Onconephrology: The Significance of Renal Function for the Development, Diagnosis, and Treatment of Cancer

Background: Modern treatment strategies have markedly improved the chances of survival for patients with cancer. As the population ages, cancer is becoming more common, as is chronic kidney disease (CKD). CKD increases the risk of cancer; conversely, cancer treatments can cause CKD.

Methods: This review is based on publications retrieved by a selective literature search concerning the epidemiology and comorbidities of cancer and kidney diseases, the renal side effects of new anticancer drugs, and the need to consider renal function in cancer treatment.

Results: The prevalence of severe CKD in Germany is 2.3%. Persons who have CKD, are on dialysis, or have undergone kidney transplantation are 1.2 to 3.5 times more likely to develop cancer than the general population. For patients who have CKD or are dialysis-dependent, the doses of approximately 67% of anticancer drugs need to be adjusted on the basis of their glomerular filtration rate and the renally excreted fraction of the drug. The optimal efficacy of therapeutic drugs, as well as of those used for diagnostic purposes, and the minimization of side effects, depend critically on adapted dosing and on proper timing of administration before or after dialysis. Modern anticancer drugs can also cause acute kidney damage (incidence with checkpoint inhibitors: 2–16%).

Conclusion: Patients who have CKD, are on dialysis, or have undergone kidney transplantation make up a considerable fraction of persons being treated for cancer, and they need interdisciplinary treatment.

Increasing life expectancy, rising incidences of cancer and the development of new anticancer treatments have led to extended patient survival. As a result, there are more and more intersections between oncology and nephrology. Key aspects of onconephrology include measurement of kidney function, epidemiological aspects of cancer in patients with chronic kidney disease (CKD), renal side effects, and the dosing of drugs in patients with impaired kidney function and on dialysis. The aim of this review is to provide an overview of important topics in the field of onconephrology.

Methods

This review is based on publications retrieved by a selective literature search in the PubMed and WebofScience databases. The search terms included “onconephrology”, “cancer“ (title) or “chemotherapy“ (title) AND “chronic kidney disease“, “glomerular filtration rate“, “hemodialysis“, and “dialysis“. The search period covered the years 2000–2023, the search date was in 2023. Peer-reviewed articles in German or English were included in our review. The guidelines of Kidney Disease Improving Global Outcome (KDIGO), the European Society of Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO), as well as the classification according to Common Terminology Criteria for Adverse Events (CTCAE) were also taken into account.In addition, the manufacturers’ summaries of product characteristics of anticancer drugs were considered. Given the small patient population with diverse relevant comorbidities and heterogeneous tumor types, no randomized or non-randomized prospective clinical trials are available

Epidemiological aspects of kidney disease and cancer

Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function of at least 3 months’ duration, with associated health implications (1). CKD is divided into in five stages (G1-G5), based on the glomerular filtration rate (GFR). CKD is classified as mildly to moderately decreased (G3a) if the GFR decreases below 60 mL/min/1.73 m², as moderately to severely decreased (G3b) if it decreases below 45 mL/min/1.73 m² and as severely decreased (G4) if it decreases below 30 mL/min/1.73 m². A GFR <15 mL/min/1.73 m² (G5) indicates renal failure, often necessitating the initiation of renal replacement therapy (RRT). As an alternative or in addition, albuminuria, electrolyte disorders, histological/structural changes, and other factors may be present and lead to the diagnosis of CKD even in patients without impairment of GFR (1).

The global prevalence of CKD is 9.1%. In Germany, the prevalence of CKD is 2.3%, if only GFR < G3 is taken into account, and 12.7%, if albuminuria is also included. This means that almost two million people in Germany live with CKD (1, 2). The risk of developing CKD increases in the presence of comorbidities, such as diabetes (prevalence ratio: 2.25) or arterial hypertension (prevalence ratio: 3.46) (2). From age 60 onwards, the prevalence of CKD rises significantly.

In 2020, approximately 14 million people were newly diagnosed with cancer, of these approximately 500 000 in Germany (3, 4). By 2045, a worldwide increase in new cancer cases to 30.2 million and a mortality rate of 16.9 million people is expected (5). For Germany, an increase of 20.9% to 716,000 new cases is predicted (excluding non-melanoma skin cancer) (6).

Cancer as a comorbidity in CKD patients pre- and post-transplantation

Cancer is the second most common cause of death in people with chronic kidney disease, only exceeded by cardiovascular disease. However, in patients with a GFR of <60 mL/min/1.73 m² and proteinuria, cancer mortality is higher than cardiovascular mortality (7). The cumulative cancer frequency is higher with a GFR of <60 mL/min/1.73 m² compared to a GFR >60 mL/min/1.73 m² and increases disproportionately over a period of 12 years (5). The causes underlying this increased occurrence are not fully understood. In men, an eGFR <40 mL/min/1.73 m² is associated with the occurrence of colorectal and lung cancers as well as urogenital tumors, and this regardless of other risk factors, such as age and smoking status. In contrast, prostate cancer is not more common in men with advanced chronic kidney disease (8). No association with cancer incidence was found for women.

Among patients who are on dialysis, the standardized risk of developing cancer is increased compared to the normal population (standardized incidence ratio [SIR] 1.2–1.8). This applies to patients who are on hemodialysis or peritoneal dialysis, and mainly to cancers of the urogenital tract, such as renal cell carcinoma or cervical cancer (SIR up to 9.0). Conversely, the risk of developing breast cancer or prostate cancer is not increased in Europe and North America (9).

Even after kidney transplantation, a 3.5-fold increase in cancer risk remains (9). The most common malignancies include non-melanoma skin cancers, tumors of the urogenital tract and post-transplantation lymphoma. For example, 30–45% of all transplant recipients develop non-melanoma skin cancers (NMSC) within ten years of transplantation (10). The clinical course of the disease is the same as for patients without immunosuppression (11, 12). In addition to the cancer screening programs for the general population, KDIGO recommends for transplant recipients further special checks, such as annual skin checks by experienced doctors, regular UV protection, annual ultrasound examinations of the patients’ own kidneys, and EBV viral load measurement in high-risk patients (R -/D +) (13).

Determining renal function in cancer patients

Renal filtration, secretion and reabsorption are the three mechanisms underlying renal excretory capacity. Renal excretory capacity is described by GFR and synonymous with renal function. The gold standard of GFR measurement is inulin or iohexol clearance; however, this method is not used for reasons of practicality. Thus, GFR is estimated by measuring the serum levels of creatinine, which are dependent on a person‘s muscle mass; then, the eGFR is calculated based on these values. The Cockcroft-Gault formula allows the determination of creatinine clearance, the Modification of Diet in Renal Disease (MDRD) or CKD-EPI equation allows the determination of eGFR. These formulas take into account factors such as sex, weight, age, and ethnicity, as well as correction factors. All formulas to estimate GFR take the decline in renal function with age into account, which amounts to 1 mL/min per year. Each of these formulas has a certain accuracy range; for example, the MDRD formula significantly underestimates the true GFR in the upper GFR range. Here, the CKD-EPI formula provides more precise values, with fewer false positive results in the upper GFR range. In a wide intermediate range, however, the CKD-EPI formula estimates the GFR higher than the MDRD, resulting in a tendency to classify patients in higher stages of CKD. Alternatively, cystatin C can be used to determine the eGFR. It was shown for patients with solid tumors that the highest accuracy is achieved when the eGFR is determined using a combination of creatinine and cystatin C measurements (14). There is no guideline that specifies measurement intervals. It is advisable to determine the baseline levels of creatinine/cystatin C prior to the initiation of treatment. In patients undergoing treatment, regular monitoring should be performed according to the treatment protocol and the manufacturer‘s instructions/summary of product characteristics: weekly in patients receiving chemotherapy treatment and every two to four weeks in patients receiving immunotherapy treatment. If deviations occur and a renal cause is suspected, a nephrologist’s assessment should be obtained as part of the work-up (consensus of the authors).

No clear evidence exists as to which method of measurement or formula should be used to determine the GFR in patients receiving specific medications. Clearance should be determined based on a 24-hour urine sample (creatinine) or the measurement of cystatin C, if the therapeutic window of a drug is very narrow, in patients with cachexia or after amputation of a limb, as this is associated with decreased creatine levels and the clearance is overestimated by the Cockcroft-Gault formula (15). Therefore, the KDIGO guideline also recommends the use of a combined measurement method, the eGFRcr-cys, to determine the eGFR in patients with solid tumors (1). Given the limitations of the various formulas and of the molecule used for measurement, it is recommended that oncologists and nephrologists consult with each other.

Dosing of medications in patients with CKD and need for dialysis

For the majority of drugs, toxic blood levels are more than twice as high as therapeutic levels. This means that dose adjustment is only necessary if the GFR falls below the no-effect boundary of 60 mL/min/1.73m² (Figure 1 and eMethods a) for an example) (17).

Figure 1

Dose reduction and the effects

For the majority of drugs, toxic blood levels are more than twice as high as therapeutic levels. This means that dose adjustment is only necessary if the GFR falls below the no-effect boundary of 60 mL/min/1.73m² (Figure 1 and eMethods a) for an example) (17).

The adjusted dose should achieve the same effect (E) as with normal renal function; thus, not only pharmacokinetics but also pharmacodynamics must be taken into account. The effects are usually mediated by receptors and can be described using the Hill equation (eFigure and eMethods “Explanation of the Hill coefficient“). Such reversible effects are large, when the maximum effect (E_max) is large, stronger at higher concentrations (C), but weaker, if a high concentration is needed to achieve the half-maximum effect (CE₅₀). The higher the Hill coefficient (H), the more sigmoid the effect-concentration relationship (eFigure).

eFigure

Pharmacodynamics

Approximately 67% of all anticancer drugs require dose adjustment for renal function. In addition, several anticancer drugs are eliminated by hemodialysis and thus require the administration of an adjusted dose before and after dialysis. However, for more than 50% of the anticancer drugs, no information on this aspect is available (Table 1 and eTable) (18, 19, 20).

Table 1

Dose adjustment of anticancer drugs in chronic kidney disease (CKD) and need for dose adjustment (according to [19] and the summaries of product characteristics of the various drugs)

Schematic dose reduction in patients with impaired renal function may cause the anticancer effect to be missed (Figure 2 und eMethods b) and can be one reason why survival rates are significantly poorer in cancer patients with a GFR <60 mL/min/1.73 m², as has been shown retrospectively (21). Studies found better survival rates in patients with NSCLC and mildly impaired GRF (<90 mL/min/1.73 m²), if the cisplatin/pemetrexed treatment was not adapted (higher cumulated dose) (22).There were no fatal side effects, which means that a higher dosage appears at least feasible in patients with CKD. However, this does not allow to draw general conclusions for all medications and unselected cohorts of patients with CKD. Here, randomized trials could help to arrive at clear recommendations. With dose adjustment, the risk of side effects must be weighed against the chance of successful treatment.

Figure 2

Anticancer drugs with chronic kidney disease—Dose reduction and its consequences

Contrast medium administration

Imaging with contrast medium (CM) is part of the diagnosis and aftercare of patients with and after cancer. The renal clearance rate of iodine-containing and iodine-substituted contrast media is 90%. Approximately 2.3–11% of patients develop acute, usually reversible, nonoliguric renal failure within 1–7 days after contrast medium administration—a contrast-induced nephropathy. Approximately 90% of cases were patients with pre-existing CKD. Only 0.4% of patients with contrast-induced nephropathy require permanent dialysis (23). Risk factors are listed in Table 2 (23). The causes are not yet fully understood. Underlying mechanisms include direct cytotoxic effects, autocrine und paracrine factors as well as changed rheological properties affecting renal hemodynamics and tubulodynamics, and regional hypoxia (24).

Table 2

Risk factors that predispose to contrast-induced nephropathy

The preventative effect of hydration, acetylcysteine, sodium bicarbonate, vasodilators, hemodialysis, and hemofiltration is controversial and appears to be beneficial only in high-risk persons (eGFR <45 mL/min). Thus, the KDIGO guideline recommends to choose the lowest possible contrast medium dose, to use low- or iso-osmolar contrast media, to administer fluid in the form of isotonic saline solution or sodium bicarbonate solution intravenously (but not only oral fluid replacement), and oral administration of acetylcysteine together with isotonic saline intravenously. The use of theophylline, fenoldopam and prophylactic hemodialysis or hemofiltration is not recommended (25). Whenever possible, imaging modalities should be used where no or non-nephrotoxic contrast media are used, such as magnetic resonance imaging and ultrasonography.

Kidney transplantation after cancer

Patients who had cancer and wish to undergo kidney transplantation are not necessarily ineligible for receiving a kidney graft. However, there is difficulty in determining the right timing. Given the ever improving treatment outcomes, fixed waiting times with the longest possible recurrence-free interval do not seem to be appropriate any longer. Waiting times should instead be determined on a prognosis-oriented and interdisciplinary basis. This is important particularly with regard to living kidney donations, long waiting times and late, i.e. not long before the transplantation, diagnosed cancer, as it means that the waiting time is extended once again. For common malignancies, such as renal cell carcinoma, the specialist societies recommend waiting times of 0–2 years for localized tumors and five years for advanced cancer (26). Recommendations are not available for all cancer entities; interdisciplinary discussions (“cancer–transplantation boards“) can be helpful in this situation (26). While survival rates in patients with cancer prior to transplantation are lower compared to those of patients without cancer, this is not associated with age, sex and cancer per se (27).

Anticancer treatment and its effect on the kidneys

The excretion of many anticancer drugs is dependent on renal function. In addition, many substances are nephrotoxic, and both aspects can add up (carboplatin). These effects can be addressed with dose adjustment. The recommend adaption of a carboplatin-containing chemotherapy leads to halving the normal dose from a GFR <60 mL/min/1.73 m²; however, this approach entails the risk that the treatment becomes ineffective due to underdosing. It is frequently recommended that patients who are on dialysis should receive anticancer drugs after dialysis (if the substances are dialyzable) and in reduced dose (19). Relevant factors influencing dialyzability include molecular weight, protein binding and volume of distribution of the substance. In deviation from this, hemodialysis can be used as a pharmacokinetic tool. With this approach, the standard dose is administered; 1–2 hours after infusion stop, a 6-hour hemodialysis is performed and then repeated daily. In this way, a drop in blood levels, similar to that seen with normal kidney function, can be achieved. This may help to minimize the loss of effectiveness of chemotherapy (Figure 3).

Figure 3

Hemodialysis as a pharmacokinetic tool

Only a few reviews on the use anticancer substances in dialysis-dependent patients have been published so far. Examples include the studies of Hann et al. on pancreatic cancer and Zhang et al. on gynecological malignancies (28, 29).

Examples of modern anticancer drugs and their effects on kidney function

IIn 2011, ipilimumab was the first immune checkpoint inhibitor (ICI) to receive approval. ICIs are generally considered to be well-tolerated treatments. Higher-grade side effects (CTCAE grade ≥3) are reported for 20% of the treated patients. The incidence of acute kidney damage is in the range of 2% und 16% (30). The rate of immune-related adverse events (irAEs) is reported to be <5%. Acute interstitial nephritis is most commonly detected in kidney biopsy specimens (80–90%). Acute tubular damage and glomerular disorders are rarer. Median occurrence of renal irAEs is approximately three months after treatment initiation. However, IrAEs can be observed with significant delay (several months) after end of treatment. These side effects are treated empirically with corticosteroids (31).

In recent years, poly (ADP-ribose) polymerase inhibitors (PARPi) have also been used for the treatment of various tumor entities. A special feature of these substances is the drug-induced increase in creatinine, which is caused by impaired tubular creatinine secretion (without influencing glomerular creatinine filtration) and does not require specific therapy. Renal function testing should be supplemented by measuring cystatin C (32). According to the summary of product characteristics, it is not recommended to use PARPi in patients with moderate CKD with dose adjustment and in patients with severe CKD. However, the benefits and risks of treatment must be weighed up on a case by case basis.

Lutetium (177Lu) vipivotide tetraxetan is a radiopharmaceutical medication targeting the prostate-specific membrane antigen (PSMA); it is approved to treat advanced prostate cancer and has increasingly found its way into earlier lines of treatment. The kidneys are dose-limiting organs with a historically described cumulative dose limit of 23 Gy (33). The dosimetry substudy of the VISIONstudy found that five of 30 patients experienced CTCAE grade 1–2 renal toxicities when having undergone up to six cycles (34).

Conclusion

Impaired renal function is associated with an increased risk of cancer. Diagnostic imaging with contrast media as part of the cancer workup can trigger renal failure, for example in patients with diabetes. Anticancer treatment in patient with impaired renal function is challenging and raises questions addressed by onconephrology. Approximately two thirds of the anticancer drugs would require adjustment—in dose and in patients who are on dialysis also with regard to the timing of treatment. These challenges should not prevent patients with chronic kidney disease from receiving treatment.

Conflict of interest
SZ received consultation and lecture fees from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Eisai, EUSA, Gilead, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi Aventis.

The remaining authors declare no conflict of interest.

Manuscript received on 24 March 2024; revised version accepted on 18 September 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
PD Dr. med. Susanne Delecluse

Universitätsklinikum Heidelberg

Fachklinik für Nierenerkrankungen, Nierenzentrum

Im Neuenheimer Feld 162, 69120 Heidelberg, Germany

Cite this as:
Delecluse S, Harder F, Keller F, Zeier M, Zschäbitz S: Onconephrology: the significance of renal function for the development, diagnosis, and treatment of cancer. Dtsch Arztebl Int 2024; 121: 793–9. DOI: 10.3238/arztebl.m2024.0193

References

1. Levin A, Ahmed SB, Carrero JJ, et al.: Executive summary of the KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease: known knowns and known unknowns. Kidney Int 2024; 105: 684–701.

2. Girndt M, Trocchi P, Scheidt-Nave C, Markau S, Stang A: The prevalence of renal failure. Results from the German health interview and examination survey for adults, 2008–2011 (DEGS1). Dtsch Arztebl Int 2016; 113: 85–91.

3. IARC: Estimated number of prevalent cases (1-year), both sexes, in 2022. https://gco.iarc.fr/today/en/dataviz/pie-prevalence?mode=population&types=2&group_populations=0 (last accessed on 04 May 2024).

4. RKI: Krebs in Deutschland. 2019/2020. https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2023/kid_2023_c00_97_krebs_gesamt.pdf?__blob=publicationFile (last accessed on 04 May 2024).

5. IARC: Estimated number of deaths from 2022 to 2045, both sexes, age [0–85+]. https://gco.iarc.fr/tomorrow/en/dataviz/isotype?types=1&single_unit=500000 (last accessed on 04 May 2024).

6. IARC: Estimated number of new cases from 2022 to 2045, both sexes, age [0–85+]. https://gco.iarc.who.int/tomorrow/en/dataviz/isotype?populations=276& group_cancers=1& multiple_cancers=1& cancers=40_41& mode=population& multiple_populations=0& sexes=0& years=2045& single_unit=50000& types=0 (last accessed on 04 May 2024).

7. Thompson S, James M, Wiebe N, et al.: Cause of death in patients with reduced kidney function. J Am Soc Nephrol 2015; 26: 2504–11.

8. Wong G, Hayen A, Chapman JR, et al.: Association of CKD and cancer risk in older people. J Am Soc Nephrol 2009; 20: 1341–50.

9. Maisonneuve P, Agodoa L, Gellert R, et al.: Cancer in patients ondialysis for end-stage renal disease: an international collaborative study. Lancet 1999; 354: 93–9.

10. Granata S, Tessari G, Stallone G, Zaza G: Skin cancer in solid organ transplant recipients: still an open problem. Front Med (Lausanne) 2023; 10: 1189680.

11. Einollahi B, Nemati E, Lessan-Pezeshki M, et al.: Skin cancer after renal transplantation: results of a multicenter study in Iran. Ann Transplant 2010; 15: 44–50.

12. Mittal A, Colegio OR: Skin cancers in organ transplant recipients. Am J Transplant 2017; 17: 2509–30.

13. Kidney disease: improving global outcomes transplant work G: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3: S1–155.

14. Costa ESVT, Gil LA, Jr, Inker LA, et al.: A prospective cross-sectional study estimated glomerular filtration rate from creatinine and cystatin C in adults with solid tumors. Kidney Int 2022; 101: 607–14.

15. Jäger D, Zeier M: Onko-Nephrologie. Berlin: Springer Nature 2019.

16. Hartmann B, Czock D, Keller F: Drug therapy in patients with chronic renal failure. Dtsch Arztebl Int 2010; 107: 647–55; quiz 55–6.

17. Lea-Henry TN, Carland JE, Stocker SL, Sevastos J, Roberts DM: Clinical pharmacokinetics in kidney disease: fundamental principles. Clin J Am Soc Nephrol 2018; 13: 1085–95.

18. Janus N, Launay-Vacher V, Thyss A, et al.: Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study. Ann Oncol 2013; 24: 501–7.

19. Alan SL, Yu GMC, Luyckx V, Marsden PA, Skorecki K, Taal MW: Brenner and Rector‘s the kidney: Elsevier 2019.

20. Kluwer W: Uptodate. www.wolterskluwer.com/de-de/solutions/uptodate (last accessed on 16 July 2024).

21. Launay-Vacher V, Spano JP, Janus N, et al.: Renal insufficiency and anticancer drugs in elderly cancer patients: a subgroup analysis of the IRMA study. Crit Rev Oncol Hematol 2009; 70: 124–33.

22. Magali L, Pascal F, Serge A, et al.: Better survival in impaired renal function patients with metastatic non-small cell lung cancer treated by cisplatin-pemetrexed. Eur J Clin Pharmacol 2020; 76: 1573–80.

23. Pannu N, Wiebe N, Tonelli M, Alberta Kidney Disease Network: Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006; 295: 2765–79.

24. Seeliger E, Sendeski M, Rihal CS, Persson PB: Contrast-induced kidney injury: mechanisms, risk factors, and prevention. Eur Heart J 2012; 33: 2007–15.

25. Khwaja A: KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012; 120: c179–84.

26. Delecluse S: Tumorerkrankungen von Dialysepatienten und vor Nierentransplantation. Der Nephrologe 2019; 1/2019.

27. Jacoby F, Holland-Letz T, Zeier M, Delecluse S: All-cause and cancer-specific overall survival in kidney transplant recipients with pre-transplant malignancies in a German cohort. Journal of Onco-Nephrology 2020; 4.

28. Hann A, Nosalski E, Hermann PC, Egger J, Seufferlein T, Keller F: Chemotherapeutic agents eligible for prior dosing in pancreatic cancer patients requiring hemodialysis: a systematic review. Clin Nephrol 2018; 90: 125–41.

29. Zhang N, Liu C, Di W: Systemic treatment for gynecological cancer patients undergoing hemodialysis. Onco Targets Ther 2023; 16: 545–58.

30. Hiller K, Delecluse S, Zeier M, Zschäbitz S: Renale Nebenwirkungen moderner Tumortherapien. internistische praxis 2023: 521–9.

31. Haanen J, Obeid M, Spain L, et al.: Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022; 33: 1217–38.

32. Zibetti Dal Molin G, Westin SN, Msaouel P, Gomes LM, Dickens A, Coleman RL: Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors. Int J Gynecol Cancer 2020; 30: 89–93.

33. Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991; 21: 109–22.

34. Herrmann K, Rahbar K, Eiber M, et al.: Renal and multiorgan safety of (177)Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer in the VISION dosimetry substudy. J Nucl Med 2024; 65: 71–8.