Coming to terms with chronic kidney disease

Chronic kidney disease (CKD) is one of the main contributors to premature mortality worldwide. It is important to recognize the unfortunate reality that CKD is incurable. There are (currently) no long-term medication solutions to slow down or stop its progression. In this sense, kidney disease is different from other life-threatening diseases such as heart failure, diabetes, and high blood pressure. Each of the above has life-extending treatment solutions already in place (and more in the pipeline). Treatments for kidney damage, on the other hand, are radical, leading ultimately to direct interventions such as regular dialysis or a kidney transplant as the only viable solutions.

Understanding the cause/effect circle in kidney disease

Kidney disease is different from other diseases. Mainly kidney problems can be the result of other specific health problems (mainly diabetes, high blood pressure (HBP), and high cholesterol) and can also cause those same conditions or make them worse if left untreated. There are very few medications that can actively prevent or slow down the progress of kidney malfunction. However, it is possible to restrict the development of the disease by properly treating underlying causes like HBP, cholesterol, or diabetes. For these conditions, many effective medications have been shown to both treat the fundamental condition and have beneficial effects on the kidneys. 

• High blood pressure is a leading cause of CKD due to the damage it causes to blood vessels throughout the body and to the glomeruli, the tiny filtering units inside the kidneys. In turn, the kidneys may stop removing wastes and extra fluid from the blood, raising blood pressure even more. The kidneys play a key role in keeping blood pressure in a healthy range. Diseased kidneys may fail to produce enough of the enzyme known as renin that helps to control blood pressure (see below).

Angiotensin receptor blockers (ARBs) like as Diovan, Edarbi, Cozaar, Atacand, Hyzaar, Entresto, or Avapro are blood pressure medications that control blood pressure by influencing the same renin angiotensin aldosterone system (RAAS) that the kidneys control, so they are usually preferred over Angiotensin-converting enzyme (ACE) inhibitors like Vasotec, Zoprotec, Vasodip Combo or Altace.

• Type 2 diabetes causes high sugar levels, which can damage the tiny filters (nephrons) inside the kidneys and the blood vessels that carry blood to and from the kidneys. Many people with diabetes also develop high blood pressure.

Treatment of diabetes with either GLP-1 RA medications like Ozempic and Mounjaro, or SGLT2 medications like Farxiga and Jardiance produce extra benefits, directly improving the outlook for patients with early kidney disease. People with conditions related to the heart and blood vessels, like hypertension (high blood pressure) and chronic kidney disease, have experienced notable improvements with the new medicines.

• High cholesterol is a direct cause of kidney damage since cholesterol plaque can clog the renal arteries and cut off blood flow to the kidneys, resulting in loss of kidney function. In turn, this raises the risk of high blood pressure which can lead to cardiovascular (CV) events. Studies have shown that CV events are one of the most common causes of death among patients with CKD.

Statins like Lipitor, Liptruzet, or Lovaza reduce LDL cholesterol levels and slow down the progression of plaque formation.

What is the main function of the kidneys?

The kidneys are vital organs, each about the size of a fist, located just below the rib cage on either side of the spine. Their primary role is to filter waste and remove waste products and excess fluids from the blood. This waste is then excreted in the urine. This process is crucial for maintaining the optimum balance of body salts and minerals such as potassium, sodium, and calcium in the blood. 

Besides filtration, what are other functions performed by the kidneys?

The kidneys are also involved in the production of hormones that regulate blood pressure and contribute to red blood cell production and bone health.

The kidneys produce an enzyme known as renin which plays a role in controlling blood pressure. Renin interacts with several proteins in the bloodstream which act as a vasoconstrictor, causing blood vessels to narrow and raising blood pressure. This mechanism is part of the renin angiotensin aldosterone system (RAAS) which helps maintain blood pressure by regulating volume and salt levels in the body. By controlling the release of renin, the kidneys help maintain blood pressure within a healthy range.

In addition to regulating blood pressure, the kidneys also play a vital role in the production of red blood cells through a hormone called erythropoietin (EPO). EPO stimulates bone marrow to generate blood cells which are essential for oxygen transport throughout the body. The kidneys produce EPO when oxygen levels in the blood are low, ensuring that the body receives a sufficient supply of oxygen-rich blood. This process is vital for sustaining energy levels supporting muscle function and overall well-being.

Another hormone produced by the kidneys is calcitriol which is a form of vitamin D. It plays a key role in keeping calcium levels balanced in the body, which is necessary for bone health and overall chemical equilibrium within the body. Vitamin D from the blood is converted into calcitriol by the kidneys, aiding in the absorption of calcium from food in the intestines. This process is vital for the development and upkeep of bones. Furthermore, the kidneys assist in regulating phosphate levels, which are also crucial for maintaining healthy bones.

What can go wrong in the kidneys?

There are three main causes of kidney failure:

• The effects of other diseases on the kidney’s glomeruli, the tiny filtering units within the kidney where blood is purified. The main causes are:
  • Type 2 diabetes, where high blood sugar levels can damage the blood vessels of the glomeruli. 
  • High blood pressure can also damage the glomeruli by increasing the pressure on the delicate structure, leading to scarring (glomerulosclerosis).
  • Autoimmune diseases like lupus and IgA nephropathy (Berger’s disease) can lead to inflammation and damage to the glomeruli.
• The side effects of toxins and medications
  • nonsteroidal anti-inflammatory drugs (NSAIDs), as well as certain antibiotics and cancer treatments, can cause glomerular damage either through direct toxicity or by triggering immune responses. 
  • medications that are toxic to the kidney’s tubular cells, including antibiotics such as aminoglycosides, antiviral drugs like acyclovir, and proton pump inhibitors (PPIs) can cause acute kidney injury (AKI) to the tubules of the kidneys, which are responsible for reabsorbing water and essential substances from the filtered blood, and the surrounding interstitial tissue.
• Kidney diseases such as:
  • Glomerulonephritis caused by infections, drugs, or defects at birth.
  • Polycystic Kidney Disease, which is a genetic disorder that causes numerous cysts to grow in the kidneys, interfering with kidney function.
  • Prolonged obstruction of the urinary tract, caused by conditions like enlarged prostate, kidney stones, and some cancers can block the urinary tract, causing pressure and damage to the kidneys over time.
  • Recurrent kidney infections that can cause scarring that lead to permanent kidney damage.
  • Development of kidney stones, which can go along with a family history of kidney failure.

What are the main symptoms of CKD?

In the early stages of chronic kidney disease (CKD), symptoms can be mild, making the condition difficult to detect without specific tests. However, as kidney function declines, people may start to notice signs and symptoms that could indicate the onset or presence of CKD. 

Symptoms that can be present in the early stages of CKD include:

• Fatigue and weakness can be caused by reduced kidney function. This can lead to a buildup of toxins and impurities in the blood. This can also be related to anemia, a common complication of CKD, where there are not enough red blood cells to carry oxygen to the body’s muscles and tissues, further contributing to feelings of fatigue and weakness.
• Anemia is also a result of reduced kidney function
• Swelling (edema) in the feet, ankles, hands, or face can occur because the kidneys cannot eliminate excess fluid from the body effectively. This fluid retention can be one of the more noticeable early signs of kidney disease.
• Flank pain, which is pain on one side of the body between the upper abdomen and the back, can be a symptom of CKD. In kidney disease, this pain can result from the stretching of the capsule that surrounds the kidneys due to fluid retention, inflammation, or the presence of cysts in conditions like polycystic kidney disease. However, it can also be caused by conditions unrelated to CKD, such as kidney stones or infections. Therefore, doctors use other tests to evaluate the relevance of this symptom in the context of other signs and symptoms of kidney disease.
• Gross hematuria refers to the visible presence of blood in the urine, causing it to appear pink, red, or cola-colored. This occurs when the kidneys or other parts of the urinary tract allow blood cells to leak into urine. Various conditions other than CKD can cause gross hematuria, including infections, kidney stones, tumors, or diseases affecting the kidneys like glomerulonephritis, and inflammation of the kidney’s filtering units (glomeruli). In the context of CKD, gross hematuria may indicate a progressing condition or an acute exacerbation of kidney damage, requiring immediate medical attention to determine the underlying cause.
• Albuminuria is the presence of albumin in the urine and is one of the earliest signs of kidney damage. Measuring albumin levels in the urine is a key part of diagnosing and monitoring the progression of CKD. Albumin is one of several protein types usually found in the blood, and healthy kidneys can filter specific proteins out while retaining albumin in the body. Its presence in urine indicates that the kidneys’ filtering system is damaged, allowing proteins to escape into the urine. Foamy urine is often a sign of proteinuria (high levels of proteins including albumin) in the urine. Failure to retain these proteins leads to a frothy or foamy appearance in the urine. This symptom suggests that the glomeruli in the kidneys are damaged and that the condition could be progressing.
• Nocturia is the condition of frequently waking up during the night because of the need to urinate. While there are many other possible causes of nocturia, in the context of CKD it reflects the kidneys’ diminished ability to concentrate urine effectively. This leads to the production of a larger volume of dilute urine, causing individuals to wake up frequently at night to urinate. Nocturia can be both a symptom of CKD and a factor that exacerbates the condition by disrupting sleep patterns and affecting overall health.
• Other changes in urination besides foamy urine, nocturia, albuminuria and hematuria can signal CKD. This can include increased or decreased frequency of urination, the urgency to urinate, or difficulty urinating. Changes in the color of urine, such as it being darker or lighter than usual, can also occur.
• Loss of appetite, vomiting, and nausea may be due to the accumulation of waste products in the blood (uremia.) The buildup of waste products can also cause pruritus, which causes severe skin itching.
• Cognitive changes, such as trouble concentrating or decreased alertness, can occur in the early stages of CKD. These changes can be due to the buildup of toxins in the blood affecting brain function.
• Hypertension (high blood pressure) is both a cause and a symptom of CKD. The kidneys play a key role in regulating blood pressure by controlling blood volume and the amount of blood vessel constriction. When the kidneys are damaged, they are less able to regulate blood pressure effectively, leading to hypertension and congestive heart disease.

How is CKD diagnosed?

While early stages of CKD often present with few or no symptoms, as the disease progresses, more noticeable signs begin to emerge. Doctors will then typically diagnose through routine blood tests and urine studies. The blood test measures creatinine levels, a product that working kidneys can remove waste. Based on a person’s age, size, and gender, the doctor can calculate how many milliliters of waste your kidneys should be able to filter in one minute. This is known as the estimated glomerular filtration rate (eGFR). Healthy kidneys should be able to filter out more than 90 ml of creatine per min. 

eGFR results are ranked from 1 (lowest) to 5 (highest):

• stage 1 (G1) shows a normal eGFR (above 90 ml/min). If there are other symptoms, other tests could still detect signs of kidney damage
• stage 2 (G2) shows a slightly reduced eGFR (60 to 89 ml/min), with other signs of kidney damage
• stage 3 (G3) shows a reduced eGFR (30 to 59 ml/min)
• stage 4 (G4) shows an eGFR of 15 to 29 ml/min, indicating acute kidney failure
• stage 5 (G5) with an eGFR below 15 ml/min means the kidneys have lost almost all of their function

A test is also done to check the levels of albumin and creatinine in the urine. This is known as the albumin:creatinine ratio, or ACR. Along with the eGFR, the ACR result can help give a more accurate picture of how well the kidneys are working. The ACR result ranked from stage A1 (lowest) to A3 (highest):

• A1 – an ACR of less than 3 mg/mmol
• A2 – an ACR of 3 to 30 mg/mmol
• A3 – an ACR of more than 30 mg/mmol

The standard definition of CKD is an eGFR of G3 or higher (less than 60 ml/min), together with ACR of A3, persisting for more than 3 months, or if there are markers of kidney damage (eg, hematuria or structural abnormalities such as polycystic or dysplastic kidneys)..

Other tests may also be necessary to assess the level of damage to the kidneys. These may include an ultrasound scan, MRI scan or CT scan, which allow the doctors to see what the kidneys look like and check whether there are any blockages. If extensive physical damage is suspected, a biopsy to gather a small sample of kidney tissue is performed and the cells are examined under a microscope.

Together, all test results can be used to determine the extent of damage to the kidneys, and the result is known as the stage of CKD. This can help doctors assess all the risk factors and decide on the most appropriate treatment and how often further tests should be conducted to monitor the condition. There are no cures for chronic kidney disease.