Residency · Residency · Nephrology

Onconephrology - Renal Complications of Malignancy

Introduction

Onconephrology is an emerging subspecialty that addresses the complex intersection of kidney disease and cancer. Acute kidney injury occurs in 12 to 17 percent of hospitalized cancer patients and in up to 50 percent of those admitted to the intensive care unit, making it one of the most common complications encountered in oncologic practice. The prevalence of chronic kidney disease is increasing among cancer survivors as a consequence of nephrotoxic therapies, aging, and the cumulative burden of treatment-related organ damage. Renal complications in cancer patients arise from three broad categories: the direct effects of the malignancy itself on the kidney, the nephrotoxicity of cancer therapies, and concurrent conditions unrelated to the malignancy. Optimal management requires close collaboration between nephrologists and oncologists, with an understanding of both the renal implications of cancer treatment and the oncologic implications of dose adjustment or drug discontinuation.

Direct Renal Effects of Malignancy

Tumor Infiltration

Direct tumor infiltration of the kidneys occurs most commonly with lymphoma and leukemia, which can cause bilateral renal parenchymal infiltration and acute kidney injury with characteristically enlarged kidneys on imaging. Metastatic solid tumors from lung, breast, or melanoma primaries can also infiltrate the kidneys, though this is a less common cause of clinically significant renal dysfunction. Diagnosis relies on imaging, with computed tomography demonstrating bilateral renal enlargement without hydronephrosis, and may require renal biopsy for definitive confirmation. Treatment is directed at the underlying malignancy with appropriate chemotherapy, and renal function often improves with effective tumor response.

Urinary Tract Obstruction

Obstructive uropathy is the most common renal complication of malignancy overall. Cervical, bladder, prostate, and colorectal cancers can directly invade or compress the ureters, while retroperitoneal lymphadenopathy from lymphoma, testicular cancer, or metastatic disease can encase and obstruct the ureters extrinsically. The presentation is acute kidney injury with hydronephrosis on imaging, which may be unilateral or bilateral. Management requires urgent decompression with percutaneous nephrostomy tubes or ureteral stent placement to restore drainage, followed by definitive treatment of the underlying malignancy.

Tumor Lysis Syndrome (TLS)

Tumor lysis syndrome results from the massive release of intracellular contents when large numbers of tumor cells undergo lysis, either spontaneously or, more commonly, following initiation of cytotoxic therapy. The highest risk malignancies are those with rapid cell turnover and high tumor burden: high-grade lymphoma, particularly Burkitt lymphoma, acute lymphoblastic leukemia, and any malignancy with a high lactate dehydrogenase level. Pre-existing chronic kidney disease amplifies the risk by limiting the renal excretion of the released metabolites.

The characteristic metabolic derangements include hyperuricemia from nucleic acid catabolism, hyperphosphatemia from release of intracellular phosphate stores, hypocalcemia resulting from calcium-phosphate complexing and precipitation, and hyperkalemia from release of intracellular potassium. Acute kidney injury in TLS is primarily mediated by uric acid crystal deposition within the renal tubules (urate nephropathy) and by calcium phosphate deposition in the renal parenchyma. The Cairo-Bishop criteria define laboratory TLS as the presence of two or more of: uric acid above 8 mg/dL, potassium above 6 mEq/L, phosphorus above 4.5 mg/dL, or calcium below 7 mg/dL. Clinical TLS additionally requires the presence of AKI, seizures, or cardiac arrhythmia.

Prevention is the cornerstone of TLS management. Aggressive intravenous hydration with isotonic fluids at 3 liters per square meter per day, initiated 24 to 48 hours before chemotherapy, increases urine volume and dilutes tubular solute concentrations. Allopurinol at 300 to 600 mg daily reduces new uric acid production by inhibiting xanthine oxidase but does not metabolize existing uric acid and therefore is most effective when started before treatment. Rasburicase, a recombinant urate oxidase administered at 0.2 mg/kg intravenously, rapidly converts uric acid to allantoin, which is highly soluble and easily excreted. Rasburicase lowers uric acid within 4 hours and is the preferred agent for high-risk patients. An absolute contraindication is glucose-6-phosphate dehydrogenase (G6PD) deficiency, because rasburicase generates hydrogen peroxide during the conversion of uric acid to allantoin, which causes severe hemolytic anemia in G6PD-deficient individuals. Importantly, routine urine alkalinization is no longer recommended in TLS with hyperphosphatemia, as alkaline urine promotes calcium phosphate precipitation and may worsen renal injury; alkalinization should only be considered in cases where uric acid is the predominant problem without significant hyperphosphatemia. Treatment of established TLS requires aggressive intravenous fluids, rasburicase for hyperuricemia, correction of electrolyte abnormalities, loop diuretics for volume management, and hemodialysis for severe AKI, refractory hyperkalemia, or metabolic derangements unresponsive to medical therapy.

<image>Pathophysiology diagram of tumor lysis syndrome. Show a lysing tumor cell releasing its intracellular contents into the bloodstream: potassium (leading to hyperkalemia and cardiac arrhythmias), phosphate (leading to hyperphosphatemia, complexing with calcium causing hypocalcemia and calcium phosphate crystal deposition in kidneys), nucleic acids (metabolized to hypoxanthine → xanthine → uric acid, with xanthine oxidase labeled, leading to uric acid crystal deposition in renal tubules). Show the kidney with two mechanisms of AKI: uric acid crystals in the collecting ducts/distal tubules (in acidic urine pH <5.5) and calcium phosphate crystals in the tubules. Include drug intervention points: allopurinol blocking xanthine oxidase, rasburicase converting uric acid to allantoin, and aggressive hydration diluting tubular concentration. Show the Cairo-Bishop classification criteria in a sidebar.</image>

Paraprotein-Related Kidney Disease

Cast Nephropathy (Myeloma Kidney)

Cast nephropathy is the most common renal manifestation of multiple myeloma, present in 40 to 50 percent of myeloma patients with renal impairment. The pathogenesis involves monoclonal free light chains, usually kappa, that are filtered at the glomerulus and reach the distal tubule, where they bind to Tamm-Horsfall protein (uromodulin). The resulting large, obstructing casts block tubular flow and provoke a surrounding inflammatory giant cell reaction, while free light chains also exert direct tubular epithelial toxicity. Precipitating factors that worsen cast formation include dehydration, which increases tubular light chain concentration; hypercalcemia, which impairs renal function and concentrates the urine; loop diuretics, which increase Tamm-Horsfall protein interaction; NSAIDs; and bisphosphonates. The historical concern about contrast-induced nephropathy in myeloma patients has been partially mitigated by modern evidence suggesting that the risk with contemporary low-osmolar and iso-osmolar contrast agents is lower than previously believed, though caution and adequate hydration remain prudent.

Renal biopsy demonstrates the characteristic large, fractured, polychromatic casts within the distal tubules surrounded by multinucleated giant cells, with associated tubular epithelial injury. Treatment centers on urgent reduction of the free light chain burden through bortezomib-based chemotherapy, which should be initiated emergently. Aggressive hydration, treatment of hypercalcemia, and avoidance of nephrotoxins are essential supportive measures. The role of therapeutic plasma exchange remains debated: the MYRE trial in 2017 demonstrated a reduction in the composite endpoint of dialysis dependence or death at 6 months in one analysis, though overall results were mixed. Plasma exchange may be considered for patients with very high free light chain levels and dialysis-dependent AKI. An important clinical message is that renal recovery is possible in 50 to 60 percent of myeloma patients even when initially dialysis-dependent, provided effective chemotherapy is delivered promptly; therefore, the treating team should not abandon hope of renal recovery.

Light Chain Deposition Disease (LCDD)

Light chain deposition disease is caused by the non-amyloid deposition of monoclonal light chains, usually kappa, along tubular basement membranes and glomerular basement membranes. On light microscopy, the hallmark finding is nodular glomerulosclerosis, which can closely mimic the appearance of diabetic nephropathy. Immunofluorescence distinguishes the two conditions by demonstrating linear kappa (or lambda) staining along the tubular and glomerular basement membranes, in contrast to amyloidosis, which is Congo red positive. Electron microscopy reveals granular electron-dense deposits along the basement membranes. Treatment requires chemotherapy to reduce monoclonal light chain production, with bortezomib-based regimens being the current standard.

AL Amyloidosis

AL amyloidosis results from the extracellular deposition of amyloid fibrils derived from misfolded monoclonal light chains, usually lambda. The amyloid deposits in the kidney involve the glomeruli, blood vessels, and interstitium, producing nephrotic-range proteinuria with progressive renal failure. On light microscopy, the deposits are Congo red positive with characteristic apple-green birefringence under polarized light. Electron microscopy reveals randomly arranged fibrils measuring 8 to 12 nm in diameter. Cardiac involvement, manifesting as restrictive cardiomyopathy, is the major determinant of survival.

Diagnosis requires tissue biopsy, which may be obtained from the kidney, abdominal fat pad, or rectum, combined with serum free light chain analysis and mass spectrometry for definitive amyloid subtyping. Treatment has been transformed by the addition of daratumumab, an anti-CD38 monoclonal antibody: the ANDROMEDA trial demonstrated the superiority of daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) over VCd alone for both hematologic and organ response rates. Autologous stem cell transplantation remains an option for eligible patients with limited organ involvement.

Other Paraprotein-Related Diseases

Fibrillary glomerulonephritis is characterized by Congo red-negative fibrils measuring 16 to 24 nm on electron microscopy. The discovery of DNAJB9 as a highly specific diagnostic biomarker by immunohistochemistry has simplified diagnosis. Immunotactoid glomerulonephritis features organized microtubules measuring 30 to 50 nm, is Congo red negative, and is frequently associated with underlying CLL or lymphoma. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) presents with monoclonal immunoglobulin deposits that mimic immune complex glomerulonephritis. Cryoglobulinemic glomerulonephritis may be type I (monoclonal IgM) or type II (monoclonal IgM with polyclonal IgG rheumatoid factor activity).

Nephrotoxicity of Cancer Therapies

Immune Checkpoint Inhibitors (ICIs)

Immune checkpoint inhibitors, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, durvalumab, avelumab), and CTLA-4 inhibitors (ipilimumab), have revolutionized oncologic treatment but carry a 2 to 5 percent incidence of AKI. The most common renal pathology is acute interstitial nephritis, reflecting immune-mediated inflammation within the renal interstitium, though podocytopathies (minimal change disease and FSGS), lupus-like glomerulonephritis, thrombotic microangiopathy, and C3 glomerulonephritis have all been reported. The median onset is 3 to 12 months after initiating therapy, though nephrotoxicity can occur at any point during treatment.

Renal biopsy is recommended before initiating high-dose steroids to confirm the diagnosis of AIN and to exclude other etiologies including acute tubular necrosis, tumor infiltration, and thrombotic microangiopathy, which require different management. Treatment consists of holding the checkpoint inhibitor and initiating prednisone at 1 mg/kg/day, with taper over 4 to 8 weeks. Recovery of renal function occurs in 70 to 90 percent of patients. Rechallenge with the same or a different checkpoint inhibitor may be considered in patients whose cancer requires ongoing immunotherapy, though the recurrence risk is higher and requires close monitoring.

Chimeric Antigen Receptor (CAR) T-Cell Therapy

CAR T-cell therapy is associated with cytokine release syndrome (CRS), a systemic inflammatory response mediated primarily by interleukin-6 that produces vasodilatory shock, capillary leak, and AKI. The incidence of AKI ranges from 10 to 30 percent in the setting of CRS and may be severe enough to require renal replacement therapy. Tumor lysis syndrome is an additional contributor to AKI, particularly in patients with ALL or lymphoma. Electrolyte disorders, including hypophosphatemia, may also occur. Treatment of CRS-associated AKI centers on tocilizumab (anti-IL-6 receptor antibody) for the inflammatory syndrome with supportive nephrology care for the renal complications.

VEGF Pathway Inhibitors

VEGF pathway inhibitors, including bevacizumab, sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, and ramucirumab, produce renal effects in a substantial proportion of treated patients. Hypertension occurs in more than 40 percent, proteinuria in 20 to 60 percent (with nephrotic-range proteinuria in 1 to 5 percent), and thrombotic microangiopathy in a smaller but clinically important subset. The mechanism reflects the essential role of VEGF in maintaining glomerular endothelial fenestrations and podocyte health; inhibition of VEGF signaling disrupts the glomerular filtration barrier, leading to endothelial injury and podocyte damage.

Renal biopsy, when performed, demonstrates either a TMA pattern with fibrin thrombi and mesangiolysis or a podocytopathy pattern. Management involves holding or reducing the dose of the VEGF inhibitor, blood pressure control with RAAS blockade for antiproteinuric effect, and serial monitoring of proteinuria and serum creatinine. In many cases, therapy can be resumed at a lower dose once the renal effects have resolved.

Other Nephrotoxic Agents

Cisplatin produces dose-dependent proximal tubular injury with characteristic renal magnesium wasting and salt wasting; prevention requires aggressive saline hydration before and after each dose. Ifosfamide causes proximal tubular injury manifesting as Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, and renal tubular acidosis) and hemorrhagic cystitis, which is prevented with MESNA (2-mercaptoethane sulfonate sodium). Methotrexate causes crystal nephropathy when insoluble methotrexate crystals precipitate in acidic urine; prevention requires urine alkalinization and hydration, and glucarpidase (carboxypeptidase G2) is available for the enzymatic degradation of methotrexate in cases of toxic levels with renal failure. Bisphosphonates can cause renal injury: pamidronate is associated with collapsing FSGS, while zoledronic acid can cause acute tubular necrosis; both require dose adjustment for renal function. Lenalidomide and pomalidomide require dose adjustment in CKD and carry a risk of tumor lysis syndrome in treated malignancies.

<image>Comprehensive reference table of cancer therapy nephrotoxicity organized by drug class. Create a matrix with columns for drug class, specific agents, mechanism of renal injury, clinical presentation, typical timeline, and management/prevention. Include: (1) Platinum agents - cisplatin (ATN, magnesium wasting, AKI); (2) Checkpoint inhibitors - nivolumab, pembrolizumab (AIN, podocytopathy, TMA); (3) VEGF inhibitors - bevacizumab, sunitinib (TMA, proteinuria, HTN); (4) Alkylating agents - ifosfamide (Fanconi syndrome), cyclophosphamide (hemorrhagic cystitis); (5) Antimetabolites - methotrexate (crystal nephropathy); (6) Targeted therapies - BRAF inhibitors (AIN, electrolyte disorders), CDK4/6 inhibitors (increased creatinine from tubular secretion inhibition, not true AKI); (7) CAR T-cells (CRS-related AKI, TLS). Use color coding for severity: red (potentially severe/permanent), yellow (moderate/reversible), green (mild/self-limiting).</image>

Electrolyte Disorders in Cancer

Hypercalcemia of Malignancy

Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients and occurs through three principal mechanisms. The most common mechanism, accounting for approximately 80 percent of cases, is parathyroid hormone-related peptide (PTHrP) secretion by squamous cell carcinomas and renal cell carcinoma, which mimics PTH action on bone and kidney. Osteolytic metastases, accounting for approximately 20 percent, cause local bone destruction with calcium release, as seen in breast cancer and multiple myeloma. Production of 1,25-dihydroxyvitamin D by lymphoma and granulomatous processes is a third, less common mechanism. Treatment follows a stepwise approach: aggressive saline hydration at 200 to 300 mL/hr to restore intravascular volume and enhance renal calcium excretion, calcitonin at 4 IU/kg every 12 hours for rapid but transient effect (tachyphylaxis develops at 48 hours), zoledronic acid 4 mg intravenously for sustained effect (onset 2 to 4 days, duration weeks), and denosumab 120 mg subcutaneously for patients refractory to bisphosphonates or with significant CKD precluding bisphosphonate use.

SIADH

SIADH is a common paraneoplastic syndrome, most classically associated with small cell lung cancer and head and neck cancers. Management follows the principles detailed in the hyponatremia lecture.

Renal Magnesium Wasting

Several cancer therapies cause significant renal magnesium wasting. Cisplatin damages the proximal tubule and thick ascending limb, impairing magnesium reabsorption. Cetuximab and other anti-EGFR antibodies block EGFR-mediated activation of the TRPM6 magnesium channel in the distal convoluted tubule, the final site of magnesium reabsorption. Amphotericin B also causes renal magnesium wasting. The hypomagnesemia can be severe and refractory to oral supplementation, requiring aggressive intravenous magnesium replacement.

Kidney Disease in Cancer Survivors

The growing population of cancer survivors represents an increasingly important source of chronic kidney disease. Childhood cancer survivors are at particularly elevated risk from prior exposure to ifosfamide, cisplatin, and radiation nephritis. Regular screening with estimated GFR and urine protein assessment is recommended as part of cancer survivorship care plans. Management principles include nephroprotection with RAAS blockade and SGLT2 inhibitors where appropriate, balanced against ongoing oncologic surveillance needs and the potential for recurrent malignancy.

Key Clinical Pearls

• Tumor lysis syndrome prevention with rasburicase is critical in high-risk malignancies; do NOT alkalinize urine in TLS with hyperphosphatemia (promotes calcium phosphate deposition); alkalinization is only for isolated uric acid nephropathy
• Cast nephropathy in myeloma requires urgent reduction of free light chain burden; bortezomib-based chemotherapy should begin emergently; renal recovery is possible in 50-60% even if initially dialysis-dependent
• ICI-associated AKI is most commonly AIN; obtain a renal biopsy before starting high-dose steroids to confirm the diagnosis and rule out other etiologies (ATN, tumor infiltration, TMA)
• VEGF inhibitors cause dose-dependent proteinuria and TMA by disrupting glomerular endothelial VEGF signaling; monitor proteinuria serially; threshold for holding therapy is typically UPCR >3 or TMA
• CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) increase serum creatinine by inhibiting tubular creatinine secretion (OCT2/MATE1), not by true GFR reduction; use cystatin C to confirm true GFR if needed

References

1. Rosner MH, Perazella MA. Acute Kidney Injury in the Patient with Cancer. Kidney Res Clin Pract. 2019;38(3):295-308.
2. Cortazar FB, Kibbelaar RE, Glezerman IG, et al. Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI. J Am Soc Nephrol. 2020;31(2):435-446.
3. Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of Monoclonal Gammopathy of Renal Significance. Kidney Int. 2015;87(4):698-711.
4. Howard SC, Jones DP, Pui CH. The Tumor Lysis Syndrome. N Engl J Med. 2011;364(19):1844-1854.
5. Perazella MA, Shirali AC. Immune Checkpoint Inhibitor Nephrotoxicity: What Do We Know and What Should We Do? Kidney Int. 2020;97(1):62-74.

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