Acute hepatic injury and AKI secondary to rhabdomyolysis This has been reported in patients receiving gem \201 brozil and \202 uvastatin. Cerivastatin was banned after similar fat al cases. Rhabdomyolysis with cardiac involvement and AKI This has been reported with rosuvastatin co mbined with feno \201 brate. Tubular proteinuria Rosuvastatin ( \211 40 mg/day) may cause a mild form of tubular protein uria without an increased risk of renal failure. Thus it is recommended that statins are us ed carefully in CKD. Herbal medicine Herbal medicines are used by 75% of the world \200\231s popula- tion, mostl y in the developing countries. Herbal medicine is also popular in the West with 15% of the population consulting a herbal medicine provider each year. Herbal products may contain nep hrotoxic compounds and, therefore, may be responsible for various renal syndromes (Table 18 .2.4). Lithium In Western countries 1 in 1000 individuals is given lithium for the treatment of u ni- or bipolar affective disorders. Lithium is eliminated by the kidney (glomerular \201 ltration and proximal tubular reabsorption) and may accumulate in distal tubular cells. Aft er long-term exposure, tubular cysts as well as tubular atrophy and interstitial \201 bro sis and some- times glomerular sclerosis may develop. CHAPTER 18.2 Drug-induced nephropathies 705 Renal side-effects of lithium include: \200 \200 \200 \200 \200 and resistance to diuretics have been related to the use of NSAIDs. The long-term (>2 years ) daily use of NSAIDs has been associated with an increased risk for developing CKD sec- on dary to chronic interstitial nephritis. Episodes of papillary necrosis have been reported w ith ibuprofen, indomethacin, phenylbutazone, fenoprofen and mefenamic acid. Suprofen may gi ve rise to AKI with unilateral or bilateral \202 ank pain ( \200\230suprofen nephropathy \200\231). This syndrome is prob- ably due to the uricosuric properties of NSAIDs leading t o an acute uric acid nephropathy. Among all NSAIDs, aspirin is the only one that is clearly associated with a low risk of renal side-effects (with the exception of lupus nephropathy) . Claims regarding the renal-sparing properties of particular NSAIDs (sulindac, nabumetone) lack convincing evidence. Thus caution must be applied when using NSAIDs (including select ive COX-2 inhibitors) chronically or in situations associated with renal hemodynamic stress . AKI (prerenal type); CKD (secondary to interstitial renal \201 brosis); nephrogenic DI (m ost frequently); incomplete distal RTA (rare, no clinical consequence); nephrotic syndrome (rare, due to FSGS). Lithium may also induce hypothyroidism and hyperparathy- roidism. The latter is responsible for hypercalcemia (in 35% of the patients) which can aggravate renal lesions. Nephrogenic diabetes insipidus Lithium induces resistance to ADH: 50% of patients will have impaired urine concentration ability and 20% develop polyuria and polydypsia. In view of t he ef \201 cacy of lithium therapy polyuria is commonly accepted as a side-effect. Treatme nt with amiloride (10 \200\22320 mg/day) can signi \201 cantly reduce daily urine output. Lithium-induced chronic kidney disease Evidence exists that lithium is responsible for chro nic interstitial nephritis sometimes leading to ESRD: \200 Development and progression of CKD are related to the average serum lithium level and the cumulative lith- ium dose. Ther efore, it is recommended to maintain a lithium serum concentration at the lowest level (if pos- sible between 0.4 and 0.8 mmol/l) to adequately control affective symptoms. Sulphasalazines (5-amino salicylic acid, 5-ASA) Sulphazalazine is effective in the treatmen t of patients with in \202 ammatory bowel disease (IBD). Second generation sul- phasalazin es (mesalazine, olsazazine, balsalazine) free of sulphapyridine were developed in order to avoid the hematological side-effects of sulphazalazine. 5-ASA therapy in chronic IBD has be en associated with renal impairment in 1.3 to 3.3 per 1000 patients. Treatment with mesalaz ine and olsalazine has been reported to induce biopsy-proven AIN. In several cases, recover y of renal function did not occur. Current recommendations are to monitor renal function in patients on 5-ASA derivatives every 3 months. If there is renal failure, a renal biopsy is required to con \201 rm the diag- nosis as patients with chronic IBD are at risk of diver se nephropathies (immune glomerulopathies, amyloidosis, oxalate stones). Once CKD is present, withdrawal of lithium after long-term use does not guarantee the stabi lization of renal function and progressive evolution to ESRD is still the rule. NSAIDs (including selective cyclo-oxygenase 2 inhibitors) NSAIDs are inhibitors of cyclo-ox ygenases (COX), which catalyze the production of prostaglandins (PG). Two COX isoforms have been isolated: COX-1 and COX-2. Selective COX-2 inhibitors are associated with fewer gastr ointesti- nal adverse effects than nonselective NSAIDs. Many of the renal effects of NSAIDs appear to be mediated by COX-2 inhibition rather than COX-1 inhibition. COX-2 inhibition d ecreases urinary PG excretion and may result in decreased GFR and sodium retention. This is particularly the case when renal PG secretion is required for the preservation of renal he modynamics: \200 \200 \200 Oral sodium phosphate solution (acute phosphate nephropathy) Oral sodium phosphate solution (OSPS; Fleet Phospho soda), widely used for bowel cleansing, may lead to acute phosphate nephropathy and AKI with a high risk of CKD. While the incidence is low this entity is pro bably under- recognized. Histologic \201 ndings are characterized by the presence of abun dant calcium phosphate crystals in renal tubules. Factors predisposing patients to acute ph osphate neph- ropathy after OSPS are: \200 volume depletion; \200 older age; \200 gen der (female); \200 hypertension; \200 concurrent therapy with diuretics, NSAIDs, ACEIs or ARBs. OSPS is contraindicated in CKD and should be used with caution in elderly patients and in patients with electrolyte disturbances. volume depletion; reduced renal blood \202 ow (cardiac failure); ineffective circulating blood volume (sepsis, cirrhosis, nephrotic syndrome); toxic injury (CsA, tacrolimus); advan ced age; pre-existing renal failure. \200 \200 In normal conditions, temporary use of NSAIDs produces negligible effects on renal hemodyna mics. In the conditions mentioned above, NSAIDs may induce prerenal AKI or ATN. Observation al studies have shown that NSAIDs were responsible for 36% of in-hospital AKI. All NSAIDs, including selective COX-2 inhibitors, may also induce AKI secondary to AIN. Most cases of N SAID-related AIN are associated with nephrotic syndrome (minimal change disease, rarely FSG S, membranous nephropathy). Various \202 uid and electrolyte disorders (hyponatremia, hyp er- kalemia, acidosis, \202 uid retention) as well as hypertension Further reading de Mattos A, Olyaei A, Bennett W. Nephrotoxicity of immunosup- pressive dru gs: long-term consequences and challenges for the future. Am J Kidney Dis 2000; 35: 333 \200\223346. J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 706 Domenica D, Gehr T. 3-Hydroxy-3-methylglutaryl coenzyme A reduct- ase inhibitors and rhabdo myolysis: considerations in the renal failure patient. Curr Opin Nephrol Hypertens 2002; 11 : 123 \200\223133. Table 18.2.4 Renal syndromes related to herbal medicine Glycyrrhiza spp. (Chinese herbal teas, gancao, Boui-ougi-tou) Ephedra spp. (ma huang) Hypertension Isnard Bagnis C, Deray G, et al. Herbs and the kidney. Am J Kidney Dis 2004; 44: 1 \200\22311. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced neph- Traditional African medicine: toxic plants (Securida longe pedunculata, Euphoria matabelens is, Callilepsis laureola, Cape aloes) or adulteration by dichromate. Chinese medicine: Taxu s celebica Marocco: Takaout roumia (para- phenylenediamine) Acute tubular necrosis rotoxicity. Am J Kidney Dis 2005; 45: 804 \200\223817. Kintzel P. Anti-cancer drug-induced kidney disorders. Drug Safety 2001; 24: 19 \200\22338. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001; 60: 804 \200\223817. Stacul F, Adam A, et al. Strategies to reduce the risk of contrast- induced nephropathy. Am J Cardiol 2006; 98: 59K \200\22377K. Peruvian medicine (Uno degatta) Tung Shueh pills (adulterated by mefenamic acid) Acute interstitial nephritis Wali R, Henrich W. Recent developments in toxic nephropathy. Curr Opin Nephrol Hypertens 2002; 11: 155 \200\223163. Internet resources Epocrates ONLINE provides continually updated infor- mation on brand a nd generic drugs (dosing, drug \200\223drug interactions, adverse reactions and mode of act ion: Chinese herbs containing AA (Akebia spp., Boui, Mokutsu) Chinese herbs adulterated by cadmi um Fanconi syndrome Chinese herbs adulterated by phenylbutazone Papillary necrosis http://www.epocrates.com A patient-friendly US-based site with drug information: Chinese herbs or Kampo containing AA (Aristolochia spp., Akebia spp., Mu-tong, Boui, Mokuts u) Chronic interstitial renal \201 brosis http://drugs.com See also Analgesic nephropathy, p. 226 NSAIDs and the kidney, p. 228 Aristolochic acid neph ropathy ( \200\230Chinese herb nephropa- thy \200\231) and other rare causes of interstitia l nephropathy), p. 240 Systemic Cancer therapies and the kidney, p. 714 Datura spp., Rhododendron molle (atropine, scopolamine) Urinary retention Ma huang (ephedrine) Cranberry juice (oxalate) Kidney stones Urothelial carcinoma Chinese herbs containing AA AA, aristolochic acids. From: Isnard Bagnis et al. (2004). This page intentionally left blank L. PLANT 708 Clinical use of diuretics Introduction Diuretics are commonly used pharmacological agents. Alone, or in combination, they are used in the management of hypertension. They are especially useful in those patho- physiological conditions in which sodium retention is a central problem (renal failure, ca rdiac failure, hepatic failure, nephrotic syndrome). Diuretics act by inhibiting sodium rea bsorption in different segments along the nephron. The objective of therapy is to initiate and sustain an increased natriuresis until the patient has returned to euvolemia, at which new steady state it is easier to maintain homeostasis, particularly if dietary salt intake is restricted. Clinical goals may not always be achieved easily and adverse effects are com mon. This relates, in part, to pathophysio- logically determined variation in the pharmacok inetics of individual agents (a phenomenon often referred to as diu- retic resistance) and, in part, to rapid changes in the phar- macodynamic response of the nephron (a phenomenon o ften referred to as diuretic blunting). Although diuretic agents have been used for many de cades, much prescribing still occurs in an ad hoc fashion. Basic and clinical research has expanded our knowledge of the mechanisms of action of these agents. Application of the phar macokinetic and pharmacodynamic principles derived from these studies should improve the ac hievement of clinical objectives. Up to 20% of \201 ltered sodium can be excreted using these agents. Individual agents dif fer in terms of bioavailability, duration of action and modes of excretion. All can be admi nistered orally or parenterally. In general terms they achieve very similar clinical outcom es. Ethacrynic acid is an uncommonly used loop diuretic indicated in patients known to have had hypersensitivity reactions to sulphonamides and related agents. Thiazide and thiazide-like diuretics Thiazide and related diuretics: \200 \200 \200 \200 \200 \200 bendro \202 umethiazide hydrochlorothiazide chlorthalidone indapamide metolazone mefruside . Are also organic anions secreted by OAT-1. These act upon the luminal aspect of the distal convoluted tubule and the connecting segment. These agents have a high af \201 nity for th e chloride-binding site of another member of Solute Carrier Family 12 \200\223 the Sodium- Chloride Co-transporter (NCC), encoded by the SLC12A3 gene on chromosome 16. In this segmen t, diuretics directly inhibit sodium and chlo- ride reabsorption. Calcium reabsorption is i ndirectly increased because of this. The maximum natriuresis achieved is less than that wit h loop diuretics, but the combination of these classes can be especially potent. Individual agents differ in terms of bioavailability, duration of action and modes of excretion. All can be administered orally. In general terms they achieve very similar clinical outcomes. Classi \201 cation of diuretic agents Site of action in different nephron segments classi \201 es the commonly used agents. Although the bulk (60 \200\22370%) of \201 ltered sodi um is reabsorbed in the proximal tubule, agents acting at this site (e.g. aceta- zolamide) are of relatively little clinical utility in edematous states, as increased sodium loss her e is offset by increased reabsorption further down the nephron, particularly in the thick a scending loop of Henle. Diuretics may also have actions at other sites (e.g. many interfere with urate absorption and secretion in the proxi- mal tubule). Potassium-sparing diuretics Potassium-sparing diuretics: \200 \200 \200 \200 amiloride triamterene spironolactone eplerenone. Loop diuretics Loop diuretics: \200 furosemide; \200 bumetanide; \200 torasemide. The \201 rst two of these are organic cations, secreted into the proximal tubule and subs equently blocking the luminal Epithelial Sodium Channel (ENaC) of the principal cells in th e cortical collecting duct. ENaC, also referred to as Sodium Channel Nonvoltage-gated chann el-1 (SCNN1), has three subunits encoded by different genes (SCNN1A on chromo- some 12; SCN N1B and SCNN1G on chromosome 16). Spironolactone and eplerenone, on the other hand, enter t he principal cells from the blood and act intracellularly to inhibit the effect of aldoster one on the intracellular aldos- terone receptor in these cells. This reduces the cellular d rive to reabsorb sodium and decreases the expression of luminal ENaC channels. Interference with sodium reabsorption affects potassium secretion by these cells \200\223 the greater the sodium reabsorp- tion, the greater the potassium secretion. Thus, increased These are organic anions and are secreted into the lumen of the proximal tubule by the orga nic anion transporter-1 (OAT-1). They then act upon the luminal aspect of the thick ascend- ing loop of Henle. Here, they exhibit high af \201 nity for the chloride-binding site of the sodium-potassium-2 chloride transporter (NKCC2). This transporter is an integral membra ne protein from Solute Carrier Family 12, and is encoded by the SLC12A1 gene on chromosome 15. Binding of diuretic directly inhibits sodium and chloride reabsorption. This minimizes the usual luminal positive charge indirectly leading to decreased reabsorption of calcium a nd magne- sium, and interferes with urinary concentrating and diluting mechanisms. CHAPTER 18.3 Clinical use of diuretics 709 delivery of sodium to the cortical collecting duct conse- quent upon successful inhibition of reabsorption in the thick ascending loop of Henle and distal convoluted seg- ment (as wo uld happen with the combined use of a loop and thiazide diuretic) will lead to increased di stal sodium reabsorption and an associated kalliuresis. This can be inhibited by potassium- sparing diuretics which also (on the same principle) minimize the magnesuric effect of the sodium-magnesium antiporter also found in distal nephron segments. Individual agents differ in terms of bioavailability, duration of action and modes of excretion. All can be adminis tered orally. In general terms they achieve very similar clinical outcomes. If a patient is passing \211 100 mmol sodium per day it will be dif \201 cult to lose wei ght/ECF volume as this does not greatly exceed the likely minimum dietary restriction. A ch ange in strategy to increase natriuresis will be needed. Pharmacokinetic and pharmacodynami c considerations are the main reasons why patients fail to achieve and sustain an adequate natriuretic response. Pharmacokinetics are important in the initiation of natriuresis; phar macodynamics in sustaining it. Pharmacokinetic considerations The natriuretic response is proportional to the rate at whic h diuretic is excreted in the tubular \202 uid, and there is a threshold level of excreti on required before it initiates. To overcome pharmacokinetic problems in initiating natriu- resis it is most important to progressively increase the initial dose (or otherwise modify the regimen) until the natriuretic threshold has been exceeded. Giving an ineffective dose more frequently (as is often observed in clinical practice) will not help. In dif \201 cu lt cases, measurement of 24 h sodium excretion may guide dosing. The barriers between admin istering an apparently adequate dose and achieving an adequate amount excreted in the urine need to be identified. Exceeding the natriuretic threshold may be dif \201 cult because o f: Other diuretics Osmotic diuretics Substances which are \201 ltered at the glomerulus but not completely reabsorbed will act as osmotic diuretics. Examples are mannitol, glycerol, g lucose (when glucose has exceeded its maximum reabsorption capacity) and urea (after relief of urinary tract obstruction). Due to the risk of rapid expansion of intravascular volume and pulmonary edema in patients with impaired glomeru- lar \201 ltration rate, these drug s are rarely used in patients with AKI and CKD, and are reserved for patients with trau- ma tic brain injury and acute angle-closure glaucoma. Decreased bioavailability Furosemide has an oral bioavailability of 60%. This may be decre ased with an edematous GI tract. Increasing the oral dose, switching to IV or using an equi va- lent oral dose of bumetanide (which has a higher bioavail- ability) may be chosen to he lp overcome this. Nesiritide This is a recombinant form of the B-type natriuretic peptide and is licensed in the USA for treatment of acute decom- pensated heart failure. Nesiritide binds to the natri uretic peptide receptor A and increases intracellular cyclic GMP. It has to be given IV and is reported to induce vasodilation (reducing preload), natriuresis and diuresis. Increased volume of distribution Diuretics are highly protein-bound. Secretion into the nep hron is predominantly of bound drug. In patients with hypoalbuminemia, free diuretic passes out of the vascular space leading to a decreased amount avail- able for secretion into the tubule. Increasing dose or taking the steps above may help. Achieving clinical objectives To achieve a decrease in total body salt and water requires t hat excretion exceeds intake. Dietary sodium intake is frequently >100 mmol/day ( 6 g salt/ day). Renal avidity for sodium is increased in the edematous clinical conditions. To lose, for example, 5 kg of excess extracellular \202 uid (ECF) volume requires a net sodium los s of 700 mmol, over and above that needed to balance daily intake. Thus, the diuretic regim en employed must initiate and sus- tain a suf \201 cient increment in natriuresis to achie ve this cumulative excretion within a reasonable period of time. It is irrational not to co ncurrently prescribe a reduction in dietary salt intake in those taking diuretics; it may, however, be dif \201 cult to achieve. Many patients \201 nd diets containing <80 mmol/da y unpalat- able and most salt intake is nondiscretionary because of addition during food pr ocessing. Unexpected failure to lose weight/ECF volume in a patient on a seemingly appropri ate dose of diuretic should prompt a systematic enquiry into salt intake. Measurement of 24 h urinary sodium excretion may help. If a patient is passing \211 150 mmol sodium per day but not losing weight it is likely that excess salt intake is the problem. Low glomerular \201 ltration rate In heart failure and renal failure the delivery of diur etic to the kidney will be decreased (as will the initial \201 ltered sodium load). Incre asing dose, taking the steps above or enhancing cardiac output by other means (e.g. ACEIs) may help. Competition for secretion in the proximal tubule Many organic ions accumulate in liver and renal failure: these compete for secretion via OAT-1, decreasing the amount of diuretic rea ching the tubular lumen. Certain medications (e.g. cimetidine) also have this effect. Avoid ing such agents and taking the steps above may help. It was formerly speculated that loop d iuretic excretion was increased if the drug was administered with albumin. Similarly it was felt that proteinuria might decrease the effective tubular concentration, by binding free drug within the tubule. Recent studies do not support these views. Pharmacodynamic considerations In a very short time (days) after the initiation of natriure sis more distal parts of the tubule will increase reabsorption of sodium, thereby blunting the natriuretic effect. L. PLANT 710 Consider more frequent doses or IV infusion to maximize natriuresis As natriuresis declines: increase dose or add thiazide-like diuretic Oedematous Patient As natriuresis declines or hypokalaemia develops: add potassium-sparing diuretic Increase dose until natriuresis commences (may need 24 hour urine collection) Target new ECF volume status/Weight loss If objective not being achieved: review overall clinical scenario and each step of this pro cess Administer once daily loop diuretic (Estimate dose based on pharmacokinetic principles) Restrict dietary sodium intake (<80mmol/day) Fig. 18.3.1 Simpli \201 ed schema illustrating basic steps in achieving clinical objective s. In individual patients each step may be simple/easily achieved or quite dif \201 cult. Potential problems are detailed in the text. Careful application of these principles should achieve the objectives of therapy \200\223 in dif \201 cult cases therapy adjustment and clinical evaluation may be time-consuming an d therapy prolonged. This is principally a local response to an increased delivery of tubular sodium to these se gments, particularly following administration of loop and thiazide diuretics where down- st ream ENaC channel abundance increases. There is now evidence that allelelic variations in t he SLC12A3 and the SCNN1B genes in \202 uence the intensity of this adaptation. Furthermor e, chronic administration of both loop and thiazide diuretics seems to increase the abundan ce of their respective target transporters. Strategies should anticipate the inevitable occ urrence of these pharmacodynamic adaptations and may include: Other uses or indications for speci \201 c diuretic agents The hypocalciuric effects of th iazides may be employed in reducing the frequency of stone events in some hypercal- ciuric patients. However, other measures to achieve this should also be used; not all patients ben e \201 t, and therapy usually needs to continue for at least 2 \200\2233 years. In some cl inical circumstances, choice of agent may be informed by other outcomes. Patients with hear t failure, particularly with more marked left ventricular impairment and low/normal serum p otassium concentrations, may have an excess mortality if potassium-sparing diuretics are no t used. Similarly the survival bene \201 t of treating hypertension with nonpotassium-spar ing diuretics may be attenuated as a consequence of an increase in cardiac deaths. In addit ion, spironolactone may have speci \201 c bene \201 cial effects in some patients with se vere heart failure. Diuretics do not alter outcomes in AKI. Previously they were used in pr otocols attempting to diminish anticipated nephrotoxicity but they have now been shown to b e more likely to increase nephrotoxicity. More frequent dosage Furosemide acts for 6 h and no enhanced natriuresis will occur for th e rest of the day. Once the initial natriuretic threshold has been exceeded, twice- or thri ce-daily dosing allows for a higher cumulative daily loss of sodium until blunting of the r esponse begins. Studies indicate that continuous drug infusion may achieve a greater cumula tive sodium loss than repeated boluses. Sequential nephron blockade As the initial response to loop diuretics declines, a structure d inhibition of the distal nephron sites is indicated. Initially, thiazide diuretics should be administered and subsequently potassium-sparing agents. The latter may, in fact, be req uired quickly \200\223 combination therapy with the other classes markedly increases potas - sium loss and this may be an additional limiting factor. Sequential strategies have been shown to be successful even in patients with advanced renal failure and cardiac failure. In crossover studies there appears to be little difference in the response to equipotent dose s of different thiazides used in this fashion \200\223 personal choice may be the best gui de. Adverse events These are common and include: ECF volume depletion This is particularly common in patients who develop other ECF-depletin g problems such as diarrhea and vomiting while continuing on diuretics. Coadministration of loop and thiazide diuretics can also rapidly deplete the ECF volume. CHAPTER 18.3 Clinical use of diuretics 711 This adverse event is often associated with raised blood urea concentrations because of ren al hypoperfusion. In many patients, glomerular \201 ltration rate (GFR) is relatively pre served due to autoregulation, but impaired renal blood \202 ow causes enhanced tubular ur ea reabsorption. Muscle cramps Ototoxicity This is a major but uncommon potential side-effect. It has been r eported with high dose (>2 g/day) infusion therapy in patients with renal failure. The mech anism is believed to be mediated via the NKCC1 transporter in the inner ear, which is struc turally similar to the NKCC2 transporter in the kidney. Decreased GFR This can occur as a consequence of ECF depletion and is more commonly seen in older patients, those with pre- existing CKD, chronic heart failure and low mean arterial pressure. Pregnancy Diuretics should be avoided in pregnancy. They can cross the placenta and may cau se fetal electrolyte disturbances. Placental perfusion may be compromised. Diuretics enter breast milk. Electrolyte disturbances Including: \200 \200 \200 hyponatremia (commoner with thiazides); hypomagnesemia (commoner with thiazides); hypokalem ia (most common when combinations of loop and thiazide diuretics are used). Further reading Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does n ot affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 2000 ; 11: 1100 \200\2231105. Avoiding a high water intake (>1.5 L/day) may reduce the incidence of hyponatremia, which i s more common in the elderly. Hypokalemia is usually manifest within 5 \200\2237 days of es tab- lishing therapy; \200\230routine screening \200\231 is not indicated in the absence o f changes in clinical circumstances, dose or other medications. Potassium-sparing diuretics may cause hyperkalemia, espe- cially in the presence of renal impairment. Hypercalcemia, d yslipidemia, and glucose intolerance (especially with associated hypokalemia) are common si de- effects of thiazide diuretics. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:38 \200\22350. Brater DC. Diure tic therapy. New Eng J Med 1998; 339: 387 \200\223395. Channer KS, McLean KA, Lawson-Matthe w P, Richardson M. Combination diuretic treatment in severe heart failure: a ran- domised c ontrolled trial. Br Heart J 1994; 71: 146 \200\223150. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100: 1311 \200\2231315. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inacti vation of the secretory Na-K-2Cl co-trans- porter. Nature Genet 1999; 22: 192 \200\223195. Metabolic alkalosis This results from chloride loss and ECF volume contraction. Potassium-s paring diuretics may, alternatively, cause acidosis. Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am J Kidney Dis 1994; 23: 623 \200\223643. Fliser D, Schroter M, Neubeck M, Ritz E. Coadministration of thiazide diuretics increases t he ef \201 cacy of loop diuretics even in patients with advanced renal failure. Kidney Int 1994; 46: 482 \200\223488. Hyperuricemia and gout Tubular handling of uric acid is complex, with both reab- sorption a nd secretion occurring in the proximal tubule. Diuretics (particularly thiazides) can inter fere with either of these processes with the usual consequence being hype- ruricemia. This effect is usually dose dependent and frequently asymp- tomatic. Combination therapy with AC EIs or ARBs may blunt the effect. Clinical gout is more likely if the patient is also ECF v olume- depleted. Fliser D, Zurbruggen I, Mutschler E, et al. Coadministration of albumin and furosemide in p atients with the nephrotic syndrome. Kidney Int 1999; 55: 629 \200\223634. Gupta S, Neyses L. Diuretic usage in heart failure: a continuing conundrum in 2005. Eur Heart J 2005; 26: 644 \200\223649. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. Br Med J 2006; 333: 406 \200\223407. Hoes AW, Grobbee DE, Lubsen J, Man in \200\231t Veld, AJ, van der Does E, Hofman, A. Diure tics, beta-blockers, and the risk of sudden car- diac death in hypertensive patients. Ann I ntern Med 1995; 123: 481 \200\223487. Kim JH. Long-term adaptation of renal ion transporters to chronic diuretic treatment. Am J Nephrol 2004; 24: 595 \200\223605. Meisler MH, Barrow LL, Canessa CM, Rossier BC. SCNN1, an epithelial cell sodium channel gen e in the conserved linkage group on mouse chromosome 6 and human chromosome 12. Genomics 19 94; 24: 185 \200\223186. Thiamine depletion This may follow prolonged diuretic use (is a water-soluble vitamin), pot entially leading to impaired cardiac function. Chronic hypercalciuria and magnesiuria This is induced by long-term use of loop diuretics. It may lead to osteopenia, subclinical hyperparathyroidism and alteration in intracellular cations leading to a potentially proin \202 ammatory vascular phenotype. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709 \200\223717. Rudy DW, Voelker JR, Greene PK, Esparza FA, Brater DC. Loop diuretics for chronic renal ins uf \201 ciency: a continuous infusion is more ef \201 cacious than bolus therapy. Ann Int ern Med 1991; 115: 360 \200\223366. Activation of the renin \200\223angiotensin \200\223aldosterone system Use of loop diuretic s as the sole therapy for cardiac failure may lead to chronic activation of the renin \200 \223angiotensin \200\223 aldosterone system and other harmful neuroendocrine alterations. Salvador DRK, Rey NR, Ramos GC, Punzalan FER. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2004; (1): CD003178 . pub3. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman \200\231s variant of Bartter \200\231s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensiti ve Na-Cl cotransporter. Nature Genet 1996; 12: 24 \200\22330. Hypersensitivity reactions These include skin rashes and interstitial nephritis. L. PLANT 712 Internet resources NICE guidelines for treatment of hypertension and heart failure: Simon DB, Karet FE, Hamdan JM, Di Pietro A, Sanjad SA, Lifton, RP. Bartter \200\231s syndro me, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl tran sporter NKCC2. Nature Genet 1996; 13: 183 \200\223188. http://www.nice.org.uk National Prescribing Center: Sun WY, Reiser IW, Chou S-Y. Risk factors for acute renal insuf \201 - ciency induced by d iuretics in patients with congestive heart fail- ure. Am J Kidney Dis 2006; 47: 798 \200 \223808. http://www.npc.co.uk/ Voilley N, Bassilana F, Mignon C, et al. Cloning, chromosomal locali- zation, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amilorid e-sen- sitive sodium channel. Genomics 1995; 28: 560 \200\223565. See also Drug-induced nephropathies, p. 698 Nephrotic syndrome, p. 80 Clinical approach to hypertension, p. 286 Medical management of stone disease, p. 270 Vormfelde SV, Sehrt D, Toliat MR, et al. Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol The r 2007; 82: 300 \200\223309. Weber KT. Furosemide in the long-term management of heart fail- ure: the good, the bad and the uncertain. J Am Coll Cardiol 2004; 44: 1308 \200\2231310. This page intentionally left blank J. FREW, C. MCBAIN AND T. ELLIOTT 714 Systemic cancer therapies and the kidney Introduction Many chemotherapeutic agents are \201 ltered by the kidneys with some also u ndergoing tubular secretion. The kidneys are therefore vulnerable to the toxic effects of c ytotoxic drugs with nephrotoxicity often the dose-limiting side- effect in chemotherapeutic regimens. Drug pharmacokinetics may be altered in patients with renal impairment if renal excretion plays a signi \201 cant role in drug elimination. Dose adjustment tailored to pa tients \200\231 renal function is necessary to avoid exposure to excessive drug levels and subsequent toxicity. Clearance of the drug by hemodialysis can lead to decreased drug exposure and therapeutic e f \201 cacy. Dialysable drugs \200 \200 \200 \200 \200 cisplatin carboplatin cyclophosphamide ifosfamide methotrexate. Nephrotoxicity of chemotherapy agents Chemotherapy agents can affect the microvasculature, glomeruli and tubules. Clinical manifestations (examples given below) depend on the site of nephron most adversely affected and include: \200 Assessment of renal function Renal function is assessed prior to chemotherapy dosing. Metho ds include: \200 EDTA-GFR (gold standard: radioisotope to measure GFR); timed urine collection to calculate creatinine clearance: (Urine Cr \227 Urine Vol) (Plasma Cr \227 Time (min)) tubulointerstitial injury causing asymptomatic decrease in GFR; hemolytic microangiopathy r esembling hemolytic uremic syndrome (HUS); tubular dysfunction with electrolyte imbalance; AKI necessitating dialysis. ; CrCl (mL/min) = \200 formulas to estimate GFR. Formulas developed to estimate creatinine clearance are based on point sampling of serum cr eatinine and incorporate patient-related factors including age, weight and gender. Formulas include: \200 \200 \200 \200 \200 Agents causing tubulointerstitial damage Cisplatin Heavy metal alkylating-like agent. Widel y used in many treatment sites including: \200 \200 \200 \200 Cockcroft and Gault (see below); Jeliffe; Wright; Chatelut; Modi \201 cation of Diet in Re nal Disease (MDRD) study formula. (most commonly employed, see Appendix) testicular; gynecological; urological; head and neck cancers. Cisplatin rapidly becomes protein-bound but concentrates in the kidneys by undetermined mec hanisms. 15 \200\22375% cleared in the urine as unchanged drug. Nephrotoxicity is major dos e-limiting side-effect. Cisplatin should be avoided if GFR <30 mL/min. Cisplatin nephrotoxi city manifestations: \200 \200 \200 \200 Prevention of nephrotoxicity: \200 vigor ous prehydration; \200 0.9% saline infusion; aim for urine output >150 mL/h; \200 magne sium replacement as cisplatin-induced hypomag- nesemia potentiates nephrotoxicity; consider mannitol. Formulas require stable creatinine and are in \202 uenced by muscle mass and \202 uid ba lance. Cockcroft and Gault formula (140 \200\223 age) \227 Weight (kg) \227 \200\230Y \200\231 CrCl (mL/min) = Serum Cr (mg/dL) subclinical reduction in GFR with each cycle; AKI; salt-wasting nephropathy; magnesium-wast ing nephropathy. Y = 1.23 in men and 1.04 in women. Chemotherapy The aim of treatment in patients with cancer needs to be clearly de \201 ned. Potential side-effect pro \201 les should be considered in the context of whether treatme nt is curative or palliative. Drugs causing signi \201 cant nephrotoxicity such as meth- o trexate and cisplatin should be avoided in patients with renal insuf \201 ciency. Renal impairment and pharmacokinetics Anticancer drugs can be eliminated from the body thro ugh metabolism, excretion in the urine, bile or feces, or through the respiratory tract. Pa tients with renal dysfunction receiving chemotherapy which is primarily eliminated via the kidneys have decreased clearance in the urine. This results in increased systemic exposure as indicated by increased area under the curve (AUC) of plasma concentration vs time (Table 18.4.1). Carboplatin A second generation platinum agent. Nephrotoxicity is rarely clinically signi \201 cant. Carboplatin dosing is safe in patients with renal impairment. Renal clearance is closely correlated with GFR. The dose is calculated using the Calvert formula (see below), which considers the GFR and desired AUC (normally 4 \200\2237 mg/mL/min). Carboplatin = target AUC \227 (EDTA-GFR + 25) dose (mg) Hemodialysis and chemotherapy There is limited data on the clearance of chemotherapeutic ag ents by dialysis. CHAPTER 18.4 Systemic cancer therapies and the kidney 715 Table 18.4.1 Chemotherapy dosing in patients with renal impairment Mortality 50%. Gemcitabine A nucleoside analog which interferes with DNA synthesis. It is used in breast, bladder, lung, gastrointestinal, gyneco- logical and germ cell tumors. Mild proteinuria and microscopic hematuria occur in up to 50% of patients and elevated creatinine in 8%. It rar ely develops into profound HUS with no clear rela- tionship between dose or time interval p ost therapy. Bleomycin Capecitabine Cisplatin Carboplatin Dacarbazine Etoposide Epirubicin Fludarabine Ifosfamide Irinotecan Melphalan Methotrexate Nitrosoureas Raltitrexed Drugs requiring dose adjustment Docetaxel Drugs not generally requiring dose adjustment Fluorouracil Agents causing urinary tract obstruction Ifosfomide and cyclophosphamide Gemcitabine Oxaliplatin Both drugs can cause obstruction secondary to hemorrhagic cystitis. This complication is ca used by metabolites including acrolein excreted in the urine. Prevention: \200 \200 Methotrexate (MTX) An antifolate drug which depletes cellular tetrahydro- folate. High dose MTX (1 \200\22312 g/m2) is used in the treatment of CNS lymphoma and osteosarcomas. It is exclusively eliminated via the kidneys. Parent drug and metabolite are highly insoluble in acid and urine. Toxicity is related to level and duration of elevated MTX levels. AKI can o ccur due to precipitation of drug within tubules and potentially a direct nephrotoxic effec t. Normally it is self-limiting with recovery over 12 7 days. Prevention of nephrotoxici ty: adequte hydration; IV bicarbonate (alkalinize urine); leukovorin rescue (tetrahydrofoli c acid derivative) com- mencing 24 \200\22336 h post MTX. vigorous hydration and frequent bladder emptying; IV Mesna \233\232 (binds acrolein to prod uce nontoxic com- pound). Biological and targeted therapies There has been a marked increase in the use of biological therapies in cancer management over recent years. The side-effect profiles of most of thes e therapies are favorable compared to conventional cytotoxic chemotherapy.