Immune-Mediated Renal Disorder

Immune-mediated renal disorders are a group of kidney diseases where the body’s own defense system mistakenly attacks the kidneys, causing inflammation and damage that can lead to serious complications if left untreated.

Table of contents

• What Are Immune-Mediated Renal Disorders?
• How These Disorders Develop
• Clinical Features and Symptoms
• Diagnosis and Testing
• Common Types of Immune-Mediated Kidney Diseases
• Treatment Approaches
• Health Problems and Complications

What Are Immune-Mediated Renal Disorders?

Immune-mediated renal disorders, also called immune-mediated glomerular diseases or glomerulonephritides (GN), represent a diverse group of conditions where the immune system causes injury to the kidneys^[1]. When considered together as one disease category, these disorders are a major cause of end-stage renal disease worldwide and are associated with significant illness and death rates^[1].

Most forms of these disorders are characterized by a harmful immune response against the kidney’s own structures or by effects of widespread autoimmune conditions in the kidney^[1]. The immune system, which normally defends the body against infections and illnesses, can sometimes malfunction, leading to various complications including kidney disease^[14].

These diseases can be classified in different ways: by the clinical syndromes they produce, by the kidney damage patterns seen under a microscope, or by the main immune mechanism causing the injury^[2]. The major clinical syndromes produced by immune-mediated kidney injury include the nephrotic syndrome (characterized by heavy protein loss in urine), the nephritic syndrome, rapidly progressive glomerulonephritis, and acute renal failure^[2].

How These Disorders Develop

The development of immune-mediated kidney disease involves complex processes. One important mechanism is the formation of immune complexes, which are products of antibody combined with antigen that form when both are present at the same time^[3]. Normally, these immune complexes are cleared by binding to red blood cells and then removed by liver cells as blood passes through the liver. Very large immune complexes are removed by special cells called macrophages^[3].

Problems occur when immune complexes deposit in the glomerulus (the kidney’s filtering unit), which happens when excessive production overwhelms the clearing mechanisms or when clearing mechanisms fail^[3]. In some cases, immune complexes may form directly in the kidney when antibodies recognize a kidney protein or a protein trapped in the glomerulus^[3].

All forms of these disorders result in kidney tissue injury, which, depending on the specific immune process in each patient, can lead to a range of symptoms from heavy protein in the urine to rapid loss of kidney function^[1].

Clinical Features and Symptoms

The clinical features of immune-mediated renal disorders are essentially those of acute kidney failure from any cause^[2]. Apart from a history of new illness or medication exposure, there are no specific signs in the medical history, physical examination, or laboratory findings that distinguish these disorders from other causes of acute kidney failure^[2].

Classic findings such as fever, rash, and joint pain may be absent in up to two thirds of patients^[2]. The most common clinical feature is proteinuria (protein in the urine), but detecting protein in the urine should not be the end of the investigation in affected patients^[3].

Depending on the immunopathology, patients can experience varying symptoms. When the kidneys are damaged and can no longer perform their important functions, waste products can build up in the body, leading to a range of health problems^[14]. Kidney disease can also cause an imbalance of electrolytes and fluids in the body, leading to complications such as high blood pressure, anemia, and weakened bones^[14].

Diagnosis and Testing

Early and accurate diagnosis is crucial for effectively managing immune-mediated kidney diseases. The diagnostic approach includes several components^[5]:

• Laboratory tests: Blood and urine tests to evaluate kidney function and detect signs of inflammation or autoimmunity, such as elevated levels of antibodies or immune system components^[5].
• Imaging studies: Ultrasound, CT scans, or MRI to assess kidney structure and detect abnormalities^[5].
• Kidney biopsy: A critical diagnostic tool for determining the specific type and extent of kidney damage, which guides treatment decisions^[5].

Diagnostic studies such as urine eosinophils and renal gallium 67 scanning can provide suggestive evidence, but they cannot reliably confirm or exclude the diagnosis^[2]. Kidney biopsy remains the gold standard for diagnosis, though it may not be required in mild cases or when clinical improvement is rapid after removal of an offending agent or medication^[2].

Urinalysis and sediment evaluation, 24-hour urine protein, and serum creatinine are helpful in screening and monitoring renal immune-related adverse effects^[10]. Multiple potential causes for acute kidney injury are involved during cancer therapy and should be differentiated from the immune mechanisms. Under these circumstances, a kidney biopsy should be considered, which is essential for clinical decision-making^[10].

Common Types of Immune-Mediated Kidney Diseases

Immune-mediated kidney diseases can manifest in various forms^[5]:

• Lupus Nephritis: Kidney inflammation caused by systemic lupus erythematosus (SLE), an autoimmune disease^[5].
• IgA Nephropathy (Berger’s Disease): Characterized by the deposition of IgA antibodies in the kidneys^[5].
• Anti-GBM Disease: A condition where antibodies attack the glomerular basement membrane in the kidneys^[5].
• Vasculitis: Inflammation of the blood vessels, which can affect kidney function^[5].

Treatment Approaches

Even though recent years have seen considerable progress in understanding how these diseases develop, most treatment strategies still consist of corticosteroids and cytotoxic agents, aimed at suppressing the complete immune system^[1]. Unfortunately, these nonspecific therapies often have incomplete effectiveness and disabling side effects, highlighting the urgent need for more specific and individualized treatment strategies^[1].

Treatment for immune-mediated kidney diseases aims to reduce inflammation, suppress the immune system’s abnormal response, and prevent further kidney damage. Personalized treatment plans may include^[5]:

• Corticosteroids: To reduce inflammation and suppress the immune system^[5].
• Immunosuppressive medications: Such as cyclophosphamide, mycophenolate mofetil, or rituximab, to target specific aspects of the immune response^[5].
• Plasma exchange: For conditions like anti-GBM disease, to remove harmful antibodies from the blood^[5].
• Targeted therapies: Including biologic agents that specifically target immune cells or pathways involved in the disease process^[5].
• Supportive care: Addressing complications and symptoms associated with kidney disease, such as hypertension, edema, and electrolyte imbalances, with medications and dietary modifications^[5].

Steroids are an effective treatment option for renal immune-related adverse events. Most patients who experience immune checkpoint inhibitor-related acute tubulointerstitial nephritis (ATIN) achieve a partial or complete kidney recovery with prompt diagnosis and treatment^[10].

The time until removal of offending agents and kidney biopsy findings provide the best information for predicting return to baseline kidney function^[2]. Corticosteroids appear to provide some benefit in terms of clinical improvement and return of kidney function, but no controlled clinical trials have been conducted to confirm this^[2].

Health Problems and Complications

The relationship between immune dysfunction and kidney disease is complex and works in both directions. On one hand, immune dysfunction can contribute to the development and progression of kidney disease. For example, autoimmune disorders such as lupus nephritis occur when the immune system mistakenly attacks the kidneys, leading to inflammation and damage. Chronic inflammation, a common feature of immune dysfunction, can also harm the kidneys over time, increasing the risk of chronic kidney disease^[14].

On the other hand, kidney disease can make immune dysfunction worse. The kidneys play an important role in regulating the body’s immune response, and when they are impaired, the immune system may become less effective at fighting infections. Patients with kidney disease are at a higher risk of infections due to a weakened immune system. Additionally, the buildup of waste products in the blood can further compromise immune function, creating a harmful cycle of declining health^[14].

One of the primary causes of immune dysfunction in patients with kidney disease is the buildup of uremic toxins—waste products that are typically filtered out by healthy kidneys. These toxins can suppress immune function and increase the risk of infections. Anemia, a common complication of kidney disease, can also weaken the immune system by reducing the oxygen supply to vital organs and tissues^[14].

For patients undergoing dialysis, a common treatment for advanced kidney disease, the treatment itself can contribute to immune dysfunction. Although dialysis is necessary for removing waste products from the blood, it can also lead to inflammation and immune system suppression. Patients undergoing dialysis are more susceptible to infections, and the treatment itself can cause complications such as catheter-related infections and bloodstream infections^[14].

Managing immune dysfunction in patients with kidney disease requires a multidisciplinary team that can provide comprehensive care, addressing all aspects of the patient’s health. Comorbidity management, regular monitoring of kidney function, and a patient-centered approach are crucial for improving outcomes and quality of life^[5]. Collaborative, individualized care approaches are recommended to improve outcomes and quality of life for patients with immune-mediated kidney diseases^[15].