Proteinuria

What is Proteinuria?

Proteinuria is a medical term used when there is a presence of protein in the urine. This protein can be of various types, including albumin, globulin, Bence-Jones protein, and mucoprotein. Normally, about half of the protein that appears in our urine comes from the part of our kidney known as the distal tubule, specifically from something called the Tamm-Horsfall glycoprotein (THG).

Proteinuria is a sign of potential kidney damage and can be useful in diagnosing, predicting, and treating kidney-related conditions. Most of the time, proteinuria is caused by disturbances in our kidney’s filtering system. It can be a sign of early kidney disease, but it can also be seen in harmless conditions.

Nowadays, doctors also use proteinuria, along with another thing called the estimated glomerular filtration rate (eGFR), to categorize chronic kidney disease (CKD). Measuring the amount of protein in your urine can indicate early kidney disease. Additionally, it has been found that people with proteinuria have a higher risk of kidney damage due to high blood pressure and heart disease. The more protein found in the urine, the more likely the disease is to advance.

According to UK guidelines for chronic kidney disease, proteinuria is when the ratio of urine protein to creatinine (which is a waste product that your kidneys normally filter out of your blood) is more than 45 mg/mmol. However, unless there’s also blood in the urine, or if the ratio is over 100 mg/mmol, there’s generally no need to investigate further.

Contrarily, guidelines by the National Institute for Health and Care Excellence (NICE) define proteinuria as a urine protein to creatinine ratio of over 50 mg/mmol, or a urine albumin (a type of protein) to creatinine ratio of more than 30 mg/mmol.

What Causes Proteinuria?

Proteinuria, or having too much protein in your urine, can be put into two categories: transient and persistent.

Transient proteinuria is temporary and can be caused by a few things:

– Urinary tract infections
– Orthostatic proteinuria, which means you have protein in your urine after being active for a while. This doesn’t usually happen with your first pee of the day and is less common in people over 30.
– Having a fever
– Heavy physical activity
– Presence of vaginal mucus
– Pregnancy

Persistent proteinuria isn’t temporary, it stays. This can be caused by primary and secondary kidney diseases:

Primary kidney diseases might be diseases that directly affects the kidney:

– Glomerular diseases like glomerulonephritis (a type of inflammation in the kidneys)
– Tubular diseases, which involve the tubes in your kidneys

Secondary kidney diseases might be conditions that indirectly affects the kidney:

– Diabetes
– Connective tissue diseases
– Issues with your blood vessels (vasculitis)
– Amyloidosis, or the buildup of abnormal proteins
– Myeloma, a type of cancer
– Congestive heart failure
– High blood pressure (hypertension)

There are also benign, or harmless causes of proteinuria, which include:

– Fever
– Acute illness
– Intense physical activity
– Orthostatic proteinuria
– Dehydration
– Emotional stress
– Head injury
– Inflammatory process in the body

These benign causes of proteinuria do not increase the risk of other diseases or death. The condition usually goes away once the cause is addressed. Lastly, it’s important to note that protein in your urine is not a normal part of aging.

Risk Factors and Frequency for Proteinuria

Proteinuria, which refers to an excess amount of protein in the urine, is a common condition found in about 8% to 33% of the general population. This wide range is due to the different methods used for its detection. Diagnosing proteinuria is so important that Japan has implemented a screening program for it. One of the primary causes for this condition and subsequent kidney disease is the increasing frequency of type 2 diabetes. Among those with this illness, around 15.3 out of every 1,000 people per year experience persistent proteinuria. However, a positive urine dipstick test, which indicates proteinuria, reveals a serious underlying condition or a urinary tract infection in less than 2% of cases. In the United States, 3.3% of the adult population has been found to have persistent albuminuria, a specific type of proteinuria, despite having a normal eGFR, a measure of kidney function.

Factors like race, sex and age also influence proteinuria prevalence:

• Non-Hispanic Blacks and Mexican Americans have been found to have a higher rate of microalbuminuria, a mild increase of albumin in the urine, compared to non-Hispanic Whites.
• Primary and secondary kidney diseases, which lead to proteinuria, occur more often in males than females. In fact, persistent proteinuria is twice as common in males as it is in females.
• The likelihood of having persistent proteinuria and microalbuminuria increases with age due to the rise in conditions like hypertension and diabetes.

Signs and Symptoms of Proteinuria

Proteinuria, a condition where there is an abnormal amount of protein in the urine, often doesn’t come with any symptoms and is usually found during routine lab tests. It’s important for doctors to take a detailed history from the patient. They will ask about things like swelling in the legs, weight changes, and whether there have been any symptoms of problems with the connective tissues (like joint pain, skin rashes, and mouth ulcers). They should also ask about any specific pain in the area of the kidneys, or abdomen, as well as trouble breathing, pain in the chest when breathing, or chills. Another thing to look out for is whether the urine has looked different (like red or frothy), especially if this happened after a respiratory infection. Additionally, they need to know about any other health conditions, like high blood pressure, diabetes, or heart failure.

Another important part of the patient’s history includes any medications they’ve taken, both prescribed and over-the-counter. This is to check if any of these medications may be causing the proteinuria. Some of these medications could include certain pain relievers, blood pressure medicine, diuretics, antibiotics, and even some herbal remedies. It’s also essential to understand if there any family history of kidney diseases or problems with the connective tissues. During the physical examination, the doctor will be checking for symptoms like fluid buildup, muscle loss, rashes, abnormal sounds in the abdomen, or small blood spots under the nails. They’ll also be looking for signs of other diseases that may be linked, like problems with the eyes, swollen or deformed joints, liver disease, heart murmurs, unusually large organs, and swelling in the lymph nodes. Checking blood pressure can also give a clue about the diagnosis.

• Swelling in the legs
• Weight changes
• Symptoms of connective tissue problems (joint pain, skin rashes, mouth ulcers)
• Pain in the kidney area or abdomen
• Trouble breathing
• Chest pain when breathing
• Chills
• Changes in the urine appearance
• Other health conditions (high blood pressure, diabetes, heart failure)
• Medication history
• Family history of kidney or connective tissue diseases
• Physical symptoms (fluid buildup, muscle loss, rashes, abdominal sounds, blood spots under nails)
• Signs of related diseases
• Blood pressure

Testing for Proteinuria

If your doctor suspects that you have protein in your urine (known as “proteinuria”), they’ll first check to make sure you don’t have a urinary tract infection or diabetes. An initial screening test can be done in the doctor’s office using a urine dipstick. This special testing strip will show if there is protein in your urine and will also give an idea of how severe the proteinuria is. However, this test isn’t perfect – for example, it might show severe proteinuria in a very well-hydrated person (who is producing a lot of diluted urine) but a less severe case in someone who is dehydrated. Furthermore, some substances, like immunoglobulins, won’t be detected by the urine dipstick, so an additional test using sulfosalicylic acid (SSA) may be done.

The urine dipstick can sometimes give false positives (say there’s protein when there isn’t) or false negatives (say there isn’t protein when there is). Dehydration, urinary tract infections, blood in the urine, high urine pH, and recent exercise can lead to false positives. While drinking too much water or having certain proteins in your urine can lead to false negatives.

A 24-hour urine collection test can give a more accurate measure of how much protein is in your urine, but it can be a bit difficult to do. An alternative is a urine protein to creatinine ratio (UPCR) test, which can be done on a single urine sample (preferably one taken first thing in the morning). This test can also help determine whether further tests are needed.

Your doctor may also check your blood levels of electrolytes, urea, and creatinine, as well as your serum albumin and cholesterol levels, depending on your protein levels. The protein levels should be looked at alongside kidney function tests. For example, someone with normal protein levels but abnormal kidney function tests should be investigated further.

Another useful test for kidney function is the “creatinine clearance” test, which measures how well your kidneys remove creatinine, a waste product, from your blood. This test considers factors such as your age, weight, and gender. Healthy adults typically have a creatinine clearance rate of more than 90 ml/min, but this can vary based on muscle mass and age.

There are also various imaging tests, such as renal (kidney) ultrasound, and blood tests for certain immune markers and viruses that can help determine the cause of the proteinuria. The severity of proteinuria can be classified as normal, ‘nephritic’ or ‘nephrotic’, based on the levels of protein in the urine.

Knowing the specific type of protein in the urine can help guide treatment. For instance, whether it’s albuminuria, characterized by abnormal amounts of a protein called albumin in the urine – this can be classified into normal, microalbuminuria and macroalbuminuria, based on the quantity of albumin in the urine.

Finally, a kidney biopsy (where a small piece of kidney tissue is removed and analysed) might be considered if your proteinuria is above 1 g per day. This can help figure out exactly what’s going on and guide treatment options.

Treatment Options for Proteinuria

The treatment of proteinuria, which is having high amounts of protein in your urine, focuses on treating its specific cause. In addition, treatment often aims to reduce how much unnatural protein, especially albuminuria (albumin, a type of protein, found in the urine), is present. This is usually achieved through drugs that act on the body’s renin-angiotensin-aldosterone system (a system that regulates blood pressure and fluid balance).

According to the 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines, adults having more than 300 mg/24 hours of persistent proteinuria are strongly recommended to use ACE inhibitors or angiotensin receptor antagonists (ARB). These are a type of medicines used for reducing blood pressure.

Research has shown that ACE inhibitors, in particular, are effective in reducing proteinuria in both diabetic and nondiabetic patients. They also significantly reduce the risk of kidney disease progressing, meaning there is less need for kidney replacement therapy (this is when your kidney function is replaced either completely by a kidney transplant, or partially by dialysis). Kidney Health Australia has stated that the goal of reducing proteinuria by 50% in the first six months to a year can lead to a similar decrease in the risk of kidney disease progression.

Interestingly, one study showed that ACE inhibitors were more effective in slowing down the progression of proteinuria in patients with higher levels of proteinuria. During treatment with ACE inhibitors, it’s necessary for doctors to regularly check the patient’s creatinine and potassium levels. It should be noted that there is no significant difference between ACE inhibitors and ARBs with regards to their effectiveness and side effect profiles. The choice depends on the patient’s response and the doctor’s experience.

Trials combining ACE inhibitors with ARBs and direct renin inhibitors (another type of blood pressure medicine) have shown an increased risk of side effects, such as having an excessively high amount of potassium in your blood, low blood pressure, kidney impairment, and fainting. Currently, there is not enough evidence to recommend a combination of ACE and ARB to prevent kidney disease progression for proteinuria patients.

Patients with moderate to severe proteinuria, who have too much fluid in the body, sometimes require diuretic therapy (medication that help to get rid of excess fluid in the body) and a dietary salt restriction. Aldosterone antagonists (a type of drug that blocks the hormone aldosterone) have shown benefits in treating proteinuria. However, combining ACE inhibitors with aldosterone antagonists can increase the risk of having too much potassium in the blood and breast enlargement in men but has been shown to significantly reduce the risk of death in patients with heart failure.

Finally, non-dihydropyridine calcium channel blockers (NDCCBs), a group of medications that are used to lower blood pressure, can help decrease proteinuria. A newer generation of NDCCBs, when used with ARBs, has shown to decrease proteinuria.

What else can Proteinuria be?

If a patient has proteinuria, which means there is an excess of proteins in their urine, they need to be fully examined and treated correctly to avoid further health issues. The following possible causes need to be considered:

• Damage to the kidneys caused by diabetes (Diabetic nephropathy)
• Protein in urine due to standing up (Orthostatic proteinuria)
• Damage to kidneys caused by toxic substances, medicines, or drugs (Nephrotoxins, drug-induced nephropathy, such as NSAIDs, lithium, heavy metals, heroin)
• Infections such as a urinary tract infection, HIV, or Hepatitis B and C
• Glomerulonephropathies or chronic disease affecting tubules in the kidneys
• Amyloidosis, a rare disease that deposits abnormal protein called amyloid in tissues and organs
• After a kidney transplant
• Preeclampsia, a condition in pregnant women marked by high blood pressure
• Certain types of cancer (like myeloma or lymphoma)
• Elevated level of lipids in the blood (Dyslipidemia)
• Connective tissue diseases
• Vasculitis, an inflammation of the blood vessels
• Heart failure
• High blood pressure (Hypertension)
• Dehydration
• Intense physical activity or exercise
• Emotional stress

What to expect with Proteinuria

Research indicates that identifying and addressing the issue early on can significantly improve outcomes for patients with protein in their urine, also known as proteinuria. Proteinuria is often used to estimate the likely course of numerous diseases. For instance, in a kidney disease called IgA nephropathy, the presence of proteinuria can lead to worse outcomes for patients.

Similarly, higher proteinuria levels are linked with worse outcomes in patients with chronic kidney disease. In another kidney disorder termed idiopathic membranous nephropathy, proteinuria is also associated with poor outcomes. Additionally, proteinuria detected after a kidney transplant can result in higher death rates and shortened longevity of the transplanted kidney.

For a pregnant woman suffering from preeclampsia – a pregnancy complication characterized by high blood pressure, the presence of proteinuria can be harmful for both the mother and the baby.

Possible Complications When Diagnosed with Proteinuria

Proteinuria, or excessive amounts of protein in the urine, can lead to several serious complications. These include increased risks of:

• Heart disease in the coronary arteries
• Brain diseases related to the blood vessels
• Bleeding in the gastrointestinal tract
• Worsening of kidney disease
• Blood clotting issues, including vein blood clots
• Lung congestion due to fluid overload
• Bacterial infections
• Kidney replacement therapy needs, such as dialysis or transplant
• Death

Research shows that having low amounts of excess protein in the urine, known as microalbuminuria, can increase the risk of heart disease and diseases associated with brain blood vessels by up to 50% and 70% respectively. In cases of macroalbuminuria, where the excess protein levels are significantly higher, the risk for both complications can double.

Preventing Proteinuria

If a patient needs to collect their urine over a 24 hours, it’s important that they clearly understand how to do this. They should receive easy-to-follow written instructions. Some medications, like ACE inhibitors and angiotensin receptor blockers, can have side effects that patients should be aware of. These side effects can include swelling in the face and throat (angioedema), feeling dizzy, coughing, fainting (syncope), low blood pressure (hypotension), high potassium levels in the blood (hyperkalemia), and a small increased chance of developing lung cancer.

Patients who have moderate to severe proteinuria, meaning there’s an excessive amount of protein in the urine, they usually have too much fluid in their body. In such cases, it’s recommended for patients to reduce their salt intake to manage this condition.