Coordinated care of oncological patients plays an important role in the effectiveness of cancer therapy. In recent years, it has been noticed that onconephrological syndromes play a significant role of in the proper diagnosis and therapy of oncological patients who experience nephrological complications in cancer treatment or patients with initial chronic kidney disease qualified for oncological therapy [1]. Nephrologists who consult oncological patients need to possess knowledge of the biology and therapy of individual cancers in order to fully cooperate with the oncologists. Recent years have seen a continuous development of therapy in clinical oncology. A number of new drugs have been introduced for the treatment of cancer, often of very sophisticated structure and action. Dynamic development of oncological therapies causes the improvement of results in the treatment of various cancers as well as longer survival. Unfortunately, the factor which may limit the effectiveness of therapy is the occurrence of various side effects, including nephrotoxicity. The dynamic development of oncological drugs, especially immuno-oncological preparations, results in discovering new pathophysiological mechanisms of potential side effects. The optimal management of a patient requiring oncological therapy should include both the prevention and treatment of possible nephrological complications.

2. Immunotherapy as a New Method of Cancer Treatment

Advances in basic science led to improvements in theour knowledge about the mechanisms of cancer growth and development. Avoiding immune destruction by altered immune recognition has been recently described as a classical hallmark of cancer ^[2][72]. As a result, rwesearchers can better understand the mechanisms of cancer progression and improve the possibilities of treatment. Immunotherapy has become a new tool for cancer therapy, significantly differing from classical chemotherapeutics. Immune therapy is an example of targeted therapy and is used in several cancers like lung, kidney, bladder, head and neck cancers, as well as melanoma (Table 1). TNFα and IL-2 was the first immunotherapy that was registered for treating renal cell carcinoma or melanoma. However, its efficacy was moderate and toxic ^[3][73]. Nowadays immune checkpoint inhibitors (ICPs) are the mainstay of immunotherapy. Programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are molecules which regulate immune response and prevent overactivation and development of autoimmunity. CTLA-4 is expressed only on T cells and regulates the early immune response. PD-1 receptor is present on the surface of antigen-presenting cells (APC), T cells, B cells, NK, monocytes, dendritic cells and regulates later immune response. The presence of PD-L1 on tumor cells decreases the activity of T- lymphocyte. Pharmacological inhibition of CTLA-4 and disruption of the PD-1/PD-L1 axis enhance the anti-tumoral activity of lymphocytes ^[4][74]. Anti-PD1 (nivolumab, pembrolizumab), anti-PDL1 (durwalumab, atezolizumab, avelumab), and anty-CTLA4 (ipilimumab) antibodies are used in radical and palliative cancer treatment in several indications. Many clinical trials confirmed clinical benefits for patients treated with ICPs inhibitors. The side effects of immunotherapy differ from side effects of chemotherapy. They are unpredictable and do not depend on the cell cycle. Classically immune-related side effects can be divided into infusion reaction and immune-related adverse events (irAE). They include skin toxicity, endocrinopathies, hepatotoxicity, gastrotoxicity, pneumonitis, which occur more frequently than neurological, cardiac, rheumatological, hematological, ocular, and renal toxicity ^[5][75].

2.1. Nephrotoxicity of Immunotherapy

The clinical problems related to kidney injury can be divided into volume depletion, acute and chronic kidney injury, electrolyte disorders, microangiopathies, nephritic syndrome, tumor lysis syndrome toxicity of chemotherapeutics and non-chemotherapeutics ^[6][76]. Among several targeted therapies directed against EGFR, HER2, PD1/PDL1 and CTLA-4 the most nephrotoxic agents are ipilimumab and cetuximab ^[7][77]. Nephrotoxicity is one of the classical side effects of cisplatin, which is used as an alkylating agent in several cancers like lungs cancer, bladder cancer, head and neck cancers ^[8][78]. Nephrotoxicity is a major factor, limiting the use of cisplatin in cancer treatment, which classically requires eGFR >60 according to the criteria of eligibility for cisplatin. There are several differences between cisplatin toxicity and immunotherapy. The mechanism of kidney injury after cisplatin treatment involves tubular death due to inflammation, vascular injury and activation of death promoting signaling pathways. The other differences include biochemical symptoms (decrease of glomerular filtration rate and magnesium, potassium disorders), risk factors and method of prevention (hydration) ^[9][18].

2.2. Types and Epidemiology of Immune-Related Nephrotoxicity

Several renal and urinary disorders were reported in clinical trials with ICPs inhibitors. They included AKI, autoimmune nephritis, dysuria, nephrolithiasis, toxic nephropathy, prerenal failure, renal colic, renal failure, renal impairments, tubulointerstitial nephritis, urinary retention, hematuria, renal tubular nephritis and glomerulonephritis ^[10][79]. In contrast to interstitial nephritis, glomerulopathies with different histological pattern occur much less often. However, some case report studies were published presenting membranoproliferative glomerulonephritis, minimal change disease, pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A nephropathy, amyloid A amyloidosis, focal segmental glomerulonephritis and lupus nephropathy ^[11][12][13][80,81,82]. The occurrence of nephrotoxicity upon ICPs inhibitors varied between 1 to 22% and occurred more frequently in anti-PD1 than anti-CTLA-4 therapy. Among irAEs nephrotoxicity is one of the rarest and reaches < 1% of patients treated with ICPs inhibitors, but, the incidence may be underestimated. Recent analysis of 48 clinical trials and 11,482 patients treated with anty- PD-1 (nivolumab and pembrolizumab) shows, that incidence rate of acute kidney injury is 2.2% ^[14][83]. In Oleas and al. review of 826 patients treated with immunotherapy, 15.1% developed AKI and among them 18.5% needed hospitalization ^[15][84]. Due to distinction in the study group, type of cancer, and differences between accessed outcomes direct comparison of kidney immune-related adverse events is difficult to manage. The incidence of immune-related kidney injury depends on treatment regimen (monotherapy or polytherapy) and type of medicine (anti -PD-1, anti-PD-L1, anti -CTLA4). In monotherapy, kidney injury occurs more rarely than polytherapy. Nephrotoxicity occurred most frequently in the Nivolumab-Ipilimumab combination and reached 4.9%, but was mostly graded 1 or 2 according to CTCAE criteria ^[5][75]. Importantly, the connection of cisplatin-based chemotherapy regimen with anti-PD-L1 therapy did not alter significantly ototoxicity and nephrotoxicity except a mild worsening of distortion product otoacoustic emissions and a mild increase in serum creatinine ^[16][85]. Time to a development of kidney injury is different and may occur just after a single dose of ICPi, but varies between studies from 3 weeks to 8 months. Nephrotoxicity may be isolated or be one of the several irAE. Secondary irAE usually occurs prior to AKI but may occur at the time or after AKI ^[12][81]. In the case series study the hypothyroidism was the most frequent synchronic irAE.

2.3. Mechanism of Nephrotoxicity

Nephrotoxicity during immunotherapy may be CTLA-4 and PD1 related but contrary to renal cell carcinoma, kidney cells have only low expression of PD-L1 in proximal segments of tubules ^[17][86]. Studies on the animal model show that mice lacking CTLA-4 developed lethal lymphoproliferative disorders ^[18][87]. Animals depleted of PD1 spontaneously developed lupus-like proliferative arthritis and glomerulonephritis with predominant IgG3 deposition ^[19][20]. The mechanism of kidney injury following ICP inhibitors is mostly based on tubule-intestinal damages by cytotoxic cells. Nephrotoxicity as a result of PD-L1 inhibition may be the result of reactivation or formation of T cells, which led to T cell proliferation, cytotoxicity, cytokine releasing, complement-mediated inflammation and potentially autoimmune reaction ^[13][82]. The precise mechanisms of autoimmune side effects of immunotherapy remain unknown but may depend on polymorphisms of the molecules ^[14][83]. Characteristics of inflammatory kidney infiltration may be precisely described with immunohistochemical studies or flow cytometry. Biopsy studies show that acute tubulointerstitial nephritis induced by ICP inhibitors consists of mononuclear cell infiltration (CD3 + T cells, CD4 + T helper cells, CD68 + macrophages, CD163 + macrophages), plasma cells, eosinophils, vasculitis lesions, or sometimes deposits of immunoglobulins and complements. Non-specific granulomatous features were also described as well. Infiltration of CD8+ cytotoxic T cells, CD20+ B cells, and CD1c+ dendritic cells were less expressed ^[20][88]. The late stage of tubulointerstitial injury is fibrosis. Additionally, kidney biopsy flow cytometry may be performed to better characterize the immune response in the blood. Analysis of patients who developed kidney injury after nivolumab and ipilimumab showed highly proliferative CD4+ and CD8+ lymphocytes. Moreover, levels of T memory cells were also increased ^[21][89]. There are reports which suggest that proton pomp inhibitors therapy may predispose to AKI. ICPs may induce drug specific T cell, which recognizes drug antigen and leads to kidney injury ^[22][90].

2.4. Diagnosis of Nephrotoxicity

The clinical symptoms of immunotherapy driven AKI are not specific. Diagnosis of kidney injury is based on laboratory tests (creatine, urea, gasometry- metabolic acidosis, electrolytes) and measurement of urine output. Additional laboratory tests include morphology (eosinophilia) and urinalyses (infection, proteinuria, hematuria, pyuria, hematuria). The most common alteration is sterile pyuria and sub-nephrotic proteinuria. Patients with grade 2 AKI may be tested for glomerulonephritis. The anti-nuclear antibodies, complement C3, C4, anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane, hepatitis, HIV, immunoglobulins, and protein electrophoresis should be considered. USG and USG doppler should also be considered to exclude obstruction and clotting. Differential diagnosis of AKI includes prerenal (hypovolemia (diuretics, infection, diarrhea), cardiotoxicity (cardiomyopathy, heart failure, pulmonary hypertension, hypo and hypertension)), renal (drugs (CT contrast, proton-pump inhibitors, nonsteroidal anti-inflammatory drugs, antibiotics) and postrenal kidney injury (obstructive (stones, benign prostatic hyperplasia). Kidney biopsy should be considered to exclude other reasons of AKI than irAE to determine a need for steroids, because administration of high dose steroids in patients treated with immunotherapy may decrease effects of treatment ^[15][84]. Biopsy is recommended since grade 2 toxicity. The material should be stained with haematoxilin and eosin, periodic acid–Schiff and Masson’s trichrome. Cases confirmed by biopsy show that the most common type of nephrotoxicity is interstitial nephritis with damage to tubules and less frequently glomerulopathies. The most common histopathological findings were edema, interstitial inflammation and tubulitis ^[20][88]. The ICPI-associated AKI may be defined according to Common Terminology Criteria for Adverse Events (CTCAE), which depends on changes in creatinine according to upper limit of normal or baseline. AKI has 4 levels (grade 1 to 4). Grade 1 irAE means that creatinine level increases between upper limit of normal (ULN) to 1.5 times above ULN. Grade 2 AKI is defined as creatinine elevation 1.5–3 times above the baseline or ULN. In grade 3 AKI, creatine is 3 times above the baseline or 3–6 times above ULN. The life-threatening grade 4 kidney injury occurs when creatinine is 6 times above the ULN. Hospitalization is recommended for patients with grade 3 toxicity.

2.5. Treatment

Steroids are basic drugs used in treatment of irAE. Prednisone (0.5–1 mg/kg/day) and methyl prednisone (1–2 mg/kg/day) are recommended in treatment of ICPs-related toxicity, but in some circumstances hydrocortisone also was used. According to case reports, treatment with steroids treatment often led to partial or complete remissions of disease, but relapses were also reported. Remission of disease is defined as an improvement of creatinine level (complete recovery- creatinine less than 0.35 mg/dL above the baseline, partial recovery- creatinine between baseline + 0.35 mg/dL and less than 2 times of baseline) ^[12][81]. Corticosteroids reduce the risk of kidney fibrosis, which may be related to chronic renal failure. Due to the risk of adrenal insufficiency, steroid withdrawal should be gradual. If steroids have been taken due to grade 2 toxicity, then steroid withdrawal should last over 2–4 weeks. In case of grade 3 and 4 toxicity, steroid withdrawal should last over 4 weeks. In case of insufficiency of steroids, other drugs should be considered to manage the toxicity such as azathioprine, cyclophosphamide, cyclosporine, infliximab and mycophenolate (NCCN). Plasmapheresis may be performed as well.