Introduction to Renal Disorders

• The lecture provides an introduction to Renal Disorders
• The lecture is presented by Mahmoud Elshal, M.Sc., Ph.D., for the 2024/2025 academic year in the Pharm D Program, Faculty of Pharmacy, Mansoura University.

Introduction to Renal Disorders

• Kidney disease is a worldwide health problem
• Renal function includes filtration, secretion, reabsorption, endocrine, and metabolic functions
• Alterations in renal functions are associated with glomerular filtration rate (GFR)
• Normal GFR is between 90-120 mL/min/1.73m²
• Renal failure represents a global loss of renal function, varying in degrees
• The body can maintain normal homeostasis with renal function reduced to about half the normal GFR
• Symptoms may not be pronounced if the decline is slow
• Renal failure is classified based on whether it is acute or chronic

Acute Kidney Injury (AKI)/Acute Renal Failure (ARF)

• Includes the discussion of definitions, outcomes, risk factors, etiology, and diagnosis

Definitions of AKI

• Defined as an acute decrease in kidney function or GFR, occurring over hours, days, or weeks
• Associated with the accumulation of waste products such as urea and creatinine
• The RIFLE criteria stratifies AKI using risk, injury, failure, loss, and end-stage kidney disease
• The criteria uses changes in baseline SCr/GFR or urine output

RIFLE Classification

• Risk: SCr increased to 1.5x baseline or GFR decreased by > 25%; urine output < 0.5 mL/kg/h for 6 hrs
• Injury: SCr increased to 2x baseline or GFR decreased by > 50%; urine output < 0.5 mL/kg/h for 12 hrs
• Failure: SCr increased to 3x baseline or GFR decreased by > 75% or SCr ≥ 4 mg/dL, urine output < 0.3 mL/kg/h for 24 hrs or anuria for 12 hrs
• Loss: Persistent ARF = complete loss of kidney function for > 4 weeks
• End-stage: Complete loss of kidney function for > 3 months

AKIN Classification

• AKIN classification depends on creatinine levels and urine output
• Risk or Stage 1: Creatinine increases by ≥ 0.3 mg/dL or ≥ 150% and < 200% from baseline; urine output < 0.5 mL/kg/h for 6 h
• Injury or Stage 2: Creatinine increases ≥ 200% and <300% than baseline; urine output <0.5 mL/kg/h for 12 h
• Failure or Stage 3: Creatinine ≥ 300% than baseline, or ≥ 4.0 mg/dL and ≥ 0.5 mg/dL; urine output is <0.3 mL/kg/h for 24 h, or anuria for 12 h

AKI-KDIGO Guideline

• Defines AKI as any of the following, without grading:
• Increase in SCr by 0.3 mg/dl within 48 hours
• Increase in SCr to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days
• Urine volume 0.5 mL/Kg/h for 6 h

ADQI Recovery Classifications

• Recovery: Reversal (Time post-AKI <48 h), Early (48 h - 7 days), Delayed
• Progression to AKD ± CKD: AKD (7 - 90 days) - Stage 0 AKD, Stage 1, Stage 2, Stage 3 & Ongoing RRT, CKD >90 Days

Outcomes of AKI

• Short-term outcomes of AKI:
  • Uraemia
  • Electrolyte/acid-base abnormalities
  • Fluid overload
  • Impaired innate immunity
• Long-term outcomes of AKI:
  • Development of chronic kidney disease and ESRD
  • Increased risk of CV events and fractures
  • Reduced quality of life and increased mortality
• AKI occurred in 1 in 10 patients admitted to a non-ICU ward
• Associated with a more than 3-fold increased risk of death and a 2-fold longer hospital stay
• AKI death rate per year is much greater than breast cancer, heart failure, diabetes and prostate cancer

Risk Factors for AKI

• Risk factors include patient factors, medications and agents, and procedures:
  • Patient factors: --Older age (> 75 years), diabetes, liver failure, preexisting chronic kidney disease, atherosclerosis --Renal artery stenosis, hypertension/hypotension, hypercalcemia/hyperuricemia, urinary obstruction --Sepsis, rhabdomyolysis, tumor lysis syndrome (TLS), and volume depletion (dehydration)
  • Medications and agents: --NSAIDs, Cox-2 inhibitors, cyclosporin or tacrolimus --ACE-Is/ARBs, iodinated radiocontrast agents, aminoglycosides, and amphotericin B
  • Procedures: --Cardiopulmonary bypass procedures, surgery involving aortic clamp --Large arterial catheter placement with risk for atheroembolization, liver and kidney transplantation

Etiology of AKI

• Includes Prerenal, Intrinsic, Postrenal
  • Prerenal includes: 30%-60% of AKI, Volume depletion, Renal artery stenosis, CHF, Hypercalcemia, NSAIDs, ACEIs, and ARBs use, and Cyclosporine, tacrolimus
  • Intrinsic includes: ~ 40% of AKI, Long-standing renal hypoperfusion, Nephrotoxins [(e.g., contrast, antibiotics (penicillins, cephalosporins), lithium, amphotericin, or NSAIDs], Pyelonephritis, SLE, Glomerulonephritis (GN), and Vasculitis
  • Postrenal includes: ~ 10% of AKI, Kidney stones, Benign Prostatic Hypertrophy (BPH), and Cancers
• Functional AKI is often classified as prerenal azotemia
• Prerenal azotemia is where the kidney is undamaged and is the most common cause of AKI
• Functional AKI, is usually caused by reduced glomerular hydrostatic pressure
• Often occurs without hypotension
• Can be related to medications (cyclosporine, ACEIs and ARBs, and NSAIDs)
• May be seen in patients with low effective blood flow (patients with CHF, patients with liver disease, and older adults)

Determining Specific AKI Etiology

• Physical Examination: Prerenal (Hypotension, Dehydration, Petechia if thrombotic, Ascites), Intrinsic (Rash, fever, with AIN), Postrenal (Distended bladder, Enlarged prostate)
• Serum BUN/SCr ratio Prerenal (> 20), Intrinsic (<20), Postrenal (<20)
• Urine concentration: -Prerenal (Urine Na+ <20meq/L, Low FENa (<1%), High urine osmolarity)
• Intrinsic (Urine Na+>40meq/L, FENa (>1%), Low urine osmolarity) -Postrenal (Urine Na+>40meq/L, FENa (>1%), low urine Osmolarity)
• Calculation of fractional excretion of sodium (FENa: percentage of Na filtered at the glomerulus that is excreted in the urine)
• FENa = [U/S]Na/[U/S]cr x 100%
• Urine sediment:
  • Prerenal (Normal)
  • Intrinsic (Muddy brown granular casts)
  • Postrenal (Variable; may be normal)
• Urinary WBC: Prerenal (Negative), Intrinsic (2-4+), Postrenal (Variable)
• Urinary RBC: Prerenal (Negative), Intrinsic (2-4+), Postrenal (1+)
• Proteinuria: Prerenal (Negative), Intrinsic (Positive), Postrenal (Negative)

Diagnosis of AKI

• Includes presentation, renal ultrasound, urine examination
  • Presentation: --History and manifestations of the cause --Anuria, oliguria, or non-oliguria --Edema, hypertension --Other symptoms are hyperkalemia and manifestations of complications
  • Urine Examination details can show cause: --Normal or few RBCs or WBCs or hyaline casts may indicate prerenal and/or postrenal etiologies --Abnormal --RBCs, RBCs casts are indicative of GN and vasculitis
• -WBCs, WBC casts are indicative of Interstitial nephritis, GN, and pyelonephritis --Granular, epithelial cell casts are indicative of ATN and vasculitis --Eosinophiluria is indicative of Allergic interstitial nephritis --Crystalluria is indicative of Acute uric acid nephropathy and calcium oxalate (ethylene glycol intoxication) --Also indicative of some drugs (amoxicillin, sulfadiazine acyclovir, indinavir)

Urine/serum biomarkers for AKI

• -Functional markers: SCr & plasma/serum CyC `cystatin c
• -Up-regulated proteins: As NGAL 'Neutrophil gelatinase-associated lipocalin' (urine/serum), KIM-1 'kidney injury molecule' (urine)
• -Low molecular weight proteins: Urine CyC
• -Enzymes: As NAG 'N-acetyl-β-D-glucosaminidase, α-GST, π-GST (urine)

AKI Biopsy

• Main indications include unexplained etiology, prolonged course, systemic disease

Furosemide Stress Test

• Used to stratify patients at risk of AKI progression

Furosemide Test Administration

• Administered intravenously at 1 mg/kg (if furosemide-naïve) or 1.5 mg/kg (if previously exposed)
• A urine output of < 200 mL over the next 2 hours shows a 87% sensitivity and 84% specificity to predict progression to stage 3 AKI