The differential diagnosis of non-proximal tubulopathies (thick ascending loop of Henle and convoluted distal tubule) is closely related to serum potassium concentrations, acid-base status, and blood pressure (1–4). The patient’s biochemical phenotype may exhibit any of the following patterns (see Table 1 ) (3, 4):

Therefore, the examination of urinary concentrations of potassium, chloride, magnesium, and calcium is extremely useful in the differential diagnosis of suspected tubulopathy. We present a series of 4 cases with association of tubulopathies directly related to chemotherapy.

Nephrotoxicity can be defined as any kidney damage caused directly or indirectly by medications. Some examples of commonly associated drugs include nonsteroidal anti-inflammatory drugs, antibiotics, and chemotherapeutic agents (5, 6). Epidemiological studies show that nephrotoxicity is the third most common cause of acute kidney injury (AKI), which has worsened in recent decades due to the more frequent use of medications with renal toxicity, studies indicate a frequency of up to 20% of all patients with AKI (5).

In the present case series report, there were several biochemical data to consider: persistent electrolyte and acid-base imbalances related to urinary loss of potassium and magnesium during subsequent evaluations, coupled with a history of platinum-based chemotherapy. This strongly indicates an acquired tubulopathy. It is crucial to confirm the absence of recent use of diuretics, proton pump inhibitors (PPI), immunosuppressants (e.g., tacrolimus, cyclosporine), antacids, laxatives, anti-EGFR/anti-VEGFR chemotherapy (e.g., cetuximab, pazopanib), or any dietary supplement such as herbal medicine, which may explain renal and/or extrarenal losses of potassium and magnesium. Tubular disorders are frequently underdiagnosed, probably due to the relative absence of specific symptoms that may be related to tubular dysfunction. Additionally, fatigue and mild muscle weakness can easily be associated with the progression of cancer or the administration of any chemotherapy. For this reason, clinician rarely requests a venous blood gas analysis or a urinary electrolyte analysis in this context. Another contributing factor to the low rate of tubular disorder diagnosis is that electrolyte abnormalities are usually managed with intravenous replacement therapy to achieve the desired electrolyte levels, without conducting a concise evaluation to determine whether the etiology is of extrarenal origin or due to a potential tubular dysfunction. This behavior can lead to high morbidity in chronically debilitated patients.

Cancer is associated with multiple fluid and electrolyte disorders. Its appearance can be related to the frequent polypharmacy: PPI, antihypertensives, diuretics, analgesics, and, of course, chemotherapy. In addition, they are frequent users of parenteral nutrition, which can cause serious potassium, phosphorous, and magnesium disorders in the context of refeeding syndrome (7) and may undergo intestinal surgeries that promote malabsorption or severe decrease in food intake, also other serious complications such as tumor lysis syndrome directly affect renal function and the body distribution of electrolytes (8).

Platinum-based drugs have as an important limitation the well-known nephrotoxicity, especially acute kidney injury and electrolyte disorders (9). The damage is mainly located in the proximal tubule (S3 portion), distal duct, and collecting duct (9). The most studied electrolyte alterations include hyponatremia (59%) and hypomagnesemia (27%) (10, 11).

Cisplatin causes dose-dependent nephrotoxicity, the tubular compartment being the most frequently affected. Within the cell, cisplatin behaves as a positively charged electrophilic molecule with high affinity for DNA, resulting in the formation of cross-links between two adjacent guanine residues, which hinders cellular synthesis and replication (12, 13). This can explain structural and functional tubular alterations leading to urinary loss of potassium, magnesium, and calcium, whose abnormalities have a prognostic effect on hospitalized patients, regardless of the cause.

Collins et al., analyzed the electronic reports of more than 911,000 patients, finding a U-shaped association between serum potassium concentrations and mortality, being cumulative for each 0.1 mEq/L change in potassium < 4 mEq/L and ≥ 5 mEq/L; the risk was higher in patients ≥ 65 years, patients with heart failure, chronic kidney disease or diabetes (14). Among patients with chronic kidney disease, where the effect of dyskalemia on mortality has been most strongly investigated, it was reported in a meta-analysis that included 11 clinical studies and 57,234 patients that a serum potassium concentration < 4 mEq/L was associated with a higher risk of all-cause mortality (HR= 1.18, 95% CI: 1.11 – 1.26), and a concentration < 3.5 mEq/L increased the risk of all-cause mortality by 105%(6). Even relatively “off-risk” serum potassium concentrations (e.g., 3.4 mEq/L) may confer an increased risk of cardiovascular complications that should be carefully considered (15).

Magnesium is another relevant cation in cellular physiology with a prognosis impact. The prevalence of hypomagnesemia is 20% in hospitalized patients, especially in patients with oncological and hematological disorders, and is related to longer hospital stay (16), although the incidence approaches 50% in patients in the ICU (17) with higher mortality compared to patients with normomagnesemia (35% vs 12%, p = 0.01) (18). Extreme values of hypomagnesemia (< 0.3 mmol/L or < 0.75 mg/dL) in hospitalized patients were evaluated by Cheminet et al., finding a prevalence of less than 0.5% (19). Of the 119 patients detected, 84% had a gastrointestinal disorder and 42% had a history of cancer. The most prescribed hypomagnesemia-related drugs were PPIs (70%), immunosuppressants (22%), platinum-based chemotherapy (17%), and diuretics (19%); the association of hypocalcemia (77%) and hypokalemia (51%) was significative (19).

Gitelman and Bartter syndromes are rare inherited tubulopathies that cause hypokalemia, metabolic alkalosis, and hypomagnesemia. Gitelman syndrome is caused by inactivating mutations in the solute transporter family 12-member 3 (SLC12A3) gen; a wide number of these mutations have been reported including nonsense, cut-and-splice site and missense mutations (20). Regarding Bartter syndrome, it is characterized by mutations in the thick ascending limb of Henle’s loop, either in NKCC2, ROMK, ClC-Ka/b, Barttin protein, CaSR, or MAGE-D2 (21) (see Table 1 ). An important characteristic in the differential diagnosis of Bartter phenotype compared to Gitelman is hypercalciuria; currently, the induction test with thiazides is no longer recommended (22). However, a genetic test is a gold standard, especially due to the overlap of biochemical phenotypes (e.g.: Gitelman and Bartter type 3). Unfortunately, genetic testing couldn’t be conducted in our institution to determine the coexistence of mutations in the co-transporters. However, the absence of electrolyte and acid-base disorders before the initiation of chemotherapy, along with the temporal association with platinum-based chemotherapy, makes the nephrotoxic effect the most plausible causal factor.

The functional tubular prognosis varies; Panichpisal et al. described the case of a patient with a 20-year follow-up who developed severe hypokalemia with metabolic alkalosis and hypocalciuria related to cisplatin administration. Although the genetic mutation status of the NCC was not determined, it is feasible that the association was causal. The same study documented 12 cases with Gitelman-like syndrome, all with persistent electrolyte abnormalities for up to 6 years (23). Tubular damage and electrolyte abnormalities may be permanent in some patients (24, 25), probably related to the toxic effect on the gene that encodes the sodium/chloride cotransporter and apoptosis of the tubular epithelial cells of the distal segment (23). To date, it is not known whether there are genetic polymorphisms associated with the risk of developing platinum-associated tubulopathy.

Despite the increasing prevalence and incidence of cancer and, therefore, the prescription of new and classic chemotherapy, the diagnosis of electrolyte disorders and especially tubular dysfunction is often an underestimated complication. Its recognition will allow a multidisciplinary management that includes oncologists, nutritionists, geriatricians, and nephrologists for an accurate assessment that improves the long-term results of patients. The relevance of diagnosing these disorders can enhance integrative management, some of which have an ominous prognosis. This holds even if they are in palliative care, as it provides relief for symptoms that can deteriorate the patient’s quality of life. Additionally, this is one of the first reports to our knowledge of Bartter phenotype tubulopathy associated with platinum-based chemotherapy.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

MA-S: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. DD: Writing – original draft, Writing – review & editing. VY: Writing – original draft, Writing – review & editing. FM: Writing – original draft, Writing – review & editing. VU: Writing – original draft, Writing – review & editing. FV: Writing – original draft, Writing – review & editing. BY: Writing – original draft, Writing – review & editing.