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Oncology
The onco-nephrology field has acquired a relevant role in internal medicine due to the growing number of cases of renal dysfunction that have been observed in cancer patients. This clinical complication can be induced by the tumor itself (for example, due to obstructive phenomena affecting the excretory tract or by neoplastic dissemination) or by chemotherapy, as it is potentially nephrotoxic.
- acute kidney injury
- chemotherapeutic drugs
- chronic kidney disease
1. The Relationship between Glomerular Disease and Cancer
Albuminuria represents an early biomarker of kidney dysfunction, and its presence is related to increased all-causes mortality [31,32]. Moreover, the rise of this biomarker is indicative not only of endothelial dysfunction, as several studies have highlighted its increase also in some types of cancer (such as lung, kidney, breast, colon/rectal and non-Hodgkin’s lymphoma) [33,34,35,36]. This data were confirmed by an interesting study conducted on 5425 subjects without diabetes mellitus or without previous history of neoplasia that examined the possible association between albuminuria and cancer incidence. This study showed that an enhanced urinary albumin-to-creatinine ratio (ACR) is directly correlated with cancer incidence [37]. In fact, an elevated ACR is associated with graft versus host disease (GVHD), bacteremia, arterial hypertension (AH), and in CKD patients, with progression of renal dysfunction. On the contrary, this biomarker is not predictive of AKI [38].
The degree of albuminuria seems to reflect the severity of the neoplastic pathology. In fact, it has been shown that patients with metastases or more extensive tumor mass had higher albuminuria levels [35,39]. Elevated albuminuria is associated with an increased cancer incidence, even after an adjustment for the traditional risk factors (such as gender, age, smoking, and body mass index—BMI).
Sometimes, glomerular pathologies can be a paraneoplastic manifestation, and, in particular, membranous nephropathy (MN) is the most frequent glomerular disease associated with cancer [40]. In the 1960s, the link between MN and cancer was described for the first time [41], and subsequently, this association has been repeatedly reported in textbooks [42]. A study by Lefaucheur et al. demonstrated, in both sexes, a higher cancer incidence in MN patients compared to the general population [43]. In detail, the cancer incidence increased in relation to age and to the number of inflammatory cells infiltrating the glomeruli, evaluated through the biopsy. The best cut-off parameter to distinguish cases of cancer-related MN was a number of inflammatory cells infiltrating the glomeruli equal to or greater than eight. This criterion allows a diagnosis of cancer-related MN with a specificity of 75% and a sensitivity of 92% [43].
Furthermore, in the differential diagnosis with the primary MN, it is useful to consider that subepithelial deposits of IgG4, detected by immunofluorescence, are more frequent in idiopathic MN, while those IgG1 and IgG2 are often present in cancer-associated MN [44]. However, many patients with malignancies and proteinuria do not undergo renal biopsy.
About 80% of MN cases have no apparent secondary causes, resulting in their classification as “idiopathic” or “primary” forms [45].
The identification of autoantibodies associated with primary MN began with the discovery of anti-phospholipase A2 receptor (Anti-PLA2R) antibodies, namely the antibodies to podocyte transmembrane glycoprotein M-type phospholipase A2 receptor, in 2009 and of anti-thrombospondin type-1 domain-containing 7A (THSDA7A) antibodies, namely the antibodies against thrombospondin type 1 domain-containing 7A, in 2014 [46]. Based on the current classification, MN in the presence of active cancer is diagnosed as a secondary form and should be negative for anti-PLA2R autoantibodies. Conversely, patients affected by MN associated with positivity for anti-PLA2R antibodies do not require the assessment for secondary causes [47].
However, in 2017 Radice et al. detected anti-PLA2R autoantibodies in 70% of primary MN patients and 28% of secondary MN patients. Whether these cases represented a true secondary MN or even a primary MN associated with concomitant secondary disease is not known. The authors concluded that the anti-PLA2R positivity in a patient with MN should not be a sufficient condition for abstaining from the research of a secondary cause, especially in patients with risk factors for malignancy [48].
Moreover, recent studies have shown that anti-THSD7A antibodies may be associated with cancer-related MN [48]. These findings highlighted the importance of age-appropriate cancer screening, even in patients with positive anti-PLA2R autoantibodies and with presumed primary MN [49].
The main clinical criteria for defining the causal relationship between MN and cancer should include the following:
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the simultaneous or close diagnosis of both the malignancy and the MN;
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the remission of proteinuria in presence of successful cancer treatment and its recurrence in case of the neoplasia relapse [50].
Nonetheless, the treatment should be focused on the fact that patients affected by cancer-associated MN are characterized by a worse prognosis compared to idiopathic MN patients [51].
Moreover, other glomerulopathies have been related to malignancies. In particular, minimal change glomerulonephritis and focal segmental glomerulosclerosis have been frequently associated with solid tumors like lung cancer, colorectal cancer, renal cell carcinoma (RCC) and thymoma, while more rarely with ovarian, breast, bladder and pancreatic cancers [45].
Rapidly progressive glomerulonephritis (RPG) or crescentic glomerulonephritis, as well as membranoproliferative glomerulonephritis (MPG), were reported in association with RCC, lung and gastric cancer [52].
MPG is also observed in hematological neoplastic pathologies [53], as in the case of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). PGNMID is a form of monoclonal gammopathy of renal significance (MGRS), namely a group of disorders that, by definition, do not meet the diagnostic criteria for MM or lymphoproliferative disease. In PGNMID, a monoclonal immunoglobulin secreted by a nonmalignant B-cell or a plasma cell clone causes renal dysfunction [2].
Finally, immunoglobulin A nephropathy is associated with oral mucosa and nasopharyngeal/respiratory tract cancer, colorectal neoplasia, RCC and cutaneous T-cell lymphoma [54,55].
2. Chemotherapeutic Drugs and Renal Insufficiency
AKI, with a prerenal, intrinsic or postrenal genesis, is the most common nephrological manifestation in cancer patients [56]. The development of AKI in these patients represents a noteworthy event that increases their morbidity and mortality [10]. Furthermore, AKI can alter the bioavailability and/or the safety profile of many chemotherapies. It can enhance the risk of toxic effects or it can lead to suboptimal treatments due to the need to reduce the dose or to use alternative therapeutic schemes [57].
Although nephrotoxicity is a major side effect of many chemotherapeutic drugs, not all patients treated with these agents develop AKI [58].
The causes of kidney failure are related to various factors, including the type of neoplastic disorder, the pharmacological treatment [59] or patient-specific parameters [60]. In particular, in older patients with reduced GFR, the nephrotoxicity is more common [61].
In addition, sex can impact on side effects related to pharmacotherapy, mainly through variables such as body weight and/or body composition. On average, men have a higher BMI and a wider body surface area compared to women. These differences in body size result in larger distribution volumes and faster clearance of most drugs. A greater amount of body fat may increase distribution volumes for lipophilic therapeutic agents [62].
Chemotherapy can cause AKI with several mechanisms. In addition to the conventional chemotherapeutic agents responsible for acute tubular toxicity, acute tubulointerstitial nephritis (ATIN) and glomerular injuries, the new lines of treatment, including immunotherapies and targeted cancer therapies, have increased the occurrence of kidney immune-mediated injury (Table 1) [2].
Among conventional chemotherapeutic drugs, cisplatin deserves a special mention. This drug is the most commonly used in cancer treatment and it can induce nephrotoxic side effects by tubular damage [63]. In detail, the nephrotoxic effect is related to its dosage, and the kidney injury induced by cisplatin seems to be reversible after its discontinuation [64]. The tubular damage seems to be mediated by a membrane transported, called organic cation transporter 2 (OCT2). OCT2 exerts its action through cisplatin transport into renal tubular epithelial cells [65]. Consequently, OCT2 is responsible for the cellular uptake of cisplatin and, thus, for its intracellular accumulation. In animal models, the deletion of Oct1 and Oct2 genes alters the urinary cisplatin excretion without affecting its plasma levels. Furthermore, carrier patients of the Oct2 polymorphism seem to have a lower risk of developing cisplatin nephrotoxicity [66]. AKI, present in 20–30% of patients’ cisplatin exposed, is usually non-oliguric. Moreover, urinalysis may detect glycosuria and a low-grade proteinuria. AKI-related cisplatin may also be associated with tubulopathies, such as Fanconi-like syndrome, hypomagnesemia, salt-loosing syndrome and distal renal tubular acidosis [67]. Tubular dysfunction is characterized by electrolyte disorders such as hyponatremia, hypokalemia and hypomagnesemia. Other reported manifestations are thrombotic microangiopathy (TMA) and anemia due to the deficit of erythropoietin [68].
The novel chemotherapeutic agents, namely vascular endothelial grow factor (VEGF) inhibitors (such as bevacizumab and sunitinib) or antimetabolites (such as gemcitabine) might cause kidney injury due to the development of TMA.
In particular, VEGF-target treatment can induce proteinuria and AH. Therefore, kidney side effects related to the use of this pharmacological treatment are due to the production of VEGF by the renal visceral epithelial cells [69]. Moreover, VEGF binds receptors sited on glomerular podocytes, mesangium and peritubular capillaries. About 80% of cancer patients treated with this chemotherapeutic drug develop AH [70]. Therefore the blood pressure monitoring plays a pivotal role in the clinical management of these patients because it represents an early clinical biomarker of renal dysfunction.
Another class of novel chemotherapeutic drugs is the immune checkpoint inhibitors (ICPIs) that might induce interstitial nephritis [63]. In detail, ICPIs, such as nivolumab and pembrolizumab, stimulate T-cells to kill cancer cells, counteracting the bind of dendritic cells with cytotoxic T-lymphocyte-associated protein (CTLA)-4 and the bind of tumor antigen ligand with the programmed death (PD)-1 receptors [71]. The incidence of renal immune-related damage induced by ICPIs ranges from 2% to 5%. In fact, these drugs not only can cause acute interstitial nephritis but also glomerular disease. The most frequently reported glomerular lesions related to the ICPIs treatment are the pauci-immune GN, the podocytopathies and the C3 GN [72].
Another innovative use of immunotherapy to treat several forms of cancers, named CAR T-cell therapy, is based on the collection of patients’ T cells in order to genetically modify them and to permit the expression of antigen receptors, normally not present [73]. The result of this new technique is the creation of a chimeric molecule characterized by T cells with their specific antibodies [74]. This therapy is associated with a storm cytokine and with an AKI induced by reduced renal perfusion related to hypotension [75].
Additionally, in cancer patients, non-steroidal anti-inflammatory drugs (NSAIDs), organo-iodinated contrast and other potentially nephrotoxic therapeutic agents (i.e., aminoglycosides, vancomycin or acyclovir), whenever possible, should be avoided to reduce the AKI risk [76].
Table 1. Main studies on chemotherapeutic drugs and renal insufficiency.
| Type of the Study |
Reference | Year | Methods | Main Findings | Conclusions |
|---|---|---|---|---|---|
| Human study |
Stewart et al. [68] |
1997 | Evaluation of factors affecting cisplatin nephrotoxicity. | Negative association between cisplatin nephrotoxicity and serum albumin levels, potassium, body surface area, and the use of vinca—alcaloid. Positive association with use of metoclopramide. |
Serum albumin, metoclopramide and phenytoin affected the nephrotoxicity by altering cisplatin uptake into the kidney. |
| Robinson et al. [70] |
2010 | Time evaluation for AH and proteinuria onset in patients receiving cediranib (a VEGF receptor inhibitor). | Cediranib induced a rapid but variable rise in blood pressure and of proteinuria. | Understanding the mechanisms that regulate VEGF inhibitor-induced will permit to manage vascular tone and endothelial health. | |
| Animal study |
Ciarimboli et al. [65] |
2005 | Investigation of the interaction of cisplatin with hOCT2 in kidney or hOCT1 in liver through a florescent cation. | Uptake of cisplatin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. | A combined administration of cis-platin with other substrates that compete for hOCT2 offers an effective therapeutic option to decrease its nephrotoxicity. |
| Filipski et al. [66] |
2009 | Comparison of cisplatin nephrotoxicity in groups of OCT1/OCT2-deficient mice. | Oct2 polymorphism seems to give a lower risk of developing cisplatin nephrotoxicity. | Critical relevance of Oct2 in the clinical and therapeutic management of cisplatin-treated patients. |
Abbreviations: OCT, organic cation transporter; VEGF, vascular endothelial grow factor.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15082254
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