**Core Concept**
Nephrotoxicity in aminoglycosides is primarily due to tubular damage, especially in the proximal renal tubules, mediated by mitochondrial dysfunction and oxidative stress. Among aminoglycosides, the degree of nephrotoxicity varies based on chemical structure, protein binding, and renal tubular accumulation.

**Why the Correct Answer is Right**
Neomycin has the highest nephrotoxic potential among aminoglycosides due to its strong affinity for renal tubular cells and high accumulation in the proximal tubules. It is metabolized by renal tubular cells, leading to direct cellular damage and mitochondrial injury. Unlike other aminoglycosides, neomycin is not used in systemic therapy and is primarily administered topically or in high-dose short-term intravenous use, which increases its risk of nephrotoxicity. Its potency in binding to tubular cells makes it the most nephrotoxic.

**Why Each Wrong Option is Incorrect**
Option A: Paromomycin is primarily used topically and has minimal systemic absorption, resulting in very low nephrotoxicity.
Option B: Streptomycin has moderate nephrotoxicity but is less than neomycin due to lower tubular accumulation.
Option C: Amikacin has a lower nephrotoxic potential compared to neomycin, despite being potent, due to reduced tubular uptake and better clearance.

**Clinical Pearl / High-Yield Fact**
Neomycin is the most nephrotoxic aminoglycoside and is contraindicated in patients with renal impairment. Always avoid systemic use of neomycin; it is only used in topical applications (e.g., ear, eye).

✓ Correct Answer: D. Neomycin