Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD)

Part I: Disease Framework - Understanding the Continuum

ACUTE KIDNEY INJURY (AKI)

1. Definition

• An absolute increase in serum creatinine of >0.3 mg/dL within 48 hours
• A relative increase in serum creatinine of ≥50% within 7 days
• Urine output <0.5 mL/kg/h for >6 hours

"AKI is a continuum of renal injury wherein reductions in renal function are linked to adverse outcomes." - Campbell Walsh Wein Urology

2. Staging (KDIGO)

• Brenner & Rector's The Kidney

3. Classification by Cause (Pathophysiology)

A. Prerenal AKI (Renal Hypoperfusion)

• True volume depletion: GI losses (vomiting, diarrhea), burns, hemorrhage, third-space losses (sepsis, nephrotic syndrome, trauma)
• Decreased effective arterial volume: Congestive heart failure, cirrhosis, severe hypoalbuminemia
• Renal vasoconstriction: NSAIDs (inhibit prostaglandin-mediated afferent vasodilation), ACE inhibitors/ARBs (impair efferent constriction), radiocontrast agents
• Salt wasting: renal or adrenal causes; Diabetes insipidus

B. Intrinsic Renal AKI (Structural Kidney Injury)

• Ischemic ATN: prolonged prerenal state progressing to tubular cell death; hypoxic-ischemic insults
• Nephrotoxic ATN:
  • Exogenous: aminoglycosides, IV contrast, cisplatin, amphotericin B, NSAIDs
  • Endogenous: myoglobin (rhabdomyolysis), hemoglobin (hemolysis), uric acid (tumor lysis syndrome), light chains (myeloma)

• Drug-induced (anticonvulsants, antibiotics - penicillins, cephalosporins, sulfonamides, NSAIDs)
• Idiopathic, autoimmune

• All causes of rapidly progressive glomerulonephritis (RPGN)
• Vasculitis, anti-GBM disease, IgA nephropathy (acute phase)

• Thrombotic microangiopathy (HUS, TTP)
• Renal artery/vein thrombosis
• Atheroembolic disease

C. Postrenal AKI (Obstruction)

• Bladder outlet obstruction (BPH, prostate cancer, urethral stricture)
• Bilateral ureteral obstruction (retroperitoneal fibrosis, bilateral calculi, pelvic malignancy)
• Bilateral renal pelvis obstruction
• Must be bilateral (or unilateral in a solitary kidney) to cause AKI

4. Epidemiology

• AKI occurs in approximately 4 cases per 1,000 pediatric hospital admissions
• Up to one-third of children admitted to ICUs develop AKI
• AKI is seen in up to one-half of pediatric patients with shock
• Patients with AKI have a nearly 15-fold increased mortality risk compared to those without (15% vs. 0.6%)
• AKI requiring dialysis occurs in 1-2% of critically ill children

5. Biomarkers

• NGAL (Neutrophil Gelatinase-Associated Lipocalin): earliest and most studied; rises within 2 hours of injury
• KIM-1 (Kidney Injury Molecule-1): proximal tubule injury marker
• Cystatin C: more sensitive than creatinine; AUC 0.86 for predicting RRT need
• α1-Microglobulin: sensitive for proximal tubule dysfunction; AUC 0.88 at ER presentation, cutoff 35 mg/g (sensitivity 80%, specificity 81%)
• β2-Microglobulin: 11.8 kDa peptide; normal urinary level ≤160 μg/L; elevated when tubular reabsorption is impaired
• NAG (N-acetyl-β-D-glucosaminidase): lysosomal enzyme released from damaged proximal tubule cells

6. Clinical Features

Symptoms

• Oliguria or anuria (though non-oliguric AKI exists and can be missed)
• Fluid retention, edema, hypertension
• Nausea, vomiting, lethargy
• Signs of the underlying cause (dehydration, sepsis, obstructive symptoms)

Laboratory findings

• Rising serum creatinine and BUN
• Hyperkalemia (life-threatening if severe)
• Metabolic acidosis (elevated anion gap)
• Hyperphosphatemia, hypocalcemia
• Anemia (dilutional or hemolytic in TMA)

Urine studies

• Prerenal: concentrated urine (SG >1.020), low UNa (<20 mEq/L), FENa <1%, hyaline casts
• ATN: isosthenuria, muddy brown granular casts, tubular epithelial cells, FENa >2%
• AIN: white cell casts, eosinophiluria (variable), mild proteinuria
• Glomerulonephritis: RBC casts, proteinuria, dysmorphic RBCs

7. Management

• Identify and treat the underlying cause
• Correct volume status: cautious IV fluid resuscitation in prerenal; avoid in volume-overloaded patients
• Avoid/stop nephrotoxins: NSAIDs, contrast, aminoglycosides, ACE inhibitors where appropriate
• Electrolyte management: treat hyperkalemia aggressively (calcium gluconate, insulin/glucose, bicarbonate, kayexalate, dialysis)
• Acid-base correction
• Nutritional support: adequate caloric and protein intake

• Acidosis (refractory metabolic acidosis)
• Electrolyte abnormalities (refractory hyperkalemia)
• Ingestions (toxin removal)
• Overload (volume overload not responsive to diuretics)
• Uremia (symptomatic: pericarditis, encephalopathy, bleeding)

• Intermittent hemodialysis (IHD): typically 3-4×/week for 4 hours
• Continuous RRT (CRRT): preferred in hemodynamically unstable patients
• Peritoneal dialysis: option when vascular access is difficult

CHRONIC KIDNEY DISEASE (CKD)

1. Definition

• Comprehensive Clinical Nephrology, 7th Edition

2. Classification (CGA Staging)

GFR Categories:

Albuminuria Categories:

3. Epidemiology and Risk Factors

• Diabetes mellitus (leading cause of CKD worldwide)
• Hypertension (second most common cause)
• Previous AKI episodes
• Cardiovascular disease
• Structural kidney tract disease, kidney stones, prostatic hypertrophy
• Multisystem diseases (SLE, vasculitis, amyloidosis)
• Family history of G5 CKD
• Hereditary kidney diseases (ADPKD, Alport syndrome)
• Opportunistic detection of hematuria or proteinuria

4. Causes (Etiology)

Primary Renal Causes:

• Diabetic nephropathy (most common cause globally)
• Hypertensive nephrosclerosis
• IgA nephropathy, focal segmental glomerulosclerosis (FSGS)
• Polycystic kidney disease (ADPKD, ARPKD)
• Chronic interstitial nephritis (analgesic nephropathy, reflux nephropathy)
• Renovascular disease (bilateral renal artery stenosis)

Systemic Disease Affecting Kidneys:

• Diabetes mellitus
• Systemic hypertension
• Systemic lupus erythematosus
• Amyloidosis, multiple myeloma
• HIV-associated nephropathy
• Vasculitides (ANCA-associated, anti-GBM)
• Sickle cell disease

5. Pathophysiology of Progression

1. Adaptive hyperfiltration - surviving nephrons increase individual GFR to compensate; intraglomerular hypertension results
2. Proteinuria - injured glomerular filtration barrier allows albumin and proteins to pass; tubular cells are damaged by protein reabsorption
3. Tubulointerstitial fibrosis - the final common pathway; mediated by TGF-β, ET-1, inflammatory cytokines
4. RAAS activation - angiotensin II promotes vasoconstriction, inflammation, and fibrosis; ACE inhibitors/ARBs are cornerstones of slowing progression
5. Uremia - accumulation of toxins (urea, creatinine, uremic solutes) with progressive loss of endocrine (EPO, 1,25-VitD) and excretory function

6. Clinical Presentation

Symptoms and Signs of Severe CKD (uremia):

7. Complications of CKD

A. Anemia

• Begins at stage G3a-G3b; prominent at G4-G5
• Caused by: relative EPO deficiency (main cause) + iron deficiency + chronic inflammation + shortened RBC survival
• Treatment: erythropoiesis-stimulating agents (ESAs - epoetin alfa, darbepoetin) + IV iron; target Hb 10-12 g/dL

B. Mineral and Bone Disease (CKD-MBD)

• As GFR falls: phosphate retention → FGF-23 rises → reduced 1α-hydroxylase activity → ↓calcitriol (1,25-OH2D) → hypocalcemia → secondary hyperparathyroidism (SHPT)
• Bone disease types: renal osteodystrophy (osteitis fibrosa cystica - high turnover, adynamic bone - low turnover, osteomalacia, mixed)
• Vascular calcification from hyperphosphatemia/elevated Ca×P product
• Treatment: phosphate binders, active vitamin D (calcitriol, paricalcitol), calcimimetics (cinacalcet for SHPT)

C. Hypertension

• Almost universal in CKD; both a cause and complication
• Salt and water retention are major drivers; RAAS activation contributes
• Target BP: <130/80 mmHg in most CKD patients
• ACE inhibitors/ARBs are first-line (reduce proteinuria and slow progression)

D. Metabolic Acidosis

• Results from reduced H+ excretion and bicarbonate production
• Contributes to bone loss, muscle wasting, progression of CKD, and hyperkalemia
• Treatment: oral sodium bicarbonate to maintain HCO3 ≥22 mEq/L

E. Hyperkalemia

• From reduced potassium excretion + metabolic acidosis (shifts K+ extracellularly)
• Risk increased with ACE inhibitors/ARBs, aldosterone antagonists
• Treatment: dietary restriction, loop diuretics, patiromer, sodium zirconium cyclosilicate

F. Cardiovascular Disease (CVD)

• Most common cause of death in CKD patients (before ESKD)
• Risk factors include: hypertension, dyslipidemia, chronic inflammation, fluid overload, anemia, vascular calcification, uremic toxins
• Management: aggressive CV risk factor modification, statins

G. Malnutrition and Protein-Energy Wasting

• Common in G4-G5; multifactorial (anorexia, acidosis, insulin resistance, inflammation, urinary protein losses)
• Protein intake recommendation: 0.8 g/kg/day for GFR <30 mL/min/1.73 m² (KDIGO); avoid high protein >1.3 g/kg/day in at-risk patients

8. Management of CKD

A. Slowing Progression

1. RAAS Blockade: ACE inhibitors or ARBs reduce intraglomerular pressure and proteinuria; first-line in diabetic and non-diabetic proteinuric CKD
2. Blood pressure control: Target <130/80 mmHg; RAAS agents preferred
3. Glycemic control: Target HbA1c ~7% in diabetics; too tight control risks hypoglycemia in advanced CKD (prolonged drug half-lives)
4. SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin): block glucose/sodium reabsorption in proximal tubule; now demonstrated renoprotective and cardioprotective effects independent of diabetes. A 2025 meta-analysis (PMID: 41082889) confirmed benefits for acute and chronic kidney outcomes across a range of patients.
5. Finerenone (nonsteroidal mineralocorticoid receptor antagonist): recently demonstrated cardiorenal benefits in CKD + type 2 diabetes

B. Dietary Management

• Protein: 0.8 g/kg/day if GFR <30; avoid high protein; monitor for malnutrition
• Sodium: restrict to <90 mmol/day (<5 g NaCl/day) to control hypertension and volume overload; avoid potassium-based salt substitutes (hyperkalemia risk)
• Potassium restriction: required in G4-G5
• Phosphate restriction: required in G4-G5; avoid phosphate-rich foods (dairy, processed foods)
• Fluid: individualized to stage; prevent volume overload
• Weight management: obesity accelerates CKD progression; weight loss recommended in early CKD

C. Avoiding Nephrotoxins

• NSAIDs: reduce renal prostaglandins, reduce GFR; avoid in advanced CKD
• Contrast agents: use low-osmolar/iso-osmolar contrast; pre/post hydration
• Aminoglycosides: reduce use; monitor levels
• ACE inhibitors/ARBs: can worsen AKI acutely in volume-depleted patients or bilateral renal artery stenosis; temporarily hold during acute illness ("sick day rules")

D. GFR Estimation

• CKD-EPI equation (updated to remove race) is the KDIGO-recommended formula for estimating GFR from serum creatinine
• Use with serum creatinine + cystatin C when more accurate assessment is needed

E. Kidney Replacement Therapy (KRT) - indication at G5 or symptomatic uremia

1. Hemodialysis: typically 3-4×/week; 4 hours/session; arteriovenous fistula preferred for access
2. Peritoneal dialysis: home-based; continuous ambulatory (CAPD) or automated (APD); glucose-based dialysate
3. Kidney transplantation: best long-term outcome; preemptive transplant (before dialysis) if living donor available

9. AKI vs. CKD - Key Differentiators

Summary

• AKI is a rapid, potentially reversible decline in kidney function (serum creatinine rise >0.3 mg/dL within 48h or >50% within 7 days or oliguria), classified as prerenal, intrinsic, or postrenal. Management centers on removing the cause, fluid balance, electrolyte management, and RRT when needed. AKI survivors have significantly elevated long-term risks for CKD.
• CKD is a sustained (>3 months) reduction in kidney function or structural damage, staged by GFR (G1-G5) and albuminuria (A1-A3). It is largely asymptomatic until late stage and progresses via glomerular hyperfiltration, proteinuria-driven tubulointerstitial fibrosis, and RAAS activation. Management targets slowing progression (RAAS blockade, SGLT2 inhibitors, BP control, glycemic control), treating complications (anemia, CKD-MBD, hyperkalemia, acidosis), and preparing for KRT in advanced stages.
• Both conditions are interconnected: AKI can precipitate or accelerate CKD, and CKD is a major risk factor for AKI.

• Brenner and Rector's The Kidney, 2-Volume Set (primary nephrology reference)
• Comprehensive Clinical Nephrology, 7th Edition
• Campbell Walsh Wein Urology, 3-Volume Set
• Sabiston Textbook of Surgery, The Biological Basis of Modern Surgical Practice
• Recent PubMed evidence: PMID 40424522 (AKI long-term outcomes, 2025); PMID 41082889 (SGLT2 inhibitors on kidney outcomes, 2025)