Onco-Nephrology 2023 MDC
Onco-Nephrology 2023 MDC
Onco-Nephrology 2023 MDC
KEYWORDS
Onco-nephrology Acute kidney injury Chronic kidney disease Proteinuria
Immune-checkpoint inhibitors Hyponatremia Hypomagnesemia Hypokalemia
KEY POINTS
Patients with cancer are at risk for kidney disease from malignancy-specific or treatment-
specific causes.
Kidney disease, particularly acute kidney injury, and hyponatremia is associated with poor
outcomes in cancer patients.
Timely referral to nephrologists experienced or trained in the care of patients with cancer
(onco-nephrologists) is encouraged for timely diagnosis and management.
INTRODUCTION
Kidney disease in cancer patients requires specialized evaluation for timely and accu-
rate diagnosis. A new Nephrology subspecialty—Onco-Nephrology—focuses on
managing acute kidney injury (AKI), chronic kidney disease (CKD), proteinuria, and
electrolyte disorders in these patients. Evaluation by onco-nephrologists may limit
treatment disruptions of anti-cancer therapies. In this review, we outline major topics
in Onco-Nephrology, focusing on those syndromes of kidney disease that all physi-
cians, including general practitioners, are likely to encounter in clinical practice.
Cancer patients experience an elevated risk of kidney disease, particularly AKI. A 2011
Danish population-based study followed 37,267 patients with an incident cancer diag-
nosis over 5 years1. At 1-year post-diagnosis, the risk of all-stage AKI was 17.5%,
increasing to 27% at 5 years1 Severe AKI (defined in this study by injury or failure cate-
gory of the Risk, Injury, Failure [RIFLE] criteria) rates were at 3.5% (injury) and 1.6%
(failure) at 1 year1 Malignancy-type influenced risk, with kidney cancer having the high-
est 1-year AKI risk at 44%, and significant risk was also seen in patients with liver
Section of Nephrology, Yale University School of Medicine, PO Box 208029, New Haven, CT
06520-8029, USA
* Corresponding author.
E-mail address: [email protected]
cancer and multiple myeloma. More contemporary data that include newer anti-
cancer therapies also support heightened AKI risk following a cancer diagnosis. A
2019 Canadian study on patients who were initiated on systemic anti-cancer therapies
reported cumulative AKI incidences of 3.9% and 7.8% at 1 and 5 years, respectively.2
AKI requiring dialysis rates were 0.4% (1 year) and 0.8% (5 years). The Canadian expe-
rience suggests that even in an era of improved cancer outcomes, AKI frequently im-
pacts cancer patients. Besides cancer type, advancing age, pre-existing CKD, male
sex, and pre-existing hypertension and diabetes increase AKI risk.2
CKD is also prevalent among cancer patients. The Renal Insufficiency and Cancer
Medications (IRMA) study retrospectively evaluated 4684 cancer patients and deter-
mined estimated glomerular filtration rate (eGFR)-based staging with Cockcroft-
Gault (C-G) and Modification of Diet in Renal Disease (MDRD) formulas.3 Depending
on the formula used, the prevalence of CKD was 12.02% (MDRD) or 19.8% (C-G).3
More recently, a Romanian database of 5831 cancer patients noted 13.4% prevalence
of CKD at the end of the study, compared with the 8.8% reference rate in the general
population.4
commonly used agents, as well as kidney disease associated with the direct effects of
cancer.
Drug Nephrotoxicity
Advances in anti-cancer therapy have improved long-term outcomes but patients are
still likely to experience kidney complications of anti-cancer therapy, including AKI,
CKD, proteinuria, and hypertension. All types of treatments—conventional chemo-
therapy, targeted therapy, and immunotherapy—have been associated with these
manifestations of kidney injury (Table 1).9,10
Conventional chemotherapy
Conventional chemotherapy is the foundational treatment of many cancers. These
agents can cause both AKI and CKD via affecting vascular, interstitial, tubular, or
glomerular compartments within the kidney.11,12
Platinum-based agents
Cisplatin, carboplatin, and oxaliplatin are alkylating agents that bind to and cross-link
DNA ultimately resulting in cell death. These agents are used for treating the following
malignancies: head and neck, small cell lung, ovarian, bladder, cervical, testicular,
advanced urothelial, and gastrointestinal malignancies such as esophageal, colo-
rectal, and cholangiocarcinoma.12
Among platinum-based agents, cisplatin has the highest rate of nephrotoxicity at
30%, followed by carboplatin at 15%, with oxaliplatin having the least nephrotoxicity
at less than 5%.12 Kidney injury with cisplatin results from direct tubular cell injury, often
involving the transport cells of the proximal tubule, as well as vasoconstriction.13 Fan-
coni syndrome can also occur with cisplatin exposure, and it is defined as the loss of
significant electrolytes, amino acids, and other molecules in the urine due to wide-
spread dysfunction of the transport capability within the proximal tubule of the nephron.
Cisplatin-induced AKI is usually dose-, duration-, and frequency-dependent, and there-
fore, kidney injury typically occurs after multiple doses.14 However, AKI has been
reported after a single exposure to cisplatin.12,15
Methotrexate
Methotrexate (MTX) is an antimetabolite that inhibits dihydrofolate reductase to inter-
fere with deoxyribonucleic acid (DNA) synthesis and cell replication.12 MTX-
associated AKI occurs in 3% to 60% of patients receiving high-dose MTX, which is
used for central nervous system (CNS) prophylaxis in high-risk lymphoma and primary
CNS lymphoma.16 MTX nephrotoxicity results from afferent arteriolar constriction,
intratubular crystal deposition, and inflammatory interstitial injury.12 More than 80%
of methotrexate and its active metabolites undergo kidney elimination, mainly by
glomerular filtration and less so by tubular secretion.17
Aggressive IV hydration, urinary alkalinization, and folinic acid (leucovorin) are used
for prevention. High-dose leucovorin along with glucarpidase and hemodialysis may
be required along with above-mentioned methods in the setting of AKI and severe
MTX toxicity.12
Ifosfamide
Ifosfamide is an alkylating agent often used with cisplatin and in the treatment of sar-
comas, testicular tumors, and certain refractory lymphomas. Chloroacetaldehyde is
the nephrotoxic metabolite of Ifosfamide. Ifosfamide-induced tubulointerstitial injury
results in AKI from ATI or progressive CKD.18 Proximal tubular injury may also cause
complete or incomplete Fanconi syndrome, or rarely, hypokalemic, distal renal tubular
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Table 1
Kidney-specific toxicity of anti-cancer therapies
Abbreviations: AIN, acute interstitial nephritis; AKI, acute kidney injury; ATN, acute tubular necrosis; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CAR-
T, chimeric antigen receptor T-cell; CDK, cyclin-dependent kinase; CKD, chronic kidney disease; DC, discontinue; dRTA, distal renal tubular acidosis; FSGS, focal
segmental glomerulosclerosis; GN, glomerulonephritis; ICI, immune-checkpoint inhibitor; IV, intravenous; MCD, minimal change disease; MEK, mitogen-
activated protein kinases; MN, membranous nephropathy; NDI, nephrogenic diabetes insipidus; NSAIDs, non-steroidal anti-inflammatory drugs; SIAD, syndrome
of inappropriate anti-diuretic hormone; TKI, tyrosine kinase inhibitors; UA, urinalysis; VEGFi, vascular endothelial growth factor pathway inhibitors.
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Targeted Therapies
Vascular endothelial growth factor pathway inhibitors/tyrosine kinase inhibitors
Examples of vascular endothelial growth factor pathway inhibitors (VEGFi) include
bevacizumab (antibody against VEGF ligand) and ramucirumab (antibody against
VEGF receptor). Tyrosine kinase inhibitors (TKI) examples are pazopanib, sorafe-
nib, sunitinib, and axitinib, pazopanib. Both classes of agents interrupt tumor
angiogenesis by inhibiting VEGF pathways and are used against renal cell carci-
noma, colorectal cancer, and various other cancers. Proteinuria and hypertension
are the most common adverse events. VEGFi may cause hypertension by altering
sodium homeostasis or endothelial dysfunction.19 VEGFi also may cause renal-
limited thrombotic microangiopathy (TMA) manifesting as new-onset hypertension
and/or proteinuria. VEGF-TKIs can cause various forms of injury to podocyte cells
in the glomerulus, also known as podocytopathies. For hypertension with or
without proteinuria, angiotensin-converting enzyme inhibitors (ACEIs) and angio-
tensin receptor blockers (ARBs) are optimal first-line treatments. In hypertension
(HTN) without proteinuria, calcium channel blockers (CCBs) or ACEIs/ARBs may
be used. TMA, malignant hypertension, or nephrotic-range proteinuria compel
discontinuation of VEGFi.20
Immunotherapies
Immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs) that enhance
tumor-directed immune responses by blocking “immune checkpoints” that down-
regulate the immune system. ICIs include mAbs against cytotoxic T-lymphocyte–
associated antigen 4 (CTLA-4) and programmed death 1 pathway (PD-1/PD-ligand-1
[PD-L1]) and have improved outcomes in several cancers.
Increased immune system activity as a result of ICIs can cause immune-related
adverse events (iRAEs). The gastrointestinal tract, skin, and endocrine system are
most commonly affected. Kidney-related adverse events can occur in up to 5% of
patients, especially when ICIs are used in combination with other anti-cancer thera-
pies. AKI from acute interstitial nephritis (AIN) is the most common kidney-related
Onco-Nephrology 755
iRAEs but other kidney injuries have been reported as well.23 Reduced estimated
glomerular filtration rate (eGFR), proton pump inhibitor (PPI) use and other extra-
renal iRAEs are major risk factors.24 Baseline laboratory workup including urine anal-
ysis should be obtained in patients started on ICIs. Proteinuria should be quantified if
present.23
Multiple myeloma
The most common kidney involvement in MM is myeloma cast nephropathy (MCN).
Casts form as a result of interaction between high concentrations of urinary free light
chains (FLC) with uromodulin or Tamm-Horsfall protein. Prompt reduction of FLCs is
important to kidney function recovery.30–32
Management of MCN mainly involves treating MM and supportive care including IV
fluids to maintain a high urine output (above 3 L per day). Hypercalcemia can be
managed by IV hydration, bisphosphonates, or receptor activator of nuclear factor
(kappa)-B ligand (RANKL) inhibitors.30
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Lymphoma/leukemia
Renal infiltration is common with leukemias and lymphomas resulting in a wide range
of renal dysfunction from asymptomatic to severe needing dialysis. AKI is common in
lymphoma and leukemia mainly as pre-renal or ATI. Glomerular disorders associated
with leukemia and lymphoma include minimal change disease, focal segmental glo-
merulosclerosis (FSGS), membranous nephropathy, IgA nephropathy and others. Kid-
ney function may remain normal with these pathologies.33,34
Monoclonal gammopathy of renal significance (MGRS) Monoclonal proteins are
nephrotoxic by nature which is well-established in MM. MGRS is a term used when
kidney damage is a result of these proteins produced by smaller amounts of clones
without meeting standard criteria for malignancies such as MM or lymphoma. Treat-
ment is based on targeting the underlying clone.30
Hyponatremia
Hyponatremia is common in cancer patients. Incidence rates are variable depending
on the type of cancer or care setting. In the HYPNOSIS study, 27% of inpatient
oncology admissions had hyponatremia.35 Although most were characterized as
mild–moderate, 4.3% had severe hyponatremia (Na<125 mEq/L). In another study
of patients facing end-of-life, 8% had moderate hyponatremia whereas 4.3% had
severe hyponatremia.36 Importantly, hyponatremia is associated with increased mor-
tality compared with normonatremic controls.35
Management of hyponatremia in cancer patients follows the same principles as the
general population. Fig. 1 illustrates a practical, cancer-specific approach to hypona-
tremia, beginning with confirming hypotonicity. Clinical status, urine osmolarity, and
urine sodium determine whether water excess in hyponatremia reflects elevated
anti-diuretic hormone (ADH) and whether high ADH is physiologically inappropriate
(syndrome of inappropriate ADH or syndrome of inappropriate anti-diuresis [SIADH])
or not (decreased effective circulating volume). Treatment of hyponatremia depends
on etiology, chronicity, severity, and clinical setting. Chronic hyponatremia should
not be corrected >6 to 8 mEq over 24 hours.37 Fluid restriction is necessary but insuf-
ficient if the sum of urine sodium and urine potassium > serum sodium. Additional in-
terventions include hypertonic saline for patients with neurologic symptoms. Loop
diuretics, salt tablets, urea, and ADH receptor antagonists may all be used in acute
and chronic management of hyponatremia secondary to SIADH. Recent reviews
and guidelines discuss this in detail.37,38
Hypomagnesemia
Magnesium (Mg) is an abundant intracellular cation important to glucose metabolism,
skeletal and cardiac myocyte function, and blood pressure regulation.39 Hypomagne-
semia (Mg < 1.8 mg/dL) is asymptomatic till severe deficiency (<1.2 mg/dL) causes
muscle cramps, constipation, or other electrolyte disorders including hypokalemia or
hypocalcemia.39 Hypomagnesemia may result from reduced intake, blunted gastroin-
testinal absorption (proton pump inhibitors), or increased gastrointestinal losses (diar-
rhea). In cancer patients, anti-neoplastic drugs such as cetuximab, cisplatin, and
anti-human epidermal growth factor receptor-2 (HER2) agents inhibit active
Onco-Nephrology 757
reabsorption of Mg at the distal nephron and cause renal Mg wasting.40 Calcineurin in-
hibitors for prophylaxis against graft-versus-host disease in allogeneic stem cell trans-
plants similarly induce Mg wasting.40 Fractional excretion of Mg >2% in patients with
normal GFR and hypomagnesemia supports renal wasting. Dose titration of supple-
ments such as Mg sulfate is limited by diarrheal side effects. Mg lactate or Mg chloride
preparations may be better tolerated in our anecdotal experience. In severe cases,
concurrent use of amiloride may increase Mg reabsorption in the collecting duct.41
Hypercalcemia
Calcium homeostasis is a balance between bone formation (osteoblastic) and bone
breakdown (osteoclastic). Hypercalcemia, which has been reported to affect 30%
of patients with malignancy and portends poor prognosis, occurs when increased
osteoclastic activity is not met with sufficient compensatory responses (ie, increased
renal calcium excretion).42 Central to increased osteoclastic activity is interaction be-
tween RANK on osteoclasts (or precursor) and RANKL on osteoblasts.43 This may
happen via humoral hypercalcemia of malignancy (HHM) when tumors, usually squa-
mous cell, secrete parathyroid-related protein (PTHrP). Some tumors may secrete
parathyroid hormone (PTH) while other cancers upregulate 1-alpha-hydroxylase enzy-
matic activity to increase 25-hydroxyvitamin D conversion to 1,25-dihydroxyvitamin D
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Table 2
Low potassium levels in cancer patients have multiple causes, both cancer-specific and cancer-independent
Abbreviations: ACTH, adrenocorticotropin hormone; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; GM-CSF, granulocyte-macrophage
colony stimulating factor; VIP, vasoactive intestinal peptide.
Onco-Nephrology 759
that increases intestinal calcium absorption.43 PTH and PTHrP increase RANK-
RANKL signaling and counter urinary calcium excretion.43 Primary or metastatic
bone tumors secrete cytokines that directly upregulate RANKL for lytic calcium
release from bone.43
Hypercalcemia may be asymptomatic if mild but levels >13 mg/dL may present with
mental status change, constipation, and nausea/vomiting. Treatment focuses on vol-
ume expansion with saline to increase calciuresis. Loop diuretics were once sug-
gested for increased distal nephron sodium delivery to increase urine calcium
excretion, but this has been proven to be ineffective or counterproductive as a primary
therapy.44 Calcitonin stimulates calciuresis and inhibits osteoclasts but decreases in
calcium are short-lived due to tachyphylaxis.42,43 Bisphosphonates inhibit osteoclasts
but are associated with FSGS (pamidronate)45 and ATI (zoledronic acid).46 RANKL in-
hibitors including denosumab may be the better option in patients with eGFR <60.
Hypokalemia/Hyperkalemia
Hyperkalemia is less common than hypokalemia in the malignancy setting, usually
occurring in the context of TLS or AKI of any cause. Pseudohyperkalemia may be noted
when fragile leukemic cells lyse during the centrifugation process of measuring serum
potassium and is ruled out if a subsequent plasma sample reveals normokalemia.47
Pseudohypokalemia may also be reported with severe leukocytosis when dividing
cells in blood samples stored at room temperature uptake serum potassium.48 Rapid
fractionation of serum or plasma from the cellular component or refrigeration of the
blood sample avoids pseudohypokalemia. Confirmed hypokalemia in the cancer pa-
tient may be directly related to the particular malignancy or only indirectly related to it
(Table 2). For example, acute myeloid leukemia (AML) may specifically release lyso-
zyme to induce proximal tubular injury and potassium loss or treatment of AML may
result in diarrhea that leads to potassium loss. Treatment of hypokalemia depends
on severity and etiology. In general, hypomagnesemia should be corrected and reple-
tion of potassium stores in cancer patients follows the same guidelines as non-cancer
patients.49
SUMMARY
Patients facing cancer have a high likelihood of experiencing AKI, CKD, proteinuria,
and/or electrolyte disorders during their post-diagnosis clinical course. These mani-
festations of kidney disease require prompt evaluation by nephrologists experienced
in the care of such patients. Major hospitals now have specialized Onco-Nephrology
clinics and we recommend that patients with kidney disease, particularly those with
AKI, CKD III, or higher, high-grade (>1.5 g) proteinuria, uncontrolled hypertension,
and refractory electrolyte derangements be referred to such clinics.
Kidney disease in cancer patients may result in acute kidney injury, chronic kidney disease,
proteinuria and/or electrolyte disorders.
Depending on the malignancy and the cancer, kidney disease in cancer patients may be due
to specific effects of the cancer or cancer-directed treatments.
Given the complexity of care of kidney disease in cancer patients, referral to nephrology is
essential and when available, referral to onco-nephrology is advisable.
760 Yarandi & Shirali
DISCLOSURES
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