C H A P T E R

11

Fluid and Electrolyte Abnormalitiesin Patients with Cancer

Ala Abudayyeh1, Maen Abdelrahim2, Abdulla Salahudeen11University of Texas MD Anderson Cancer Center, Houston, TX, USA2Baylor College of Medicine and Institute of Biosciences and Technology,

Texas A&M Health Science Centre, Houston, TX, USA

INTRODUCTION

There has been increased survival of cancerpatients due to advancement in chemotherapyand conditioning regimes, hematopoietic stemcell transplantation (HSCT) and general ICUcare. However, challenges in cancer are stillpresent such as increasing incidence rates andcontinued low survival for some cancers. More-over, increased cancer survivorship and the useof new and stronger anti-cancer agents haveleft more patients with abnormalities of fluidand electrolyte balance. In this chapter wewill discuss the delicate balance of electrolyteand water that the kidney maintains and thedisturbances that can occur in the setting ofcancer and cancer therapy. Acidebase and fluidelectrolyte abnormalities are present in a size-able proportion of patients, for example lightchain loading of proximal tubules occasionallyleading to severe tubular acidosis, hypokalemiaand hypomagnesemia known as Fanconi’s syn-drome. Occasionally, ectopic secretion of hor-mones or hormone-like substances can lead to

Renal Disease in Cancer Patients

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fluid and electrolyte disturbances; Syndromeof inappropriate antidiuretic hormone (SIADH)is the prototype that was first described incancer patients [1,2]. A recent survey in hos-pitalized cancer patients reports that hypona-tremia is as common as one in two patientsand that it is strongly related to poor clinicaloutcomes [3]. Tumor lysis syndromes exclu-sive to cancer can be associated with severeacidebase and electrolyte abnormalities [4].Furthermore, derangement in calcium, phos-phorous and magnesium is common in cancerpatients, often through unique mechanisms[5,6].

SODIUM AND WATER

The concentration of serum sodium, the pri-mary extracellular cation, is tightly regulated,and a level lower than the lower limit of the lab-oratory range, usually 135 mEq/L, constituteshyponatremia [7]. Often, the presence of hypo-natremia indicates excess of total body water

Copyright � 2014 Elsevier Inc. All rights reserved.

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER168

relative to sodium. The converse is also true inthat water depletion leads to hypernatremia[7,8]. The pituitary-secreted antidiuretic hor-mone (ADH) (vasopressin) plays a key role inmaintaining water balance primarily by regu-lating water excretion through the kidneys.When water content is low, the concentrationof serum sodium increases vis-a-vis serumosmolality triggering the secretion of ADH.ADH in turn binds to the V2-receptors on thebasolateral side of the medullary collecting tu-bules causing water reabsorption from thetubular lumen (Figure 11.1).

Higher serum sodium also leads to thirststimulation resulting in increased water intake.Thus both reduced water loss and increasedwater intake restore water balance and thussodium concentration. The converse is alsotrue in that excess water intake, e.g. compulsive

FIGURE 11.1 The principal cell of the kidney collecting du

basolateral cell surface binds to AVP present in the interstitialprotein G increases the activity of the membrane-bound enzycellular levels of cAMP. This in turn stimulates the activity ofphosphorylation cascade that promotes the insertion of aquAVP-regulated AQP2 increases the water permeability of the athe hypotonic processed filtrate into the surrounding hypertaquaporin 3 and aquaporin 4 water channels, constitutivelysynthetic vasopressin receptor antagonists. By interfering witwater reabsorption. This figure is reproduced in color in the c

water drinking, can reduce serum sodium con-centration that in turn shuts off the ADH secre-tion. This allows water loss through the kidneyrestoring water balance and sodium concentra-tion. In cancer patients with dysnatremia,disruption in these efficient feedback mecha-nisms occurs at multiple levels leading to hypo-natremia or hypernatremia.

Hyponatremia

Several drugs and conditions that are uniqueto cancer patients can cause hyponatremia(Table 11.1). Vincristine, vinblastine, cisplatinand cyclophosphamide are the chemothera-peutic agents most frequently associated withhyponatremia [10]. Hyponatremia has also beenreportedwith carboplatin and ifosfamide admin-istration, and recently with the administration

ct. The V2 vasopressin receptor (V2-receptor) located in thefluid, and activates the heterotrimeric protein G. Activatedme adenylyl cyclase (AC) causing an increase in the intra-the cAMP-dependent protein kinase A (PKA), triggering aaporin 2 (AQP2) into the apical membrane of the cell.pical membrane and allows the reabsorption of water fromonic interstitium. The water can exit the cell through thepresent in the basolateral surface of the cells. Vaptans areh AVPeV2R interaction they prevent aquaporin-mediatedolor plate section. Modified from Mayinger and Hensen [9].

TABLE 11.1 Causes of Hyperkalemia and Hypokalemiain Cancer Patients

Hypokalemia

Decreased potassiumintakeElevation inextracellular PHIncrease inhematopoietic cellproductionHypothermiaDiarrheaIncreasedmineralocorticoidactivity

Hyperkalemia

Tumor lysis syndromeType I RTAAcidosisDrugs: Bactrim,pentamidine, amiloridetriameterene,cyclosporine, ACEinhibitors and ARB

SODIUM AND WATER 169

of immunomodulators such as interferon andinterleukin-2 [10e13]. The precise mechanismby which all these drugs derange the salt andwater homeostasis is generally not known. Forvinca alkaloids and cisplatin and possibly withother alkylating agents, SIADH is described asa potential mechanism [14]. In one study admin-istration of cyclophosphamide was not associ-ated with increase in ADH levels, but studyfindings were consistent with potentiation bycyclophosphamide or its metabolites of ADHeffects at tubular level [15]. Renal salt wastinghas been described with platinum compounds,a likely mechanism for hyponatremia. Whileectopic ADH secretion by small cell lung tumoris the prototype of SIADH [16], relative excessof ADH levels in the systemic circulation oftenoccurs due to ineffective plasma volume as aresult of volume depletion (vomiting and diar-rhea, for example, from chemotherapy). Relativeexcess of ADH coupled with excessive fluidintake, often hypotonic, that often accompanieschemotherapy is probably the most commonclinical scenario that leads to mild to moderatehyponatremia in hospitalized cancer patients[17]. Furthermore, cancer patients receivingchemotherapy are encouraged to drink plentyof fluid which often leads to excessive waterintake. In a prospective study limited to 106

cancer patients with hyponatremia, volumedepletion and SIADH accounted for nearlytwo-thirds of all causes of hyponatremia,although such clear separation of causes in clin-ical practice can be difficult as multiple factorsfor hyponatremia can coexist in cancer patients[17]. The cause of hyponatremia in cancer pa-tients can often be multifactorial as illustratedin this example: A patient is on thiazide diureticfor hypertension, who is now hypovolemic dueto vomiting and diarrhea from chemotherapyfor diffuse B-cell lymphoma that includescyclophosphamide. The patient is now onlyable to keep clear water down. In this clinical sce-nario, volume depletion is a strong stimulus forADH secretion thus increasing this patient’sADH levels. Further, cyclophosphamide isknown to potentiate ADH water reabsorptionat the tubular level, whereas thiazide and excesswater intake are well known to aggravatehyponatremia.

Pain and pain medications commonly usedin cancer patients are associated with potentia-tion of ADH and so contribute to hyponatremiain cancer patients [18]. Antidepressants arewidely used in cancer patients and they eespecially the SSRIs e are well known to beassociated with hyponatremia [19]. Ectopic hor-mones, notably ectopic ADH secretion, cancause hyponatremia and nearly one-third ofhyponatremia in small cell lung cancer (SCLC)is due to SIADH [1,2]. Some patients withSCLC may have ectopic production of ANP asthe cause of their hyponatremia, although inone study AVP appears to be elevated in nearlyall patients with SCLC and hyponatremia[20,21]. In clinical practice the classical featuresof SIADH may not always be present in cancerpatients, but the cardinal features such asinappropriately elevated urine osmolality>100 mOsm/kg in the setting of decreasedserum osmolality (<275 mOsm/kg) and urinesodium concentration adequate to excludehypovolemia (>20 mmol/L) often point to-wards absolute or relative excess of ADH [22].

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER170

HYPOALBUMINEMIA,INTRAVASCULAR VOLUME

CONTRACTION ANDHYPONATREMIA

Hypoalbuminemia is quite common in can-cer patients especially during the treatmentphase or in the terminal stage. In both occasionsmalnutrition is an important cause for chronichypoalbuminemia, although acute hypoalbumi-nemia as a reflection of possible acute hepaticchemotoxicity can occur in patients receivingchemotherapy as noted in this case report(Figure 11.2). The patient was a 53-year-oldman with myeloma-related end stage renal dis-ease who had been on dialysis for 2 years. Hismyeloma had relapsed after recent chemo-therapy and SCT and he was readmitted toreceive additional chemotherapy consisting ofcyclophosphamide, doxorubicin, bortezomiband dexamethasone. The graph shows the acutedepressive effect of chemotherapy on serumalbumin levels. Hypoalbuminemia can reduce

Chemother

5.02

4.8

4.57

4.35

4.12

3.9

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ALBUMIN SERUM

g/dL

FIGURE 11.2 Acute depressive effect of chemotherapy on

the color plate section.

the effective plasma volume triggering ADHsecretion and this combined with customaryhigh fluid intake during chemotherapy can bea potential mechanism that contributes to hypo-natremia in chemo-treated cancer patients.

CLINICAL OUTCOMES IN CANCERPATIENTS WITH HYPONATREMIA

Although a large body of literature is avail-able on the epidemiology of hyponatremia inpatients with non-cancer conditions, such infor-mation in patients with cancer, especially itsfrequency or impact on clinical outcomes, islimited [23e27]. In a recent analysis of prospec-tively collected data on 3357 patients admittedto the University of Texas MD Anderson CancerCenter (MDACC) over a 3-month period in2006, we reported a hyponatremia (sodium<135 mEq/L) rate of 48% in hospitalized cancerpatients, which is almost one in two patientshospitalized [3]. This frequency is higher than

apy

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(90 Day Trend)

serum albumin levels. This figure is reproduced in color in

POTASSIUM 171

some of the highest frequencies reported inhospitalized non-cancer patients [27]. In oursurvey, eunatremia and hypernatremia werecategorized as: eunatremia¼ 135e147 mEq/L,mild hyponatremia¼ 134e130 mEq/L, moder-ate hyponatremia¼ 129e120 mEq/L and severehyponatremia¼<120 mEq/L. Severe hypona-tremia was noted in 1%, moderate in 10% andthe majority was mild in 36%. Hyponatremiawas acquired during a hospital stay in 24%. Asin non-cancer patients, a strong and indepen-dent association was demonstrable betweenhyponatremia and clinical outcomes in hospital-ized cancer patients [27e29]. The mean lengthof stay was found to be prolonged in hyponatre-mic patients: 5.6� 5.0 (mean� SD) days foreunatremics, and 9.9� 9.2, 13.0� 14.1 and11.5� 12.6 days for mild, moderate and severehyponatremics, respectively. Similarly thehazard ratio for 90-day mortality (HR, 95% CI)in the multivariate model was also higherfor patients with hyponatremia comparedto eunatremic patients: mild vs. eunatremia2.04 (1.42e2.91), moderate vs. eunatremia 4.74(3.21e7.01) and severe vs. eunatremia 3.46(1.05e11.44). In general, hyponatremia patientsin our survey were sicker and often terminallyill. While there is little doubt that hyponatremiain hospitalized patients is associated with verypoor clinical outcomes, what is less certain atthis time is whether correction of hyponatremiaespecially with the availability of orally activeV2-receptor antagonist will improve outcomesof these patients.

POTASSIUM

The concentration of serum potassium, themain intracellular cation, is primarily regulatedby the handling of its excretion by the kidneys.Of the estimated 3500 meq of potassium(50 meq/kg) present in the intracellular space,there is 3.5e5.0 meq/L in the extracellular spacebecause of the presence of Naþ/Kþ ATPase in

every cell membrane. Different stimuli such asinsulin, ephinephrine, alkalosis and acidosisinduce changes in potassium. To maintain po-tassium balance and serum potassium withinthe range, the bodymust excrete the daily intakeof potassium (50e150 meq/day) through thekidneys. Almost all of the filtered Kþ is reab-sorbed in the proximal tubule and the loop ofHenle, so that less than 10% of the filtered loadis delivered to the early distal tubule passivelyfollowing that of Naþ and water from the prox-imal tubule. The reabsorption in the thickascending limb of the loop of Henle is mediatedby the Naþ/Kþ/2Cl� carrier in the luminalmembrane. Kþ is secreted mainly by the prin-cipal cells in the cortical and outer medullarycollecting tubule. This distal secretion can bepartially counteracted by Kþ reabsorption bythe intercalated cells Type A in the cortical andouter medullary collecting tubules. In Type Aintercalated cells the process of potassium reab-sorption may be mediated by an active Hþ-Kþ-ATPase pump in the luminal membrane, whichresults in both Hþ secretion and Kþ reabsorp-tion. The activity of this pump is increasedwith Kþ depletion and is reduced with Kþ

loading. Potassium secretion mainly occurs inthe sodium reabsorbing principal cells in thecollecting tubules. The selective sodium chan-nels or ENaC creates an electronegative gradientin the lumen by which potassium is secretedinto the lumen via K channels (ROMK) in theapical membrane. The two most importantdeterminants are mineralocorticoid activityand distal delivery of salt and water, both haverelevance in the derangement of Kþ balance incancer patients such as aldosterone secretingtumors or reduced urine flow rate in post-chemotherapy hypovolemic patients. Aldoste-rone causes ENaC channels to be more openand increases Naþ reabsorption. This leads toincreased electro-negativity of the lumen andfurther secretion of potassium. Also aldosteroneincreases intracellular potassium by increasingNaþ/Kþ ATPase and increases luminal

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER172

membrane permeability to potassium. Distal de-livery of sodium will increase sodium reabsorp-tion and therefore create increased luminalelectro-negativity and increase potassium secre-tion. With increased flow rate this will continueto maintain low potassium concentration inthe luminal membrane and be the driving forcefor potassium continued secretion [30]. Theconverse is true in that in the prerenal statedistal sodium delivery is reduced decreasingthe luminal potassium secretion. Two importantpotassium channels have been noted in thecortical collecting duct. The renal outer medul-lary Kþ (ROMK) channel has a low conductanceand high probability of being open under phys-iological conditions. The other channel is themaxi-Kþ channel which is a large conductancechannel activated under increased flow. In theprincipal cells increased flow leads to increasedintracellular calcium and therefore activates themaxi-Kþ channels. The cilium on the principalcells is believed to detect the increased flowrate and therefore lead to increased intracellularcalcium. Increased potassium intake has beenshown to increase ROMK and maxi-K potas-sium channel expression [31]. Long WNK1antagonizes kidney-specific kinases named kid-ney specific with-no-lysine (KS-WNK1) effects.Long WNK1 inhibits effects of ROMK by stimu-lating endocytosis of the channel which isappropriate in the setting of hypokalemia.Long-WNK1 also stimulates activity of EnaC.The ratio of long WNK1 to KS-WNK1 is impor-tant in maintaining potassium balance [32].Hypokalemia can lead to an increase in BP bydecreased potassium; there is an increased ratioof WNK-1 to KS-WNK1 and therefore there isdecreased ROMK channels but also increasedNA/Cl channels and EnaC activity.

Plasma concentration of potassium is a deter-minant of potassium excretion and vice versa.A faster tubular flow rate allows tubular potas-sium loss leading to lower serum potassium.Alkalosis increases potassium secretion becausea decrease in intracellular hydrogen results in an

intracellular potassium increase and hencesecretion. Aldosterone effects in the principalcells combine with the cytosolic mineralocorti-coid receptor (Aldo-R) and lead to enhancedNa reabsorption and potassium secretion byincreasing both the number of open Na chan-nels and the number of Na,K-ATPase pumps.Increased aldosterone secretion is directly stim-ulated by increased plasma potassium concen-tration. Atrial natriuretic peptide, on the otherhand, acts primarily in the inner medullarycollecting duct by combining with its baso-lateral membrane receptor (ANP-R) and acti-vating guanylate cyclase. ANP inhibits sodiumreabsorption by closing the Na channels [33].The potassium-sparing diuretics act by clos-ing Na channels, amiloride and triamterenedirectly and spironolactone by competing withaldosterone.

Serum potassium is tightly regulated and aswe discussed kidney plays a central role. Distur-bance in serum potassium is common in cancerpatients through a variety of mechanisms (Table11.1). One of the most common clinical settingsis tumor lysis syndrome (TLS), which is causedby the disintegration of malignant cells, usuallyfollowing the initiation of chemotherapy orrapidly growing tumor, especially hematologicmalignancies such as acute leukemia with highwhite cell counts at presentation or diffuseBurkitt-type non-Hodgkin lymphoma.

When these cells start to break down intracel-lular ions, proteins, nucleic acids and their me-tabolites are released into the plasma causingthe characteristic metabolic abnormalities ofhyperuricemia, hyperkalemia, hyperphosphate-mia and hypocalcemia. Hyperkalemia is oftenthe earliest and potentially the most serious clin-ical consequence. In order for patient stabilitythere has to be increased potassium and phos-phate ions and uric acid excretion. By increasingfluid intake and the use of uricosuric drugs, thismay be achieved. However, crystallization ofuric acid and calcium phosphate in the renaltubules leads to reduced renal excretion of

MAGNESIUM 173

potassium with consequent worsening ofplasma hyperkalemia, which can contribute tohypocalcemia and as a result lead to cardiacdeath [34]. Potassium load will be extremelyhigh in urate crystals and calcium phosphateprecipitation leading to acute tubular necrosis(ATN). The thick ascending loop of Henle andprincipal cells of the collecting duct will nolonger adequately secrete excess potassium.Therefore in order to increase kaliuresis, urinaryflow rate should be increased using intravenousinfusion of saline with sodium bicarbonate solu-tions. This increase will lead to activation ofmaxi-K channels and potassium secretion intothe tubules.

Cancer patients following chemotherapy willbe immunocompromised and at high risk ofdeveloping infections possibly leading tosepsis/hypotension, increased lactic acidosisand hyperkalemia. During episodes of sepsisand neutropenic fevers antifungal use is themainstay in the critically ill which can result inFanconi’s-like syndrome and cause multipleelectrolyte loss, especially potassium.

Development of both proximal and distalrenal tubular acidosis associated with multiplemyeloma, monoclonal gammopathies and useof ifosfamide can cause potassium disturbances.Proximal RTA in adults includes light chain-inducedproximal tubular toxicity andhypokale-mia/acidosis. Long-term effects can also lead todistal RTA with impaired tubular acidificationand hyperkalemia (Type 1 RTA) [35]. Steroidsare also used as part of the chemotherapeuticregimen or in acute sepsis can havemineralocor-ticoid effects leading to hypokalemia. Othercauses of hyperkalemia are the following:potassium-sparing diuretics such as amilorideand triameterene; antibiotics such as bactrim,pentamidine block ENaC leading to hyperkale-mia; immunosuppressive agents such as cyclo-sporin blocks Naþ/Kþ ATPase in the distalnephron, leading to hyperkalemia; and the useof ACEi and ARB, which can lead to hyperkale-mia due to their aldosterone inhibitory effects

and therefore decreased potassium secretion inthe collecting tubule principal cells.

MAGNESIUM

Derangement in magnesium metabolism orbody content is rare in the general patientpopulation but fairly common in patients withcancer, often related to renal toxicity of drugsused for chemotherapy, HCT or both. We willreview the renal handling of magnesium fol-lowed by its derangements in cancer patients.The average daily magnesium intake is 360 mg(15 mmol). Forty to fifty percent of dietarymagnesium is reabsorbed in the gastrointestinaltract mediated by a channel encoded by theTRPM6 gene. Total body magnesium in thebody is 25 g with 60e65% in the bone andthe rest in the intracellular muscle and softtissue. One percent of total body magnesium ispresent in the extracellular fluid compartment.Serum magnesium in a healthy individual isclosely maintained at 1.50e2.30 meq/L. Only20% is protein bound, therefore variations inserum albumin have less of an effect, unlikecalcium. One to two percent of the 28 g of mag-nesium in an adult body is present in the extra-cellular fluid compartment e 350 meq is inmuscle complexed to intracellular organic phos-phates and proteins. Bone has 1200 meq of themagnesium content.

Regarding the renal handling of magnesium,about 95e97% of filtered magnesium is reab-sorbed by the kidney with only 15e25% in theproximal tubule. The thick ascending loop ofHenle absorbs 60e70% of the filtered load via aparacellular process. The lumen (þ) in thissegment drives this process via tight junctionproteins, Claudin-16 and -19, which control par-acellular permeability to magnesium. The extra-cellular Ca2þ/Mg2þ sensing receptor (caSR) ifactivated then reduces calcium and magnesiumreabsorption in the thick ascending loop ofHenle. Inhibition of ROMK apical potassium

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER174

channels in the thick ascending loop of Henlewould decrease the gradient that fuels theNaþ/Kþ/2Cl� (NKCC2) cotransporter andtherefore causes reduction in transepithelialvoltage and paracellular permeability of magne-sium and calcium. Final urinary magnesium isregulated by the distal convoluted tubule.Cellular uptake is mediated in the cortical col-lecting tubule by a channel in the luminal mem-brane called TRPM6 (transient receptor potentialcation channel, subfamily M, member 6). It isbelieved to be a sodium/magnesium exchangerand in the presence of low intracellular sodium(10 to 15 meq/L) compared to that in the extracel-lular fluid, there is an increasedmagnesium reab-sorption. Therefore the use of thiazide diureticsand amiloride which inhibit sodium chloridereabsorption in the distal tubule will lead to lowintracellular sodium and increased activity ofTRMP6, and therefore reabsorb magnesium asexplained above. Enhanced magnesium reab-sorption via TRMP6 channels is increased dueto increased sex hormones, parathyroid hormone(PTH), calcitonin, glucagon, arginine, vaso-pressin and acidebase status [36]. Epidermalgrowth factor has also been implicated in in-creased TRMP6 activity and therefore increasedmagnesium reabsorption. Therefore in colorectalcancer patients treated with cetuximab and EGFreceptor targeted monoclonal antibody, hypo-magnesemia is common. Also, tacrolimus andcyclosporine A decrease TRMP6 expression andtherefore contribute to hypomagnesemia.

Magnesium excretion is determined by theplasma magnesium concentration. Also, hypo-calcemia leads to a decrease in magnesium reab-sorption in the thick ascending limb and distalconvoluted tubule. This is all mediated by thecalcium sensing receptor in the basolateralmembrane. Volume contraction increases reab-sorption in the proximal tubule while volumeexpansion decreases. Aldosterone can increasereabsorption in the thick ascending loop andthe distal convoluted tubule. Loop diureticsreduce reabsorption of magnesium because of

the reduction of the lumen-positive transepithe-lial membrane.

Although several causes such as GI losses,malabsorption, or rare gene mutation inTRPM6 can lead to hypomagnesemia, drugsthat impair magnesium reabsorption in thedistal convoluted tubule and thick ascendingloop of Henle are the commonest cause in can-cer patients. They include cisplatin, ifosfamide,cetuximab, amphotericin B, carboplatin, amino-glycosides, foscarnet, pemtamidine and calce-neurin inhibitors to mention the most clinicallyencountered drugs [37]. These drugs can causesevere tubular injury and take months to resolveeven after cessation of the drug for hypomagne-semia. Cetuximab, a human/mouse chimericmonoclonal antibody, causes reversible urinarymagnesium wasting by binding to the EGFand EGFR which are expressed in the kidneyDCT and contribute to magnesium balance[37]. Long-term parenteral nutrition is requiredespecially in GI cancers and can lead to magne-sium deficiency. Other rare causes of hypomag-nesemia that occur in non-cancer patients areGitelman’s syndrome where there is a mutationof the DCT Naþ/Cl� cotransporter, pancreatitisfrom precipitation of calcium and magnesiumin the pancreas and low PTH after thyroideparathyroid surgery [38]. Also, increased mag-nesium wasting is noted in hyperthyroidisim,hyperaldosteronism and SIADH contributingto hypomagnesemia.

Hypermagnesemia is rare and usually occursif there is excessive supplementation with laxa-tives, antacids, Epsom salts and magnesium-containing enemas especially in patients withimpaired magnesium excretion as in AKI orCKD. In order to treat such patients effectivelyand prevent respiratory depression or cardiacarrhythmias, serum calcium can be increasedwhich would act as a direct antagonist. Also,use of saline and diuretics as explained earliercan lead to increased magnesium excretion. Ifrenal function is poor in patients with severehypomagnesemia use of hemodialysis can help

URIC ACID 175

to lower magnesium to safer levels as in severehypercalcemia.

URIC ACID

Uric acid is the end product of purine meta-bolism. Purine degradation involves the break-down of the purine mononucleotides, guanylicacid (GMP), inosinic acid (IMP) and adenylicacid (AMP) into guanine and hypoxanthine.The latter two compounds are then metabolizedto xanthine. Xanthine oxidase irreversibly oxi-dizes xanthine to produce uric acid. Humansdo not have the ability to metabolize urate,therefore it needs to be eliminated via the GItract or the kidney. In the intestines there arebacteria that would be able to degrade uricacid (uricolysis) which is a third of total urateexcretion. Urinary uric acid excretion accountsfor the remaining two-thirds of the daily uricacid disposal. Uric acid dissociates in tohydrogen ion and urate and it is handled exclu-sively by the proximal tubule in three differentstages. Uric acid excretion involves glomerularfiltration. In the proximal tubule the followingoccurs: presecretory reabsorption; secretion;and postsecretory reabsorption. Less than 5%of urate is bound to serum proteins and thereis a net 90% absorption of the filtered urate inthe early proximal tubule. Tubular secretion,which is the source of most of the uric acidexcreted, occurs in the S2 segment of the prox-imal tubule, which returns 50% of the filteredurate to the tubular lumen. Finally, in the S3segment of the proximal tubule there is reab-sorption of the urate.

Two transporters belonging to the organicacid transporter (OAT) family, URAT1 encodedby the SLC22A12gene andGlut9, are responsibleforurate balance. In the luminalmembraneof theproximal renal tubular epithelial cells urate/organic anion exchanger (URAT1) is present.The function of this transporter is independent

of direct sodiumeurate cotransport and is notdriven by membrane potential. Inhibition ofURAT1 ismediated by the followingmetabolitesand drugs: probenecid, losartan, nonsteroidalanti-inflammatory agents, lactate, nicotinate,acetoacetate, hydroxybutyrate and succinate.To drive the entry of uric acid into the cell viathe organic anion transporter (OAT) 1, alpha-ketoglutarate, a citric acid intermediate, canenter the cell by cotransport with sodium acrossthe basolateral membrane (via the sodium-dicarboxylate symporter [NaDC-3]). Thisaccumulation of alpha-ketoglutarate creates afavorable outward gradient for this compoundand the entry of uric acid into the cell. Glucosetransporter 9 (GLUT9), a voltage-driven urateefflux transporter, mediates urate reabsorptionfrom the tubular cell to the circulation. GLUT9is inhibited also by the uricosuric agents proben-ecid and benzbromarone. Overall energy fortransport is provided by the Naþ/Kþ ATPasepump by maintaining a low cell Naþ concentra-tion and a concentration gradient is created fa-voring sodium to enter the cell.

The net effect is the excretion of 6e12% of theamount filtered. Alterations in excretion accord-ing to urate homeostasis are thought to be medi-ated primarily by changes in the rate of tubularsecretion. Net urate reabsorption also variesdirectly with proximal Naþ transport and, inthe presence of volume depletion, both Naþ

and urate excretion are reduced. In the settingof diuretic therapy there is increased sodiumloss and therefore increased sodium and uricacid reabsorption in the proximal tubule lead-ing to hyperuricemia which is common withdiuretic therapy.

Acute uric acid nephropathy (UAN) is aresult of undissociated uric acid precipitationin renal tubules and crystals of monosodiumurate in the renal interstitium, leading to acuteoliguric renal failure. This is most often due tooverproduction and overexcretion of uric acidin patients with lymphoma, leukemia, or a

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER176

myeloproliferative disease (such as polycy-themia vera), especially after chemotherapy orradiation has induced rapid cell lysis. Plasmauric acid concentration generally above15 mg/dL and many uric acid crystals can beseen on urinanalysis. Chronic exposure to highlevels of uric acid may lead to chronic renal dis-ease. It has been shown in rats that experimentalhyperuricemia induced by oxonic acid (uricaseinhibitor) induced systemic hypertension,glomerular hypertrophy/hypertension, afferentarteriolar sclerosis, macrophage infiltration innormal rat kidney, tubulointerstitial fibrosisand eventually glomerulosclerosis [39]. Uricacid may have a key role in initiating renal arte-riolar lesions in high-risk patients such as theelderly, obese black population, subjects withgout or hyperuricemia, chronic lead ingestion,metabolic syndrome and chronic diuretic use,therefore increasing their risk for early renaldisease progression [40]. There is also evidencethat an elevated uric acid may potentiate theeffects of angiotensin II to induce renal vasocon-striction which could possibly be mediatedby its effect to upregulate angiotensin type I re-ceptors on vascular smooth muscle cells andlead to hypertension [41]. In cyclosporinenephropathy, which is a progressive renaldisease, it has been shown in remnant kidneythat there is glomerular hypertension andcortical vasoconstriction. Also, it has beenshown that an increase in uric acid exacerbatescyclosporine nephropathy in the rat. Concomi-tant treatment with allopurinol or benzbromar-one reduced the severity of renal disease [42].In addition, uric acid stimulated inflammatorymediators in the vascular [43]. A study pub-lished in 2008 examined the association betweenuric acid and progression of renal disease. Datafrom 21,475 healthy volunteers who werefollowed prospectively for a median of 7 yearswere analyzed. The data indicated that the riskfor incident kidney disease increased roughlylinearly with uric acid level to a level of approx-imately 6 to 7 mg/dl in women and 7 to 8 mg/dl

in men; above these levels, the associated riskincreased rapidly [44].

In the setting of cancer, acute kidney injury(AKI) associated with tumor lysis syndrome(TLS) may both have a crystal-dependent and acrystallin-dependent mechanism of renal injury.Uric acid has antiangiogenic effects such asinhibition of endothelial cell proliferation andmigration, and stimulation of endothelial cellapoptosis. It also stimulates pro-inflammatorymechanisms such asMCP-1 andCRP, and activa-tion of NF-kB and p38 MAPK [41]. Uric acid hasbeen shown even with absence of crystal forma-tion to have pro-oxidative properties (stimula-tion of oxidants and peroxynitrite-associatedradicals) that may perpetuate renal injury. Inthe presence of crystal formation there is ofcourse mechanical obstructive nephropathywhich results during TLS [45].

Rasburicase is highly effective for preventionand management of hyperuricemia in adults atrisk for tumor lysis syndrome (TLS). In a recentstudy published in Annals of Oncology (2011), asingle-dose rasburicase was effective in themanagement of a patient with hyperuricemiasecondary to TLS; only a subset of high-risk pa-tients required a second dose {Vadhan-Raj, 2011#143}.

PHOSPHATE

Serum phosphate is present in two forms:organic and inorganic. Organic phosphorusis composed entirely of phospholipid-boundproteins. Inorganic phosphorus is the form thatis measured and used. Ninety percent of inor-ganic phosphorus is ultrafilterable of which 53%is dissociated in a 1:4 ratio of H2PO4- to H2PO4-2and the rest are in salts form sodium,magnesiumand calcium. When phosphorus reaches levels>8 mg/dl it complexes with calcium and isremoved from the circulation. Phosphorusdecreases during hyperventilation and alkalosisand increases during acidosis. Insulin, glucose

CALCIUM 177

and epinephrine cause decreases in serumphosphorus. Most of the phosphorus is absorbedin the jejunum and is an active process cou-pled to sodium via the NaPiIIb cotransporter.1,25-Dihydroxyvitamin D3 increases stimulationof this pump and therefore absorption ofphosphorus. This is maintained by the Naþ/Kþ

ATPase pump in the basolateral membrane.In the kidney 85% of serum inorganic phos-

phorus is filtered and the ratio of H2PO4� toH2PO4�2 depends on the PH. Seventy percentof phosphorus is reabsorbed in the proximaltubule via the NaPi cotransporter (70e80% ofthe filtered load) against electrochemical gra-dient which is maintained by the basolateralsodium pump. Increased dietary content ofphosphorus is an important stimulus for urinaryexcretion of phosphorus. The remaining 20e30%is reabsorbed in the distal tubule. Metabolicacidosis, TSH, insulin and insulin-like growthfactor increase phosphorus reabsorption and up-regulation of the NaPi cotransporter. IncreasedECF increases urinary excretion of phosphoruswhile depletion decreases. High calcium intakedecreases urinary excretion of phosphorus.There are three types of NaPi cotransporter:type I, II and III. Type I and II are predominantlyexpressed in the kidneys. Type II cotransporter isthe main site of most of the phosphorus reab-sorption and a major target for regulation byPTH, fibrioblast growth factor 23 (FGF23),vitamin D and dietary phosphates. Urinaryphosphorus excretion is directly related to die-tary intake of phosphorus. Hypophosphatemiastimulates 1alpha-hydroxylase to convert calci-diol to calcitriol and increases phosphorusreabsorption in the intestine and kidney. Hyper-phosphatemia can lead to increased excretion ofphosphorus mediated by increased phosphorus,PTH and FGF23 [46].

Cytotoxic agents given for malignancy canlead to hyperphosphatemia, phosphaturia andhypocalcemia. Also, rapidly growing ma-lignancies can lead to hypophosphatemia byincorporating phosphorus into new cells. In

denervated kidneys such as kidney transplantsthere is an increased phosphorus excretion; thisis believed to be due to increased dopamine pro-duction and decreased alpha/beta-adrenergicrenal receptor activity. Hyperphosphatemia canalso occur in the use of enemas and laxativescontaining phosphorus. Cow’s milk to infantscan lead to tetany since there are higher phos-phorus levels that lead to hypocalcemia, asobserved when infusing phosphate can leadto hypocalcemia. This may be as a result ofincreased deposition in the bone, organs andsoft tissues. Also in cancer patients, when treat-ing tumors hyperphosphatemia may developas a result of cytolysis. Tumor lysis from largetumor burdens can also lead to hyperphosphate-mia and hypocalcemia.

CALCIUM

Forty percent of serum calcium is bound toserum proteins with 80e90% bound to albumin.An increase in serum albumin by 1 g/dl causesan increase in serum calcium by 0.8 mg/dl.Also, hyponatremia can lead to an increase incalcium-bound albumin, and hypernatremiacan cause a decrease in calcium binding. Theactive form of calcium is ionized calcium, whichis 47% of total serum calcium. Calcium can alsobe found in a complexed form e it complexeswith bicarbonate, phosphate and acetate. Asan example, complexed calcium is increasedtwo-fold in uremic patients. A normal adultmay ingest 1000 mg of Ca2þ per day, of whichroughly 400 to 500 mg may be absorbed. Threehundred milligrams of calcium from digestivesecretions are lost in the stool, resulting in anet absorption of only 100 to 200 mg. Calciumand phosphorus are regulated in the intestine,kidney and bone via PTH and vitamin D.

PTH controls calcium via increasing bonedemineralization therefore resulting in phos-phorus and calcium since the major form of cal-cium is in hydroxyapatite, Ca10(PO4)6(OH)2, the

FIGURE 11.3 EGFR pathway. The epidermal growth factor (EGF) was discovered as the first hormone to regulate activemagnesium reabsorption through TRPM6. Reabsorption of magnesium is primarily driven by the luminal membranepotential established by the voltage-gated potassium channel. Cetuximab targets EGFR and leads to decreased TRMP6-mediated magnesium reabsorption. This figure is reproduced in color in the color plate section.

FIGURE 11.4 Mechanisms of hypercalcemia in cancer patients.

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER178

main mineral component of bone (Figure 11.4).Also, increasing renal reabsorption of calciumand excretion of phosphorus will result inenhancing GI absorption of both calcium andphosphorus mediated by activated vitamin D(1,25(OH)2D3) or calcitriol. PTH secretion is aresult of hypocalcemia, hyperphosphatemiaand calcitriol deficiency. Calcium-sensing re-ceptors are present in both the thyroid C cells

and the kidney in the thick ascending loop ofHenle and are responsible for sensing cal-cium levels; in hypocalcemia they causeincreased secretion of PTH. PTH affects the kid-ney by activation of specific adenylyl cyclasesystems in the proximal tubule and the earlycortical distal nephron, including the corticalthick ascending limb, the distal tubule andthe connecting segments. PTH diminishes the

CAUSES OF HYPOCALCEMIA 179

proximal reabsorption of phosphate by de-creasing the activity of the type II Naþ-phos-phate cotransporter in the luminal membrane[47].

An acidic environment will cause an increasein PTH and therefore net phosphorus excretionto act as a buffer for the excess hydrogen load. Italso promotes bone buffering in the presence ofacidosis. Vitamin D is manufactured in the skinvia conversion of 7-dehydrocholestrol to vitaminD3 in response to sunlight. Vitamin D2 fromplants or vitamin D3 cholecalciferol from fish isalso carried in the blood while bound to vitaminD-binding proteins and in the liver is convertedto 25(OH)D, also called calcidiol. In the kidneycalcidiol is converted to calcitriol via 1alpha-hydroxylase CYP27B. This enzyme is affected byPTH, estrogen, calcitonin, prolactin, growth hor-mone low serum calcium and low serum phos-phorus, and is inhibited by calcitriol. Theformation of calcitriol is primarily stimulated byPTH and hypophosphatemia in an attempt tomaintain Ca2þ and phosphate balance.

Calcium is absorbed more in the small intes-tine in the duodenum and proximal jejunumthan in the ileum. It is absorbed trancellularlyand paracellularly. The epithelial calcium chan-nels TRPV5 (ECaC) are regulated by vitamin D.ECaC1 are channels in the kidney and ECaC2are the channels in the intestine.

RENAL

Only ultrafilterable calcium crosses the glom-erlular capillary walls and is absorbed by thetubular cells. Ninety-seven to ninety-ninepercent of filterable calcium is reabsorbedmore in the ionized form. Most of urinary cal-cium is chelated to citrate. Urinary excretion ofcalcium is linked to urinary excretion of sodium.Seventy percent is absorbed in the proximaltubule with the last 10% in the distal tubule.Eighty to ninety percent of reabsorbed calciumis via paracellular gradient created in the

proximal and thick ascending loop of Henle.In the distal tubule and the connecting tubulethe transport is via the epithelial calcium chan-nels TRVP5 (ECaC1).

Extracellular calcium-sensing receptors(CaSR) are important in calcium and magne-sium reabsorption in (thick ascending loop)TAL via altering the permeability of calcium inthe paracellular pathway and changing theapical transport which generates the TALluminal electropositivity, and is the drivingforce for calcium reabsorption. PTH and1,25-dihydroxycholecalciferol are the major reg-ulators of TRVP5 in the distal nephron. Highextracellular PH stimulates activity of TRVP5(ECaC1) and low PH decreases its activity.Acute or chronic load of phosphorus also leadsto a decrease in calcium excretion secondary tolikely deposition of calcium/phosphorus inthe bones and other tissues. Medullary carci-noma of the thyroid is a tumor derived fromparafolicular cells and as a result has high levelsof calcitonin. Hyperuricemia may also developin association with osteoblastic metastasessuch as osteoblastic disease in carcinoma ofbreast and prostate as a result of rapidly devel-oping matrix and deposition of minerals.

CAUSES OF HYPOCALCEMIA

Citrate and sodium ethylenediaminetetra-acetate (Na-EDTA) when given intravenouslycan bind to calcium and lead to hypocalcemia.Also, ethylene glycol toxicity can lead to hypo-calcemia by binding to the oxalate crystals.Excessive chloride can lead to hypocalcemia.Foscarnet can lead to hypocalcemia by causingchelation of calcium and hypomagnesemia.Also ketoconazole and pentamidine can leadto hypocalcemia. Mithramycin potent inhibitorof RNA synthesis decreases serum calciumand phosphorus and urinary hydroxyprolineexcretion. In malignancy, in order to correct hy-percalcemia, mithramycin has been used where

11. FLUID AND ELECTROLYTE ABNORMALITIES IN PATIENTS WITH CANCER180

it has been shown to inhibit the rate of osteo-clastic resorption induced by PTH [48]. In can-cer patients that are critically ill and ICUpatients there is a notable presence of hypocal-cemia. This also correlates with septic patients.Circulating levels of calcitonin precursorsappear to be elevated in such patients [49].

Malignancy-associated hypercalcemia ismost commonly associated with breast, lung,kidney, ovary and hematological malignancies.In malignant cells there is an excess of intra-cellular organic and inorganic phosphate, upto four times as much compared to non-malignant cells. There is an increase in phos-phorus which is beyond the kidney’s capacityto reabsorb and is worsened in uric acidnephropathy. Twenty-four to forty-eight hoursafter initiation of chemotherapy there is an in-crease of phosphorus. A large amount of ste-roids can also increase the circulatingphosphate [4]. Hypocalcemia is also related tohyperphosphatemia where, due to the excessphosphorus, it precipitates in the soft tissuesand tubular system which further leads to wors-ening hypocalcemia [4].

Hypercalcemia is a poor prognostic indicatorwith survival of 3 months thereafter. It is usefulto divide malignancy-associated hypercalcemiainto humoral hypercalcemia of malignancy(HHM) usually mediated by PTHrP, whichwill be discussed further below, local osteolytichypercalcemia and hypercalcemia caused bythe dysregulated production of calcitriol, theactive metabolite of vitamin D. Humoral hyper-calcemia is a result of circulating factors fromthe malignant cells. In HHM this is induced byPTHrP. This peptide has effects of PTH and asa result will cause reduced phosphate reabsorp-tion in the kidney, increase calcium reabsorptionin the kidney, increase osteoclast activity in thebone and increase excretion of cAMP. The pres-ence of hypercalcemia with normal PTH butincreased urinary cAMP would confirm thediagnosis of HHM mediated by PTHrP. HHMpatients not as primary hyperparathyroid

patients have elevated calcitriol instead due toFGF23 that are released from the tumors andcause suppression of 25(OH) 1alpha(OH)aseand inhibit production of 1,25(OH)2D3 fromthe precursor 25(OH)D3 [50]. In HHM boneformation and reabsorption are not matchedas in hyperparathyroidism. Calcium-sensingreceptor CaSR is expressed in many cells andhypercalcemia leads to activation and increasedsecretion of PTHrP leading to increased osteoly-sis, growth and tumor spread [51]. In Hodgkinand non-Hodgkin lymphoma there is develop-ment of hypercalcemia from the increased1,25(OH)2D3 levels that are believed to be aresult of the tumor’s ability to produce calcitrioland lead to hypercalcemia. Successful treatmentwith chemotherapywill lead to normalization ofcalcium. Overall, PTHrP and tumor-producedcalcitriol act synergistically in malignancy-related hypercalcemia.

Tumors also have the ability to release fac-tors called osteoclast activating cytokinesknown as IL-1, IL-6, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, lymphotoxin,transforming growth factor-alpha (TGF-alpha)and arachadonic acid metabolites. Malignantcells also produce mediators such as granulo-cyte macrophage colony-stimulating factors(M-CSF) that induce immune cells to produceTNF and IL-1 [52]. Patients with hematologicmalignancies complicated by hypercalcemiado not have elevated systemic levels of PTHrPbut increased calcitriol production. On the con-trary solid tumors have suppressed levels ofcacitriols. Hodgkin disease, NHL and HTLV-1-related ATLL, where hypercalcemia hasbeen reported to occur in 5% and 15% of pa-tients, respectively, are directly related toincreased calcitriol levels [53]. However, somepatients have been triggered to develop hyper-calcemia only after significant sun exposurepresumably secondary to enhanced productionof 25(OH)D and vitamin D supplementation.The following are the associated changes: anincreased osteoclastic bone resorption and

REFERENCES 181

excessive gastrointestinal calcium absorption;lab abnormalities such as a normal or sup-pressed PTH concentration; a normal or slightlyelevated serum phosphate; and normal levels ofthe inactive precursor 25(OH)D, with anelevated calcitriol level, or a calcitriol levelthat is inadequately suppressed for the degreeof hypercalcemia. If measured, the tubularreabsorption of phosphate is normal orincreased. This is all in contrast to PTHrP--mediated HHM. Many patients had bulky oradvanced-stage disease, none had bone lesionsidentified clinically or radiographically, whichhelps in implicating mostly the high calcitoninlevels and not humoral osteolysis as a majorcontributor to hypercalcemia. The most effec-tive treatment initially is steroids. The third ma-jor category of malignancy-associatedhypercalcemia acts locally as osteolytic factors.In multiple myeloma the cells produce osteo-clastic activating factors such as TGF-beta, IL-1 and IL-6; there is also increased bone resorp-tion and decreased osteoblastic bone formation.Patients with multiple myeloma and lytic lesionare secondary to the presence of high levels ofWnt-signaling antagonist Dickkopf1 (DKK1).Wnt (wingles/int) is an important gene andits products promote growth, maturation anddifferentiation of osteoblasts. In the presenceof an antagonist DKK1 there is a block on pro-liferation and differentiation of osteoblasts [54].

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