Background <p>Primary renal lymphoma is a rare form of kidney tumor, accounting for less than 1% of all kidney masses, and with only a few pediatric cases reported in the literature. Bilateral forms can present with kidney failure, constituting a therapeutic challenge for both hematologists and nephrologists, with the need to combine complex chemotherapy regimens and kidney replacement therapy.</p> Methods <p>We present a rare case of primary bilateral renal diffuse large B-cell lymphoma in a teenage girl presenting with kidney failure (eGFR of 7&#xa0;ml/min/1.73 m²), proposing a practical approach to optimize chemotherapy on kidney replacement therapy. We discuss diagnostic methods, the management and adjustment of chemotherapy and hyperhydration protocols, and the tailoring of highly efficient hemodiafiltration sessions to grant sufficient drug exposure while avoiding drug accumulation and toxicity in the context of kidney failure.</p> Results <p>This approach permitted a substantial reduction of chemotherapy adverse effects while inducing remission and partial recovery of kidney function in our patient, with hemodialysis discontinuation after 6&#xa0;months, and an eGFR that had improved to 28&#xa0;ml/min/1.73 m² at 12&#xa0;months.</p> Conclusions <p>Managing complex chemotherapy protocols in kidney failure can be challenging, and the collaboration of a multidisciplinary team is essential. The adjustment of drug dosing and the tailoring of hemodialysis can increase patients’ tolerance while maintaining chemotherapy efficiency.</p> Graphical abstract <p></p>