Immunological_Aspects_of_the_Renal_System

Page 1: Immunological Aspect of the Renal System

Page 2: Ischemic Kidney Injury

Page 3: End-Stage Renal Disease (ESRD)

• ESRD refers to kidney failure.

• There is a 30% higher risk of ESRD in blacks compared to whites.

Page 4: Definitions

Acute Kidney Injury (AKI)

• Functional Criteria: Increase in serum creatinine (SCr) by 50% within 7 days, or an increase by 0.3 mg/dL within 2 days, or oliguria.

• Structural Criteria: Glomerular sclerosis.

Chronic Kidney Disease (CKD)

• Functional Criteria: GFR < 60 mL/min per 1.73 m² for over 3 months.

• Structural Criteria: Kidney damage characterized by tubulointerstitial fibrosis for over 3 months.

Page 5: Renal Physiology

• The kidneys serve as the principal filtering organs in the body.

• Despite representing only 0.5% of body mass, they receive 20% of cardiac output (approximately 1 L/min).

• High renal perfusion is necessary due to substantial oxygen consumption in tubular cells for ATP production, crucial for solute reabsorption.

• Ischemic AKI results in metabolic acidosis and ATP depletion, potentially leading to acute renal failure (ARF).

• ARF is characterized as an abrupt decrease in kidney function, affecting 5% of hospitalized patients and 30% of critically ill individuals.

Page 6: Causes of Kidney Hypoperfusion

• Major causes include:

  • Intravascular volume depletion

  • Gastrointestinal tract losses

  • Hemorrhage

  • Congestive heart failure

  • Renal vascular disease (e.g. renal artery thrombosis)

  • Medications (e.g. NSAIDs, ACE inhibitors)

• Most common AKI cause: sterile inflammation.

Page 7: Case Study Example

• A 65-year-old male presents with oliguria, hypotension, and elevated serum creatinine.

• Past medical history includes hypertension and diabetes.

• Lab results indicate metabolic acidosis and hyperkalemia, with muddy brown casts observed in urinalysis.

• Diagnosed with acute renal failure; pathogenesis is related to tubular apoptosis due to ATP depletion and oxidative stress.

• Practice Question #1: Identify best explanation for patient’s disease mechanisms.

Page 8: Role of Sterile Inflammation in AKI

Page 9: DAMPs and Inflammation

• DAMPs (Damage-Associated Molecular Patterns) drive sterile inflammation without microbial involvement.

• DAMPs trigger innate immune activation, causing cytokine release leading to kidney damage, with potential biomarkers including HMGB1 and IL-1β.

• Targeting DAMP pathways could lead to new AKI therapeutics.

Page 10: Comparing Necrosis and Apoptosis

Features of Necrosis

• Uncontrolled cell death due to injury; triggers inflammation.

• Cell swelling and rupture leads to tissue damage.

Features of Apoptosis

• Programmed cell death for homeostasis; generally no inflammation.

• Cell shrinkage and membrane blebbing; maintain membrane integrity until late stages.

Page 11: Inflammatory Triggers

• PAMPs (Pathogen-Associated Molecular Patterns) and DAMPs activate inflammation.

• Both are sensed by pattern recognition receptors (PRRs).

Page 12: Induction of Sterile Renal Inflammation

• DAMPs released from necrotic kidney cells due to ECM degradation.

• Versatile DAMPs include HMGB1, uric acid, and HSPs.

• Recognized by TLRs, leading to renal inflammation.

Page 13: DAMPs and Immune Activation

• Cell injury from factors like ischemia or toxins results in DAMP release.

• DAMPs lead to activation of immune cells (e.g., TNF-α and IL-1 release).

Page 14: Case Study Example

• A 56-year-old female with diabetes shows signs of AKI post-sepsis. Renal biopsy reveals necrosis.

• Practice Question #2: Determine role of DAMPs in AKI pathogenesis.

Page 15: Immune Mechanisms Triggered by DAMPs

• The renal system’s filtering rate can lead to deposition of immune complexes and activate complement pathways.

Page 16: Immune Cells in AKI

Role of Macrophages

• M1 macrophages (pro-inflammatory) promote tissue damage; M2 macrophages (anti-inflammatory) support repair.

• Neutrophils are early responders that can further damage tissue.

Page 17: Case Study Example

• A 36-year-old male marathoner shows signs of AKI. Biopsy indicates tubular injury.

• Practice Question #3: Distinguish roles of M1 and M2 macrophages.

Page 18: Key Points of AKI Mechanisms

• Pro-inflammatory cells include neutrophils and M1 macrophages; anti-inflammatory cells include M2 macrophages and Treg cells.

Page 19: Complement Activation in AKI

Page 20: Role of Complement in AKI

• Pathways: Classical, Lectin, and Alternative Pathways.

• Activation leads to recruitment of immune cells and contributes to renal injury.

Page 21: Clinical Significance of Complement in AKI

• Presence of complement proteins observed in AKI biopsies; within multiple pathways’ roles in graft rejection.

Page 22: Unique Susceptibility of Kidneys to Complement Damage

• High filtration rate in kidneys leads to activation and deposition of complement components.

• DAMPs lead to increased complement activation and tissue damage.

Page 23: Mechanisms of Complement-Induced Damage

Page 24: Case Study Example

• A 48-year-old male presents with AKI complications due to UTI.

• Practice Question #4: Understand the role of complement activation in the patient’s AKI.

Page 25: Hypersensitivity Reactions in AKI

Page 26: Anti-GBM Antibodies in AKI

Page 27: Activation of Immune Cells in AKI

• Neutrophils and monocytes infiltrate renal tissue, driven primarily by complement activation.

Page 28: Role of Immune Cells

• Neutrophils release proteases and free radicals leading to kidney injury.

Page 29: Summary of Immune Cell Responses

• M1 macrophages are key in early AKI; M2 macrophages promote repair.

Page 30: The Role of Th1 and Treg Cells

Page 31: Mechanisms of Repair in AKI

Page 32: Final Summary of Immune Responses

Page 33: Generation and Function of Th17 Cells

• IL-17 produced by Th17 cells is involved in the inflammatory response.

Page 34: Th17 Role in AKI

• IL-17 stimulates inflammatory cytokine release, leading to further immune cell recruitment.

Page 35: Generation and Functions of Th1 Cells

Page 36: Immune Cell Responses in AKI - Summary

Page 37: Role of Treg Cells in AKI

• Treg cells prevent AKI progression and promote repair.

Page 38: Case Study Example

• A 55-year-old male with UTI shows elevated serum creatinine; accumulation of Th17 cells noted.

Page 39: Comparison of T Cell Types in AKI

Pathogenic vs. Functional Roles

Page 40: Kidney Transplantation Overview

Page 41: Transplantation Considerations

• Genetic incompatibility is a major barrier to successful transplantation.

Page 42: Graft Classification

• Autografts, Isografts, Allografts, and Xenografts have different immune responses.

Page 43: Factors Influencing Transplant Outcomes

Page 44: Organ Preservation Principles

Page 45: Graft Condition Implications

Page 46: Factors Influencing Transplant Outcomes

Page 47: Donor and Recipient Compatibility

Page 48: Methods for Matching Donor and Recipient

Page 49: Importance of ABO System in Transplants

Page 50: ABO System Overview

Page 51: Comparison of Blood Testing Methods

Page 52: Blood Group Determination Process

Page 53: Blood Group Compatibility

Page 54: Evolution of Blood Products

Page 55: Blood Group Antigens and Antibodies

Page 56: Distribution of Blood Types in the US

Page 57: Rh Antigens Importance

Page 58: Blood Compatibility Summary

Page 59: Considerations for Type O Negative Blood

Page 60: Recent Developments in ABOi-KT

Page 61: Question on Transfusion Reaction

Page 62: HLA Matching Importance

Page 63: HLA Polymorphism

Page 64: HLA Testing Methods

Page 65: Important HLA Testing Considerations

Page 66: Explanation of Microcytotoxicity Test

Page 67: Factors Affecting Pre-formed Abs Testing

Page 68: Evaluating Class I HLA Compatibility

Page 69: Methods for Class I HLA Testing

Page 70: Process Overview of HLA Testing

Page 71: HLA Testing Results Interpretation

Page 72: Mismatched HLA Example

Page 73: Overview of Matching Examples

Page 74: Class II HLA Compatibility Testing

Page 75: MLR Overview

Page 76: MLR Testing Methodology

Page 77: MLR Results Interpretation

Page 78: Factors Influencing Transplant Outcomes

Page 79: Understanding HVGD and GVHD

Page 80: Mechanism of Host vs. Graft Disease

Page 81: Characteristics of Allograft Rejection

Page 82: Types of Allorecognition

Page 83: Comparing Direct and Indirect Allorecognition

Page 84: Mechanism of Direct Allorecognition

Page 85: Involvement of Indirect Allorecognition

Page 86: Immune System Activation and DAMPs

Page 87: Rejection Types in Allografts

Page 88: Mechanisms of Rejection

Page 89: Hyperacute Rejection Dynamics

Page 90: Acute Rejection and Its Mechanisms

Page 91: Chronic Rejection Mechanism Overview

Page 92: Case Study on Post-Transplant Complications

Page 93: Overview of Graft-versus-Host Disease

Page 94: Mechanism and Risk Factors in GVHD

Page 95: Mechanisms of GVHD Activation

Page 96: Phases of GVHD Development

Page 97: Types and Classifications of GVHD

Page 98: Reference Materials for HLA Information

Page 99: MHC History in Humans

Page 100: Gene Map of HLA Region

Page 101: HLA Gene Nomenclature

Page 102: Detailed HLA Alleles

Page 103: Structure and Function of HLA Molecules

Page 104: The End

Page 105: Question Keys and Rationales

• Question 1: Understanding ischemic injury in AKI.

• Question 2: Understanding DAMPs role in AKI.

• Question 3: Clarifying M1 and M2 macrophage functions.

• Question 4: Recognizing complement activation in AKI.

• Question 5: Analyzing Th17 cells' contributions to AKI.

• Question 6: Understanding hyperacute rejection in transplants.

Immunological Aspect of the Renal System

Ischemic Kidney Injury

Background: Ischemic kidney injury occurs when there is a significant reduction in blood flow to the kidneys, leading to cellular injury and dysfunction.

End-Stage Renal Disease (ESRD)

• Definition: End-Stage Renal Disease (ESRD) refers to a severe progression of chronic kidney disease, wherein the kidneys can no longer maintain the necessary functions to support life.

• Demographics: Studies indicate that the risk of developing ESRD is approximately 30% higher in Black individuals compared to Caucasian individuals, reflecting underlying genetic, environmental, and socioeconomic factors that contribute to kidney health.

Definitions

• Acute Kidney Injury (AKI)

  • Functional Criteria: Defined by a 50% increase in serum creatinine (SCr) within 7 days, or a rise in SCr of 0.3 mg/dL within 2 days, or the presence of oliguria (reduced urine output).

  • Structural Criteria: Often associated with glomerular sclerosis, indicating long-term kidney damage.

• Chronic Kidney Disease (CKD)

  • Functional Criteria: A glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m² sustained for over three months delineates CKD.

  • Structural Criteria: Evidence of kidney damage, often characterized by tubulointerstitial fibrosis effectively assessed via imaging or biopsy.

Renal Physiology

• The kidneys function as essential filtering organs, responsible for maintaining fluid and electrolyte balance, regulating blood pressure, and eliminating metabolic waste. Despite constituting only 0.5% of total body mass, kidneys receive around 20% of the total cardiac output, approximately 1 liter per minute.

• The high renal perfusion is critical due to the significant oxygen demand by tubular cells for Adenosine Triphosphate (ATP) production necessary for solute reabsorption and metabolic activities.

• Ischemic Acute Kidney Injury (AKI) precipitates metabolic acidosis and ATP depletion, which can lead to acute renal failure (ARF), characterized by a sudden, substantial decline in kidney function that affects around 5% of hospitalized patients and as many as 30% of critically ill patients.

Causes of Kidney Hypoperfusion

Major causes of kidney hypoperfusion include:

• Intravascular volume depletion resulting from dehydration or blood loss.

• Gastrointestinal tract fluid losses due to vomiting or diarrhea.

• Hemorrhage leading to a drop in blood volume.

• Congestive heart failure, which reduces effective circulating volume.

• Renal vascular diseases such as renal artery thrombosis narrowing blood flow to the kidneys.

• Certain medications (e.g., Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), ACE inhibitors) that may impair renal blood flow.

• It’s important to recognize that sterile inflammation is the most common cause of acute kidney injury.

Case Study Example

A 65-year-old male patient presents with:

• Symptoms: Oliguria (significant reduction in urine output), hypotension (indicating possible shock), and elevated serum creatinine levels suggesting impaired kidney function.

• Past Medical History: Patient has a history of hypertension and diabetes, both risk factors for renal impairment.

• Lab Results: Additional findings include metabolic acidosis (indicating kidney dysfunction) and hyperkalemia (elevated potassium levels), along with muddy brown casts in urinalysis, which are indicative of tubular injury.

• Diagnosis: Patient is diagnosed with acute renal failure, with the pathophysiological mechanism primarily attributed to tubular apoptosis due to ATP depletion and oxidative stress from ischemia.

Practice Question #1

• Question: Identify the best explanation for the patient’s disease mechanisms.