Understanding Kidney Impairment And Solid-organ Malignancies, And Managing Kidney Cancer

Contact: emily.li@wecistanche.com

Camillo Porta, et al

The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on the tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO(Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on conephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as the management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described.

KEYWORDS: glomerular filtration rate; nephrotoxicity; oncology; renal cell carcinoma

Cistanche is good for Kidney Disease

Kidney disease and cancer have a multifaceted association. Persons with chronic kidney disease (CKD) have an increased incidence of cancer relative to patients without CKD.1,2 In addition, both cancer and cancer treatments can cause impaired kidney function, including acute kidney injury (AKI) or CKD. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. Patients whose cancer is potentially curable can experience multiorgan failure requiring intensive care and kidney replacement therapy. In some countries, the amelioration of cancer mortality caused by greater treatment effificacy has resulted in a growing population of cancer survivors3 who are at increased risk for kidney disease. Finally, advanced malignancy complicated by multiorgan illness raises questions related to the appropriateness of aggressive treatment versus palliative therapy.

The complex relationship between kidney disease and cancer is confounded by a rapidly changing treatment landscape. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving GlobalOutcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in Milan, Italy in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as the management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and priorities for research are described.

KIDNEY IMPAIRMENT AND SOLID ORGAN MALIGNANCIES 

CKD is highly prevalent in cancer patients; the prevalence of estimated glomerular filtrate rate (eGFR) <60 ml/min per 1.73 m2 in cancer patients is estimated to be 12% to 25%.4–9 Certain cancers, such as renal cell carcinoma (RCC)7,10 and bladder cancer,11 have a higher prevalence of CKD than others. The presence of CKD worsens the survival rates of cancer patients.5,8,12–14 Patients with CKD G5 are at a higher risk of certain types of cancers: kidney, bladder, and infection-associated cancers such as tongue, liver, and cervix.15–19 In men, CKD G3 or higher has been associated with an elevated risk of urinary tract cancers.20 It is unknown why patients with CKD have increased cancer-related mortality relative to those who do not have CKD (Table 1).21,22

Pathophysiologic causes and mechanisms of AKI and CKD in solid cancers have prerenal (e.g., volume depletion, hypotension, vascular compression, cancer cachexia), renal (e.g., glomerular diseases, tubulointerstitial disease, renovascular disease), and postrenal (e.g., bulky obstruction, urinary retention, nephrolithiasis) origins.23,24 Common cancer therapies that can induce AKI are listed in Table 2. 21,24

Assessment of kidney function Precise GFR measurement is crucial when deciding on treatment and drug dosing, and monitoring kidney function. Unfortunately, all available formulas can under- or overestimate GFR.25 In addition, the presence of sarcopenia causes inaccuracies in GFR estimation. Different creatinine-based equations are used to estimate GFR in cancer: the Cockcroft-Gault formula, the Modification of Diet in Renal Disease study equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. However, these models for GFR estimation were developed mainly in non-cancer populations, and their usefulness in oncologic settings is uncertain. Recently a large study by Janowitz et al. demonstrated that the CKDEPI equation adjusted for body surface area was the most accurate and least biased estimator of GFR in patients with cancer, based on a comparison with radioisotopic clearance with chromium-51 ethylenediaminetetraacetic acid.26

The conference workgroup agreed that CKD-EPI equation27 is the current best approach for dosing chemotherapeutic agents in patients with CKD. The use of cystatin C–based equations can confer better accuracy in predicting the elimination of drugs by the kidneys28; however, with targeted oncology treatments, cathepsin D–mediated proteolysis may lower cystatin C irrespective of kidney function. Therefore, the universal use of cystatin C-based equations is not recommended.29 Use of the Cockcroft-Gault formula in determining dosing of chemotherapeutic agents is problematic because it may underestimate creatinine clearance, leading to inappropriate dose reductions of cancer treatments.30 Better methods for estimating GFR are needed, as are point-of-care tests that can rapidly measure GFR.31,32

Applicability and effificacy of various diagnostics in the onco-nephrology setting 

Renal investigations in patients with solid-organ malignancies. For patients with solid organ malignancy, the key renal investigations at diagnosis are assessment of kidney function, comorbidities, acid-base balance, and electrolytes, as well as urine analysis. Renal ultrasound is useful in cancer patients who develop AKI unless the kidneys have already been adequately evaluated with other radiologic imaging. In candidates for nephrectomy, renal scintigraphy can be used to evaluate the single-kidney function, or it can support the choice of radical versus partial surgery with RCC. During oncologic treatment, for patients with or without AKI, renal investigations would include the usual follow-up tests based on the type of cancer and therapies. For patients in whom AKI is developing (Supplementary Table S1),33 key renal assessments are similar to those suggested at cancer diagnosis, with the addition of spot urine protein-to-creatinine ratio. During follow-up after cancer treatment, nephrology consultations are indicated if patients show changes in kidney function or increasing proteinuria.

Cancer screening in dialysis patients. 

Cancer screening in the setting of kidney failure can be cost-effective if the expected survival is long enough or the patient is a transplant candidate. Conversely, comprehensive screening in patients with a limited life expectancy may not be beneficial.34 Therefore, decisions regarding cancer screening in patients with CKD G5 should be made on an individual basis, taking into account expected survival, risk factors, and transplant status.

Cancer screening in patients with glomerulonephritis. 

All patients with membranous nephropathy, particularly those older than 60 years, should be considered for cancer screening following age-appropriate guidelines. Patients with membranous nephropathy who have features of secondary membranous nephropathy on kidney biopsy (subendothelial or mesangial deposits, >8 white blood cells per glomerulus, non-IgG-4 subtype) should be more intensively screened for underlying malignancy.35 Patients with minimal change disease who have unexplained anemia, abnormal serum protein electrophoresis, hepatosplenomegaly, or lymphadenopathy should also be screened for underlying malignancy, especially Hodgkin lymphoma.36

Kidney biopsy in cancer patients with urinary abnormalities.

Kidney biopsy should be considered in cancer patients with significant new-onset proteinuria (defined as >1 g/d by conference participants) or worsening kidney function when the diagnosis of kidney disease cannot be otherwise established and may change care management. Kidney biopsy should not be performed in cancer patients with a poor prognosis; if the expected gain for an appropriate diagnosis is less than the patient’s expected survival, then a biopsy is unlikely to be useful.

In patients with kidney cancer undergoing surgery, nonneoplastic kidney tissue examination is highly recommended to identify coexisting kidney parenchymal diseases.37,38 The indication for kidney biopsy in cancer survivors, without active cancer and a good prognosis, should be similar to general population guidelines. However, biopsy and eventually rebiopsy could be considered for evaluating the long-term consequences of systematic therapy and radiation-induced kidney toxicity.38,39

To date, too few biopsies are being performed on cancer patients with kidney complications. Indeed, a biobank of kidney samples or an international biopsy registry could be helpful in understanding the spectrum of disease and outcomes (Table 1).

Preventing the development or progression of AKI or CKD 

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in CKD or nephrectomized cancer patients. 

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should be considered in nephrectomized patients with CKD in whom there is clinical indication for renin-angiotensin system (RAS) inhibition (e.g., hypertension, proteinuria, or cardiac indication).40–42 ACE inhibitors or ARBs may be beneficial in patients with vascular endothelial growth factor (VEGF) inhibitor-associated hypertension/proteinuria, although CKD-specifific outcomes data are needed. ACE inhibitor or ARB use in patients with cancer may be associated with improved overall survival.43–48 A meta-analysis including 11 studies showed benefits in urinary tract cancer (hazard ratio [HR] 0.22), colorectal cancer (HR 0.22), pancreatic cancer (HR 0.58), and prostate cancer (HR 0.14), but not in breast cancer or hepatocellular carcinoma.47 The meta-analysis indicated that using ACE inhibitors or ARBs in cancer patients could lead to a 40% reduction in the risk of cancer recurrence and a 25% reduction in mortality risk. A separate meta-analysis including 55 studies indicated RAS inhibitors can improve the survival of cancer patients, depending on cancer type and type of RAS inhibitor.48 The beneficial effect of RAS inhibition was shown in urinary tract malignancies, such as RCC, upper tract urothelial cancer, and bladder cancer, as well as gastric cancer and hepatocellular carcinoma. Again, CKD-specifific outcomes data are needed.

ACE inhibitors or ARBs may be associated with increased AKI risk in patients receiving active systemic therapy,49,50, and, therefore, treatment decisions should be made using an individualized approach in such patients. For example, temporary discontinuation of ACE inhibitors and ARBs may be considered during cancer treatment.

Contrast-induced AKI. 

Intravenous contrast-induced AKI is a relevant issue in cancer patients, especially in those with comorbidities and/or reduced GFR (CKD G3b–G5). High doses of contrast media and repeated contrast-enhanced scans may increase the risk of AKI. Stable ambulatory patients (outpatients) have a lower AKI risk compared with sick, unstable inpatients with similar GFR.51 In non-cancer patients, those with CKD G4–G5 have a signifificantly higher incidence of contrast-induced AKI (13.6% vs. 2.7% in patients with CKD G3a–G3b), even after prophylactic i.v. hydration.52 There have been no randomized studies of the risk of radiocontrast administration in oncology patients, and there are insufficient data to determine whether CKD patients with cancer should receive fewer contrast media computed tomography (CT) scans. In a retrospective analysis of cancer patients,53 contrast-induced nephropathy (CIN) prevalence was 9% with pre-existing kidney disease (50% had irreversible CIN) and approximately 5% without kidney disease. Cousin et al. 54 reported a 4.5-fold higher risk of CIN among oncology patients undergoing CT within 45 days after completing chemotherapy relative to those not given chemotherapy or undergoing CT more than 45 days after completing chemotherapy. However, the concept of CIN has been questioned based on results of multiple propensity score-matched analyses encompassing more than 60,000 patients, including those with cancer, in whom AKI risk was not signifificantly different with contrast-enhanced versus unenhanced CT scans. 55,56 A systemic review demonstrated similar risks of AKI, dialysis initiation, and mortality with enhanced or unenhanced CT.57

An exaggerated fear of radiocontrast nephropathy could lead to the withholding of beneficial diagnostic studies or interventions in CKD patients and reduce the diagnostic power of follow-up protocols. Therefore, CKD patients should not be denied a contrast media CT scan if benefits are believed to outweigh the risks of post-contrast AKI. In CKD G4–G5, reducing contrast dose and using iso-osmolar contrast media is preferable to withholding CT scans, although their cost-effectiveness should be validated by a controlled study.

Currently, periprocedural use of i.v. saline and/or oral hydration, depending on the GFR level, is often used, although the results of prospective studies and meta-analyses are somewhat conflicting.58 For example, in the AMAZING randomized controlled trial of non-cancer patients with CKD G3a–G3b, no prophylaxis was non-inferior and cost-saving compared with i.v. hydration in preventing post-contrast AKI.59 Results from the PRESERVE trial of more than 5000 non-cancer patients did not support the effificacy of sodium bicarbonate and acetylcysteine in preventing post-contrast AKI.60

A randomized, controlled trial of iso-osmolar versus lowosmolar contrast media in cancer patients with CKD G3b– G4, stratified for outpatients and inpatients, is a priority for research (Table 1). A second priority would be evaluating oral versus i.v. hydration in cancer patients with CKD G3b–G5 (not treated by dialysis) undergoing repeated CT scans.

Managing renal toxicities from treatments 

Nephrotoxicity of oncologic treatments. Radiation nephropathy can occur after hematopoietic stem cell transplantation or after treatment with radioisotopes. Anti-cancer drugs are a relatively common cause of acute and CKD as well as electrolyte and acid-base disturbances (Figure 124). Anti-cancer drugs can be generally classified as (i) cytotoxic chemotherapeutic drugs, (ii) targeted cancer agents, and (iii) cancer immunotherapies (Table 2). Cytotoxic chemotherapeutic drugs are the most common cause of kidney injury and include a number of agents, such as platinum-containing compounds (especially cisplatin), ifosfamide, gemcitabine, methotrexate, and pemetrexed. Acute tubular injury (ATI) is the most common kidney lesion; however, a number of other kidney lesions have also been described, such as thrombotic microangiopathy (TMA), podocytopathies, tubulopathies (Fanconi syndrome, salt and magnesium wasting, nephrogenic diabetes insipidus), acute/chronic tubulointerstitial nephritis, and crystalline nephropathy.

Targeted cancer drugs have become increasingly important for the treatment of various malignancies, but adverse renal effects also complicate therapy. Anti-angiogenesis drugs are associated with new or worsened hypertension, proteinuria (sometimes nephrotic), and lesions such as TMA, minimal change disease/focal segmental glomerulosclerosis, and acute interstitial nephritis (AIN). Other agents such as the B-Raf and anaplastic lymphoma kinase inhibitors cause AKI (ATI and AIN) less commonly, whereas proteasome inhibitors may be associated with TMA; notably, ALK anaplastic lymphoma kinase inhibitors (e.g., crizotinib) and CDK4 and CDK6 inhibitors (e.g., abemaciclib) may cause a noninjurious increase in serum creatinine owing to an inhibitory effect of these drugs on the secretion of creatinine, and this should be differentiated from genuine renal toxicity.61,62 Epidermal growth factor inhibitors, in particular cetuximab, have been associated with hypomagnesemia from renal magnesium wasting.

Cancer immunotherapies may also cause kidney disease. The older immunotherapies and their effects are well known; interferon is associated with different types of glomerulonephritis (e.g., focal glomerulosclerosis, membranous nephropathy, lupus-like nephritis, minimal change disease), as well as with TMA, whereas high-dose interleukin 2 is associated with cytokine storm syndrome and capillary leak syndrome with prerenal AKI and ATI. Immune checkpoint inhibitors are a relatively new and effective therapy for an increasing number of solid cancers. These drugs have been described as causing AKI and proteinuria (sometimes nephrotic); AKI is due primarily to AIN, but ATI also occurs. Minimal change disease and immune complex–related glomerular disease have also been described with these drugs.

Both the mechanisms of nephrotoxicity of oncologic treatments and the best management strategies for such toxicity are largely unknown. Research approaches are described in Table 1. Nephrotoxicity should be included in the surveillance of patients treated with immunotherapy and reported in drug registries.

Erythropoietin-stimulating agents and iron therapy. Currently, the indications for treatment with erythropoietin-stimulating agents (ESAs) and iron therapy are no different for CKD patients with or without malignancy.63,64 Most available guidelines of nephrology and oncology suggest the same target hemoglobin level (10–12 g/dl).63–66 KDIGO guidelines recommend a lower range of 9.0–11.5 g/dl.67 Using a range of 9–11.5 g/dl allows individualization for determining the best risk-benefit profile. For ESA, the nephrology dose is suggested for cancer patients with CKD.68 Meta-analysis data from 2009 have suggested treatment with ESAs in patients with cancer increases mortality and worsens overall survival69; however, a 2012 meta-analysis of 91 trials with more than 20,000 participants failed to show a direct impact of ESAs on cancer disease progression.70 In a recent article, Thavarajah, and Choi71 underscored that while current evidence suggests ESAs may promote progression or worsen outcomes in some cancers, there are no data on the likelihood of developing new cancers in patients undergoing dialysis or those in earlier stages of CKD during ESA therapy.

Registry studies could aid in a better understanding of cancer-related survival in cancer patients treated with ESAs. Evaluating new anemia treatments that stimulate endogenous erythropoietin production and enhance iron availability, such as hypoxia-inducible factor prolyl hydroxylase inhibitors,22 in cancer patients with CKD will also be important.

Timing and dosing adjustments of anticancer drugs in patients with CKD G3–G5D. 

Available evidence suggests that failing to adjust the doses of anticancer drugs in patients with CKD is deleterious. In a prospective study of 143 colorectal cancer patients who received standard doses of capecitabine and oxaliplatin, among the 50 patients with creatinine clearance <60 ml/min, cytopenia and diarrhea were significantly higher relative to patients with creatinine clearance of $ 60 ml/min, and effificacy of the drugs was reduced.72 Alternatively, in a prospective study of more than 600 breast cancer patients, adjusting the dosage of anticancer drugs in patients with creatinine clearance <60 ml/min when necessary resulted in comparable toxicity and effectiveness relative to standard dosing in patients with creatinine clearance of $60 ml/ min.73 In hemodialysis patients, active catabolites of certain drugs have the potential to accumulate and lead to unexpected adverse events,74–76 and dose adjustment is crucial to avoid accumulation and toxicity. Published clinical recommendations regarding optimal timing and dose adjustment of anticancer drugs (also in timing related to the start of the dialysis session) in CKD G5D cancer patients do exist77,78; however, the recommendations were derived based on case reports or small case series. In addition, a nationwide study in Japan has indicated there is a gap between recommendations and clinical practice in dose adjustment of anticancer agents in CKD G5D patients.79

No data are available regarding advanced CKD and peritoneal dialysis patients, and therefore pharmacokinetic and pharmacodynamic studies are needed.

Decision-making for initiating or terminating kidney replacement therapy in patients with solid organ cancer.

Currently, there are country-specifific variations in approaches to starting or withholding dialysis in patients with solid organ (or hematologic) cancers. Although scoring systems to predict the survival of dialysis patients are available, they could and should be enhanced by including the presence of active cancer and/or its prognosis. Withdrawal from chronic dialysis leads to death in a few weeks; therefore, when cancer-related prognosis for survival is less than 2 weeks, dialysis should be stopped. Actively requesting advanced directives through interdisciplinary teamwork could help physicians and patients avoid making difficult decisions in emergency situations. Determining patients’ preferences regarding long-term dialysis, time-limited trial dialysis, conservative CKD treatment, or palliative care is key.

MANAGEMENT AND TREATMENT OF KIDNEY CANCER 

Epidemiology, prevalence, and type of renal cell carcinoma 

The World Health Organization has estimated that the age-standardized incidence of kidney cancer worldwide was 4.5 per 100,000 persons in 2018.80 RCC, which refers to cancer that originated from renal epithelium, accounts for >90% of cancers in the kidney.81 RCC incidence predominates in men (1.5:1.0, males to females) and has a peak incidence in persons aged 60–70 years.81 The incidence of RCC varies widely globally but is increasing in many countries.82 The increased incidence is mainly related to changes in tumor detection and diagnostic practices (spread of CT/ultrasound), leading to the increase in diagnoses of early-stage RCC. Established risk factors are smoking, obesity, hypertension, CKD, diabetes, and certain genetic factors.82 Whether physical activity, diet, alcohol consumption, and environmental exposures increase the risk for RCC is unclear.

Despite recent improvements in its treatment, RCC, when metastatic, remains a lethal disease. RCC mortality rates vary based on the extent of available urologic-oncology facilities and treatments.83 In the majority of developed countries, RCC mortality rates are stable or decreasing as a result of screening efforts, early diagnosis, and improved treatments and their availability.82

Hereditary RCC syndromes account for 2% to 3% of all RCC cases,84, and many gene variants have been associated with RCC.84,85 The most common inherited cause of RCC is von Hippel-Lindau syndrome, in which there is a lifetime cumulative RCC incidence of approximately 70%.84 Sporadic forms are generally associated with structural alterations of the short arm of chromosome 3.

Kidney function in RCC 

Impaired kidney function is common in patients with RCC, either as a pre-existing condition or as a consequence of cancer and its therapy.86 RCC and impaired kidney function share intrinsic kidney risk factors and systemic comorbidities (Figure 2).87,88 Cancer-related risk factors for impaired kidney function in RCC include the following: malignant infiltration, which might involve renal parenchyma and/or renal vein and inferior vena cava; paraneoplastic syndromes caused by cytokine disease or immunogenic disease, including paraneoplastic nephropathies or hypercalcemia from parathyroid hormone-like protein production89; and obstruction of the urinary tract.

Surgical resection remains the preferred treatment modality in most cases of RCC. Unfortunately, nephrectomy has been recognized as an independent risk factor for kidney injury (Figure 3).86,90 After nephrectomy, the reduction in renal mass is followed by a decrease in kidney function, especially in patients with pre-existing kidney disease; furthermore, the remaining glomeruli can incur hyper-filtration injuries.87,91

Patients with CKD are known to have an increased risk of RCC.92,93 Although the cause of kidney cancer in CKD is unknown, several factors related to kidney injury have been proposed to explain this relationship,94 including renal fifibrosis and tubular atrophy, as well as uremia-related chronic inflflammation, oxidative stress, compromised immune function, the dialysis process, medications, and comorbid diseases.86 The risk of RCC is increased with increasing severity of kidney disease.92 The observed association between CKD and future risk of RCC is not necessarily causative; individuals with impaired kidney function undergo more intensive medical surveillance relative to the general population, and this may lead to increased incidental detection of localized, indolent kidney tumors through abdominal imaging.

CKD is a prognostic factor for RCC and increases the risks of mortality,95 cardiovascular events, kidney failure, and prolonged hospitalization.10 Worsening kidney function can preclude or delay antineoplastic therapy. In addition, drug dosing may be inadequate in dialysis patients, who have increased clearance of certain drugs.

Type of surgery and kidney outcomes 

Current guidelines recommend partial nephrectomy for the resection of tumors stage T1 (i.e., tumors #7 cm, confined to the kidney) to preserve as much normal renal parenchyma as possible.96,97 The technique can also be considered for tumors staged T2 (i.e., tumors >7 cm, confined to the kidney) and T3a (i.e., tumors extending macroscopically into the renal vein, affecting its branches, or invading the perinephric or renal sinus fat). Cytoreductive nephrectomy should not be performed in patients classified as poor risk based upon the Memorial Sloan Kettering Cancer Center classification.98 Although criticized for methodology, the recently reported CARMENA and SURTIME randomized trials support offering systemic therapy prior to cytoreductive nephrectomy for metastatic RCC.99,100 Reliable criteria for selecting patients for neoadjuvant tyrosine kinase inhibitors (TKIs) with cytoreductive nephrectomy remain largely elusive. Nevertheless, the results of the above-mentioned trials indicate that patients with risk features should be offered systemic therapy, and not cytoreductive nephrectomy, as the initial disease management. It is also important to stress that surgery is still a valuable tool in managing metastatic RCC. Therefore, intermediate-risk patients with potentially resectable metastases could be considered for cytoreductive nephrectomy and metastasectomy without systemic therapy as the initial disease management. Currently, there are no data regarding the use of checkpoint inhibitors prior to cytoreductive nephrectomy.

Concerns related to perioperative risks and postoperative follow-up 

Preventing CKD G5 after surgery involves identifying and reducing the risks of AKI and treating its complications.91 Patients at risk for AKI include those with CKD, diabetes mellitus, hypertension, proteinuria, older age, or abnormal nonneoplastic tissue near the tumor, as well as patients who smoke.91 Bhindi et al.101 recently developed models for predicting kidney function outcomes after partial and radical nephrectomy based on these and other preoperative features; however, the formulas need to be validated and confirmed for generalizability. Having more accurate GFR measurements, better imaging, and better identification of risk groups would aid in processes related to prediction.

Intraoperative steps for preventing kidney injury include minimizing nephron loss and devascularization, avoiding irreversible ischemic damage, and maintaining adequate renal perfusion during surgery. A variety of pharmacologic manipulations (mannitol, dopamine, fenoldopam, antioxidants, growth factors, porphyrins, mitochondria-protecting amino acids) have been used in an effort to abrogate the negative effects of ischemia, although results of most translational studies to date have been negative. Intraoperative maneuvers for preventing irreversible ischemic injury include the use of hypothermia, early unclamping, and zero ischemia. Results of a systematic review102 indicate there is no evidence to suggest that limited ischemia time (#25 min) has a higher risk of reduced kidney function after partial nephrectomy compared with a zero ischemia technique. Prolonged warm ischemia (>25–30 min) could cause an irreversible ischemic insult to the surgically treated kidney.

Postoperative general management includes having an adequate follow-up with early recognition and timely intervention, early nephrology referral of high-risk patients, avoiding post-surgery complications, avoiding nephrotoxins and renal hypoperfusion, and correcting reversible factors related to AKI. Strategies to prevent the progression of CKD to kidney failure include both regular monitoring of kidney function by measuring serum creatinine and eGFR, as well as prompt interventions to limit kidney disease onset or progression, including managing hypertension and diabetes mellitus, avoiding nephrotoxins and other aggravating factors, and correcting anemia, malnutrition, and metabolic acidosis. Repeated long-term monitoring of eGFR is indicated in cases of impaired kidney function before or after surgery.

New targeted therapies and renal side effects 

Targeting agents for treating metastatic RCC include anti-vascular endothelial growth factor receptor/vascular endothelial growth factor treatments, mammalian target of rapamycin inhibitors, and immune checkpoint inhibitors. These are used as monotherapies and combination therapies. Anticancer drug-related nephrotoxicity is a common and notable cause of kidney injury, potentially causing hypertension, proteinuria, AKI, and electrolyte disorders.91 Etiologies include acute tubular necrosis or injury and a variety of glomerular and vascular injuries.

Tyrosine kinase inhibitors. 

In patients undergoing dialysis, treatment with TKIs is safe and effective.103–111 Retrospective studies indicate that the use of multitargeted TKIs (sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib) might prolong life expectancy in the setting of metastatic renal clear cell carcinoma, even in patients undergoing dialysis.107

Dialysis patients receiving TKIs do not require an increased number of dialysis sessions. Most adverse events with TKIs in dialysis patients are mild in severity, with anemia the most common adverse event reported.103 Monitoring heparin use in dialysis patients undergoing TKI treatment may help to mitigate the risk of bleeding. For patients not undergoing dialysis but with CKD G3a–G5, age, and comorbidities are associated with increased blood pressure.23 Blood pressure normalization at baseline and monitoring during treatment is of paramount importance,112 although blood pressure control may be more challenging than in patients with better kidney function.113 As a practical point, for patients with kidney disease, including those undergoing dialysis, TKIs may be started at a lower than standard dose and titrated up based upon tolerability. Because of the large distribution volume of TKIs, overhydration should be avoided with TKI use.

Immune checkpoint inhibitors. Although rare, autoimmune nephritis has been reported in patients treated with immune checkpoint inhibitors.23 Serious renal toxicity (grade $3) is encountered in approximately 1% of patients and is usually reversed with discontinuation of the responsible agent and steroid therapy.114 Checkpoint inhibitors can be restarted when prednisone dosing is #10 mg (although this recommendation is not supported by any prospective study). Nonsteroidal options include mycophenolate mofetil and rituximab and are indicated in rare steroid-refractory cases. In selected cases of kidney injury, a kidney biopsy can be considered.

Data on checkpoint inhibitors in patients with kidney disease or undergoing dialysis are extremely limited, generally to case reports or case series. Currently, there is no evidence to support reducing the number of treatments with checkpoint inhibitors in patients with lowered GFR or undergoing dialysis.

CONCLUSIONS 

Conference participants emphasized the importance of collaboration between nephrology and hematology/oncology specialists in clinical care as well as clinical trials.115 Important gender-related issues in onco-nephrology that have not been investigated include the epidemiology of cancer in CKD patients and kidney impairment in cancer patients as well as response to cancer treatment in the setting of CKD. The limitations of current methods for estimating GFR and determining kidney function have negative clinical implications, and it is hoped that new approaches to measuring kidney function will be available in the near future. Nonetheless, hematology/oncology patients should undergo kidney function evaluations, including estimating GFR and determining the degree of proteinuria. In the setting of solid organ malignancy, important renal investigations include assessment of kidney function as well as comorbidities, acid-base balance, electrolytes, and urine analysis. In CKD patients, the current best approach for dosing chemotherapeutic agents is using the CKD-EPI equation. Postmarketing studies that include patients with CKD could inform the dosing of oncology drugs in patients with CKD G3b–G5D, an area greatly lacking data. Trials specififically focused on RCC patients with impaired kidney function are an area of urgent need.

From: ' Understanding kidney impairment and solid-organ malignancies, and managing kidney cancer' by Camillo Porta, et al

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