What is papillary necrosis?

Renal papillary necrosis is a disorder of the kidneys where the renal papillae die. These are regions where urine enters the ureters and collecting duct holes enter the kidney. The clinical development of papillary necrosis depends on multiple factors which include vascular impairment, the overall health of the individual and the number of affected papillae.

This condition can lead to the development of secondary effects which are more harmful to the body. For instance, sloughing of the papillae is a common effect which leads to destruction and eventually kidney failure. This condition has been increasingly linked to multiple autoimmune diseases suggesting there is a complex interplay between immune system dysfunction and renal health.

Overview of papillary necrosis

How does papillary necrosis develop?

When papillary necrosis begins to develop it may affect a single papillae or the entire kidney depending on the severity of the disease. Renal papillary necrosis is a disease that only affects the inner, more distal zone of the medulla and the papilla; it never affects the entire medulla.

This condition can develop through multiple mechanisms, the first one being vascular impairment particularly observed in individuals with sickle cell anemia. The vasa recta (the small blood vessels in the renal medulla) are obstructed by erythrocytes that are sickle-cell based.

Another mechanism is ischaemia which is present in individuals who take NSAIDs or analgesics. This happens when the vasa recta also gets blocked as a result of the inhibition of cyclooxygenase-mediated production of prostaglandins.

This leads to a direct toxic effect on cells of the medulla and this damage affects the vascular system of the medulla. The medulla’s main function is to synthesize prostaglandins and when this is blocked there is reduced prostaglandin production, resulting in decreased vascular perfusion and vasoconstriction.

Causes and risk factors

There are many causes of papillary necrosis: 

• Infections
• Drugs (especially NSAIDs and analgesics)
• Vascular diseases
• Diabetes
• Autoimmune diseases 

There has been ongoing research and multiple case studies to define the main risk factors of papillary necrosis. According to a case report by the Department of Urology in Iran, the common risk factors include the following: 

• Abuse of NSAIDs
• Diabetes mellitus 
• COVID-19
• Hypertension 
• Obstruction of the urogenital tract 
• Sickle cell disease 
• Cirrhosis of the liver
• Renal vein thrombosis 

Clinical presentation and symptoms

Symptoms of Papillary Necrosis:

• Flank pain
• Hematuria (blood in urine)
• Fever
• Renal colic

Autoimmune diseases associated with papillary necrosis

Autoimmune diseases are diseases of the immune system, in which the cells of the immune system attack the body’s healthy tissues. Autoimmune disorders can impact almost every tissue type and organ in the body. Numerous symptoms, including discomfort, exhaustion, rashes, headaches, nausea, dizziness, and more.

Key autoimmune diseases linked to papillary necrosis

Systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune illness that causes chronic inflammation and damage to multiple organs. Autoantibodies are used to make a clinical and serological diagnosis. Lupus nephritis is a frequent symptom of SLE. It is primarily triggered by a type-3 hypersensitivity reaction that produces immune complexes.

The immune complexes formed then deposit on the glomerular part of the kidney which leads to an inflammatory response activating neutrophils to recruit to the site affecting the kidneys. Furthermore, this can cause cell damage as the immune system is exposed to self-antigens which target healthy cells leading to overactivation of the immune response. This is due to the production of autoantibodies which lead to kidney damage.

Rheumatoid arthritis (RA)

RA is an autoimmune disease that causes inflammation which can affect and damage various organs including the kidney. If RA persists it can develop into rheumatoid vasculitis which is a long-term complication of RA, this affects the blood vessels of the kidney leading to a reduction in the function of the kidney.

These effects are direct whereas indirect involve chronic inflammation associated with RA which can lead to the development of cardiovascular disease. This can then affect the kidney function. In order to treat RA, NSAIDs are used to reduce inflammation by inhibiting cyclooxygenase (COX), these are responsible for producing prostaglandins. Prostaglandins are important as they play a key role in regulating kidney function and blood flow, especially in situations where blood pressure is low.

The decreased prostaglandin production can lead to reduced blood flow and therefore ischemia in the renal papillae. Consequently, this is a risk factor in the development of papillary necrosis as there is a lack of blood supply to the kidney.  

Sjögren’s syndrome

Sjögren’s syndrome (SS) is an autoimmune condition which arises due to lymphocytic infiltration of exocrine glands including the salivary glands. This can lead to symptoms including dry eyes and mouth linked to SS. The kidneys can be affected by this autoimmune condition as a result of the chronic inflammation leading to various renal dysfunctions.

One particular complication is Tubulointerstitial Nephritis, which is where inflammation affects the tissue and tubules of the kidney resulting in interstitial inflammation which is accompanied by fibrosis. This can lead to impaired tubular function where there is a lack of secretion of hydrogen ions and loss of potassium resulting in hypokalemia and impaired water reabsorption.

Another complication is glomerular involvement, although less common in SS,  can cause nephritic syndrome if it rapidly progresses causing hypertension and decreased kidney function. Studies have suggested that this happens due to a mechanism of the immune complex pathway (classical complement pathway).

Vasculitis (e.g., Polyarteritis nodosa)

Vasculitis is characterized by a group of disorders that lead to the inflammation of blood vessels, this can result in the damage and destruction of the walls of the vessel. Consequently, this effect leads to the development of Ischemia as there is reduced blood supply and therefore organs are damaged. In the context of the kidney, a common disorder is Polyarteritis Nodosa (PN).

This is a vasculitis disorder that affects medium-sized blood vessels that are supplied to the kidney and bowel. Individuals with PN have inflamed renal arteries which lead to necrosis and deposition of the vessels causing Ischemia and restricted blood flow. As the inflammation continues, the blood vessels can form a clot known as thrombosis further restricting blood flow and supply.

Renal papillae are susceptible to Ischemia as they are already narrow and blood flow is further restricted. The tips of the renal papillae can undergo Ischemic injury and will detach itself from the urinary tract leading to infection and blood in urine. Consistent Ischemia can lead to loss of kidney function due to structural damage.

Diagnosis

Imaging examinations, laboratory testing, and, in certain situations, kidney biopsies are needed to diagnose papillary necrosis and determine the degree of tissue destruction. Furthermore, determining whether an autoimmune disease is present at all is essential to figuring out the underlying cause and designing a course of treatment.

Diagnostic methods for papillary necrosis

Urography: This includes an X-ray, CT scan or MRI of the kidneys. Before individuals undergo the examination, a specific dye which is intravenous (IV) is given. This makes it easier to highlight and detect the kidney, bladder and uterus for any abnormalities. The dye is important as it outlines the renal papillae making it easier to detect areas of necrosis. 

 Uretescopy: This involves a thin, flexible tube with a camera attached known as a ureteroscope inserted through the urethra and bladder to instantly visualize the ureters and the inside of the kidney. This is generally performed under local anaesthesia and is important in allowing direct visualization of the renal papillae to detect sloughed tissue.

Kidney Biopsy: This is where a small tissue sample from the kidney is extracted using a needle when a patient is being examined under ultrasound or CT scans. The biopsy sample is then taken to a laboratory for microscopic examination to assess the inflammation present, and any necrosis or vascular damage.

Autoimmune disease testing 

The first test involves an antinuclear antibody test (ANA) which is used to indicate the presence of specific antibodies against a component in the nucleus of a cell. It does not entirely detect a single disease but is suggestive of an autoimmune process that is active. The second test is a Rheumatoid Factor (RF) test which is used to help diagnose RA through detection of antibodies. 

Treatment and management

Immunosuppressive therapy

• Corticosteroids such as prednisone are useful in reducing inflammation in multiple autoimmune diseases
• Methotrexate helps suppress and downplay the immune response leading to reduced activation, particularly in autoimmune diseases like lupus and RA

Anti-inflammatory medications

Balancing the consumption of pain relief medications while minimizing kidney damage is important. NSAIDs should generally be avoided as they exert nephrotoxic effects.

General management and preventive strategies

Patients with renal papillary necrosis should avoid taking analgesics like NSAIDs or combination analgesics containing aspirin as they increase the risk of kidney damage. Moreover, other nephrotoxic agents should be avoided such as certain antibiotics like Aminoglycosides and diuretics. The use of catheters should be discouraged as they increase the risk of urinary tract infection (UTI) and should only be used if necessary. Furthermore, ensuring that the patient maintains good hydration to prevent the risk of UTIs. Regular assessment of the renal function is important to help detect any complications

Summary 

Kidney failure may result from renal papillary necrosis, a condition in which the renal papillae, the regions where urine enters the ureters die. It arises from conditions such as impaired blood flow, particularly in sickle cell anaemia, or from taking NSAIDs, which damage renal tissue. Infections, substance abuse, diabetes, and autoimmune conditions including RA and Systemic Lupus Erythematosus (SLE) are common causes. Renal colic, fever, blood in the urine, and flank pain are common symptoms.

Urine analysis and imaging tests are used in the diagnosis process. Medicines are used to treat the condition by decreasing inflammation, avoiding dangerous substances, and keeping an eye on kidney health. Prompt diagnosis and intervention are essential to avoid severe consequences.