Kidney Failure: Definitions, Classification, Pathophysiology, and Management

Kidney failure (renal failure) occurs when the kidneys lose the ability to filter waste and maintain fluid/electrolyte balance. It includes both chronic kidney disease (CKD) and acute kidney injury (AKI) (formerly acute renal failure). CKD is defined as kidney damage or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² for ≥3 months, reflecting a progressive loss of function often culminating in the need for renal replacement therapy (dialysis or transplantation). AKI denotes a rapid (hours to days) decline in kidney function, usually measured by a rise in serum creatinine or reduced urine output. Importantly, CKD is typically insidious and irreversible, whereas AKI is often reversible if treated promptly.

Classification and Stages

Chronic Kidney Disease (CKD) Stages

CKD is stratified by KDIGO into five stages (G1–G5) based on GFR, with G3 subdivided into 3a and 3b. An accompanying albuminuria (A) category (A1–A3) further refines risk. (In stages G1–G2, evidence of kidney damage—e.g. proteinuria or structural changes—is required for diagnosis.) Table 1 summarizes the GFR-based stages:

CKD Stage (G Category)	GFR (mL/min/1.73 m²)	Description
G1 (Stage 1)	≥ 90 (with kidney damage)	Normal or high GFR with evidence of kidney damage (e.g. proteinuria)
G2 (Stage 2)	60–89 (mild ↓)	Mildly decreased GFR (CKD only if damage markers present)
G3a (Stage 3)	45–59 (mild–moderate ↓)	Moderately decreased GFR
G3b (Stage 3)	30–44 (moderate–severe ↓)	Moderately to severely decreased GFR
G4 (Stage 4)	15–29 (severe ↓)	Severely decreased GFR
G5 (Stage 5)	< 15 or dialysis	Kidney failure (ESRD)

Table 1. KDIGO CKD stages by GFR category. Albuminuria categories (A1: <30 mg/g; A2: 30–300 mg/g; A3: >300 mg/g) further stratify risk.

The combination of G and A categories (e.g. G3bA3) provides a heatmap of risk – higher albuminuria (A3) and lower GFR (G4–G5) each confer greater risk of progression and complications. Note: End-stage renal disease (ESRD) refers to stage G5 when GFR <15 or dialysis/transplant is required.

Acute Kidney Injury (AKI) Stages

AKI is defined by KDIGO as any of: an increase in serum creatinine by ≥0.3 mg/dL within 48 hours, or to ≥1.5× baseline within 7 days, or urine output <0.5 mL/kg/h for ≥6 hours. Severity is staged as:

Stage 1: 1.5–1.9× baseline creatinine or ≥0.3 mg/dL increase, or UO <0.5 mL/kg/h for 6–12 h.
Stage 2: 2.0–2.9× baseline creatinine, or UO <0.5 mL/kg/h for ≥12 h.
Stage 3: ≥3.0× baseline creatinine, or creatinine ≥4.0 mg/dL, or dialysis initiation, or UO <0.3 mL/kg/h for ≥24 h or anuria for 12 h.

(These criteria are adapted from KDIGO 2012 AKI guidelines.)

Pathophysiology

In CKD, progressive nephron loss leads to compensatory hyperfiltration in remaining nephrons. This causes glomerular hypertension, sclerosis, and further nephron injury. Over time, chronic insults (e.g. high glucose, hypertension) and maladaptive responses (RAAS activation, oxidative stress) produce glomerulosclerosis and tubulointerstitial fibrosis. The high intraglomerular pressure and filtration in hyperfiltrating nephrons eventually damage the filtration barrier, allowing proteinuria. Thus CKD is usually a chronic, insidious process driven by systemic and intrarenal mechanisms (e.g. diabetes-mediated microangiopathy, hypertensive arteriosclerosis).

In AKI, an acute insult rapidly decreases GFR. Pathophysiologically, AKI is categorized as:

Prerenal AKI: due to diminished renal perfusion (hypovolemia, heart failure, sepsis, vasodilation, renal artery stenosis). Decreased renal blood flow reduces GFR without direct parenchymal damage.
Intrinsic (renal) AKI: due to direct injury to the kidney (e.g. acute tubular necrosis from ischemia or nephrotoxins, acute glomerulonephritis, interstitial nephritis). These insults impair the renal parenchyma and tubules, sharply dropping GFR.
Postrenal AKI: due to urinary tract obstruction (stones, BPH, tumors) causing back-pressure and decreased filtration.

Each category disrupts the pressure gradients driving filtration, but intrinsic AKI often involves cell injury (e.g. tubular epithelial necrosis) with casts on sediment. Early identification of the cause (e.g. prerenal volume loss vs obstruction) is critical to reverse AKI before intrinsic damage ensues.

Causes of Kidney Failure

Chronic Kidney Disease (CKD) arises from long-term insults. The most common causes worldwide are:

Diabetic nephropathy: Chronic hyperglycemia damages glomeruli. (Type 2 DM accounts for ~30–50% of CKD, type 1 ~4%.)
Hypertensive nephrosclerosis: Long-standing hypertension leads to vascular and glomerular damage (~27% of CKD).
Chronic glomerulonephritis: Primary glomerular diseases (IgA nephropathy, focal segmental glomerulosclerosis, membranous GN) and secondary GN (SLE, vasculitis) comprise ~10–15% of ESRD cases.
Hereditary/Cystic diseases: Polycystic kidney disease and other genetic disorders (~3%).
Tubulointerstitial nephritis: Chronic interstitial diseases (analgesic nephropathy, reflux nephropathy, sarcoidosis) (~3–4%).
Obstruction: Chronic obstruction (e.g. BPH, stones) leads to postrenal CKD over time.
Other: Toxins (lead, analgesics), infections (chronic pyelonephritis), sickle cell nephropathy, paraproteinemias, etc.

These causes often overlap (e.g. diabetic patients also have hypertension). Together, diabetes and hypertension account for roughly two-thirds of CKD. CKD may also be categorized etiologically as prerenal (e.g. chronic heart failure, cirrhosis causing low perfusion), intrinsic renal (nephrosclerosis, chronic GN, PKD), or postrenal (chronic obstruction).

Acute Kidney Injury (AKI) is precipitated by:

Prerenal causes: Volume depletion (bleeding, dehydration), hypotension, shock, sepsis; cardiac failure or cirrhosis (low effective perfusion); over-diuresis; and drugs that reduce perfusion (NSAIDs, ACE inhibitors in bilateral renal artery stenosis).
Intrinsic causes:
- Acute tubular necrosis (ATN): most common AKI cause; from ischemia (shock) or nephrotoxins (aminoglycosides, radiocontrast, cisplatin, myoglobin).
- Acute glomerulonephritis: e.g. postinfectious GN, rapidly progressive GN (vasculitis, lupus, Goodpasture).
- Acute interstitial nephritis: often drug-induced (antibiotics, NSAIDs, proton-pump inhibitors) or infection-related.
- Vascular: e.g. malignant hypertension, thrombotic microangiopathy.
Postrenal causes: Bilateral urinary obstruction (BPH, stones, tumors, clots) causing back-pressure; relief of the obstruction usually restores function.

In practice, AKI etiologies can overlap, and prompt identification (e.g. via history, fluid status, urine sediment) guides therapy.

Clinical Manifestations

CKD is often asymptomatic in early stages. As kidney function declines, uremic symptoms emerge:

General: Fatigue, anorexia, nausea/vomiting, pruritus (itching), and weight loss due to toxin buildup.
Volume and BP: Hypertension is common; fluid retention causes peripheral and pulmonary edema.
Neurological: Encephalopathy (confusion, lethargy, asterixis) when urea accumulates; neuropathy (restless legs).
Hematologic: Normocytic anemia from low erythropoietin (leading to pallor, fatigue); bleeding diathesis (platelet dysfunction).
Cardiovascular: Left ventricular hypertrophy, heart failure, and pericarditis (uremic pericarditis).
Skeletal: Renal osteodystrophy (bone pain, fractures) due to phosphate retention, hypocalcemia, secondary hyperparathyroidism.
Electrolyte/metabolic: Hyperkalemia (arrhythmias), metabolic acidosis, hyperphosphatemia, hypocalcemia.
Endocrine: Dyslipidemia, insulin resistance.

Physical exam may reveal edema, hypertension, anemia, bone tenderness, and uremic breath odor. In contrast, AKI often presents with rapid onset of oliguria (urine output <400–500 mL/day) or anuria, fluid overload (pulmonary edema, hypertension), uremic symptoms, and acute electrolyte imbalances (hyperkalemia, acidosis). Prerenal AKI may show signs of volume depletion (tachycardia, low JVP), whereas intrinsic AKI may show muddy brown casts (ATN) or RBC casts (GN) on urine microscopy.

Common laboratory findings include elevated serum creatinine and BUN, with an increasing BUN:Cr ratio in prerenal states (>20:1). eGFR (using CKD-EPI equation) declines as creatinine rises. Urinalysis may show proteinuria (especially with glomerular diseases), RBCs, casts, or tubular epithelial cells depending on cause. Electrolyte abnormalities (e.g. K^+↑, HCO₃⁻↓) and anemia (↓Hb) are frequent in CKD. Regular monitoring of GFR and creatinine is recommended to detect trends.

Diagnosis and Evaluation

CKD diagnosis requires evidence of reduced kidney function or damage for ≥3 months. Key criteria (KDIGO) are: eGFR <60 mL/min/1.73 m² for >3 months or markers of kidney damage (albuminuria, hematuria, imaging abnormalities) present for >3 months. eGFR is estimated from serum creatinine (CKD-EPI formula preferred). Persistent albuminuria (ACR ≥30 mg/g) indicates glomerular injury. Repeated testing (e.g. 2 of 3 measurements over 3 months) is necessary to confirm chronicity. Additional evaluation includes renal ultrasound (to assess size, obstruction), urinalysis, and possibly biopsy if the etiology is unclear (especially if rapid progression or glomerulonephritis is suspected).

AKI diagnosis uses the KDIGO criteria: rise in serum creatinine ≥0.3 mg/dL in 48 h, or ≥1.5× baseline in 7 days, or urine output <0.5 mL/kg/h for 6 h. A thorough history and exam help determine cause (e.g. medications, dehydration, obstruction). Initial labs include BUN, creatinine, electrolytes, and urinalysis. A fractional excretion of sodium (FeNa) or urine microscopy can distinguish prerenal (FeNa <1%, bland sediment) from intrinsic (FeNa >2%, muddy casts) injury. Imaging (renal ultrasound) should be done early to rule out obstruction.

Laboratory monitoring: Declining GFR is monitored via creatinine and eGFR; rising BUN/Cr; worsening albuminuria. In practice, eGFR <60 alerts to CKD. Other tests include electrolytes (to catch hyperkalemia, acidosis), CBC (for anemia), PTH, calcium/phosphate, and iron studies (for anemia management). In acute settings, serial creatinine, urinary output, and supportive labs guide care.

Management

CKD Management

Treatment aims to slow progression, manage complications, and prepare for renal replacement. Key strategies include:

Blood pressure control: Maintain BP targets to protect kidneys. KDIGO 2024 recommends systolic BP <120 mmHg in most adults with CKD. First-line agents are RAAS blockers (ACE inhibitors or ARBs), especially if proteinuria is present. These reduce glomerular pressure and proteinuria, delaying CKD progression. (KDIGO 2013 strongly recommends ACEI/ARB for patients with persistent proteinuria >300 mg/day.) Diuretics often assist in volume control.
Glycemic control: In diabetic CKD, tight blood sugar control (HbA1c ~7% or individualized) prevents further nephropathy. SGLT2 inhibitors are now recommended for DM patients with CKD to slow progression (per KDIGO Diabetes 2022).
Lifestyle/diet: Low-sodium diet (<2–3 g Na/day) helps BP control. Moderately reduced protein intake (0.8 g/kg/day) may be advised once GFR <30, balanced against risk of malnutrition. Avoid NSAIDs and nephrotoxins. Smoking cessation and weight management are essential.
Albuminuria reduction: In addition to ACEI/ARB, other antiproteinuric measures include aldosterone antagonists (spironolactone, careful of hyperkalemia) or SGLT2 inhibitors (reduce albuminuria). Treat underlying cause (e.g. immunosuppression for glomerulonephritis).
Mineral bone disorder: Manage CKD-related bone disease by controlling phosphate (dietary restriction, phosphate binders if needed), supplementing active vitamin D, and controlling parathyroid hormone. Monitor and correct calcium, phosphorus, and PTH per guidelines.
Anemia management: When CKD GFR <60 or Hb <11 g/dL, screen for anemia of CKD. Give iron if iron-deficient, and erythropoiesis-stimulating agents (ESAs) if Hb <10 with symptoms, aiming for ~11–12 g/dL.
Metabolic acidosis: In CKD stage 3–5 with serum bicarbonate <22 mEq/L, treat with oral bicarbonate to slow bone disease and muscle breakdown.
Cardiovascular risk: Use statins for dyslipidemia in CKD stages 3–5 to reduce CV events (per KDIGO, unless on dialysis, then consider individually). Antiplatelet therapy as indicated.
Referral to nephrology: Refer earlier for advanced CKD: generally CKD stage 4 (GFR <30) or rapidly declining GFR, significant albuminuria, or difficult-to-control complications. Educate and prepare patients for possible dialysis (vascular access planning) or transplant evaluation in ESRD (Stage 5).

AKI Management

Treatment of AKI focuses on reversing the cause and supportive care:

Prerenal AKI: Restore perfusion. This may require IV fluids (crystalloids) for volume depletion, blood transfusion for hemorrhage, or inotropes for cardiac failure. Hold or adjust offending medications (NSAIDs, diuretics, ACEI/ARB) until kidney function recovers. Monitor urine output; often AKI resolves when perfusion is corrected.
Intrinsic AKI: Address specific cause. For ischemic or nephrotoxic ATN, supportive care (fluid/electrolyte management) and removal of the toxin are key. In glomerulonephritis, high-dose steroids or immunosuppressives may be needed. In interstitial nephritis, stop the culprit drug and consider steroids.
Postrenal AKI: Relieve obstruction urgently (catheterize, lithotripsy, stent). Kidney function often recovers once obstruction is cleared.
General measures: Discontinue nephrotoxins (e.g. aminoglycosides, contrast, NSAIDs). Maintain appropriate volume (avoid both under- and over-hydration). Manage hyperkalemia (insulin/dextrose, bicarbonate, albuterol, cation exchange resins) and acidosis medically. Monitor serial creatinine and electrolytes closely.
Renal replacement therapy (RRT): Initiate dialysis if life-threatening indications arise (AEIOU): Acidosis (pH <7.1 despite therapy), Electrolytes (refractory hyperkalemia), Intoxications (salicylates, lithium, etc.), Overload (pulmonary edema not responsive to diuretics), Uremia (pericarditis, encephalopathy). Modalities include intermittent hemodialysis, continuous renal replacement therapy (CRRT) in ICU settings, or sustained low-efficiency dialysis (SLED).

Renal Replacement Therapy (RRT)

In ESRD (CKD G5) or severe AKI, RRT replaces kidney function. Options:

Hemodialysis: Extracorporeal filtration (usually 3×/week) removes solutes/fluids. Requires vascular access (fistula or graft). Manages uremia, acidosis, hyperkalemia, and volume.
Peritoneal dialysis: Uses peritoneum as dialysis membrane (fluid in abdomen exchanges solutes/fluids). Often done daily at home (CAPD or automated PD).
Kidney transplantation: The best long-term treatment for ESRD if available. Living or deceased donor transplant restores renal function.

Patients on RRT require multidisciplinary care (nephrologist, dietitian, etc.) and supportive treatments (anemia management, bone disease control). Conservative (non-dialytic) management is an option in selected elderly with heavy comorbidity, focusing on quality of life.

Guidelines and Key Recommendations

KDIGO 2023–24 CKD Guideline: (In Kidney Int. 2024) provides comprehensive recommendations for CKD evaluation and management. Key points include using CKD-EPI creatinine to estimate GFR, combining GFR and albuminuria for risk stratification, and targeting SBP <120 mmHg in most CKD patients. It also emphasizes treating modifiable factors (e.g. BP, diabetes, diet) and preparing for RRT as GFR declines.
KDIGO 2012 AKI Guideline: Defines AKI criteria (as above) and recommends judicious fluid management and avoidance of nephrotoxins.
NICE CKD Guideline (NG203, 2021): Recommends routine eGFR reporting, CKD staging with albuminuria, ACEI/ARB for proteinuric CKD, and investigation/referral criteria.
KDIGO 2021 BP Guideline: (Co-sponsored by AHA) supports intensive BP control (target <120 SBP) to protect CKD patients.
KDIGO Diabetes 2022: In CKD with type 2 DM, recommends SGLT2 inhibitors for nephroprotection.

These guidelines (KDIGO, NICE, KDOQI) serve as the evidence-based backbone for CKD/AKI care, but clinical judgment remains essential.

Summary

Kidney failure encompasses acute and chronic syndromes leading to reduced GFR. Chronic kidney disease is defined by kidney damage or eGFR <60 mL/min/1.73 m² for ≥3 months, with five stages (G1–G5) indicating severity. Common causes include diabetes, hypertension, and chronic glomerulonephritis. Acute kidney injury is diagnosed by rapid rises in creatinine or oliguria, and is classified as prerenal, intrinsic, or postrenal based on cause. Management focuses on treating the underlying cause, controlling BP and volume, and minimizing complications. For CKD, slowing progression with RAAS blockade, BP control (<120 mmHg systolic), glycemic control, and complication management are priorities. End-stage disease requires dialysis or transplantation.

Clinicians should follow current guidelines (KDIGO, NICE, etc.) to ensure standardized care. Early detection (e.g. routine eGFR and ACR screening in at-risk patients) and a multidisciplinary approach improve outcomes in kidney failure.

Key Reference: Definition and staging of CKD and AKI are grounded in KDIGO guidelines; ACEI/ARB use for proteinuria is strongly recommended by KDIGO; recent KDIGO 2024 guidance suggests intensive BP control in CKD.