Cancer is the second cause of death and morbidity in Europe (3.7 million new cases per year). The median age of patients at the time of Cancer diagnosis is 65 years. From the 47% of cancer survivors, half of then are older than 70 years.1 In a aging population it is expected to have an increase in the number of patients whose cancer is complicated by acute or chronic kidney diseases (CKD).

The EPIRCE study2 done in Spain by the SEN, observed that 23% of patients older than 65 years had CKD stages 3–5. Therefore in the aging population coincide cancer and CKD that explains the large amount of consultations between Oncology and Nephrology. This justifies the generation of this working group.

The is an interrelationship between CKD and cancer. Cancer may affect the kidney through the so-called paraneoplastic nephropathies, mainly as glomerular lesions,3 or through the toxic effects of the medication or radiation,4,5 or even after reduction of renal mass post nephrectomy due to renal cancer.6 In addition, patients on dialysis7 and particularly transplanted8 are at a high risk for the onset of cancer due to the status of immunosuppression.

In oncology patients there are a large number of reasons that explains the increasing number to nephrology consultations.

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  Acute Renal Failure of several causes: nephrotoxicity induced by chemotherapy (tubular necrosis, thrombotic microangiopathy, acute interstitial nephropathy), hemodynamic factors (sepsis), obstructive processes, etc.

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  Nephrotic range proteinuria cased by certain cancers (Hodgkin's disease, leukemia, Multiple Myeloma, Colon cancer, lung, etc.) associated to minimal glomerular lesions, segmental and focal hyalinosis or membranous nephropathy. The glomerular disease associated with cancer could be summarize as follows9:

• 1.

  Treatment of Cancer may result in the resolution glomerular process.

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  Membranous nephropathy has been classically associated with solid tumors.

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  Minimal change disease has been commonly described in hematological malignancies, especially Hodgkin lymphoma.

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  Membranoproliferative glomerulonephritis is increasingly recognized as a pathology associated to chronic hematological malignancies such as Chronic lymphocytic leukemia.

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  Injuries related to chemotherapy with different drugs: Interferon, Lenalidomide, Pamidronate, Anthracyclines, mTOR inhibitors or renal manifestations associated to with new therapies whose effect at the renal level is not well characterized yet such as antiEGFR, anti VEGF, anti PD1 and PDL1 or CAR T Cells, etc. that will be commented further in this manuscript.

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  Water and electrolyte disorders such as: hyponatremia, hypercalcemia, hypokalemia, hypomagnesemia, hypophosphatemia, acid-base abnormalities, disorders of the calcium and mineral metabolism.

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  Problems related to doses and timing of chemotherapy in patients with end stage renal disease on dialysis.

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  Consensus on the protocols for inclusion in the transplant waiting list, and times latency in potentially resolved pathologies; both for the recipient and donor.

There should be special interest in cancer patients with contrast-induced renal damage.10 These patients are frequently exposed to examinations that require the use of iodized contrasts to control the disease progression. With repeated procedures the cumulative dose of iodinated contrast increases the risk of kidney injury reducing the survival.11 A work published by Hong demonstrated an association between the need to perform a CT scan with contrast and acute renal injury secondary to this procedure.12 In fact, the KDIGO guidelines recommend to delay new exposures to contrast in cancer patients with kidney injury.13

There is an area not yet sufficiently explored in relation with the Renal Functional Reserve (RFR) that may be altered after repeated kidney aggressions induced by contrast infusions without evidence of deterioration of renal function. Certainly, in the absence of elevation of the serum creatinine it cannot be ruled out subclinical acute structural kidney injury with kidney damage.14 Similarly to the measurement of cardiac troponin as a valid marker of in acute myocardial infarction without ST elevation, it is necessary to have precise markers of structural renal damage in cases of acute renal injury without elevation of serum creatinine. Among these biomarkers or “renal troponins” it should be noted the cell cycle markers, as the urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and protein 7 bound to insulin-like growth factor (IGFBP-7) that are commercialised together in Spain.

Therefore the nephrologist should evaluate both functional and structural kidney damage more precisely in a cancer patient subjected to toxicity of medications and repeated explorations with iodinated contrast. The idea is to prevent long term kidney deterioration.

The Societies of Nephrology, Oncology and Hematology must advance together in the study of associations between CKD and cancer as reciprocal risk factors. These questions could be answered by the analysis of existing databases in different countries.

The Belgian study BIRMA, showed an estimated glomerular filtration rate (eGFR) by MDRD less than 60ml/min/1.73m2 in 18% of cancer patients.15 In other series from different countries, the data is similar. In United States it was found chronic renal dysfunction in 22% of in cancer patients,16 25% in Japan17 and 15.5% in Austria.18 One of the few studies generated in Spain, revealed that in 594 patients hospitalized in Oncology a 18.2% presented an eGFR by MDRD<60ml/min/1.73m2.19 In any case, it is clear that epidemiological studies with a large number of patients are needed to know the true prevalence CKD in cancer patients. It is also necessary to know if CKD is a risk factor for cancer. In a meta-analysis of 32,057 participants there was no association between CKD and the risk of cancer, however there was evidence of increased incidence of certain types of cancer in dialysis patients, such as the urinary tract, endocrine and gastrointestinal.20 The prevalence of cancer in transplant patients is high21; data from the SEN Registry reveal that the mortality caused by cancer in the kidney transplant patient is 20% and a consensus document on its prevention has been developed.22 Currently, the age of patients undergoing kidney transplant is increasing progressively and cancer constitutes one of the most important complications, both in patients who are kidney transplant candidates as in patients who have already received it. In fact, the ANZDATA registry data (Australia and New Zealand) show, as in Spain, that cancer has become a cause of mortality as frequent as that of cardiovascular origin in the kidney transplant population.23

Dialysis facilities frequently receive patients who have undergone nephrectomy due to kidney cancer. Kim et al.24 showed that up to 22% of patients with renal tumors had eGFR<60mL/min per 1.73m2 before nephrectomy. The two surgical options radical nephrectomy or partial nephrectomy (“nephron-sparing surgery”) do not differ in terms of oncological evolution but it makes a difference in terms of postoperative incidence of CKD and cardiovascular complications.25 That is why the American and European Urology societies support partial nephrectomy as a new standard of treatment for tumors restricted to the organ≤4cm (T1a) and suggested that it be considered an option for patients with tumors>4 but ≤7cm (T1b).26,27

According to the SEN it is very important to analyze the epidemiology and evolution of nephrectomized patients (or simply starting dialysis with an active tumor) mainly in relation with the initiation of renal replacement therapy, anntineoplastic treatments, tolerance and survival.

Treatment of cancer evolves quickly. For the Nephrology specialist it is difficult to be updated on indications and side effects. Conventional chemotherapy (cisplatin, metrotexate, melphalan, cyclophosphamide, etc.) may produce renal injury mainly acute tubular necrosis and thrombotic microangiopathy, among others (Table 1).

But there are other more recent therapeutic approaches directed to a specific target (Targeted Therapy). Such treatment is directed at the molecules that are essential for the survival of cancer cells. Molecular therapy has the advantage of the selectivity of the therapeutic target, which is different from chemotherapy and radiotherapy, because does not affect the surrounding healthy tissue, thus reducing significantly the side effects.

For the most part, all patients with the same type of cancer are not necessarily treated with the same medications or procedures. The therapy based on molecular targeting creates a personalized system of therapy in which patients are treated based on the unique molecular structure of its specific cancer. Using fundamental tissue stains, doctors can see which are the target molecules present in the patient's cancer and determine which drugs should be administered.

It is one of the most important innovations in the history of medicine. Immunotherapy, also called biological therapy, is a type of cancer treatment that stimulates the body's natural defenses to fight cancer. It uses substances produced by the body or manufactured in a laboratory to improve or restore the function of the immune system. There are different types of immunotherapy:a. Improving the immune system and making it stronger.

a1 Vaccine: by identifying mutated proteins of the tumor, small neoantigens are created that are injected intravenously to activate T cells against specific tumor antigens.

a2 Adoptive cell therapy. CAR T cell: T cells samples from the patient are grown in the laboratory. This procedure increases the number of T cells capable of destroying cancer cells or fighting infections. These T cells are returned to the patient to help the immune system to fight the tumor. One form of adoptive cell therapy is T-cell therapy and CAR (CAR T cells). This therapy requires a separation of T cells from the patient's blood sample. Thereafter, using an unarmed virus, T cells are genetically modified to produce receptors on their surfaces called chimeric antigen receptors. These synthetic receptors allow T cells to recognize and bind to a specific protein, in this case, a tumor antigen. These designed T cells expand by hundreds of millions in a cell manufacturing facility. Finally, CAR T cells are infused into the patient (preceded by a lymphodepletion chemotherapy regime). These CAR T cells can selectively attack and kill cells that express the tumor antigen. This treatment is not exempt of serious side effects, such as syndrome of cytokine release or tumor lysis syndrome,35 A T-cell and CAR therapy was approved in August 2017 for the treatment of children with acute lymphoblastic leukemia. A second therapy will be approved soon for adults with advanced lymphomas.

a3 Stimulating factors: A third technique of “enhancement” of immune response is the use stimulating factors such as cytokines, which stimulate T cells to multiply and become stronger.

a4 Antibodies: Antibody-based therapy for cancer has been established for the past 15 years and is now one of the most successful and relevant strategies for treatment of patients with hematologic malignancies and solid tumors. The death of tumor cells using mAB may be the direct result of the antibody's action (through receptor blockage, for example), immune response mechanisms of cell death or specific effects of an antibody on the vasculature and tumor stroma.

Tumor antigens that have been used successfully include EGFR, ERBB2, vascular endothelial growth factor (VEGF), CTLA-4, CD20, CD30 and CD52. Serological, genomic, proteomic and bioinformatic databases have been used to identify antigens and receptors that are overexpressed in tumor cells or that are linked to genetic mutations identified as drivers of cancer cell proliferation.36

Administration of Conjugates of antibody and drug is an effective strategy of drug delivery that uses the directed action of the antibody together with cell death induced by a potent cytotoxic agent. Drug and antibody are bound together by a molecule. This modality of treatment helps to reduce the toxicity in non-target cells, guarantee a wide therapeutic window and overcome resistance to multiple drugs.37

b. Medications that inhibit the immunosuppressive effect of tumors.

Another strategy is to decrease the tumor cell defenses against the T lymphocyte. For example, neutralizing with antibodies the inhibitory factors and cytokines such as anti-interleukin-10 and transforming growth factor beta. Another possible strategy, already discussed, is to decrease the defenses of the tumor cell against T lymphocyte usingcheckpoint inhibitors, such as anti-PDL1 and anti-CTLA 4 antibodies which have been approved by the FDA (Table 7).

The nephrotoxic effect of conventional chemotherapy is well known by oncologists and nephrologists. In addition, the enormous growth of “target” treatments and modern immunotherapy, just commented, may lead to acute or chronic renal complications and alterations of water, electrolytes a acid-base regulation. Nephrologists and oncologists must be aware of these complications, not only to prevent and treat kidney damage but also for epidemiological pharmacological and therapeutic reasons.

Tables 1–6 show the most frequent renal alterations associated with the different treatments against cancer.38,39

Likewise, it should be kept in mind that excessive external or internal radiation may produce renal damage that is not observed after radiation received for diagnostic purposes. Clinically it is expressed as acute or chronic kidney disease, and may be associated with malignant hypertension. Histological lesions include endothelial damage with capillary thrombosis and fibrosis.5

Regarding hematological diseases, Onco-Nephrology should cover very relevant aspects of renal complications. Tumor lysis syndrome (observed in non-Hodgkin lymphoma, acute lymphocytic, lymphoblastic or myeloid leukemia, and less frequently in chronic leukemia, myeloma and solid tumors) causes hydroelectrolytic complications that are frequent reasons for consultation: hyperuricemia, hyperphosphatemia, hypocalcemia and hyperkalemia.

There are a large number of objectives to be covered by a SEN working group that deals with the cancer-kidney combination. The objectives are:

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  Measurement of renal function in cancer patients.

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  Cancer epidemiology in patients with CKD.

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  Chemotherapy nephrotoxicity (ARI, crystal nephropathy, acute interstitial nephritis, thrombotic microangiopathy, segmental and focal hyalinosis, etc.).

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  Hydroelectrolytic alterations secondary to the use of certain agents.

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  Adjustment of doses and schedule of chemotherapy in patients with CKD.

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  Treatments against cancer in dialysis patient.

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  Kidney transplant and cancer in donor or recipient.

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  Clinical efficacy and complications of new cancer treatments (anti/EGFR, anti/VEGF, anti/mTOR, anti/PD1 and PDL1, CAR T cell).

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  Acute renal injury after administration of an iodinated contrast in patients with cancer and the influence of repeated examinations.

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  Myeloma and dialysis management of light chains.

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  Renal function after a nephrectomy.

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  ...

Future plans of the Spanish Society of Medical Oncology and the Society of Hematology include the development of training courses in epidemiology, patient monitoring, guidelines for the management of renal patients with cancer and the cancer patients with impaired renal function, and many other activities, including any relevant proposal by members of the SEN. Epidemiological data support the possibility of developing specific onconephrology clinic initially attended by a multidisciplinary team of oncologists, hematologists and nephrologists in first level hospitals covering the healthcare of at least half a million inhabitants. Including, if necessary, other medical specialists such as urologists, radiotherapists, pathologists, radiologists, palliative care, etc. It is about putting together the necessary health care specialist to provide optimal care to these patients with generation of protocols and educational activities.40

The authors declare no conflict of interest.