Radiation Nephropathy

Radiation nephropathy is progressive kidney injury caused by ionising radiation to the kidneys. Sources include external beam radiotherapy, total body irradiation before haematopoietic stem cell transplantation, stereotactic body radiotherapy, and targeted radionuclide therapy (for example, lutetium-177 labelled somatostatin analogues and PSMA ligands).

The kidney is a radiosensitive organ. Injury is dose and volume dependent. It rarely occurs below 18 to 20 Gy delivered to both kidneys in conventional fractions. It occurs in a high proportion of people receiving more than 23 Gy to the whole kidney.

• The acute form appears 6 to 12 months after exposure with hypertension, proteinuria, oedema and anaemia.
• The chronic form appears after 18 months to many years as slowly progressive chronic kidney disease.
• Haematopoietic stem cell transplant nephropathy follows total body irradiation, often combined with calcineurin inhibitors and nephrotoxic drugs. It occurs in 5 to 20% at 3 to 12 months.

Pathophysiology. Radiation causes endothelial injury of glomerular capillaries and small vessels (thrombotic microangiopathy, mesangiolysis). It also causes tubular epithelial damage, activation of the renin angiotensin system and progressive fibrosis (transforming growth factor beta).

• Acute: hypertension (sometimes malignant), oedema, proteinuria (often nephrotic range), anaemia out of proportion to kidney function, microangiopathic haemolysis, rapidly rising creatinine, 6 to 12 months after exposure.
• Chronic: slowly rising creatinine, hypertension, mild proteinuria, tubular dysfunction, anaemia, small kidneys.
• Renal artery stenosis (late) with refractory hypertension; focal renal atrophy in the irradiated field.
• Targeted radionuclide therapy: gradual loss of eGFR over 1 to 3 years (reduction of 20 to 40% in some).
• Hypertension, nephrotic syndrome and thrombotic microangiopathy after total body irradiation.

Red flags

• New severe hypertension or oedema after abdominal or total body irradiation.
• Haemolytic anaemia, falling platelets and rising creatinine (thrombotic microangiopathy).
• Creatinine rising by more than 30% after radionuclide therapy.
• Pre-existing chronic kidney disease or one functioning kidney before radiotherapy.
• Concurrent nephrotoxins (cisplatin, ifosfamide, calcineurin inhibitors).

• Radiation history: field, dose (Gy), fractionation, and combined chemotherapy; time since exposure.
• Creatinine, eGFR (preferably measured), cystatin C, urea, electrolytes, urine protein:creatinine ratio, urine microscopy, full blood count and film (schistocytes), lactate dehydrogenase, haptoglobin, blood pressure.
• Kidney ultrasound: small kidneys, focal atrophy in the irradiated field; Doppler for renal artery stenosis.
• Exclude other causes: tumour recurrence or obstruction, drug nephrotoxicity, infection, thrombotic microangiopathy from other causes (calcineurin inhibitor, graft-versus-host disease, complement mediated), glomerulonephritis.
• Kidney biopsy when diagnosis is unclear: glomerular capillary congestion and mesangiolysis, double contours, thrombi, arteriolar fibrinoid change, tubular atrophy and interstitial fibrosis within the field.

Differential diagnosis

• Thrombotic microangiopathy from other causes, hypertensive nephrosclerosis, renal artery stenosis, chemotherapy nephrotoxicity (cisplatin), calcineurin inhibitor toxicity, tumour lysis, obstruction, tubulointerstitial nephritis, primary glomerular disease.

Prevention

• Plan radiotherapy to limit kidney dose. Keep the volume of both kidneys that receive 20 Gy under 30% where possible and the mean dose under 15 Gy. Use shielding, conformal techniques and image based targeting. Avoid irradiating a solitary kidney.
• Lutetium radionuclide therapy: infuse amino acids (lysine 25 g with arginine 25 g in 1 litre of saline over 4 hours, starting 30 minutes before the infusion) to reduce kidney uptake. Monitor eGFR and give a limited number of cycles.
• Avoid concurrent nephrotoxins, treat hypertension early, and monitor creatinine in all patients who have had kidney irradiation.

Treatment

• ACE inhibitors reduce progression and may reverse early injury. Start as soon as hypertension or proteinuria appears.
• ACE inhibitor dosing: captopril 6.25 mg three times daily increasing to 50 mg three times daily (or ramipril 2.5 mg daily increased to 10 mg daily). Check creatinine and potassium at 1 to 2 weeks. Accept a rise up to 30%. Stop if potassium exceeds 6.0 mmol/L.
• Blood pressure below 130/80 mmHg. Add amlodipine 5 to 10 mg daily and diuretics (furosemide 40 to 80 mg once or twice daily) as needed.
• Hypertension in thrombotic microangiopathy may need intravenous labetalol (20 mg bolus, then 1 to 2 mg/minute, up to 300 mg).
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) for persistent proteinuria.
• Thrombotic microangiopathy: reduce or stop calcineurin inhibitors. Give plasma exchange when features are severe (1 plasma volume daily for 5 to 7 days). Consider eculizumab 900 mg weekly for 4 doses, 1200 mg at week 5, then every 2 weeks in complement mediated disease.
• Anaemia: iron when ferritin is under 200 microg/L or transferrin saturation under 20%. Epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is under 100 g/L. Target 100 to 120 g/L.
• Sodium under 2 g daily. Treat dyslipidaemia (atorvastatin 20 mg daily). Correct acidosis (sodium bicarbonate 500 mg to 1 g two to three times daily). Manage bone and mineral disorder at usual thresholds.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms or complications (haemodialysis Kt/V at least 1.2). Kidney transplantation after remission of cancer (usually 2 to 5 years cancer free, depending on type).

Monitoring. Creatinine, eGFR, urine protein:creatinine ratio and blood pressure at 3, 6 and 12 months after irradiation, then yearly for at least 10 years (and every 3 months after targeted radionuclide therapy). Full blood count in thrombotic microangiopathy.

Referral and escalation. Nephrology and oncology together. Urgent for malignant hypertension, haemolysis, or creatinine doubling.

Special groups

• Children: very sensitive to radiation; lifelong yearly blood pressure and urine screening after abdominal or total body irradiation.
• Haematopoietic stem cell transplant recipients: avoid nephrotoxins, monitor blood pressure and calcineurin inhibitor levels (tacrolimus 5 to 8 ng/mL), and manage hypertension aggressively.
• Pregnancy: avoid ACE inhibitors; monitor blood pressure and proteinuria.