a) Medical management of primary hyperoxaluria. [4] b) Indications of Eculizumab in kidney disorders and kidney transplantation. [6]
Definition
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder characterized by hepatic overproduction of oxalate, leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive renal failure (Brenner & Rector's The Kidney, 11th ed, Ch. 61).
Etiopathogenesis
PH results from mutations in enzymes involved in glyoxylate metabolism causing excessive oxalate synthesis:
| Type | Defective Enzyme | Gene | Pathophysiology |
|---|---|---|---|
| PH1 | Alanine-glyoxylate aminotransferase | AGXT | Conversion of glyoxylate to glycine impaired; glyoxylate converted to oxalate ↑ (Brenner & Rector's The Kidney, 11th ed) |
| PH2 | Glyoxylate reductase/hydroxypyruvate reductase | GRHPR | Reduced conversion of glyoxylate to glycolate, increasing oxalate production |
| PH3 | 4-hydroxy-2-oxoglutarate aldolase | HOGA1 | Defect in hydroxyproline metabolism leading to oxalate overproduction |
Clinical Features
- Recurrent calcium oxalate nephrolithiasis (kidney stones)
- Nephrocalcinosis on imaging
- Progressive chronic kidney disease (CKD)
- Systemic oxalosis in advanced renal failure: bone pain, fractures, cardiac and ocular deposits
- Early-onset presentation (infancy to adolescence)
Diagnosis
- Urinary oxalate excretion: markedly elevated (>1 mmol/1.73 m²/day)
- Genetic testing confirming mutation in AGXT, GRHPR, or HOGA1
- Liver biopsy for enzyme assay (rarely done)
- Stone analysis: calcium oxalate composition
- Imaging: ultrasound/CT showing nephrocalcinosis and stones
| Diagnostic Criteria | Findings |
|---|---|
| 24-hour urinary oxalate | Elevated (>1 mmol/1.73 m²/day) |
| Genetic testing | Pathogenic mutations |
| Stone analysis | Calcium oxalate crystals |
| Imaging (USG/CT) | Nephrocalcinosis, stones |
(Brenner & Rector's The Kidney, 11th ed)
Management
- General measures:
- High fluid intake (>3 L/day) to dilute urine
- Dietary oxalate restriction (limited fruits/vegetables rich in oxalate)
- Avoid excessive vitamin C (precursor of oxalate)
- Pharmacological treatment:
- Pyridoxine (Vitamin B6) (50–200 mg/day) for PH1 to reduce oxalate synthesis (responsive in ~30% cases)
- Potassium citrate to alkalinize urine and inhibit stone formation
- Advanced management:
- Dialysis for renal failure (intensive hemodialysis to reduce systemic oxalosis)
- Combined liver-kidney transplantation in end-stage renal disease (addressing enzyme deficiency and renal failure)
| Treatment Aspect | Intervention |
|---|---|
| Hydration | >3 L/day |
| Diet | Low oxalate intake |
| Vitamin B6 | 50–200 mg/day (PH1 sensitive) |
| Alkali therapy | Potassium citrate |
| Dialysis | Intensive hemodialysis in renal failure |
| Transplantation | Combined liver-kidney transplantation |
(Brenner & Rector's The Kidney, 11th ed)
Recent Advances
- RNA interference therapy (Lumasiran) targeting glycolate oxidase (phase III trials showing reduction in oxalate excretion in PH1)
- Oxalobacter formigenes probiotics under investigation for oxalate degradation in the gut
- Gene editing approaches being explored experimentally
(Brenner & Rector's The Kidney, 11th ed; recent clinical trials)
Definition
Eculizumab is a humanized monoclonal antibody that inhibits complement component C5, preventing terminal complement complex (C5b-9) formation (Harrison's 21e, Ch. 265).
Etiopathogenesis
Overactivation of complement plays a key role in various renal diseases causing endothelial injury and microangiopathy. Eculizumab blocks complement-mediated damage.
Clinical Features
Indications depend on underlying diagnosis, including:
| Kidney Disorder | Mechanism | Indication for Eculizumab |
|---|---|---|
| Atypical Hemolytic Uremic Syndrome (aHUS) | Dysregulated alternative complement pathway causing TMA | First-line therapy for complement-mediated aHUS (prevents microangiopathy) (Brenner & Rector's The Kidney) |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) | Complement-mediated RBC lysis | Prevents hemolysis affecting renal function |
| C3 Glomerulopathy (C3G) | Abnormal complement activation | Off-label use in refractory cases |
| Antibody-mediated rejection (AMR) post-transplant | Complement activation causing graft injury | Adjunctive therapy in severe or refractory AMR in kidney transplantation |
Diagnosis
Clinical-laboratory features based on underlying condition; complement assays and biopsy guide indication.
Management
- aHUS: Eculizumab administered early to prevent progression of TMA and renal failure
- Kidney transplant: Used in recipients with aHUS to prevent recurrence post-transplant; in refractory AMR as salvage therapy
- Monitoring includes hematologic parameters, renal function, and complement activity.
| Indication | Dose and Duration | Remarks |
|---|---|---|
| aHUS (native or recurrent post-transplant) | Initial: 900 mg weekly x 4 weeks; then 1200 mg every 2 weeks | Lifelong or as per disease activity |
| AMR (refractory) | Variable dosing | Adjunctive therapy; evidence limited |
(Harrison's 21e, Ch. 265; Brenner & Rector's The Kidney)
Recent Advances
- Extended indications explored in C3G and membranoproliferative GN
- Development of newer complement inhibitors with longer half-life and subcutaneous formulations
- Biomarker-driven individualized therapy in complement-mediated kidney diseases
Key Points for Exam
- PH is a hepatic enzymatic defect causing oxalate overproduction; types: PH1 (AGXT), PH2 (GRHPR), PH3 (HOGA1)
- Vitamin B6 is first-line medical therapy in PH1; high fluid intake and citrate supplementation are essential
- Eculizumab inhibits complement C5, indicated for aHUS, PNH, refractory AMR in kidney transplant
- Combined liver-kidney transplant is definitive treatment in PH with ESRD
- New therapies like Lumasiran (RNAi) show promise in PH1 management
References:
- Brenner & Rector’s The Kidney, 11th edition, Ch. 61
- Harrison’s Principles of Internal Medicine, 21st edition, Ch. 265