# Student Handout: Chemotherapy Nephrotoxicity

> **Learning objective:** Understand the epidemiology, mechanisms, prevention, and management of traditional chemotherapy and targeted therapy-induced kidney injury

------------------------------------------------------------------------

## Overview

Chemotherapy-induced nephrotoxicity is one of the most important medication-related complications in oncology. This handout focuses on:

1.  **Platinum agents** (cisplatin) — most common & most toxic
2.  **VEGF/TKI agents** (tyrosine kinase inhibitors) — increasingly used, different injury pattern

------------------------------------------------------------------------

## PLATINUM NEPHROTOXICITY (Cisplatin-Focused)

### Epidemiology

- **Cisplatin:** Highly effective chemotherapy for solid tumors (lung, testicular, ovarian, bladder)
- **Frequency of AKI:** 10–30% at standard doses; up to 60% with high-dose regimens
- **Chronic kidney disease:** 10–20% of patients develop long-term renal insufficiency
- **Risk factors:**
  - Age \>60 years
  - Pre-existing CKD or low GFR
  - Dehydration
  - Concomitant nephrotoxic drugs (NSAIDs, aminoglycosides, amphotericin B)
  - Smoking
  - Hypomagnesemia

### Mechanism of Cisplatin Nephrotoxicity

**Step-by-step (simplified):**

1.  **Glomerular filtration** → Cisplatin freely filtered into tubular lumen
2.  **Uptake** → Proximal tubular cells take up cisplatin via organic cation transporters
3.  **Intracellular activation** → Cisplatin undergoes aquation, loses chloride, forms reactive platinum species
4.  **DNA binding** → Binds DNA in tubular cell nuclei → Formation of DNA adducts
5.  **Cell death** → Apoptosis and necrosis of proximal tubular cells
6.  **Clinical result:** Acute tubular necrosis (ATN), primarily proximal tubule damage

### Clinical Presentation

**Acute Kidney Injury (usually 3–7 days post-infusion):**

| Finding | Details |
|----|----|
| **Timing** | Typically 3–7 days after cisplatin dose |
| **Labs** | ↑ Creatinine (20–30% of baseline is “normal”; \>50% is concerning) |
| **BUN** | Often ↑ proportionally (BUN/Cr ratio ~20) |
| **Urinalysis** | Muddy casts, epithelial cells, hyaline casts |
| **K+** | Often ↓ (hypokalemia from renal wasting) |
| **Mg2+** | Often ↓ (renal wasting) |
| **Ca2+** | May be ↓ (secondary to Mg2+ loss) |

**Chronic Kidney Disease (develops over weeks–months):** - Progressive ↓ GFR even after cisplatin discontinuation - Irreversible tubular atrophy and fibrosis in severe cases

### Prevention Strategy (CRITICAL)

**Aggressive hydration is the \#1 prevention tool:**

1.  **Before cisplatin:**
    - 1–2 L IV normal saline over 30–60 min pre-infusion
    - Goal: Urine output \>150 mL/h during chemotherapy
2.  **During cisplatin infusion:**
    - Continuous 0.9% or 0.45% NaCl at rates to maintain urine output \>100 mL/h
3.  **After cisplatin:**
    - 1–2 L IV hydration post-infusion (24–48 hours)
    - Encourage PO hydration if tolerated

**Additional preventive measures:**

| Strategy | Details | Evidence |
|----|----|----|
| **Amifostine** | Mesna analog; free radical scavenger | ↓ AKI risk by 30–40%; use if CrCl \>60 |
| **Magnesium repletion** | Keep Mg \>2 mg/dL; supplement if low | Prevents renal Mg wasting |
| **Loop diuretics** | Furosemide during hydration | Maintains high urine flow |
| **Avoid NSAIDs** | Hold for ≥48 h pre and post | Reduces GFR; increases cisplatin uptake |
| **ACEi/ARB consideration** | May offer some protection | Not first-line prevention |
| **Antiemetics** | Ondansetron, aprepitant | Prevent dehydration from vomiting |

### Management of Acute Cisplatin Nephrotoxicity

**Grade 1–2 (Cr ↑ \<50% or \<2× baseline):** - Continue hydration (1–2 L daily) - Monitor daily Cr, BUN, K+, Mg - Supplement Mg if low - Consider dose reduction or interval prolongation for next cycle - Most recover within 2–3 weeks

**Grade 3–4 (Cr ↑ \>50% or \>2× baseline, or need RRT):** - Aggressive hydration (3–4 L daily) - Renal replacement therapy if oliguria, severe hyperkalemia, or fluid overload - Discontinue or substantially delay cisplatin - Nephrology consult recommended - Expect some permanent renal function loss; recovery incomplete

### Long-Term Outcomes

- **Recovery timeline:** Most recovery occurs within 4–6 weeks; full recovery can take months
- **Chronic sequelae:** 10–20% of patients develop CKD even after initial recovery
- **Monitoring:** Annual renal function checks for 5+ years post-treatment

------------------------------------------------------------------------

## VEGF/TKI NEPHROTOXICITY

### Common Agents

| Drug Class | Examples | Cancer Types |
|----|----|----|
| **VEGF inhibitors** | Bevacizumab (antibody), aflibercept | Colorectal, lung, RCC |
| **VEGFR TKIs** | Sunitinib, sorafenib, pazopanib | RCC, hepatocellular carcinoma |
| **Other TKIs** | Axitinib, cabozantinib | RCC, various solid tumors |

### Mechanism of VEGF/TKI-Induced Nephrotoxicity

**Unlike cisplatin:**

1.  **VEGF inhibition** → Blocks VEGF signaling in endothelial cells
2.  **Glomerular consequence:** Loss of VEGF → Endothelial cell dysfunction, capillary rarefaction, podocyte injury
3.  **Result:** **Proteinuria** (hallmark) + **hypertension** + mild-moderate AKI
4.  **Histology:** If biopsied: FSGS, thrombotic microangiopathy (TMA), or minimal change disease

### Epidemiology

- **Proteinuria:** 5–15% of VEGF/TKI patients develop proteinuria (\>0.5 g/day)
- **Hypertension:** 20–35% develop or worsen hypertension
- **Severe AKI:** Less common than cisplatin (~2–5%)
- **Risk factors:**
  - Pre-existing HTN or albuminuria
  - Diabetes
  - Pre-existing CKD
  - Concomitant ACEi/ARB use (may protect against proteinuria)

### Clinical Presentation

| Feature | Typical Pattern |
|----|----|
| **Proteinuria** | 0.5–3 g/day; usually non-nephrotic |
| **Hematuria** | Microscopic; not prominent |
| **AKI** | Mild-moderate; Cr ↑ 20–50% |
| **Hypertension** | New onset or worsening in ~30% of patients |
| **Reversibility** | Often **reversible** on drug discontinuation (unlike cisplatin) |

### Management of VEGF/TKI-Induced Nephrotoxicity

**Monitoring:** - Baseline: BMP, urinalysis, urine Pt-Cr, BP measurement - During therapy: BMP every 2–4 weeks; urinalysis every 1–2 months

**Mild (proteinuria \<1 g/day, Cr stable/↑ \<20%):** - Continue VEGF/TKI therapy - ACEi/ARB at standard doses to reduce proteinuria - Monitor Pt-Cr monthly; repeat q 3 months - BP control — goal \<130/80 (2025 AHA/ACC, ADA); KDIGO 2021 suggests systolic \<120 on standardized measurement

**Moderate (proteinuria 1–3 g/day, Cr ↑ 20–50%):** - Continue therapy OR consider dose reduction - Intensify ACEi/ARB (use maximal tolerated doses) - Add amlodipine or hydralazine for BP control - Monitor Pt-Cr q 2 weeks - Nephrology referral if progressive

**Severe (proteinuria \>3 g/day, Cr ↑ \>50%, or nephrotic syndrome):** - Consider temporary pause or permanent discontinuation - ACEi/ARB at high doses - Diuretics if edema present - Frequent monitoring (BMP q 1–2 weeks) - Nephrology evaluation mandatory - Some patients recover fully upon discontinuation

### Key Difference from Cisplatin

| Feature           | Cisplatin             | VEGF/TKI              |
|-------------------|-----------------------|-----------------------|
| **Injury type**   | ATN (tubular)         | Glomerular (podocyte) |
| **Presentation**  | ↑ Cr, ↓ urine output  | Proteinuria, HTN      |
| **Reversibility** | Often permanent loss  | Often reversible      |
| **Prevention**    | Hydration, amifostine | BP control, ACEi/ARB  |

------------------------------------------------------------------------

## Other Chemotherapy Agents (Brief Reference)

| Agent | Injury | Key Features |
|----|----|----|
| **Gemcitabine** | Hemolytic uremic syndrome (HUS) | Rare; severe; monitor CBC |
| **Ifosfamide** | Tubular dysfunction, AKI | Mesna use standard; hydration critical |
| **Methotrexate** | Crystalline nephropathy | High-dose MTX → aggressive hydration, alkalinization |
| **5-Fluorouracil** | Volume depletion, AKI | Supportive care |
| **Nitrosoureas** | Chronic GFD | Cumulative dose-related |

------------------------------------------------------------------------

## Integration with Management

**Before each cycle:** - ✓ Check BMP (especially K, Mg, Cr) - ✓ Baseline BP - ✓ Urine dipstick if on VEGF/TKI - ✓ Ensure adequate hydration status

**After cycle:** - ✓ Monitor Cr at 3–5 days (cisplatin peak AKI window) - ✓ Replace Mg if \<2 mg/dL - ✓ Hydration support

**Long-term:** - ✓ Annual renal function check post-treatment - ✓ Ongoing HTN management (especially VEGF/TKI patients)

------------------------------------------------------------------------

## Clinical Pearls

✓ **Cisplatin = Hydration is prevention** (\>1 L pre/post-infusion) ✓ **Cisplatin AKI = ATN** (muddy casts, high BUN/Cr ratio) ✓ **VEGF/TKI = Proteinuria + HTN** (glomerular injury pattern) ✓ **VEGF/TKI often reversible** on drug withdrawal (unlike cisplatin) ✓ **Escalate magnesium support** for cisplatin patients ✓ **Amifostine if CrCl \>60 mL/min** for high-dose cisplatin

------------------------------------------------------------------------

## Related Content

**Onconephrology Hub:** - Platinum Nephrotoxicity Review — Detailed mechanisms, advanced prevention strategies - VEGF/TKI Nephrotoxicity Review — Comprehensive pathology and management algorithms

**Student Resources:** - Acute Kidney Injury Hub — General AKI framework and differential diagnosis - Student Handout: ATN — Acute tubular necrosis mechanisms and management

------------------------------------------------------------------------

## References

- Perazella MA, Rosner MH. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17(8):1220-1233. [PubMed](https://pubmed.ncbi.nlm.nih.gov/35273009/)
- Perazella MA, Rosner MH. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17(8):1220-1233. [PubMed](https://pubmed.ncbi.nlm.nih.gov/35273009/)
- Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949-1964. [PubMed](https://pubmed.ncbi.nlm.nih.gov/31777389/)
- Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129-1136. [PubMed](https://pubmed.ncbi.nlm.nih.gov/18337603/)

------------------------------------------------------------------------

**Study Tips:** - **CISPLATIN:** Memorize prevention protocol (hydration + amifostine ± loop diuretic) - **VEGF/TKI:** Remember it causes glomerular proteinuria, not tubular AKI - **Use the management tables** for quick decision-making in clinical practice - **Key insight:** Different mechanisms → different prevention and management strategies

*Created: 2026-02-28*


---

[Website version](https://urinenephrology.org/student-resources/toxic-nephropathies/onconephrology-chemotherapy-student-handout.html) · Markdown synchronized October 3, 2026.