Azotemia

Classification

Figure from Harrison's Principles of Internal Medicine 22E (2025)

1. Prerenal Azotemia

Mechanism

Causes

• Hypovolemia: GI hemorrhage, diarrhea, vomiting, burns, diuretics
• Decreased cardiac output: Cardiogenic shock, congestive heart failure
• Decreased effective circulating volume: Liver failure (hepatorenal syndrome), sepsis, pancreatitis, peritonitis
• Impaired renal autoregulation: NSAIDs, ACE inhibitors/ARBs, cyclosporine
• Renal vasoconstriction: Severe heart failure, hepatorenal syndrome

Compensatory Response

Lab Findings (Prerenal vs. ATN)

Key caveat: FENa can be <1% in early/nonoliguric ATN (e.g., rhabdomyolysis, contrast nephropathy) and in patients with CHF or cirrhosis - so it is not perfectly specific for prerenal azotemia.

Important Notes

• Prolonged prerenal azotemia progresses to acute tubular necrosis (ATN) - ischemic injury with tubular cell death
• SGLT-2 inhibitors (despite lowering intraglomerular pressure) appear to have a protective effect against AKI rather than causing it, per recent data

2. Intrinsic (Renal) Azotemia

a. Tubules and Interstitium

• ATN (Acute Tubular Necrosis): Most common intrinsic cause
  • Ischemic ATN: Progression from severe prerenal
  • Sepsis-associated ATN: AKI complicates >50% of severe sepsis; mechanisms include efferent arteriolar vasodilation, renal vasoconstriction, endothelial damage, microvascular thrombosis, and reactive oxygen species
  • Nephrotoxic ATN: Aminoglycosides, cisplatin, amphotericin B, iodinated contrast, NSAIDs, PPIs, immune checkpoint inhibitors
  • Endogenous toxins: Hemolysis (hemoglobin), rhabdomyolysis (myoglobin), myeloma (light chains), intratubular crystals (uric acid, oxalate)
• Acute interstitial nephritis (AIN): Drug-induced (penicillins, NSAIDs, PPIs), infection

b. Glomeruli

• Acute glomerulonephritis (post-infectious, IgA nephropathy, RPGN)
• Associated with nephrotic/nephritic syndrome

c. Vasculature

• Vasculitis
• Malignant hypertension
• TTP/HUS (thrombotic microangiopathy)

3. Postrenal Azotemia

Requirements for Complete Obstruction

• Obstruction at urethra or bladder outlet (e.g., BPH, stricture), OR
• Bilateral ureteral obstruction, OR
• Unilateral obstruction of a solitary functioning kidney

Causes

• Bladder outlet obstruction (BPH is most common in older men)
• Bilateral ureteral obstruction: Pelvic tumors, retroperitoneal fibrosis, bilateral stones
• Urethral stricture

Mechanism of Azotemia

Diagnosis

Azotemia vs. Uremia

Evaluation Approach

1. History: Volume losses (vomiting, diarrhea, hemorrhage), medications (NSAIDs, ACE-I, diuretics), heart failure, urinary symptoms
2. Compare to prior creatinine values - to distinguish acute from chronic
3. Urinalysis + microscopy: Casts, protein, blood
4. Renal ultrasound: Size (small = chronic), echogenicity, hydronephrosis
5. Urinary indices: UNa, FENa, urine osmolality
6. Biomarkers: NGAL, KIM-1 (emerging tools for detecting subclinical ATN)

Measurement of GFR in Azotemia

• Gold standard: Inulin or iothalamate clearance (not clinically feasible)
• Creatinine clearance (CrCl): 24-hour urine collection; overestimates GFR slightly because creatinine is secreted by proximal tubule
• Serum creatinine: Most widely used surrogate; inversely proportional to GFR. Falls in GFR are reflected proportionally in rising creatinine. Drug dosing adjustments are critical when GFR falls.
• Serum urea (BUN): Underestimates GFR because tubular reabsorption of urea varies with volume status

"Failure to account for GFR reductions in drug dosing can lead to significant morbidity and death from drug toxicities (e.g., digoxin, imipenem)." - Harrison's Principles of Internal Medicine 22E

• Harrison's Principles of Internal Medicine, 22E (2025), Chapters 55 and 321
• Goldman-Cecil Medicine International Edition, Chapter on Azotemia
• Morgan & Mikhail's Clinical Anesthesiology, 7e

Treatment of Azotemia

Universal Principles (All Types)

1. Optimize hemodynamics - volume resuscitation + vasopressors as needed; maintain mean arterial pressure (MAP) >65 mmHg
2. Eliminate nephrotoxins - stop NSAIDs, ACE inhibitors/ARBs, aminoglycosides, contrast agents, chemotherapy, checkpoint inhibitors if at all possible
3. Adjust drug doses to current GFR (especially digoxin, imipenem, renally-cleared antibiotics)
4. Nutritional support - 20-30 kcal/kg/day; protein 0.8-1.0 g/kg/day (non-dialysis), 1.0-1.5 g/kg/day (dialysis-requiring); prefer enteral route
5. Monitor closely - daily serum creatinine, electrolytes, urine output, body weight

1. Prerenal Azotemia

Fluid Resuscitation

• Match the fluid to the fluid lost:
  • Blood loss → packed red blood cells
  • Isotonic losses → isotonic crystalloids (preferred over colloids)
  • 0.9% saline - most common; avoid in hyperchloremic metabolic acidosis
  • Buffered crystalloids (Ringer's lactate, Hartmann's, Plasma-Lyte) - preferred for most patients; avoid if hypernatremic (slightly hypotonic)
  • Bicarbonate-containing solutions (e.g., D5W + 150 mEq NaHCO₃) - for metabolic acidosis
• Colloids: Hyperoncotic albumin may be used in liver failure (cirrhosis). Hydroxyethyl starch is no longer available for hospitalized patients due to increased AKI risk.

Optimizing Cardiac Function

• Inotropes (e.g., dobutamine) for cardiogenic causes
• Preload/afterload reduction
• Antiarrhythmics if arrhythmia is compromising output
• Mechanical circulatory support (ventricular assist device) in severe cases
• Consider invasive hemodynamic monitoring (central venous pressure, pulmonary artery catheter) to guide therapy

Hepatorenal Syndrome (Cirrhosis)

• Exclude spontaneous bacterial peritonitis (SBP) - paracentesis with cell count and culture; albumin infusion reduces AKI risk in SBP treated with antibiotics
• Bridge vasopressor therapy: norepinephrine, terlipressin (vasopressin analogue), or octreotide + midodrine
• Definitive treatment: orthotopic liver transplantation

2. Intrinsic (Renal) Azotemia

General Measures

• Remove the offending nephrotoxin immediately
• Maintain adequate perfusion pressure
• Treat the underlying cause (e.g., antibiotics for sepsis, steroids for AIN, immunosuppression for glomerulonephritis)

Specific Situations

Prevention of Progression to ATN

• Early recognition and correction of prerenal state before tubular necrosis occurs
• Aggressive volume expansion before major surgery, burns, or trauma
• For sepsis: early antibiotics + rapid hemodynamic stabilization + MAP >65 mmHg; blood glucose target ~140-180 mg/dL (intensive insulin therapy shown to reduce AKI in some studies but increases hypoglycemia risk)

3. Postrenal Azotemia

Post-Obstructive Diuresis

4. Management of Electrolyte and Metabolic Complications

5. Renal Replacement Therapy (RRT)

Absolute Indications ("AEIOU")

• Acidosis - severe metabolic acidosis refractory to medical management
• Electrolytes - life-threatening hyperkalemia (>6.5 mEq/L or ECG changes) not responding to medical therapy
• Ingestion/Intoxication - dialyzable toxins (e.g., methanol, ethylene glycol, salicylates, lithium)
• Overload - volume overload refractory to diuretics
• Uremia - uremic pericarditis, encephalopathy, neuropathy, or platelet dysfunction (typically BUN >100 mg/dL)

Relative Indications

• Progressive azotemia without uremic manifestations
• Persistent oliguria

Modalities

Timing of RRT

• The STARRT-AKI trial (NEJM 2020) found no benefit of accelerated (early) vs. standard initiation of RRT, supporting waiting for a clear clinical indication before starting dialysis.

6. Prognosis and Post-AKI Care

• Prerenal azotemia (excluding cardiorenal/hepatorenal syndromes) and postrenal azotemia carry a better prognosis than intrinsic AKI
• The kidney has remarkable self-repair capacity even after dialysis-requiring AKI, when prior renal function was intact
• ~10% of AKI survivors requiring temporary dialysis progress to end-stage kidney disease (ESKD)
• AKI and CKD are interrelated: AKI accelerates CKD progression
• Post-discharge: nephrology follow-up; measure albuminuria (predicts CKD progression risk); aggressive secondary prevention

• Harrison's Principles of Internal Medicine, 22E (2025), Chapter 321 - Prevention and Treatment of AKI
• Brenner and Rector's The Kidney, 2-Volume Set, Chapter 29 - Supportive Management of Acute Kidney Injury
• KDIGO Clinical Practice Guidelines for Acute Kidney Injury (Kidney Int Supp 2:1, 2012)
• STARRT-AKI Investigators: Timing of initiation of RRT in AKI. N Engl J Med 383:240, 2020

Bridge Vasopressor Therapy in Hepatorenal Syndrome (HRS)

Background - Why "Bridge" Therapy?

• Severe splanchnic vasodilation (from portal hypertension)
• Compensatory systemic vasoconstriction that paradoxically impairs renal perfusion
• Activation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and ADH

The Three Bridge Vasopressor Regimens

1. Terlipressin + Albumin (First-Line / Most Evidence)

2. Norepinephrine + Albumin (Alternative When Terlipressin Unavailable)

3. Octreotide + Midodrine + Albumin (Least Effective - Outpatient Option)

Comparison Summary

Other Bridge Strategies (Non-Vasopressor)

• TIPS (Transjugular Intrahepatic Portosystemic Shunt): Reduces portal hypertension directly; can reverse HRS by improving effective circulatory volume. Used in select patients without contraindications (severe hepatic encephalopathy, high MELD score). A 2024 Cochrane systematic review (PMID: 38235907) evaluated TIPS for HRS.
• RRT (Renal Replacement Therapy): Controversial - generally reserved for patients being bridged to transplant when medical therapy fails. Does not treat the underlying hemodynamic cause.
• Extracorporeal Albumin Dialysis (MARS): Experimental; uses albumin dialysate to remove albumin-bound toxins contributing to hemodynamic instability.

Albumin - Why It's Always Co-administered

1. Expands intravascular volume (combats the "effective" hypovolemia)
2. Binds circulating vasodilatory substances (e.g., bacterial DNA, endotoxins, reactive oxygen species) that drive splanchnic vasodilation
3. Reduces systemic inflammation

• Goldman-Cecil Medicine International Edition - Hepatorenal Syndrome
• Miller's Anesthesia, 10e - Acute Kidney Injury and Hepatorenal Syndrome
• Harrison's Principles of Internal Medicine, 22E - Prevention and Treatment of AKI
• Malik et al. (2024) - Terlipressin vs. Noradrenaline in HRS: Systematic Review & Meta-Analysis - Ann Hepatol [PMID: 38460713]

TIPS (Transjugular Intrahepatic Portosystemic Shunt) for Portal Hypertension

What Is TIPS?

Procedure - Step by Step

TIPS placement. (A) Balloon inflated to dilate the intrahepatic tract between portal and hepatic vein. (B) Wall stent expanded across the tract. Courtesy Johns Hopkins Medical Institutions.

1. Access: A catheter is introduced through the right internal jugular vein in the neck
2. Navigation: Guidewire and introducer sheath pass through the superior vena cava → inferior vena cava → into a hepatic venous branch
3. Portal vein puncture: A needle is passed through the liver parenchyma from the hepatic vein into the portal vein (under fluoroscopic guidance with contrast injection to locate the portal vein)
4. Tract dilation: An angioplasty balloon inflates to create a channel along the needle tract
5. Stent placement: A polytetrafluoroethylene (PTFE)-covered stent is placed to maintain the shunt. Covered stents have higher patency than older uncovered stents and are now the standard of care.
6. Pressure check: The hepatic venous pressure gradient (HVPG) should fall to <12 mmHg after the procedure. Above 12 mmHg, variceal bleeding risk remains elevated.

Why 12 mmHg Matters

Indications

Primary / Established Indications

1. Refractory variceal hemorrhage - bleeding not controlled by endoscopy (band ligation/sclerotherapy) + pharmacotherapy (vasopressin analogues, beta-blockers)
2. Secondary prevention of variceal rebleeding - after a first episode of hemorrhage that failed or is high-risk for endoscopic treatment
3. Refractory ascites - ascites not responding to diuretics (spironolactone + furosemide at maximum doses); TIPS reduces need for large-volume paracentesis (LVP)
4. Acute variceal hemorrhage in high-risk patients (HVPG >20 mmHg) - early TIPS placement (within 72 hours of endoscopy) reduces rebleeding

Other Indications

• Hepatorenal syndrome (HRS) - as a "bridge" to transplant when vasopressor therapy fails
• Hepatic hydrothorax (refractory pleural effusion from cirrhosis)
• Portal hypertensive gastropathy (refractory to medical therapy)
• Budd-Chiari syndrome (hepatic vein thrombosis causing portal hypertension)

Contraindications

Stent Size

• Standard stents: 10 mm diameter
• Smaller 8 mm stents have been associated with a lower incidence of hepatic encephalopathy post-TIPS without reducing ascites clearance - a clinically important trade-off in patient selection

Patient Selection - MELD Score

Complications

Current Evidence

• 2-year further decompensation rate: 48% with TIPS vs. 63% with standard of care (HR 0.44; 95% CI 0.37-0.54)
• 2-year survival: 71% (TIPS) vs. 63% (standard of care), p = 0.0001
• Benefit was consistent across both indications (refractory ascites and variceal rebleeding prevention)

TIPS vs. Alternatives

• Current Surgical Therapy 14e - Transjugular Intrahepatic Portosystemic Shunt
• Miller's Anesthesia, 10e - TIPS Procedure and Anesthesia
• Larrue et al. (2023) - TIPS prevents decompensation and improves survival: IPD meta-analysis, J Hepatol [PMID: 37141993]
• EASL Clinical Practice Guidelines on TIPS (2025), J Hepatol [PMID: 40180845]

🔬 Tumor Biology & Mechanisms

1. Oncogene addiction - How cancers become "addicted" to a single activated oncogene (e.g., EGFR, BCR-ABL) and why this makes them exquisitely sensitive to targeted inhibitors
2. Tumor microenvironment (TME) - The complex ecosystem of cancer cells, immune cells, fibroblasts, and vasculature inside a tumor - and how tumors manipulate it to evade immunity
3. Synthetic lethality - Exploiting two gene defects that are individually tolerable but lethal in combination (e.g., PARP inhibitors in BRCA1/2-mutated cancers)
4. Cancer stem cells - A small subpopulation of cells within tumors with self-renewal capacity, thought to drive recurrence and metastasis
5. Liquid biopsy and circulating tumor DNA (ctDNA) - Detecting and monitoring cancer through blood tests, enabling real-time tracking of tumor evolution and resistance

💊 Treatment & Therapeutics

1. Immune checkpoint inhibitors - PD-1/PD-L1 and CTLA-4 blockade: how they unleash T-cells against tumors, which cancers respond, and the puzzle of why many patients don't
2. CAR-T cell therapy - Engineering a patient's own T-cells to carry a chimeric antigen receptor; remarkable in hematologic malignancies, but hitting walls in solid tumors
3. Antibody-drug conjugates (ADCs) - "Guided missiles" that attach chemotherapy directly to a cancer-targeting antibody; a rapidly expanding field (trastuzumab deruxtecan, sacituzumab govitecan)
4. Bispecific antibodies - Engineered to bind two targets simultaneously - typically a tumor antigen and a T-cell activating receptor (CD3), bringing immune cells directly to tumor cells
5. Tumor-infiltrating lymphocytes (TIL) therapy - Harvesting, expanding, and reinfusing T-cells that have already entered the tumor; FDA approved for melanoma in 2024

🧬 Genetics & Precision Oncology

1. Tumor mutational burden (TMB) - How measuring the total number of mutations in a tumor predicts immunotherapy response, independent of cancer type
2. Microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) - A pan-cancer biomarker for pembrolizumab response, regardless of tumor origin
3. Clonal hematopoiesis of indeterminate potential (CHIP) - Age-related somatic mutations in blood stem cells; a precursor to hematologic malignancy and a cardiovascular risk factor
4. Epigenetic reprogramming in cancer - How DNA methylation and histone modification patterns are disrupted in cancer, and drugs (DNMT inhibitors, HDAC inhibitors) that target them

⚡ Hot & Emerging Areas

1. Cancer vaccines - Personalized neoantigen mRNA vaccines (Moderna/Merck's mRNA-4157 with pembrolizumab showed strong results in melanoma) - a rapidly evolving space
2. Oncolytic viruses - Genetically engineered viruses that selectively infect and destroy cancer cells while stimulating anti-tumor immunity (T-VEC/talimogene in melanoma)
3. Radioligand therapy - Delivering radiation precisely to cancer cells via targeting molecules (Lutetium-177 PSMA for prostate cancer, Lutetium-177 DOTATATE for neuroendocrine tumors)
4. Resistance mechanisms to targeted therapy - Why cancers almost invariably develop resistance (secondary mutations, bypass signaling, lineage plasticity) and strategies to overcome it
5. Paraneoplastic syndromes - Systemic effects of cancer mediated not by direct invasion but by hormones, antibodies, or immune responses (SIADH, Cushing's, Lambert-Eaton syndrome)
6. Tumor lysis syndrome - The metabolic emergency triggered when rapidly dividing cancers are treated, releasing massive amounts of potassium, phosphate, and uric acid

Tumor-Infiltrating Lymphocytes (TILs): A Deep Dive

1. What Are TILs?

• CD8+ cytotoxic T cells (CTLs): The primary tumor-killing subset; recognize tumor peptides on MHC class I and directly lyse cancer cells
• CD4+ helper T cells: Support CTL function, activate macrophages, and sustain immune responses
• CD4+ regulatory T cells (Tregs): Immunosuppressive; high Treg density in tumors is associated with worse prognosis
• NK cells, B cells, dendritic cells: Also present in varying proportions

2. Why TILs Fail Naturally - T-Cell Exhaustion & Immune Evasion

T-Cell Exhaustion

• Impaired effector functions (reduced IFN-γ, perforin, granzyme production)
• Progressive loss of proliferative capacity
• Upregulation of multiple inhibitory receptors: PD-1, CTLA-4, LAG-3, TIM-3, TIGIT

Checkpoint-Mediated Suppression

Other TME Suppression Mechanisms

• TGF-β secretion by tumor cells - directly inhibits lymphocyte and macrophage proliferation and effector function
• Regulatory T cells (Tregs) within tumors suppress anti-tumor CTL responses
• IDO (indoleamine 2,3-dioxygenase) expression - depletes tryptophan, impairing T-cell proliferation
• Myeloid-derived suppressor cells (MDSCs) - produce reactive oxygen species and nitric oxide that impair TIL function
• Hypoxia and nutrient deprivation in the TME further impair T-cell metabolism

3. TIL Therapy: The Process (Manufacturing Protocol)

Tumor Resection → Fragment/Digest Tumor → 
Initial Expansion (IL-2) → REP (Rapid Expansion Protocol) → 
Patient Lymphodepletion → TIL Infusion → IL-2 Support

Step 1 - Tumor Harvest (Surgical)

• A tumor fragment (≥1.5 cm is typically required) is surgically resected
• The tumor is dissected into small fragments or enzymatically digested into single-cell suspensions
• TILs are extracted from the tumor tissue

Step 2 - Initial Expansion ("Pre-REP")

• Extracted TIL fragments are cultured in media containing high-dose IL-2 (interleukin-2)
• IL-2 drives T-cell proliferation and survival
• Duration: ~2 weeks; produces a preliminary TIL population from the tumor fragments

Step 3 - Rapid Expansion Protocol (REP)

• TILs undergo a second, more aggressive expansion using:
  • Anti-CD3 antibody (OKT3) - provides non-specific TCR stimulation
  • High-dose IL-2
  • Irradiated feeder cells (allogeneic PBMCs) - provide co-stimulatory signals
• REP expands TILs by 1,000-fold or more over ~2 weeks
• Final product: 50 billion - 150 billion TIL cells

Step 4 - Non-Myeloablative Lymphodepletion (Preparative Regimen)

• Cyclophosphamide 60 mg/kg/day × 2 days
• Fludarabine 25 mg/m²/day × 5 days

1. Eliminates endogenous lymphocytes that would compete with TILs for homeostatic cytokines (IL-7, IL-15, IL-2)
2. Removes immunosuppressive Tregs from circulation
3. Creates "homeostatic space" - a cytokine-rich environment that drives rapid TIL expansion after infusion
4. Eliminates MDSCs and other immunosuppressive cells temporarily

Step 5 - TIL Infusion

• Billions of TILs are infused intravenously (single infusion)
• TILs home to tumor sites via adhesion molecules and chemokine gradients

Step 6 - High-Dose IL-2 Support

• After TIL infusion, patients receive high-dose IL-2 (aldesleukin, 600,000-720,000 IU/kg IV every 8 hours, up to 5 doses)
• IL-2 supports the survival and expansion of infused TILs in vivo
• Major toxicity: capillary leak syndrome (hypotension, pulmonary edema, fever) - requires ICU-level monitoring; limits use to fit patients

4. FDA Approval - Lifileucel (Amtagvi)

Indication

• A prior anti-PD-1 therapy (pembrolizumab/nivolumab)
• If BRAF V600-mutant: also a prior BRAF inhibitor ± MEK inhibitor

Pivotal Trial - C-144-01 (KEYNOTE-119 substudy)

• Single-arm, multicenter Phase 2 trial
• Overall Response Rate (ORR): 31.5% in heavily pre-treated patients
• Complete response rate: ~5% (potentially durable/curative)
• Median duration of response: not reached in responders at time of analysis
• Population: patients who had failed checkpoint inhibitors and often targeted therapies

Real-World Data (2026)

• Only 51% of referred patients completed TIL infusion (barriers: small tumor size <1.5 cm, comorbidities, rapid disease progression, out-of-spec product)
• 1-year OS: 79.2% in patients who successfully received TIL therapy vs. 42% in those who did not (p = 0.007)
• Median time from referral to TIL infusion was 128 days (reduced to 96 days with workflow optimization)
• Highlights that real-world outcomes may be lower than clinical trial ORR due to patient selection issues

5. TIL Density as a Prognostic Biomarker

6. Challenges and Limitations

7. Next-Generation TIL Approaches

• Selected/enriched TILs: Selecting for tumor-reactive T cells (e.g., by PD-1 selection or neoantigen reactivity screening) rather than bulk expansion - higher potency with fewer cells
• Shorter manufacturing ("Fresh TIL"): Bypassing the REP step to reduce time to infusion
• Reduced-dose IL-2 regimens: Using IL-2 variants (e.g., bempegaldesleukin) or other cytokines (IL-15, IL-21) to support TIL survival with less toxicity
• TIL + checkpoint inhibitor combinations: Combining TIL infusion with anti-PD-1 to prevent re-exhaustion
• Genetically engineered TILs: Inserting transgenes into TILs (e.g., knockout of PD-1, insertion of cytokine transgenes) to make them exhaustion-resistant
• Allogeneic TIL therapy ("off-the-shelf"): Manufacturing TILs from healthy donors to reduce lead time and cost
• Expansion to other solid tumors: Active trials in cervical cancer, NSCLC, head and neck, colorectal cancer

8. TIL Therapy vs. Other Adoptive Cell Therapies

• Cellular and Molecular Immunology (Abbas) - Molecules and Cells That Inhibit Immune Responses to Tumors
• Schwartz's Principles of Surgery, 11e - Immunotherapy in Cancer
• Sarnaik et al. (2024) - "Tumor-Infiltrating Lymphocytes: A New Hope", Cancer Cell [PMID: 39029463]
• Betof Warner et al. (2024) - Expert Consensus Guidelines on TIL Cell Therapy, J Immunother Cancer [PMID: 38423748]
• Desai et al. (2026) - Real-World Outcomes with Commercial Lifileucel, Transplant Cell Ther [PMID: 42044727]
• Zhang et al. (2023) - Challenges and New Technologies in Adoptive Cell Therapy, J Hematol Oncol [PMID: 37596653]