathy and other complications.
  • Treat diabetes: with effective treatment, you may be able to prevent or delay Diabetic Nephropathy.
  • Control high blood pressure or other conditions: high blood pressure and other conditions can increase your risk of kidney disease, so work with your doctor to control them.
  • Follow instructions on over-the-counter medications: follow the instructions on the packaging of pain relievers, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, ibuprofen, Diclofenac. Taking this type of painkillers can cause kidney damage to people with Diabetic Nephropathy, so their use should be avoided.
  • Maintain a healthy weight: it is important to be physically active most days of the week. Talk to your doctor about weight loss strategies if necessary, as well as increasing daily physical activity and consuming fewer calories.
  • Don’t smoke. Cigarette smoking can damage your kidneys and worsen existing kidney damage. If you are a smoker talk to your doctor to work on strategies for quitting. Support groups, some medications and counseling can help you quit smoking.
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How is it treated?

The best way to prevent or delay diabetic nephropathy is to maintain a healthy lifestyle with smoking cessation, physical activity, proper nutrition (low protein diet and reduced salt intake) and weight loss, if necessary. In addition, it is also important for the nephrology specialist to adequately control diabetes and high blood pressure.

Regarding the use of medications, drugs are recommended to slow the progression of renal disease (RAS blockers such as ACE inhibitors and ARA II, SGLT2 inhibitors, GLP1 agonists, antialdosteronics, etc.), reduce the risk of cardiovascular disease, reduce the risk of cardiovascular disease, and reduce the risk of heart disease. ), to reduce Cardiovascular Risk (Antihypertensives, Hypoglycemic Agents, Hypolipidemic Agents, Diuretics, etc.) and to treat other Renal Complications (Metabolic Acidosis, Hyperkalemia, Anemia, Hyperparathyroidism 2, etc.).

Blockade of the Renin-Angiotensin System (RAS) by treatment with ACEI or ARA II has been shown to reduce proteinuria and progression to DKD, and is therefore currently considered a fundamental therapeutic pillar in patients with this pathology, mainly in proteinuric DKD.

In the last 5 years, the treatment of Diabetic Kidney Disease (DKD) in terms of renal and cardiovascular protection has undergone an enormous advance, which represents a change in the paradigm of treatment of this entity. All this, thanks to sodium-glucose linked transporter 2 inhibitors (iSGLT2), glucagon-like peptide-1 receptor agonists (aRGLP1) and other treatments such as atrasentan and finerenone.

The most commonly prescribed iSGLT2 are empagliflozin, canagliflozin and dapagliflozin (more indicated in patients with CKD without diabetes). While ertugliflozin is in the trial phase.

Liraglutide and semaglutide are aRGLP1 aRGLP1s suitable for diabetic patients at high cardiovascular risk with decreased glycosylated hemoglobin (HbA1c) and for patients with decreased eGFR. Long-acting aRGLP1 can be administered in advanced CKD up to eGFR – 15 ml/min/m2.

The Kidney Disease Improving Global Outcomes (KDIGO) guidelines for diabetic kidney disease recommend treatment with metformin and iSGLT2, adding aRGLP1 aRGLP1 as the next option. Also, there is the possibility of associating different drugs to achieve good glycemic control, such as: DPP4 inhibitor, Insulin, Sulfonylurea, TZD, Alpha-glucosidase inhibitor.

Soluble guanylate cyclase activator, the combination iSGLT2 + endothelin receptor antagonist and mesenchymal stem cells are under trial for nephroprotection.

What are the possible complications?

In terms of organ involvement, Macrovascular complications can appear such as Cardiovascular conditions (Ischemic Heart Disease and Heart Failure), Cerebrovascular Disease (Stroke), Peripheral Arteriopathy. As well as Microvascular complications, such as DM Retinopathy, DM Neuropathy and DM Nephropathy.

Diabetic patients with both Renal alterations (Albuminuria and GFR alteration) presented an increase in Cardiovascular complications and Renal progression.

Early treatment could prevent or delay the progression of the disease and reduce the possibility of complications, which may appear progressively over months or years.

These complications may include:

  • Fluid retention, which could cause swelling (fluid accumulation edema) in the arms and legs,
  • Fluid in the lungs (Pulmonary Edema).
  • High blood pressure
  • Increased levels of potassium in the blood (hyperkalemia).
  • Heart and Vascular Disease (Cardiovascular Disease), which could lead to a stroke.
  • Damage to the blood vessels in the light-sensitive tissue at the back of the eye (Diabetic Retinopathy).
  • Reduced number of red blood cells to carry oxygen (Anemia).
  • Foot injuries, erectile dysfunction, diarrhea and other problems related to damaged nerves and blood vessels.
  • Bone and mineral disorders caused by the kidneys’ inability to maintain the correct balance of calcium and phosphorus in the blood.
  • Complications in pregnancy that imply risks for the mother and the developing fetus.
  • Irreversible damage to the kidneys (advanced stage renal disease), which eventually leads to the need for dialysis or a kidney transplant in order to survive.

In conclusion, the existence and persistence in DM of a hyperglycemic environment, together with the effect that this exerts on a great variety of factors (enzymatic systems, cytokines, growth factors, etc.), as well as the interactions between them, will condition the development and progression of RDD.

This complex web of factors and interactions is influenced by genetic factors, which can modulate the evolution of the disease and the response to the different treatment options.

All this forces us to establish complex therapeutic strategies and to maintain the risk/benefit balance in order to achieve an optimal response, with maximum guarantees, and also preserving the criteria of efficiency and scientific evidence.

Key points

1. Hyperglycemia is the determining factor in the development of complications associated with diabetes. Likewise, its control is fundamental from a preventive point of view.

2. Hyperglycemia and the increase in intracellular glucose result in the activation of alternative metabolic pathways and progressive deterioration of renal function.

3. Advanced Glycation Products are associated with the pathogenesis and progression of Diabetic Nephropathy.

4. In diabetic nephropathy, the direct relationship between the severity of renal injury and the degree of oxidative stress due to the presence of free radicals has been demonstrated.

5. The critical role of the Renin-Angiotensin-Aldosterone System (RAS) in the development and progression of diabetic nephropathy has been demonstrated with solid evidence. Inhibition of this system at different levels is currently one of the most important treatment strategies and continues to be an area of research of great interest.

6. One of the most recent and novel contributions to the knowledge of the pathophysiology of diabetic nephropathy derives from the participation of the inflammatory phenomenon, specifically inflammatory cytokines, which opens up new avenues of research and treatment.

7. We are learning in increasing detail how genetic variability between individuals is a determining element in the susceptibility to the development and progression of diabetic nephropathy. It is also an important factor that determines the response to different therapeutic strategies.