5.1 Acute Kidney Injury & Glomerular Diseases
Key Takeaways
- KDIGO AKI criteria require an increase in serum creatinine by ≥26.5 μmol/L within 48 hours, a ≥1.5-fold baseline increase within 7 days, or urine output <0.5 mL/kg/h for >6 consecutive hours.
- Pre-renal azotemia is characterized by a fractional excretion of sodium (FENa) <1% and urine sodium <20 mmol/L, whereas intrinsic acute tubular necrosis (ATN) demonstrates FENa >2%, urine sodium >40 mmol/L, and muddy brown granular casts.
- Nephrotic syndrome is defined by heavy proteinuria (>3.5 g/24h or urine protein-to-creatinine ratio >350 mg/mmol), hypoalbuminemia (<30 g/L), hyperlipidemia, and edema; nephritic syndrome features dysmorphic hematuria, red blood cell casts, hypertension, oliguria, and mild-to-moderate proteinuria (<3.0 g/24h).
- Rapidly progressive glomerulonephritis (RPGN) causes acute renal failure over days to weeks with >50% crescent formation on renal biopsy, divided into anti-GBM (linear IgG deposition), immune complex (granular deposition), and pauci-immune ANCA-associated vasculitis (PR3/c-ANCA or MPO/p-ANCA).
- IgA nephropathy typically presents with synpharyngitic macroscopic hematuria (1-2 days after upper respiratory tract infection) with normal serum C3/C4 levels, contrasting with post-streptococcal glomerulonephritis which manifests 2-4 weeks post-infection with low complement C3 levels.
Acute Kidney Injury & Glomerular Diseases
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid reduction in renal excretory function, resulting in the accumulation of nitrogenous waste products (uremia) and the dysregulation of extracellular fluid volume, electrolytes, and acid-base homeostasis. In hospital medicine, AKI occurs in approximately 15–20% of emergency admissions and up to 50% of patients in intensive care units.
KDIGO Definition & Staging System
The Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines define AKI by the presence of any one of the following parameters:
- Increase in serum creatinine by $\ge 26.5,\mu\text{mol/L}$ ($≥ 0.3,\text{mg/dL}$) within 48 hours.
- Increase in serum creatinine to $\ge 1.5$ times baseline value within the prior 7 days.
- Urine volume $< 0.5,\text{mL/kg/hour}$ for at least 6 consecutive hours.
| KDIGO Stage | Serum Creatinine Criteria | Urine Output Criteria |
|---|---|---|
| Stage 1 | $1.5\text{--}1.9 \times$ baseline OR $\ge 26.5,\mu\text{mol/L}$ rise | $< 0.5,\text{mL/kg/h}$ for 6–12 hours |
| Stage 2 | $2.0\text{--}2.9 \times$ baseline | $< 0.5,\text{mL/kg/h}$ for $\ge 12$ hours |
| Stage 3 | $3.0 \times$ baseline OR serum creatinine $\ge 353.6,\mu\text{mol/L}$ OR initiation of RRT OR eGFR $< 35,\text{mL/min/1.73m}^2$ in patients $< 18$ years | $< 0.3,\text{mL/kg/h}$ for $\ge 24$ hours OR anuria for $\ge 12$ hours |
Diagnostic Differentiation of AKI Etiologies
AKI is etiologically classified into three broad functional categories: Pre-renal azotemia, Intrinsic renal parenchymal disease, and Post-renal obstructive uropathy.
Pre-Renal vs. Intrinsic Acute Tubular Necrosis (ATN)
Pre-renal AKI stems from renal hypoperfusion without structural parenchymal injury. Under hypoperfusion, intact tubular function maximally reabsorbs water and sodium (driven by aldosterone and antidiuretic hormone). In contrast, acute tubular necrosis (ATN)—the predominant cause of intrinsic AKI in hospitalized adults resulting from prolonged ischemia or nephrotoxins—features tubular epithelial cell necrosis, loss of the brush border, and impaired sodium reabsorption.
| Diagnostic Parameter | Pre-Renal Azotemia | Acute Tubular Necrosis (ATN) |
|---|---|---|
| Fractional Excretion of $\text{Na}^+$ ($\text{FE}_{\text{Na}}$) | $< 1.0%$ | $> 2.0%$ |
| Fractional Excretion of Urea ($\text{FE}_{\text{Urea}}$) (used if on diuretics) | $< 35%$ | $> 50%$ |
| Urinary Sodium Concentration | $< 20,\text{mmol/L}$ | $> 40,\text{mmol/L}$ |
| Urine Osmolality | $> 500,\text{mOsm/kg}$ | $< 350,\text{mOsm/kg}$ |
| Serum Urea to Creatinine Ratio | $> 100:1$ (in $\mu\text{mol}/\mu\text{mol}$) | $< 40:1$ |
| Urine Microscopy Sediment | Normal / Hyaline casts | Muddy brown granular casts, tubular epithelial cells |
Exam Pearl: In patients taking loop or thiazide diuretics, $\text{FE}{\text{Na}}$ is frequently elevated despite pre-renal hypoperfusion due to drug-induced natriuresis. In this clinical scenario, the **Fractional Excretion of Urea ($\text{FE}{\text{Urea}}$)** is the preferred diagnostic test; a value $< 35%$ confirms pre-renal azotemia.
Acute Interstitial Nephritis (AIN)
AIN is an immune-mediated hypersensitivity reaction involving the renal interstitium, accounting for up to 15% of unexplained intrinsic AKI.
- Etiologies: Drugs cause $> 75%$ of cases—notably NSAIDs, penicillins, cephalosporins, fluoroquinolones, proton pump inhibitors (PPIs), sulfonamides, and allopurinol. Autoimmune causes include Sjogren syndrome and sarcoidosis.
- Clinical Presentation: The classic clinical triad of fever, maculopapular rash, and peripheral eosinophilia is present in only 10–30% of patients.
- Urinary Findings: Sterile pyuria, white blood cell (WBC) casts, eosinophiluria (Hansel stain), and mild sub-nephrotic proteinuria.
Glomerular Diseases: Nephrotic vs. Nephritic Syndromes
Glomerulonephritis represents immune-mediated inflammatory or non-inflammatory disruption of the glomerular filtration barrier.
| Feature | Nephrotic Syndrome | Nephritic Syndrome |
|---|---|---|
| Primary Pathology | Podocyte / epithelial cell injury resulting in charge/size selectivity loss | Endothelial / mesangial inflammatory breakdown and hypercellularity |
| Proteinuria | Heavy: $> 3.5,\text{g/24h}$ (PCR $> 350,\text{mg/mmol}$) | Sub-nephrotic: $< 3.0,\text{g/24h}$ |
| Serum Albumin | Hypoalbuminemia ($< 30,\text{g/L}$) | Normal or mildly reduced |
| Edema | Marked peripheral edema, anasarca | Mild dependent edema, periorbital edema |
| Hematuria | Absent or microscopic without dysmorphism | Macroscopic / microscopic with dysmorphic RBCs and RBC casts |
| Blood Pressure | Usually normal (hypovolemic activation of RAAS) | Elevated / Severe hypertension (salt and water retention) |
| Renal Function | eGFR preserved initially (except late stage) | Acute rise in creatinine, oliguria |
Major Causes of Nephrotic Syndrome
- Minimal Change Disease: Responsible for 80% of nephrotic syndrome in children and 10–15% in adults. Light microscopy shows normal glomeruli; electron microscopy reveals diffuse foot process effacement (podocytopathy). Excellent response to corticosteroids.
- Focal Segmental Glomerulosclerosis (FSGS): Commonest cause in adults of African descent. Associated with APOL1 risk alleles, HIV infection, obesity, and heroin use. Light microscopy demonstrates segmental sclerosis in $< 50%$ of glomeruli. High rate of steroid resistance and progression to end-stage renal disease (ESRD).
- Membranous Nephropathy: Primary form accounts for 70% of adult cases, driven by autoantibodies against the Phospholipase A2 Receptor (PLA2R). Secondary causes include solid organ malignancies (lung, colon, breast), hepatitis B/C, NSAIDs, and SLE (Class V). Light microscopy displays diffuse capillary wall thickening; silver stain shows subepithelial "spike and dome" projections.
- Renal Amyloidosis: Deposition of AL (light chain) or AA (serum amyloid A) fibrils. Biopsy confirms apple-green birefringence under polarized light after Congo red staining.
Major Causes of Nephritic Syndrome
- IgA Nephropathy (Berger Disease): The commonest primary glomerulonephritis worldwide. Characterized by synpharyngitic macroscopic hematuria developing 1–2 days after an upper respiratory or gastrointestinal infection. Immunofluorescence demonstrates mesangial IgA deposition. Serum C3 and C4 levels remain normal.
- Post-Streptococcal Glomerulonephritis (PSGN): Occurs 2–4 weeks following Group A $\beta$-hemolytic streptococcal pharyngitis or impetigo (due to nephritogenic strains with SpeB/NAPI antigens). Features low serum complement C3, elevated anti-streptolysin O (ASO) or anti-DNase B titers. Electron microscopy shows classic subepithelial "humps".
- Rapidly Progressive Glomerulonephritis (RPGN): A nephrological emergency characterized by rapid loss of renal function over days to weeks with crescent formation in $> 50%$ of glomeruli on biopsy.
| RPGN Subtype | Pathogenetic Mechanism | Key Diagnostic Biomarkers | Biopsy Immunofluorescence |
|---|---|---|---|
| Type 1: Anti-GBM Disease | Autoantibodies against $\alpha_3$ chain of type IV collagen | Anti-GBM antibodies positive | Smooth, linear IgG deposition along basement membrane |
| Type 2: Immune Complex | Deposition of circulating antigen-antibody complexes | Low C3/C4, positive ANA/dsDNA, ASO, cryoglobulins | Granular "lumpy bumpy" immune complex deposition |
| Type 3: Pauci-Immune | ANCA-associated small vessel vasculitis (GPA, MPA, EGPA) | c-ANCA (PR3-ANCA) or p-ANCA (MPO-ANCA) positive | Negative or minimal immune deposition ("pauci-immune") |
Exam Pearl: Distinguishing IgA Nephropathy from PSGN is a classic MRCPI Part I question:
- IgA Nephropathy: Synpharyngitic onset (1–2 days post-URI), normal serum complement levels.
- PSGN: Post-infectious delay (2–4 weeks post-strep), transiently depressed serum complement C3 level that normalizes within 6–8 weeks.
A 68-year-old man with a history of hypertension and osteoarthritis presents with a 3-day history of severe diarrhea and poor oral intake. On examination, he is lethargic, pulse is 112 bpm, and blood pressure is 88/54 mmHg. Serum creatinine is 285 μmol/L (baseline 80 μmol/L), urea is 24.2 mmol/L, and urine output over the past 6 hours is 90 mL. Urine chemistry shows a sodium concentration of 12 mmol/L and fractional excretion of sodium (FENa) of 0.4%. Urine microscopy shows hyaline casts. Which of the following is the most appropriate immediate management step?
A 24-year-old medical student presents with dark, tea-colored urine that began 24 hours after developing a fever and sore throat. He reports a similar episode 6 months ago during an upper respiratory tract infection. Physical examination reveals blood pressure of 138/86 mmHg and mild ankle swelling. Dipstick urinalysis shows 3+ blood and 1+ protein. Serum creatinine is 110 μmol/L. Serum complement C3 and C4 levels are within reference limits. Which of the following is the most likely underlying renal pathology?
A 58-year-old woman presents with malaise, hemoptysis, and oliguria developing over two weeks. Serum creatinine has risen from 90 μmol/L to 490 μmol/L. Urinalysis reveals dysmorphic red blood cells and red cell casts. Serological testing demonstrates high titers of anti-neutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA / anti-PR3). Renal biopsy reveals crescentic formation in 70% of glomeruli. What is the characteristic immunofluorescence pattern seen on renal biopsy in this patient's condition?