Introduction

Acid-base disorders (ABDs) are frequently present in hospitalized patients and are often a manifestation of systemic disorders. Analysis of ABDs must be performed in a standardized manner. Calculating the serum anion gap (AG) is the first step to differentiate between ABDs [1–5]. The AG must be corrected for serum albumin levels, and it must be considered that several factors (e.g., paraproteinemia, lithium, and bromide intoxication; hypercalcemia; hypermagnesemia; syndrome of inappropriate antidiuretic hormone secretion (SIADH); severe hyperphosphatemia), as well as the laboratory measurement method used [1], could interfere with the calculation. Clinical information, including medical history and laboratory data, must be obtained from the patient, especially in differentiating possible mixed acid-base disturbances. The urine AG (UAG) is a useful tool for differentiating ABDs, especially in patients with metabolic acidosis with normal serum AG. UAG can be used as a parameter for acid excretion by the kidney: ([urine sodium ions (Na+)] + [urine potassium ions (K+)]) − [urine chloride (Cl−)]), normal range −10 to +10 mmol/L). A negative UAG (average ≥15 mmol/l) indicates an increased ammonium (NH4 +) excretion (e.g., diarrhea) in metabolic acidosis with normal serum AG. In such cases, positive UAG (>20 mmol/l) indicates a low urinary NH4 + excretion [altered distal urinary acidification, e.g., altered renal tubular acidosis (RTA)]. It should be noted that UAG is influenced by exogenous anions (ketonuria, penicillins, and high doses of acetylsalicylic acid). In patients with positive UAG, determining urine pH could help distinguish between the different types of RTA: type 1 is characterized by a fixed urine pH of >5.5 and decreased or normal serum K+ levels; type 2 by urine pH levels <5.5; and type 4 commonly by hyperkalemia and urine pH levels <5.5 (Fig. 1).

Fig. 1
figure 1

Standardized approach for analyzing disturbances in acid-base physiology. AG anion gap, HCO 3 − bicarbonate, K + potassium ions, Na + sodium ions, Cl − chloride ions, BUN blood urea nitrogen, ABD acid-base disorders, GI gastrointestinal tract, EABV effective arterial blood volume, CDA chloride depletion alkalosis, RTA renal tubular acidosis, fK +e fractional K+ excretion, N normal, I increased, D decreased

Full size image

The AG can be calculated using the simplified formula [Na+] − ([Cl−] + [bicarbonate (HCO3 −)]) (normal range, 3–11 mEq/L), measured with ion-selective electrodes, up to 18 mEq/L in newborns; if serum K+ is included in AG measurement, normal range is ~4 mEq/L higher [1, 6–9]. It is noteworthy that the AG depends on plasma albumin levels, and hypoalbuminemia is a common finding in hospitalized patients. A decrease of 1.0 g/dl (from 4.5 g/dl) of albumin concentration decreases the AG by roughly 2.5 mEq/L [10–12]. Increased AG indicates acid overload caused by ketoacidosis, lactic acidosis, uremia, salicylates, methanol, or ethylene glycol intoxication. If there is an increased AG, the osmolar gap (OG), defined as the difference between measured and calculated serum osmolality, should be calculated to detect methanol or ethylene glycol intoxication, which will result in an increased OG ([2 Na + glucose]/18) + (blood urea nitrogen [BUN/2.81]); correction factors for calculating the OG are only required in if nonstandard units (i.e., mg/dl) are used. However, simple alcohol (ethanol) intoxication with lactate acidosis can resemble changes [13]. The normal OG range is wide in children (from + 8.9 to −13.5 mOsm/L), but intoxication must be considered when the OG is positive (>10 mOsm) [14]. Furthermore, in high-AG metabolic acidosis, the change in AG should correlate with the change in serum HCO3 − concentration. A further hint to the presence of mixed metabolic ABD is the relationship between the increase in AG (ΔAG) and decrease in HCO3 − (ΔHCO3). It has been suggested that mixed ABD should be considered if the ΔAG/ΔHCO3 − ratio is <0.8 or >1.2 [15–17]. Additionally, calculating the UAG could be useful to differentiate ABDs. A negative UAG indicates increased NH4 + excretion (e.g., diarrhea) of the kidney. In metabolic acidosis without elevated AG, positive UAG is associated with low urinary NH4 + (e.g., RTA) [18–20].

Drug-induced ABDs (DABDs) are very common in everyday clinical practice. Renal clearance of the drug and/or its metabolite(s) is an important mechanism of drug elimination. Renal drug clearance can be reduced in patients with acute and chronic kidney injury, and the drug and/or its metabolites can cause tubular necrosis or interstitial nephritis. In this review, we focus on direct drug-induced effects on the proximal tubule cell, the thick ascending limb cell, the collecting duct principal cell and the collecting duct intercalated cell. Mechanisms of acute kidney failure due to tubular necrosis and interstitial nephritis caused by antibiotics are beyond the scope of this review and are reviewed elsewhere [21, 22]. First, we give a short summary of the pathophysiology of the different disorders of acid-base homeostasis based on the different findings in analysis of arterial or, if not available, venous blood gases, which is usually the first diagnostic step in everyday clinical practice (Fig. 1). Second, we go into detail about the selected drugs and their potential to cause ABDs, especially in children.

Metabolic acidosis

Increased acid production (normochloremic metabolic acidosis with elevated anion gap)

Pathophysiology

In metabolic acidosis with increased acid production, the arterial partial pressure of carbon dioxide (pCO2) is appropriately decreased because of respiratory compensation. Furthermore, increased acid production leads to a decrease in HCO3. In patients without appropriately decreased pCO2, an additional respiratory acidosis must be considered. If pCO2 is lower as expected, a further respiratory alkalosis might be present. Next step, AG must be calculated to detect addition of acids (Fig. 1) and must be adjusted for serum albumin levels. In patients with otherwise (e.g., lactic acidosis, uremia, or ketoacidosis), unexplained high-AG metabolic acidosis, the serum OG should be calculated. In patients with elevated AG and high OG intoxication of methanol, ethylene glycol or ingestion of propylene-glycol-containing drugs must be considered. However, it should be noted that ethanol itself leads to an elevated OG without resulting necessarily in metabolic acidosis. Furthermore, severe ethanol ingestion might cause ketoacidosis. Other considerations in regard to normochloremic metabolic acidosis with elevated AG are drugs such as linezolid, propofol infusion syndrome (PRIS), metformin-associated lactic acidosis (MALA), and—rarely—penicillins (Table 1).

Table 1 Acid-base disturbances caused by drugs
Full size table

Linezolid

Linezolid is the first member of the oxazolidinone drug family. The efficacy of linezolid in children is similar to those of vancomycin and cefadroxil. The most common side effects are diarrhea, nausea, vomiting, and thrombocytopenia. Linezolid is used in children to treat infections, mainly those caused by resistant Gram-positive organisms or drug-resistant tuberculosis [23–26]. Linezolid can cause lactic acidosis in a small proportion of patients [27]. The risk for linezolid-induced lactic acidosis is associated with duration of therapy [28], but early linezolid-induced lactic acidosis has also been reported [29]. Some studies using cell-culture experiments have suggested that linezolid toxicity is caused by inhibition of mitochondrial protein synthesis [30–32]. There is some evidence that polymorphisms in the mitochondrial 16S ribosomal RNA (rRNA) (e.g., A1036G) may contribute to severe linezolid-associated lactic acidosis in adults [33, 34]. The prognosis of linezolid-induced lactic acidosis is unclear; in some cases, the outcome was excellent, but there are also some reports of patients with fatal outcome [28, 35].

Propofol infusion syndrome

Propofol is a short-acting intravenously administered anesthetic agent widely used in both adults and children for sedation or anesthesia [36, 37]. PRIS is a rare complication, which is associated with high doses (>4 mg/kg/h) and long-term use (>48 h) of propofol, concomitant steroid therapy, high consumption of vasopressors, and patient age <18 years [38, 39]. The incidence of PRIS is ~1 % in adult patients [40]. There are no valid data for children, but propofol use in children in pediatric intensive care units (PICUs) appeared to be safe when doses did not exceed 4 mg/kg/h and use was restricted to <24 h [41, 42]. Patients should be monitored closely for the presence of elevated triglycerides and lactic acidosis [43]. PRIS leads to characteristic symptoms and clinical signs, including hepatomegaly, severe metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, dyslipidemia, and progressive myocardial failure with dysrhythmias [44].

Most patients with PRIS present with severe metabolic acidosis with elevated lactate levels and metabolic alkalosis. Elevated lactate levels in patients receiving propofol infusion, which cannot be explained otherwise, might be an early marker of PRIS [45]. There is experimental evidence that in states of increased metabolic demand with reduced glycogen reserves and increased fatty-acid oxidation, propofol affects mitochondrial fatty-acid oxidation, leading to PRIS, and inhibits the level of mitochondrial oxidative phosphorylation and lipid metabolism [46, 47].

Drugs containing glycols

Propylene glycol (PG) is a water-soluble alcohol that serves as a solvent in a variety of intravenously administered drugs. Physicochemically, it is similar to ethylene glycol but less toxic [48]. PG toxicity is typically characterized by acidosis, increased AG and/or OG, hypernatremia, or hepatic dysfunction, with increase in direct serum bilirubin and acute kidney injury [49]. There is a variety of drugs containing PG (Table 2). For example, lorazepam and diazepam IV are widely used drugs containing PG [50]. The incidence of PG toxicity is still unknown. Severity of PG toxicity ranges from common metabolic abnormalities to infrequent cases of clinical deterioration with systemic inflammatory response syndrome (SIRS) [51]. High-dose application of benzodiazepine in patients with impaired kidney function appears to be a risk factor for PG toxicity [52]. The incidence of PG toxicity in children is unknown. Critically ill neonates receiving medications by continuous infusions are at higher risk of being exposed to PG. However, a median PG exposure of 34 mg/kg per 24 h seems to be well tolerated [53–55]. Treatment of toxicity includes termination of any PG-containing medication and initiation of hemodialysis in severe cases to effectively remove PG [49]. Although PG is metabolized by alcohol dehydrogenase (ADH), such as ethanol, methanol, and ethylene glycol, there is no evidence for fomepizole as an inhibitor of ADH in PG toxicity [56].

Table 2 Frequently used intravenously administered drugs containing varying amounts of propylene glycol
Full size table

Biguanide

The biguanide hypoglycemic agents phenformin and metformin became available for clinical use in the 1950s, and metformin is still considered the first choice for treatment of type 2 diabetes (T2D). In December 2000, the US Food and Drug Administration (FDA) approved the use of metformin for children with T2D. Studies have not been conducted in children younger than 10 years of age [57, 58]. MALA is a possible side effect, but it seems to be a rare event. Recently, a Cochrane Review demonstrated a low incidence for MALA in adult patients with type 2 diabetes receiving metformin in the context of clinical studies. Poisson statistics reported 5.1 cases per 100,000 patient-years [59, 60]. There is some evidence that high doses of metformin lead to MALA, especially in patients with impaired kidney function [61, 62]. No large, prospective, randomized trials of metformin have been carried out in children. In 2000, a multicenter case series in a pediatric patient cohort reported no evidence of lactic acidosis (median dose of metformin was 1,700 mg) [63]. The pathophysiology of MALA is complex and not fully understood. Studies on rat liver mitochondria hypothesized that metformin inhibits mitochondrial oxidation, leading to inhibition of respiratory chain function [64, 65]. In addition, metformin inhibits hepatic gluconeogenesis, possibly via a decrease in the cytosolic adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio, resulting in reduced utilization of lactate [66]. In critically ill patients with MALA and severe metabolic acidosis (pH <7.1), hemodialysis should be considered [67].

Penicillins

Rarely, penicillins may cause a disturbance in the gamma glutamyl cycle, with decreased 5-oxoproline and pyroglutamate, analogous to acetaminophen, causing metabolic acidosis with elevated AG [68–70].

Decreased renal acid excretion (hyperchloremic metabolic acidosis with normal anion gap)

Pathophysiology

Hyperchloremic metabolic acidosis with normal AG could be caused by loss of HCO3 − via the gastrointestinal (GI) tract or hydrochloric acid ingestion. Furthermore, an altered distal urinary acidification of the kidney (RTA type 1) or impairment of HCO3 − reabsorption in the proximal tubule, which results in decreased renal HCO3 − threshold (RTA type 2), can occur. Other common causes for hyperchloremic metabolic acidosis with normal AG include mineralocorticoid deficiency or a reduced NH4 + excretion in the context of impaired glomerular filtration rate (GFR). Rarely, decreased NH4 + excretion causing disturbances of aminogenesis (glutamine metabolism) might lead to hyperchloremic metabolic acidosis with normal AG.

In patients with hyperchloremic metabolic acidosis with normal serum AG, analyses of the urine serum gap can help distinguish between gastrointestinal loss of HCO3 − and the presence of altered distal urinary acidification or HCO3 − wasting (e.g., RTA) (Fig. 1). Aldosterone deficiency, antagonisms, or resistance might lead to loss of function of the epithelial sodium channel (ENaC) (Fig. 3). ENaC inhibition might result in hyperkalemia, which raises intracellular pH and could interfere with enzymes involved in aminogenesis, leading to decreased NH4 + excretion. Reduced NH4 + excretion might lead to impaired hydeogen ion (H+) secretion, with hyperkalemic RTA (type 4 distal RTA) [71, 72].

Angiotensin-converting enzyme (ACE) and angiotensin II receptor antagonists (AT2RA) decrease Na+ reabsorption and could induce hyperkalemic RTA via the aldosterone axis. Furthermore, drugs interfering with Na+- channel function can cause hyperkalemic RTA due to decreased distal H+ secretion.

Inhibition of the aldosterone axis (angiotensin inhibition and heparin-induced selective aldosterone deficiency)

Aldosterone deficiency or antagonism with renal tubular acidosis type 4 (mineralocorticoid deficiency)

Renin inhibition can be triggered by simultaneous use of cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs; NSAIDs), leading to hyperkalemia and metabolic hyperchloremic acidosis [73, 74]. Heparin impairs aldosterone synthesis as a result of direct toxicity to the zona glomerulosa, with inhibition of aldosterone synthase (adrenal 18-hydroxylase). Additionally, heparin can decrease the number and affinity of angiotensin II receptors in the adrenal zona glomerulosa [75, 76]. There is also an effect of low-molecular-weight heparin on K+ levels [77, 78]. ACE inhibitors and AT2RA can cause hyperkalemia and acidosis, particularly in patients with advanced renal insufficiency [79–81]. The risk of hyperkalemia is increased by simultaneous administration of ACE inhibitors and heparin [82].

Secondary to drugs that interfere with Na+-channel function

K+-sparing diuretics and mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone, amiloride, triamterene) can lead to moderate hyperchloremic metabolic acidosis. This is the result of inhibition of Na+-reabsorbing ENaC in the collecting duct, which impairs creation of the lumen-negative voltage gradient and inhibits renal electrogenic distal H+ secretion into the tubular lumen . In addition, the impaired K+ secretion by principal cells results in an increase in serum K+ levels [83–85]. Coexisting hyperkalemia impairs renal ammoniagenesis [86], tand These two effects reduce distal H+ secretion.

Figure 2 demonstrates how drug interplay affects proximal tubule cells and the thick ascending limb of the loop of Henle. In this depiction, gentamicin enters the proximal tubule cell via the megalin–cubilin system. In the thick ascending, limb aminoglycosides can stimulate the calcium-sensing receptor (CaSR). As a consequence, the function of mitochondrial ribosomes and conversion of ADP to ATP can be disturbed and the Na+/K+-ATPase pump is inhibited. CaSR activation in the thick ascending limb cell could impair electrolyte transport via inhibition of four different pathways: the kidney-specific Na+/K+/Cl− symporter (NKCC2), renal outer medullary potassium channel (ROMK), and Na+/K+-ATPase and/or paracellular diffusion. This results in increased urinary excretion of Na+, K+, magnesium (Mg2+) and Ca2+. Tetracyclines could enter the proximal tubule cell through apical or basolateral organic anion transporters (OATs) and inhibit the Na+/K+-ATPase pump.

Fig. 2
figure 2

Interplay of drugs that affect proximal tubule cells and thick ascending limb of the loop of Henle. Ca 2+ calcium ions, CaSR calcium-sensing receptor, Cl − chloride ions, K + potassium ions, Mg 2+ magnesium ions, Na + sodium ions, NKCC2 kidney-specific Na +//K +/Cl − symporter, ROMK renal outer medullary potassium channel, H + hydrogen ions, hOAT organic anion transporter, collecting-duct principal and intercalated cells. AC adenylate cyclase, AQP2 aquaporin 2, cAMP cyclic adenosine monophosphate (AMP), ENaC epithelial sodium channel, hOAT organic anion transporter, K + potassium ions, Na + sodium ions, V2 vasopressin 2 receptor. H + hydrogen ions. Adapted from [185], with permission

Full size image

Figure 3 demonstrateshow drugs that interfere with collecting-duct principal and intercalated cells. Trimethoprim and amiloride inhibit ENaC, causing Na+ wasting, reducing kaliuresis, and causing distal RTA via a decrease in H+ excretion. Penicillin acts as a nonresorbable anion, leading to a luminal negative charge if aldosterone-driven Na+ reabsorption is increased. The consequences are K+ secretion with hypokalemia. Demeclocycline (a tetracycline) and amphotericin B could cause nephrogenic diabetes insipidus by inhibiting vasopressin-stimulated vasopressin-2–aquaporin-2 (V2–AQP2) signaling. Demeclocycline enters the cell via hOAT1 or 3. The mechanism of V2–AQP2 signaling interruption is still unknown. Amphotericin B might lead to pores in collecting duct cell membranes. This results in K+ waste via inhibition of adenylate cyclase and a back-flux of H+ into the cells, which inhibits urinary H+ excretion, resulting in distal RTA.

Fig. 3
figure 3

Drugs that interfere with frameworks of collecting-duct principal and intercalated cells. AC adenylate cyclase, AQP2 aquaporin 2, cAMP cyclic adenosine monophosphate (AMP), ENaC epithelial sodium channel, hOAT organic anion transporter, K + potassium ions, Na + sodium ions, V2 vasopressin 2 receptor. H + hydrogen ions. Adapted from [185], with permission

Full size image

Trimethoprim

Similarly, trimethoprim, commonly administered in combination with sulfamethoxazole as cotrimoxazole, can interfere with the ENaC (Fig. 3) [87].

Pentamidine

Luminal pentamidine directly and reversibly blocks apical Na+ channels in the same way as K+-sparing diuretics, causing a decrease in the electrochemical gradient for both K+ and H+ secretion in the cortical collecting tubule. This leads to hyperchloremic metabolic acidosis with hyperkalemia [88].

Distal (type 1) renal tubular acidosis with hypokalemia

Pathophysiology

Distal RTA is characterized by impairment of H+ secretion by the distal nephron, which results in reduced NH4 + excretion. Primary distal RTA occurs in children, and clinical features include growth impairment, polyuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and K+ depletion [89]. Furthermore, distal RTA is associated with a variety of genetic diseases in childhood. In adults, autoimmune and renal diseases play an important role in secondary distal RTA [90]. Additionally, distal RTA presents as normochloremic metabolic acidosis with elevated AG. Urinary findings are at first glance similar to hyperkalemic RTA (type 4), but serum K+ levels and fractional urinary K+ excretion (fK+e) are different (Fig. 1). Distal RTA is accompanied by normal or decreased serum K+ levels and increased fK+e in the urine (rarely, a small proportion of patients with hyperkalemic distal RTA present with decreased fK+e). Remarkably, drugs might cause distal RTA in a proportion of patients.

Amphotericin B

Amphotericin B can bind to cholesterol in mammalian cell membranes and modify their ion permeability. This results in a broad spectrum of renal toxic effects [91]. In addition to the effects of amphotericin B on membrane permeability to monovalent cations, there is a direct effect on tubular function. Amphotericin B induces RTA type 1 by increasing membrane permeability in the collecting duct. This results in back-diffusion of secreted H+ ions and K+ wasting, which leads to hypokalemia [92, 93]. Patients with significant proteinuria (>3 g/l) seem to have a reduced risk of renal tubular toxic effects caused by amphotericin B [94], which might be related to a reduced concentration of free amphotericin B in tubular fluid.

RTA is a rare side effect in amphotericin B therapy [95]. Polyuria and nephrogenic diabetes insipidus are more frequent findings in patients during amphotericin B therapy [96]. Often, there is a combination of RTA and nephrogenic diabetes insipidus (Fig. 3) [97].

Foscarnet

Foscarnet is a structural mimic of the anion pyrophosphate, which selectively inhibits pyrophosphate-binding sites of various viral DNA sequences and inhibits viral nucleic acid synthesis. The drug needs no prior metabolic activation by viral or cellular enzymes. It is used in immune-compromised patients with life-threatening herpes simplex or cytomegalovirus infections [98, 99]. Intensive IV hydration dramatically reduces the incidence of foscarnet-induced acute kidney injury [100]. Foscarnet can lead to acute tubular toxicity; rarely, a direct effect on tubular function can be detected, which may lead to mitochondrial dysfunction, inducing mitochondrial DNA (mtDNA) in renal tubule cells [101]. This can result in distal RTA [102].

Renal loss of bicarbonate (hyperchloremic metabolic acidosis with normal anion gap)

Proximal renal tubular acidosis in the context of drug-induced renal Fanconi syndrome

Pathophysiology

Proximal RTA (type 2) is caused by impairment of HCO3 − reabsorption in the proximal tubule, leading to HCO3 − wasting. Patients present with hyperchloremic metabolic acidosis with normal serum AG. However, distal H+ secretion is still intact, which leads to urine pH <5.5. If plasma HCO3 − concentration is normalized by administration of alkali, urine pH is increased. Furthermore, there is a negative urine AG (≥15 mmol/l) in proximal RTA. Diagnosis of proximal RTA is confirmed after exclusion of GI HCO3 − loss or excessive use of laxatives (Fig. 1). Proximal RTA may be primary [103, 104] or accompanied by other proximal tubular defects in the context of Fanconi syndrome. Drug therapy often causes secondary proximal RTA and is often associated with drug-induced renal Fanconi syndrome (RFS), with generalized dysfunction of the proximal tubule system and HCO3 − loss. Furthermore, a variety of clinical entities (e.g., vitamin D deficiency, hyperparathyroidism, congenital heart disease, Alport syndrome, corticoresistant nephrotic syndrome, renal transplantation, amyloidosis, and recurrent nephrolithiasis) could cause proximal RTA. In children with metabolic acidosis and growth impairment, it is mandatory to differentiate between proximal RTA and RFS, because correction of metabolic acidosis can improve growth in proximal RTA but not in RFS [105].

Ifosfamide

Ifosfamide, a structural analog of the oxazaphosphorine cyclophosphamide, is an alkylating agent. Since the 1980s, ifosfamide has been the standard therapy for childhood soft-tissue and bone sarcomas and is also used to treat germinal tumors. There are various renal side effects associated with ifosfamide. Toxicity involves mainly the proximal—and in rare cases, the distal—renal tubules [106]. It leads to ifosfamide-induced proximal tubulopathy, which results in a loss of phosphate and HCO3 − (proximal RTA) [107]. In a study of 75 patients, the incidence of acidosis was 7 % [108]. In another study of 22 children, proximal tubular, glomerular, and distal tubular impairment (in descending order of frequency) was identified [109].

Proximal RTA as an isolated defect in HCO3 − reabsorption is rarely observed. It is characterized by a decrease in HCO3 − reabsorption in the proximal tubule, without any modification in the transport of other solutes. This disturbance is characterized by a decrease in the threshold value for HCO3 − reabsorption [90, 110]. A more frequent ABD in patients receiving ifosfamide is RFS [111, 112], a disorder of the proximal tubule cell associated with RTA in combination with glycosuria, aminoaciduria, phosphaturia, and normal AG [113]. Proximal RTA in the context of RFS is not rare in patients treated with ifosfamide (4.6 % of patients). Risk factors include cumulative dose of ifosfamide and younger age [106]. The frequency of subclinical tubular dysfunction is up to 90 % [114, 115]. However, there is also a report of complete recovery after severe RFS [116].

There are reports that one metabolite of ifosfamide, chloroacetaldehyde (CAA), can cause renal injury by inhibiting nicotinamide adenine dinucleotide (NADH), resulting in inhibition of ubiquinone oxidoreductase, an important enzyme in the oxidative phosphorylation pathway of the cell. Another suspected pathway in rat proximal tubules is endocytosis inhibition resulting from CAA-induced decrease in ATP levels [117].

Oxaplatin and cisplatin

Platin-induced proximal RTA has been described as both isolated proximal RTA and as part of RFS [118–120]. Cisplatin-induced RFS is caused by a direct toxic effect on the amino acid transporter in the proximal convoluted tubule. This can be caused by an effect similar to that of aminoglycoside toxicity. Aminoglycosides reduce glucose reabsorption in kidney tissue by reducing mRNA and protein expression and by disrupting the sodium-dependent glucose transporter (SGLT1) function, which is located in the apical membrane of the proximal tubule [121]. This causes a reduction in glucose reabsorption in the kidney [122]. It has been suggested that one possible mechanism of cisplatin-induced proximal tubule toxicity is reduced expression of SGLTs [121, 123]. However, in patients with familial renal glucosuria (mutations in SGLT1/SGLT2 coding gene, SLC5A2), no acid-base homeostasis disturbances have been reported [124, 125].

Acetazolamide (carbonic anhydrase inhibitors)

Acetazolamide is used to treat idiopathic intracranial hypertension (pseudotumor cerebri) in children and particularly in obese women of childbearing age but also adult patients with glaucoma. It is well known that carbonic anhydrase (CA) inhibitors cause isolated proximal RTA [111]. There are two main isoforms of CA in the kidneys: membrane-bound and cytoplasmic: CA IV and CA II, respectively [126, 127]. Both isoforms play an important role. CA II is widely distributed in the various compartments of the kidney and is present in almost all cell types. The membrane-bound CA IV is mainly located in the proximal tubule and is absent from or poorly expressed in the collecting duct and the proximal tubule [127]. Defects in HCO3 − reabsorption cause inhibition of CA IV in the apical membrane of the proximal tubule cell. The inhibition of CA IV leads to an isolated blocking of the membrane-bound CA IV isoform, which causes an isolated inhibition of HCO3 − reabsorption without signs of RFS [128, 129].

Antiretrovirals

Human immune deficiency (HIV) infection represents one of the most serious pediatric diseases worldwide, with an estimated 3.3 million children younger than 15 years being infected [130]. Currently available antiretroviral therapy (ART) utilizes five major classes of antiretroviral (ARV) drugs: nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs/NtRTIs), nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), entry and fusion inhibitors, and integrase inhibitors. Combination ART, also defined as highly active ART (HAART), is composed of three ARV drugs from at least two major classes in order to achieve maximal suppression of HIV replication and preserve immune function disrupted by HIV.

Tenofovir disoproxil fumarate (TDF) is an NtRTI that has been licensed by the FDA for use in children >2 years of age [131]; TDF can cause FS [132]. Several mechanisms of TDF nephrotoxicity have been investigated: It enters proximal tubule cells through basolateral OATs and exits by using an apical transporter, the multidrug-resistance-associated protein 4 (MRP 4) [133, 134]. TDF toxicity in the proximal tubule cell can lead to damaged and dysmorphic mitochondria, with loss of matrix cristae; in some cases, it can result in giant mitochondria. Phosphate is reabsorbed from the glomerular filtrate across the apical proximal tubule membrane by the Na+–phosphate cotransporter subtype 2a (NaPi-IIa). Mitochondrial failure leads to energy failure and impaired phosphate transport, leading to urinary phosphate wasting.

There are various treatments for TDF toxicity. Probenecid is increases uric acid excretion and is primarily used to treat gout and hyperuricemia. Probenecid inhibits TDF uptake into proximal tubule cells by OATs. Rosiglitazone binds to peroxisome-proliferator-activated receptor-γ (PPAR-γ) and causes an increase in NaPi expression. Treatment with rosiglitazone increases expression levels of NaPi-IIa and sodium–hydrogen exchanger 3 (NHE3), acting against electrolyte and acid-base disturbances caused by TDF [135, 136].

Valproic acid

In rare cases, long-term treatment with valproic acid can also cause FS. There are some case reports of FS developing in patients on long-term valproic acid therapy [137–140]. The mechanism of valproic acid toxicity is not clear. A direct toxic effect on mitochondria of the proximal tubules has been suggested [141, 142].

Aminoglycosides and tetracyclines

Aminoglycosides and tetracyclines can affect proximal tubular function and cause fluid and electrolyte disorders. Gentamicin can interfere with specific transport mechanisms in the primal tubular system or can induce RFS. Usually, aminoglycoside-induced RFS is seen in patients with impaired renal function, but some reports of patients with normal kidney function exist [143]. Gentamicin enters the cell through the megalin–cubulin system [41]. Intracellular gentamicin can decrease the function of mitochondrial ribosomes [144] and interfere with the conversion of ADP to ATP [145]. Consequently, gentamycin inhibits the Na+/K+-ATPase pump, which is dependent upon ATP, and inhibits NHE-3 and other Na+-dependent solute transporters, including transporters for amino acids, uric acid, and glucose (Fig. 2) [146].

The second group of antibiotics that causes RFS are the tetracyclines, which can cause proximal tubular damage within 1 week after start of therapy [147]. Tetracyclines enter the proximal tubule cell via apical or basolateral OATs. Basolateral transport of tetracyclines into the tubule cell is mediated by OATs 1, 2, and 3, and reabsorption from the luminal side of the tubule cell is mediated by OAT 4 [148]. Similar to the toxic mechanism of aminoglycosides, tetracyclines can impair the function of mitochondrial ribosomes (Fig. 2) [149, 150].

Metabolic alkalosis

Pathophysiology

Metabolic alkalosis is a common but often underdiagnosed ABD in hospitalized patients [90]. However, metabolic alkalosis may contribute to increased mortality in hospitalized and critically ill patients [151–153]. Increased blood pH may disturb the respiratory center and lead to respiratory depression [154, 155]. Furthermore, metabolic alkalosis leads to a shift in the oxygen dissociation curve of hemoglobin, which could cause hypoxemia [156]. Additionally, alkalosis leads to vasoconstriction, and the subsequent decreased blood flow could compound hypoxemia of peripheral tissue. Appropriately, it has been demonstrated in humans that alkalosis might cause coronary vasoconstriction and angina [156, 157]. In patients with metabolic alkalosis, it is mandatory to distinguish between a disturbed HCO3 − clearance caused by renal failure and metabolic alkalosis, which is maintained by a decreased effective arterial blood volume (EABV) or in which alkalosis is maintained by the combination of high aldosterone and high distal Na+ delivery. The first step in analyzing metabolic alkalosis is determining EABV. The next step involves analyses of urinary electrolytes (Fig. 1). In patients with decreased EABV and decreased urine Cl−, urine Na+ should be measured to distinguish between the two most common reasons for metabolic alkalosis [chloride-depletion alkalosis (CDA) under remote use of diuretics, and loss of Na+ and Cl− via the gastrointestinal tract]. Furthermore, acid loss with Cl− depletion without loss of Na+ occurs in active vomiting and nasogastric suction. In patients with decreased EABV and increased urine Cl−, diuretic use with increased natriuresis or Bartter syndrome should be considered. In patients with hypercalcemia, metabolic alkalosis with or without renal failure calcium–alkali syndrome must be taken into consideration.

Renal acid and/or chloride and potassium loss (CDA)

Loop and thiazide diuretics

High doses of loop and thiazide diuretics can lead to metabolic alkalosis, which can result in diuretic resistance [158]. Severe metabolic alkalosis is rare but is usually associated with high dosages of loop diuretics [159]. Three phases have been distinguished: (1) generation, (2) maintenance, and (3) recovery. In 1965, Cannon et al. [160] established the concept of “contraction alkalosis” in the context of loop diuretics. They suggested that distal H+ excretion with renal acid loss and rapid contraction of the extracellular fluid (ECF) volume at constant extracellular HCO3 − leads to metabolic alkalosis. It was observed that Cl− loss influences HCO3 − reabsorption [161]. The concept of contraction alkalosis is still widely used, but the preferred term is now chloride-depletion alkalosis (CDA). Recently, Luke et al. showed that CDA can be corrected by selective Cl− administration despite continued or increased negative Na+ or K+ balance, continuing HCO3 − loading, and continuing high levels of angiotensin II or aldosterone. CDA is not corrected by Na+ or K+ administration without Cl− repletion [162, 163]. CDA persisted in rats infused with albumin that increased ECF by 15 % [163]. CDA was corrected by Cl− infusion and persistent volume depletion and decreased GFR [164]. In summary, Cl− administration without volume expansion is necessary and sufficient to correct CDA, and the term chloride depletion alkalosis should be used instead of contraction alkalosis. In the maintenance phase of CDA, pendrin activity is increased but HCO3 − secretion is inhibited due to the reduced Cl− delivery for anion exchange with HCO3 −. From a therapeutic point of view, at this step, substitution of Cl− is mandatory. After Cl− substitution, HCO3 − secretion increases and medullary HCO3 − reabsorption decreases [186]. This leads to bicarbonaturia, with adjustment of hypochloremic alkalosis (Fig. 4).

Fig. 4
figure 4

Different phases of chloride-depletion alkalosis (CDA). K +, potassium ions; Na +, sodium ions; Cl −, chloride ions; H +, hydrogen ions; HCO 3 −, bicarbonate; ENaC, epithelial sodium channel; Pn, pendrin (sodium-independent chloride/iodide transporter); AEI, anion exchanger isoform 1. Adapted from [186], with permission

Full size image

Penicillins

Penicillins are frequently used worldwide and have a large therapeutic window. Hypokalemia has been reported in patients receiving penicillin derivatives [165]. It has been suspected that penicillins act as nonreabsorbable anions, which maintain a transmembrane potential gradient that is negative on the lumen side in the cortical collecting duct, while the delivery of Cl− ions in the distal collecting duct is reduced (Fig. 3) [166]. This effect is enhanced by volume depletion, which leads to increased aldosterone synthesis and K+ secretion. Laboratory findings in patients with hypokalemia are a low urinary Cl− concentration and decreased K+ levels in urine, in combination with a metabolic alkalosis. Additionally, severe hypokalemia has been reported in patients treated with flucloxacillin: Cl− level in urine was increased, suggesting that an additional direct penicillin-induced tubule toxicity occurs [167].

Aminoglycosides

Aminoglycosides affect the tubular system in the thick ascending limb of the loop of Henle. It has been hypothesized that gentamicin activates the CaSR in this area and in the distal convoluted tubule [168–170]. Under physiological conditions, the increased serum Ca2+ levels stimulate this receptor and decrease the active reabsorption of Na+. This reduces the luminal positive driving force and results in increased urinary Ca excretion [171]. Activation of the CaSR can disrupt electrolyte transport via inhibition of four different pathways: (1) renal channel proteins, such as the Na-K-2Cl cotransporter (NKCC2), (2) ROMK, (3) Na+/K+-ATPase, and (4) paracellular diffusion [146]. Inhibition of these transport mechanisms leads to increased urinary excretion of Na+, K+, Mg2+, and Ca2+ (Fig. 2). This results in hypokalemic metabolic alkalosis with hypermagnesuria and hypercalciuria and a normal serum creatinine (Bartter-like syndrome) [172, 173]. Furthermore, gentamicin might cause Mg2+ wasting; animal experiments have shown a causal relationship between gentamicin administration and Mg2+ wasting [174]. In healthy people, gentamicin causes immediate and transient renal calcium (Ca2+) and Mg2+ wasting (Fig. 2) [175].

Extrarenal acid and/or chloride loss (chloride-depletion metabolic alkalosis)

Laxative abuse in adults (e.g., bisacodyl, sodium picosulfate, saline laxatives, lactulose, and cisapride) results in electrolyte disturbances (mainly hypokalemia), metabolic alkalosis, and renal tubular dysfunction [176]. Laxative abuse occurs in children with, for example, Munchausen's syndrome, by proxy and in adolescents with eating disorders [177]. Therefore, this should be especially considered in patients with unexplainable chloride-depletion metabolic alkalosis (CDA).

Alkali administration (non-chloride-depletion metabolic alkalosis)

Milk–alkali or calcium–alkali syndrome

Milk–alkali syndrome was a very common cause of hypercalcemia, metabolic alkalosis, and renal failure at the beginning of the last century. The syndrome was associated with the ingestion of large quantities of milk and absorbable alkali to treat peptic ulcer disease [178]. Nowadays, this syndrome is called calcium–alkali syndrome (CAS) [179]. The incidence of CAS in children is not clear. Vitamin D supplementation to prevent vitamin-D-deficient rickets in children is generally recommended [180], but there are some reports of children with hypercalcemia after treatment with vitamin D [181]. The classic symptoms consist of hypercalcemia, various degrees of renal failure, and metabolic alkalosis [182]. There are several risk factors for development of CAS: The use of thiazide diuretics predisposes to CAS by increasing Ca2+ reabsorption in combination with volume depletion and metabolic alkalosis. ACE inhibitors and NSAIDs increase the risk of CAS by reducing GFR, leading to decreased Ca2+ excretion [183]. The increased serum Ca2+ levels (via increased intestinal supply or elevated vitamin D levels) lead to activation of the CaSR in the thick ascending limb of Henle and the medullary collecting duct and to parathyroid hormone suppression. Concomitant metabolic alkalosis also increases tubular reabsorption of Ca2+.

Key summary points

  • Drug- nduced ABDs are frequently present in hospitalized patients.

  • Analysis of ABDs should be performed systematically in a standardized manner.

  • Drug-induced ABDs can be classified into five different categories in terms of pathophysiology:

  • (1) Metabolic acidosis caused by acid overload

  • (2) Base loss

  • (3) Alkalosis resulting from acid loss

  • (4) Exogenous HCO3 − loads

  • (5) Respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment

  • Chloride administration without volume expansion is necessary and sufficient to correct CDA, and the term chloride-depletion alkalosis should be used instead of contraction alkalosis.

Multiple-choice questions (answers are provided following the reference list)

Q1: A newborn developed diarrhea at day 10 after birth, and on the subsequent day, lethargy and refusal to eat. Rapidly, he developed diffuse cyanosis, hypotonia, and areflexia. After symptom onset, he was immediately transferred to the intensive care unit. First blood gas analyses showed: pH 6.9, pCO2 29.8 mmHg, pO2 90.1 mmHg (under oxygen therapy), HCO3 − 3 mEq/l, base excess 22, lactic acid 17 mmol/l (normal  < 2 mmol/l). What kind of disturbance is present?

  1. (a)

    Metabolic acidosis

  2. (b)

    Respiratory alkalosis

  3. (c)

    Metabolic alkalosis

  4. (d)

    Respiratory acidosis

Q2: A 14-year-old boy receives chronic furosemide treatment. The dose of furosemide was accidentally increased for 10 days. His medical history was notable for the diagnosis of severe heart failure due to myocarditis at the age of 12 years. What acid-base disorder would you expect?

  1. (a)

    Hyperchloremic metabolic acidosis

  2. (b)

    Hypochloremic metabolic alkalosis

  3. (c)

    Normochloremic respiratory alkalosis

  4. (d)

    Hypochloremic metabolic acidosis

Q3: How would you calculate the AG, and in which cases would you expect to have an increased AG?

  1. (a)

    ([Na+] + [K+]) + ([Cl−] + [HCO3 −]): diabetic ketoacidosis

  2. (b)

    ([Na+] + [K+]) − ([Cl−] - [HCO3 −]): uremia

  3. (c)

    ([Na+] + [K+]) − ([Cl−] + [HCO3 −]): diabetic ketoacidosis

  4. (d)

    ([Na+] + [K+]) + ([Cl−] + [HCO3 −]): uremia

Q4: What acid-base disorder would you expected in patients with propofol infusion syndrome?

  1. (a)

    Metabolic alkalosis with normal lactate levels

  2. (b)

    Metabolic acidosis with elevated lactate levels

  3. (c)

    Respiratory acidosis with normal lactate levels

  4. (d)

    Respiratory alkalosis with normal lactate levels

Q5: Aminoglycosides might cause which of the following?

  1. (a)

    Hyperkalemic metabolic acidosis

  2. (b)

    Hypokalemic respiratory alkalosis

  3. (c)

    Hyperkalemic metabolic alkalosis

  4. (d)

    Hypokalemic metabolic alkalosis