TLS occurs when malignant cells rapidly release cytosolic contents into the extracellular space. TLS is an oncologic emergency.³

Cellular release of adenosine triphosphate also causes hyperphosphatemia, which is also nephrotoxic through precipitation in tubules (phosphate nephropathy).

Nucleic acid breakdown can lead to severe hyperuricemia.

Uric acid is poorly soluble in an acidic milieu and crystallizes at high concentrations.

Hyperuricemia leads to urate crystal formation within the nephron as well as the vasa recta, causing AKI.

Cellular release of potassium can cause rapid-onset hyperkalemia, which is life threatening and may require hemodialysis.

TLS is defined as a collection of metabolic complications that occur in the setting of a rapidly proliferating neoplasm and large tumor burden.

It is characterized by hyperuricemia, hyperphosphatemia, hypocalcemia, hyperkalemia, elevated uric acid, and lactate dehydrogenase (LDH).

TLS occurs most frequently in hematologic malignancies such as lymphoma (especially Burkitt lymphoma), acute lymphocytic leukemia, and acute myeloid leukemia.

It most commonly develops in the setting cytotoxic chemotherapy or radiotherapy, but can also occur spontaneously in rapidly growing cancers.

Patients at high risk require frequent monitoring of electrolytes and aggressive intravenous fluid administration (at least 3 L/day) if no contraindications to volume expansion.

Allopurinol (xanthine oxidase inhibitor) can be used prophylactically to prevent acute hyperuricemia during treatment in high-risk patients.

Febuxostat is another xanthine oxidase inhibitor and might have a role in TLS treatment given hepatic rather renal excretion; however, no clinical trials evidence supports its efficacy in this setting to date.

Rasburicase is recombinant urate oxidase that enzymatically degrades uric acid and rapidly reduces elevated uric acid levels. Rasburicase should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. It is also occasionally used prophylactically in high-risk patients.^4,5

Urine alkalinization can improve uric acid solubility; however, this will also increase intratubular calcium phosphate deposition therefore normal saline is preferred over sodium-bicarbonate–containing solutions.

Antiangiogenic therapies typically target the vascular endothelial growth factor (VEGF) pathway.⁶

Examples include bevacizumab, sunitinib, sorafenib, axitinib, and pazopanib.

The VEGF pathway is important for maintenance of glomerular function in the kidney as well as maintenance of endothelial cell health in the systemic vasculature.

Blocking the pathway therefore has kidney and vascular toxicities, including proteinuria, kidney dysfunction, and hypertension.

New or exacerbated hypertension is relatively common after patients start antiangiogenic therapies, usually within the first few months of starting therapy. In some cases, blood pressure rise can occur much later.

Urinalysis should be performed at baseline and quarterly on patients receiving antiangiogenic therapies in order to detect new proteinuria. A positive result should be followed up with a spot urine protein to creatinine ratio.

Kidney function should also be routinely monitored on this class of targeted therapy.

The kidney lesion induced by antiangiogenic therapy is TMA, which is typically diagnosed by renal biopsy. In most cases this is not required because the clinical picture is sufficient to make a diagnosis.

The vast majority of patients developing new or exacerbated hypertension on antiangiogenic therapies can be treated medically. First-line agents include ACE inhibitors, ARBs, and calcium channel blockers, with second-line agents including diuretics. β-Blockers are less effective and should not be used for first-line therapy, though combined α and β blockade such as labetalol is effective.

Patients that develop proteinuria should be monitored closely but do not necessarily need to be taken off therapy. Proteinuria is typically subnephrotic. An ACE inhibitor or ARB should be started as long as tolerated and proteinuria monitored by urine protein to creatinine ratio at each visit. If proteinuria rises to nephrotic levels or is accompanied by a fall in estimated glomerular filtration rate (eGFR), referral to a nephrologist and/or dose reduction or drug holiday should be considered.

Some patients develop AKI on antiangiogenic therapy, which reflects a TMA. In this situation, referral to a nephrologist is suggested. Some patients can continue on a lower dose but others may develop CKD if continued on therapy.

Cisplatin (cis-diamminedichloroplatinum II) is both the most frequent platinum-based chemotherapy used and the most nephrotoxic.⁷

Cisplatin becomes activated within cells, reacting with DNA to cause intra-strand cross-linking leading to cytotoxicity.

Cisplatin is concentrated in the renal cortex in proximal tubule via organic cation transporter 2 and this partly explains its predilection for nephrotoxicity.⁸

Renal dysfunction occurs in up to one-third of patients and is characterized by a stuttering rise in serum creatinine 1 to 2 weeks after starting therapy.

Carboplatin is another platinum-based agent with a safer nephrotoxic profile but can induce renal toxicity at high doses (>800 mg/m²).

Oxaliplatin has the least risk of nephrotoxicity.

Nephrotoxicity is characterized by delayed but often progressive azotemia. The urine sediment is bland and there is minimal proteinuria.

Electrolyte disturbances are common including partial or full Fanconi syndrome, characterized by hypomagnesemia, hyponatremia, and nephrogenic diabetes insipidus. Glycosuria and hypomagnesemia are clues to the diagnosis.

Long-term cisplatin exposure may lead to interstitial fibrosis and CKD.

Hypomagnesemia is a frequent complication, can be severe, and may persist for years even after discontinuation.

Efforts to prevent cisplatin-induced AKI center on hydration during treatment, with the goal to induce high urine flow.

Forced diuresis with saline plus furosemide or saline plus mannitol is also used in many centers, based on older studies; however, the effectiveness of mannitol is still an open question and prehydration with normal saline is current standard of care.

Immune checkpoint inhibitor (ICIs) antibodies such as ipilimumab (anticytotoxic T-lymphocyte–associated protein 4, CTLA-4), nivolumab, and pembrolizumab (antiprogrammed death 1, PD-1) are increasingly used to treat nonsmall cell lung cancer, melanoma, and renal cell cancer; renal toxicity is a known complication of these therapies.

The overall incidence of renal toxicity has been estimated to range between 13% and 29%, with a higher incidence reported in patients receiving combination therapy with ipilimumab and nivolumab.⁹