Acute on Chronic Kidney Disease (AoCKD)

1. Definition and Terminology

"AKI can develop de novo in the setting of intact kidney function or can be superimposed on underlying chronic kidney disease (acute on chronic kidney injury), and the presence of underlying impaired kidney function has been shown to be one of the most important risk factors for the development of AKI."

• Brenner and Rector's The Kidney, 2-Volume Set

• AKI: Rapid (hours to days) decline in GFR - serum creatinine rise ≥0.3 mg/dL within 48 hours, or ≥50% rise within 7 days, or urine output <0.5 mL/kg/h for >6 hours
• CKD: Impaired kidney function or structural damage present for >3 months
• Acute Kidney Disease (AKD): A KDIGO concept - kidney disease lasting <3 months but >7 days (a bridge between AKI and CKD)
• AoCKD: AKI criteria met in a patient with known underlying CKD

2. KDIGO Staging Criteria (Applied in AoCKD)

3. Epidemiology

• CKD is one of the most important risk factors for AKI development
• Among inpatients, prerenal azotemia and acute tubular injury (ATI) account for most AKI/AoCKD cases
• Patients with CKD have diminished renal functional reserve, making them especially vulnerable to acute insults
• Geographic variation exists - tropical countries have a different AKI spectrum (e.g., infectious, toxin-related causes)

4. Why CKD Predisposes to Acute Injury - Pathophysiology

1. Diminished renal functional reserve - fewer functioning nephrons mean less capacity to compensate for acute insults
2. Impaired salt and water conservation - predisposes to intravascular volume contraction (pre-renal component)
3. Decreased detoxification mechanisms - reduced clearance of nephrotoxins, prolonging toxic exposure
4. Increased susceptibility to cytotoxic injury - from uremic milieu and oxidative stress
5. Macrovascular and microvascular disease - atherosclerosis, arteriosclerosis increase risk of ischemic injury
6. Chronic inflammation - ongoing low-grade inflammation lowers the threshold for acute tubular injury

5. Etiology - Causes of the Acute Component

Prerenal Causes

• Hypovolemia: hemorrhage, GI losses (diarrhea, vomiting), diuretic overuse, burns
• Reduced cardiac output: heart failure, cardiogenic shock, pericardial disease
• Sepsis (systemic vasodilation + renal vasoconstriction)
• Medications: NSAIDs (reduce prostaglandin-mediated afferent dilation), ACE inhibitors/ARBs (block efferent vasoconstriction), calcineurin inhibitors, iodinated contrast agents
• Abdominal compartment syndrome

Intrinsic Renal Causes

• Acute Tubular Injury (ATI/ATN) - most common in critically ill CKD patients
• Acute glomerulonephritis (crescentic GN, IgA nephropathy flare)
• Acute interstitial nephritis (drug-induced, autoimmune, infectious)
• Vascular: thrombotic microangiopathy, renal artery stenosis ("flash" pulmonary edema + AoCKD is a classic clue - Comprehensive Clinical Nephrology, 7th Ed.)
• Malignant hypertension, vasculitis, scleroderma renal crisis

Postrenal Causes

• Urinary obstruction - more impactful in solitary kidney or bilateral obstruction (BPH, stones, malignancy)

6. Diagnosis

History and Clinical Clues

• Known CKD with abrupt worsening of renal function beyond expected trajectory
• Symptoms of uremia: nausea, vomiting, encephalopathy, pericarditis
• Oliguria/anuria - though nonoliguric AoCKD also occurs
• Identify precipitants: recent medications (NSAIDs, contrast, antibiotics), infections, dehydration, cardiac events

Laboratory Features

Note: FENa can be unreliable in CKD patients because tubular reabsorptive capacity is already impaired. Fractional excretion of urea (FEurea) is preferred when diuretics have been given.

Imaging

• Renal ultrasound: First-line - assess kidney size (small echogenic kidneys = CKD), cortical thickness, exclude obstruction (hydronephrosis). Doppler can assess renal artery stenosis.
• CT scan: Useful for obstruction, stone disease, or infarction (avoid contrast if possible)
• Renal biopsy: Consider if intrinsic cause is suspected and unclear - especially in rapidly progressive GN, suspected AIN, or unexplained AoCKD. Higher risk in CKD (smaller kidneys, fragile parenchyma).

Distinguishing Acute from Chronic Component

7. Complications

• Fluid overload / pulmonary edema - already impaired ability to excrete volume
• Severe hyperkalemia - reduced tubular potassium secretion + acidosis
• Metabolic acidosis - worsened by acute tubular dysfunction on a background of reduced acid excretion
• Uremic pericarditis / encephalopathy - uremic toxin accumulation faster due to reduced baseline clearance
• Anemia - EPO deficiency compounded by acute blood loss or hemolysis
• Cardiovascular events - high risk given CKD-related vascular disease
• Increased susceptibility to infections - uremic immunosuppression

8. Management

General Principles

1. Identify and remove the precipitant (stop nephrotoxins, treat sepsis, relieve obstruction, treat heart failure)
2. Fluid resuscitation - carefully titrated; avoid both under- and over-resuscitation (CKD patients are less forgiving of fluid overload)
3. Electrolyte correction - urgent treatment of hyperkalemia (calcium gluconate, insulin-dextrose, salbutamol, sodium bicarbonate, kayexalate, emergency dialysis)
4. Acid-base management - bicarbonate supplementation in severe acidosis
5. Blood pressure control - avoid hypotension (worsens ischemia); avoid hypertension (accelerates CKD progression)

Medication Management

• Hold ACE inhibitors/ARBs during the acute phase (worsen GFR in hypoperfused state)
• Avoid/stop NSAIDs, aminoglycosides, contrast agents
• Adjust doses of all renally cleared drugs to current GFR (not CKD baseline)
• Diuretics: Loop diuretics for volume overload, but use cautiously - they do not improve outcomes or accelerate recovery, only manage fluid status

Renal Replacement Therapy (RRT)

• Acidosis - refractory metabolic acidosis (pH <7.1)
• Electrolytes - refractory hyperkalemia
• Intoxication - dialyzable toxins
• Overload - fluid overload refractory to diuretics
• Uremia - uremic pericarditis, encephalopathy, bleeding

Nutrition

• Protein restriction: 0.6-0.8 g/kg/day in non-dialyzed patients; increase to 1.2-1.5 g/kg/day if on dialysis
• High-caloric intake (30-35 kcal/kg/day) to prevent catabolism

9. Prognosis

• Higher in-hospital mortality compared to AKI on normal kidney function
• Non-recovery of kidney function is more common - patients often progress to end-stage kidney disease (ESKD) requiring permanent dialysis
• Each episode of AKI accelerates CKD progression through additional nephron loss, fibrosis, and proteinuria
• Underlying CKD stage at the time of the acute event is the strongest predictor of non-recovery:
  • CKD Stage 3-5 patients have significantly higher rates of progression to ESKD after AKI
• Cardiovascular mortality is a leading cause of death in survivors

"Nonrecovery of kidney function and death after acute on chronic renal failure" is cited as a major outcomes study in Brenner and Rector's The Kidney (Clin J Am Soc Nephrol. 2009;4:891-898).

10. Prevention

• Regular monitoring of CKD patients for acute deteriorations (baseline creatinine trends)
• Avoid nephrotoxic medications where possible; if unavoidable, closely monitor renal function
• Pre-hydration before iodinated contrast or surgery in high-risk CKD patients
• Optimize CKD management: blood pressure control (target <130/80 mmHg), ACE inhibitor/ARB use (reduce proteinuria and progression when hemodynamically stable), glycemic control in diabetic CKD
• Prompt treatment of urinary tract infections and obstruction
• Volume status optimization during hospitalizations and acute illnesses

Summary Table

• Comprehensive Clinical Nephrology, 7th Edition - Paine, Jefferson & Velez, Chapter 70: Pathophysiology and Etiology of Acute Kidney Injury
• Brenner and Rector's The Kidney, 2-Volume Set - Chapter 29: Definition of Acute Kidney Injury, Staging Criteria
• National Kidney Foundation Primer on Kidney Diseases, 8e