: s i x a l y h p o r P y l i a d : t n e m t a e r T : t n e m t a e r T g m 0 0 1 \200\223 0 5 g m 0 0 1 \200\223 0 5 h 2 1 j j h 6 l a m r o N l a m r o N g m 0 0 1 e s o D e s o D y r e v e y r e v e ) d e u n i t n o C n o t n a r u f o r t i m i i r p o h t e m i r T ( l a i b o r c i m l a i b o r c i m N 2 2 1 . e l b a T i t n A i t n A ) d e u n i t n o C ( h t i d e d n e m m o c e r s g u r d y t i c x o t o r u e N k s i r p u s o e y m n o i t a n b m o c s t n e m m o C w r u c c o n a c r o s s e n i s w o r d n i r e h t o h t i / n o i s u f n o c p u s o e y m m u m x a m f i d e s a e r c n I n o i s s e r p y l l o s r o t i n o m e v i s s e r p l i u f e r a c , e s o d l i f w o y t i l a d o m n m / L m 0 2 \200\223 0 1 n m / L m 0 2 \200\223 0 1 n m / L m 0 2 \200\223 0 1 i i i e g n a h c o N e g n a h c o N h 4 2 g k / g m 5 2 R F G e R F G e R F G e s a s a s a H V V C y r e v e e s o D e s o D e s o D s i s y l a i d o t g n d r o c c a t n e m n n n . i i i / L m 0 1 < R F G e / L m 0 1 < R F G e n m / L m 0 1 < n m / L m 0 1 < e g n a h c o N e g n a h c o N n n n n i i i i i i i s a s a s a s a D P A C R F G e R F G e e s o D e s o D e s o D e s o D n m n m i i / L m 0 1 < R F G e / L m 0 1 < R F G e / L m 0 1 < R F G e t s u d a e s o D n m / L m 0 1 < e g n a h c o N e g n a h c o N n n n n i i i i i j s a s a s a s a R F G e e s o D e s o D e s o D e s o D y r e v e n m n m n m D H i i i h \200\223 0 0 4 / x 3 \200\223 2 y r e v e n m L m 0 1 < 2 1 \200\223 8 : s i x a l y h p o r P 3 \200\223 2 g k / g m 5 \200\223 5 2 : t n e m t a e r T i k e e w / x 2 \200\223 1 e g n a h c o N e g n a h c o N g k / g m 5 2 1 h 4 2 r o / s k e e w 3 : r e t s o Z r o f g m 0 0 2 g m 0 0 8 g m 0 5 4 g m 0 5 4 s k e e w y r e v e k e e w f h 2 1 h 4 2 . . s k e e w 3 r o y r e v e n m L m 0 2 \200\223 0 1 g m 0 0 8 i y r e v e g m 0 5 4 e c w 3 \200\223 2 : s i x a l y h p o r P e g n a h c o N g k / g m 0 1 \200\223 5 : t n e m t a e r T / e g n a h c o N i h 4 2 y a d / x 4 \200\223 3 g k / g m 5 2 t : r e t s o Z y l k e e w r o g m 0 0 2 g m 0 5 4 s k e e w h 2 1 \200\223 8 y r e v e f f h 8 4 h 4 2 R F G e o t . s k e e w 3 r o h 8 4 y r e v e g m 0 5 y r e v e n m L m 0 5 \200\223 0 2 g m 0 0 8 i 4 y r e v e g m 0 5 4 3 \200\223 2 : s i x a l y h p o r P g m 0 0 4 \200\223 0 0 2 e g n a h c o N e g n a h c o N g k / g m 0 1 \200\223 5 : t n e m t a e r T / h 2 1 g n d r o c c a g k / g m 5 2 : r e t s o Z r o i y a d / 5 x y a d s k e e w y r e v e f f h 4 2 h 2 1 x 5 . t n e m g m 0 0 9 h 2 1 h 4 2 y l i a d , 1 g m 0 0 8 s k e e w 3 \200\223 2 y a d \200\223 0 0 2 y a d / 5 x r o y r e v e t s u d a y r e v e : s i x a l y h p o r P g m 0 0 1 f e g n a h c o N g k / g m 0 1 \200\223 5 : t n e m t a e r T n o g m 0 0 2 h 2 1 j h 8 l a m r o N : s k e e w 3 x e p m S : r e t s o Z g k / g m 5 g m 0 0 4 g m 0 0 9 y a d e s o D y r e v e y r e v e l n e h t r o x 5 i f ) V I ( ) r i v o l c c n a g l a V O P ( ) V I ( e n n c y m a d n r i v o l c c n a G i i l c y c y x o D r i v o l c c A r i v o l c c A i i ) O P ( i i i l l a i b o r c i m C e d i s o e l c u n s e u g o l a n a c i t e h t n y S i t n A , y t i c x o t o r h p e n r e b m u n s e s a e r c n f d n a n s t n e m m o C o y l r a l u c i t r a P e s a e s i d i s t n e m m o C h t i f i d e s u n o i t a c d e m n o i t c a r e t n n i r u e n c l a c o y l l a i t n e t o P d e t a c o s s a w s r o t i b h n l r e h t o n i r a f r a w e v e o t s u o i r e s t n e i t a p a i i y l e r a r l a n e r i e t o n l h t i i e u D i e h t f w o i i y t i l a d o m y t i l a d o m n m / L m 0 2 \200\223 0 1 i g m 0 0 8 \200\223 0 0 4 e g n a h c o N e g n a h c o N e g n a h c o N h 4 2 H V V C R F G e s a H V V C s i s y l a i d o t g n d r o c c a t n e m y r e v e e s o D s i s y l a i d o t g n d r o c c a t n e m n i n m / L m 0 1 < n m / L m 0 1 < e g n a h c o N e g n a h c o N e g n a h c o N n n i i i i i i D P A C s a s a D P A C R F G e R F G e e s o D R F G e e s o D R F G e n y l i a d n m / L m 0 1 < l a m r o n % 0 0 1 r o t s u d a e s o D t s u d a e s o D s e m r e t f a n m / L m 0 1 < e g n a h c o N e g n a h c o N e g n a h c o N n i j i i j i i t 3 e s o d s a s a e s o D k e e w a s i s y l a d e s o D D H D H i n m L m 0 1 < y r e v e n m L m 0 1 < i n e h t y a d / g k / g m 6 i e g n a h c o N e g n a h c o N e g n a h c o N 3 \200\223 2 g m 0 0 2 \200\223 0 5 / / g k / g m 6 , s k e e w r o y l i a d f h 8 n m L m 0 2 \200\223 0 1 n m L m 0 2 \200\223 0 1 y r e v e i i y a d / g k / g m 5 1 n e h t / e g n a h c o N e g n a h c o N e g n a h c o N / 3 \200\223 2 g m 0 0 4 \200\223 0 5 g k / g m 5 1 , s k e e w r o y l i a d R F G e o t f R F G e o t h 8 n m L m 0 5 \200\223 0 2 n m L m 0 5 \200\223 0 2 y r e v e i i y a d / g k / g m 8 2 n e h t / e g n a h c o N e g n a h c o N e g n a h c o N g n d r o c c a / 3 \200\223 2 g m 0 0 4 \200\223 0 5 g n d r o c c a g k / g m 8 2 i i , s k e e w r o y l i a d f h 8 n e h t / g m 4 \200\223 3 n e h t t n e m y l r u o h - 2 1 g k / g m 6 t n e m h 8 y r e v e , e c n o g m 0 0 4 \200\223 0 0 2 h 4 2 r o g m 0 0 3 \200\223 0 0 2 n e h t y l i a d , s k e e w 3 \200\223 2 y r e v e t s u d a t s u d a y a d / g k / g m 0 6 y l r u o h - 2 1 g k g m 0 0 4 g m 0 0 2 \200\223 0 0 1 j f g m 0 0 4 \200\223 0 5 j l a m r o N y l r u o h - 2 1 y l r u o h - 2 1 l a m r o N g k / g m 0 6 , h 4 2 \200\223 2 1 h 4 2 r o e s o D e s o D : l a r O y l i a d r o : V I f f ) d e u n i t n o C e o z a n o c o t e K e o z a n o c i r o V l e o z a n o c a r t I l e o z a n o c u F l l t e n r a c s o F l a i b o r c i m ( l a i b l o a r g c n i m u f i i t t n n A A l 2 2 1 . c n o h p s o h P i s e o z a d m e v i t a v i r e d s e o z a i r T l e l b a T l i t n A d c a d n a i i i d n a , s i s o d c a n o m m o c l a t s i d e s u a c n a c r o h t i s i w o r r a m e n o B , c i l , a m e a l o v o p y h n c i r e t o h p m A a m e a l a k o p y h e s a e s i d n c i r e t o h p m a f s t n e m m o C h t i e s a e s i d i i i n o i s s e r p p u s w c x o t o r h p e n o b a t e m d n a i d e r r e f e r p s i i i w s t n e i t a p t n e i t a p l a m o s o p , ; s i s o d c a a i r u y l o p y l h g h s i r a l u b u t e r o m l a n e r l a n e r i i n i l i y t i l a d o m n m / L m 0 2 \200\223 0 1 i e g n a h c o N e g n a h c o N e g n a h c o N e g n a h c o N R F G e s a H V V C e s o D s i s y l a i d o t g n d r o c c a t n e m n i y r e v e s e s o d r u o e g n a h c o N e g n a h c o N e g n a h c o N e g n a h c o N i g k / g m 0 5 R F G e f d e d v d D P A C n i h 4 2 i i t s u d a e s o D n m / L m 0 1 < e g n a h c o N e g n a h c o N e g n a h c o N e g n a h c o N n i i j s a e s o D D H o t n m L m 0 1 < e s o d e r i e g n a h c o N e g n a h c o N e g n a h c o N e g n a h c o N g n d r o c c a , g k / g m 0 5 / i s l e v e n e h t l n m L m 0 2 \200\223 0 1 y r e v e i e g n a h c o N e g n a h c o N e g n a h c o N e g n a h c o N / g k / g m 0 5 h 4 2 R F G e o t n m L m 0 5 \200\223 0 2 y r e v e i e g n a h c o N e g n a h c o N e g n a h c o N e s o d e g n a h c o N / g n d r o c c a g k / g m 0 5 i h 2 1 , , t n e m e s o d d e d v d r e p s s e n u \200\223 s m a r g o r c m 0 5 2 y l i a d e s u y l i a d / g m 5 m u m x a m i g n d a o g k / g m 0 0 2 \200\223 0 0 1 l , y a d / g k / g m 3 \200\223 1 i g n d a o t s u d a i n e h t g m 0 0 1 i r u o y l i a d g m 0 5 , r e t f a e r e h t j / g k / g m 5 1 l a m r o N l f i , l g m 0 0 2 y a d / g k g k 0 7 > n s e s o d e s o D g m 0 7 g m 0 7 i i n e h t n e h t y a d y a d . ) n c i r e t o h p m A n g n u f o u d n A n c i r e t o h p m A i i n g n u f o p s a C i e m o s i B m A e n i s o t y c u F i l a m o s o p l i l a i b o r c i m i l ( l d e t a n i r o u F e n d m s e n e y l o P e u g o l a n a i o n h c E s n d n a c i i i t n A i i r y p l CHAPTER 12 Drugs and the kidney 892 Cardiovascular drugs Introduction (cid:2) Cardiovascular disease is a signi \201 cant caus e of morbidity and mortality in patients with kidney disease ( b p. 198). However, most of the large practice-changing cardiology trials have speci \201 cally excluded patients with renal impairment. This means that the robust evidence base developed for many CV drugs in the general population is not necessarily transferable to individuals with renal disease. X In fact, in certain situations, there may be a risk of more harm than good. 2 Hypertension in dialysis patients is often driven by salt and water over- load, with volume expansion. Discuss changes in an antihypertensive regi- men with the patient \200\231 s renal team to avoid hypotensive episodes during dialysis treatment. Speci \201 c drug groups Beta-blockers Atenolol is excreted by the kidneys and is removed by HD (but not PD). It is still used widely in advanced CKD, but the dose is best titrated to avoid the effects of accumulation (e.g. bradycardia). Similarly, metoprolol, bisoprolol, and carvedilol should be titrated cautiously, accord- ing to clinical circumstances. The l atter three are not removed by dialysis. Calcium channel blockers, -blockers, and nitrat es Do not require dose reduction, although caution around the precipitation of postural hyp otension should be exercised. Aspirin Is prescribed in standard doses in CKD for primary and secondary CV risk modi \201 cation, although bleeding risk is likely to increase as renal dysfunction progresses. Use with caution when combined with other antiplatelet agents. Consider gastric protection. Clopidogrel Indications, bene \201 ts, and ideal dose in more advanced CKD are unknown. Mo st clinicians use as for non-renal patients, but caution is required, as the risk of bleedi ng is likely to be increased. Heparin LMWHs undergo renal clearance and accumulate in advanced CKD (particularly GFR <30m L/min). (cid:2) While the doses used for prophylaxis against venous thromboembolism are gen erally well tolerated, larger \200\230 treatment \200\231 doses have been associated with signi \201 cant, and serious, bleeding complications. Monitoring of activated factor Xa l evels has been advocated but may not always be practical. While suggestions for dose modi \201 cation are available for some LMWHs, unfractionated heparin may be preferred in many s ituations. 2 It is vital that a local guideline is developed and adhered to. At present, ma ny patients with CKD do not receive, or receive inappropriate doses of, anticoagulants in e mergency situations, such as acute coronary syndrome \200\224 even though CKD places them in a high-risk group. Unfractionated heparin is usually commenced in standard dosage and adjusted, according to APTT. Fondaparinux is a factor Xa inhibitor that can be used at a reduced dose in mild to moderat e renal impairment but is best avoided in more advanced CKD (GFR <30mL/min). CARDIOVASCULAR DRUGS 893 Oral anticoagulants Risk/bene \201 t assessment must be carefully undertaken for many indi cations (such as prevention of dialysis access thrombosis or prevention of thromboembolism in AF), particularly as CKD progresses. (cid:2) Individuals with CKD often require lower do ses of warfarin, have poorer control of anticoagulation, and are at increased risk of bleed ing complications. Anticoagulants may 6 need lower dosage at initiation and closer monitori ng. The risks (as well as uncertainties regarding bene \201 t) increase in CKD stage 5 and 5D. There is much more experience with warfarin than other oral anticoagulants, such as ph enindione. However, there is increasing recognition that warfarin therapy in CKD 5D may sig ni \201 cantly contribute to ectopic vascular calci \201 cation. Experience with the direct thrombin inhibitor dabigatran is limited in CKD. Patients with a CrCl <30mL/min were excluded from the RE-LY study that de \201 ned its utility in AF. Whi le dose reductions have been sug- gested, it is best avoided if GFR <30mL/min and certainly if <15mL/min. Its anticoagulant effect is more dif \201 cult to reverse. It undergoes ren al clear- ance and is also removed by dialysis (which has been proposed as a poten- tial me ans of reversal in emergency situations). Thrombolytics No dose reduction recommended, although the potential for bleeding complicati ons rises as CKD advances. ACE inhibitors (and ARBs) Widely prescribed in CKD ( b p. 203). Clinical trials show a good safety pro \201 le, even in higher CKD stages. Check eGFR and K + before and 3 \200\223 5 days after. Expect (and allow) a rise in SCr or d eGFR of up t o 20%, but recheck within 2 \200\223 4 weeks. (cid:2) A precipitous fall in GFR may be see n in situations where renal perfusion is dependent on RAS activation ( l CCF, bilateral ren al artery stenosis, stenosis to a solitary kidney). 2 Rapid d GFR and AKI are always made m ore likely by volume depletion (diuretics, GI upset, etc.). It is sensible to advise patien ts to temporarily stop these medications in the event of intercurrent illness, particularly if dehydration is a factor. Digoxin Is less tissue-bound in the presence of impaired renal function and 6 has a reduced volume of distribution. Dose reductions are necessary from relatively early CKD, and monit oring of levels can guide maintenance treatment. Loading doses are also reduced at ESRD (e. g. 750 micrograms \200\224 1mg in three divided doses). Digoxin is not removed by dialysis or \201 ltration. Digitoxin, an alternative cardiac glycoside, undergoes liver metabolis m and does not require such substantial dose adjustments. Amiodarone Does not require dose modi \201 cation, but beware multiple drug interactions. Statins Evidence of bene \201 t for lipid-lowering therapy in CKD is limited ( b p. 205), but statins can be used at standard doses. Myopathy is more common, so high doses should be used with caution. There is an important interaction with ciclosporin in transplant recipi ents ( l i myopathy risk). (cid:2) Fibrates require dose reduction in moderate renal impair ment (GFR <40mL/min) and should be avoided in advanced CKD. They are also associated with a reversible increase in SCr (thought to be mediated by peroxisome proliferator-activated re ceptor A ). Ezetimibe is considered safe for use with no dose modi \201 cation. CHAPTER 12 Drugs and the kidney 894 Prescribing in speci \201 c situations Diabetic CKD Close working between renal and diabet ic teams is highly desirable. Collaboration can ensure a patient \200\231 s treatment rema ins appropriate as CKD progresses. Medications must be adjusted for optimal control of glyc aemia, reduction of proteinuria, modi \201 cation of cardiovascular risk, and prevention o f CKD progression. Diabetic patients may also require intervention for CKD-related complica tions, including anemia, at a higher eGFR, and these can be more symptomatic in the presenc e of other diabetes-related comorbidities. Insulin (cid:2) Metabolized, rather than excrete d, by the kidneys. Careful prospective review of an individual \200\231 s insulin regimen is necessary, as GFR falls, if hypoglycaemia is to be avoided. Educate the patient that ins ulin requirements may decrease, independent of changes in diet or activity. Insulin also ha s a role in the management of hyperkalaemia ( b p. 130). Insulin is not removed by dialysis . Metformin 90 \200\223 100% renal excretion and 6 contraindicated in advanced CKD. Consid er switching to alternatives (often insulin) once eGFR <40mL/ min and certainly once <30mL/ min. 2 Accumulation in renal insuf \201 ciency can rarely cause profound lactic acidosis, particularly during episodes of acute-on-chronic kidney injury ( (cid:2) contrast) or durin g intercurrent illnesses involving hypoxaemia (e.g. sepsis, MI). Sulfonylureas Gliclazide and glipizide undergo minimal renal clearance and require no dose adjustment. However, since they increase insulin secretion, which itself may have a prolong ed action in CKD, they should be titrated with caution. (cid:2) The metabolites of glibencl amide and glimepiride may accumulate and cause unpredictable hypoglycaemia, so these agents are best avoided. Acarbose Avoid if eGFR <25mL/min, as metabolites accumulate. Metglitinides Repaglinide and nateglinide can be used without a dose adjustment. Thiazolidinediones Undergo biliary excretion and do not require dose adjustment. However, t hey have been associated with problematic \202 uid retention and oedema in patients with NYHA class III or IV heart failure. Given the incidence of cardiac disease and volume overl oad in CKD, they should be avoided or used with extreme caution. Gliptins predominantly undergo renal excretion (except linagliptin-bile and GI tract). Sita gliptin requires dose reduction; e.g. 50mg daily for GFR 30 \200\22350mL/min and 25mg for G FR <30ml/min. Sitagliptin is not dialysed and can be used in HD and CAPD patients (generall y 25mg daily). Linagliptin \200\231s route of elimination means that it does not require do se adjustment. There is less experience with other gliptins. Thyroid disease Thyroid hormone Replacement does not require dose adjustment. However, co-a dministration with phosphate binders or oral iron impairs absorption. T3 and T4 are both hi ghly protein-bound. In profound PRESCRIBING IN SPECIFIC SITUATIONS 895 hypoalbuminaemia, such as in the nephrotic syndrome, changes in the unbound fraction of T3 and T4 may cause temporary toxicity. In addition, TFTs should be interpreted with caution in advanced CKD, as uraemia is associa ted with d peripheral enzymatic conversion of T4 l T3, as well as d protein binding. Practi cally, this means titrating dose changes more slowly against clinical, not just biochemical , response. Hyperuricaemia and gout Fractional excretion of uric acid falls as GFR declines, and this m ay be aggravated by drugs that reduce urate clearance (e.g. diuretics, ciclosporin, NSAIDs) . Gout is, therefore, highly prevalent in CKD. Colchicine Accumulates in renal impairment, so lower doses are recommended to avoid GI and hematological side effects. e.g. 500mcg bd. Allopurinol Is metabolized to oxypurinol, an active metabolite that accumulates in renal im pairment. This means it should be introduced at lower dosage (e.g. 100mg daily) and titrate d. Side effects include cutaneous reactions and bone marrow suppression. (cid:2) There is a n important drug interaction between azathioprine and allopurinol ( l profound bone marrow suppression). Concomitant administration should be avoided. There is limited experience with febuxostat , a newer xanthine oxi- dase inhibitor once GFR <30mL/min. Concomitant use with azathioprine should be avoided. NSAIDs Are best avoided, where possible, but may be useful for brief administration under c lose supervision. Corticosteroids may be helpful in severe or refractory cases, with no dos e adjustments. Rasburicase Is an intravenously administered urate oxidase inhibitor that potently reduces uric acid levels in the prophylaxis and treatment of acute hyperuricaemia during chemothera py. No dose adjustment is required. Bone metabolism Bisphosphonates Are extensively excreted in the urine. They are assimilated into bone and promote osteoclast apoptosis. The normal bone remodel- ling cycle (the coupl ing of osteoclastic resorption with osteoblastic forma- tion) lasts 7 200 days but may exce ed 1,000 days, following bisphosphonate administration. Impaired clearance in renal insuf \201 ciency increases the amount incorporated in the skeleton where it may cause or exacerb ate low bone turnover and 6 adynamic bone disorder. Safety in CKD 4 \200\223 5 is unproven , and bisphosphonates should be avoided in this context ( b p. 234). Rapid administration o f IV bisphosphonates (e.g. pamidronate) without adequate hydration has also been associated with acute nephrotoxicity and AKI. Nausea Dopamine antagonists Such as domperidone, metoclopramide, and pro chlorperazine, are not renally excreted and can be used in renal insuf \201 ciency. However, extrapyramidal side effects are more common, so titrate doses carefully. Domperidone does not cross the bl ood \200\223 brain barrier and may be preferred. 5-HT3 antagonists Such as ondansetron and granisetron, do not require dose modi \201 catio n. CHAPTER 12 Drugs and the kidney 896 Dyspepsia Dyspeptic symptoms are common in advanced CKD. Uraemia may affect autonomic and e nteric nervous system function. CAPD may delay gastric emptying and promote re \202 ux. In addition, gastric irritants, such as aspirin, are widely prescribed in this population. Antacids Are safe, although aluminum or magnesium can accumulate if taken in excess. Proton pump inhibitors Can be safely prescribed in standard doses. PPIs have been implicate d in the development of interstitial nephritis. Although this is a rare side effect, the nu mber of individuals taking them means that they are now the most important cause of acute i nterstitial nephritis in many countries. H2 receptor antagonists Are renally excreted but generally prescribed safely, with no dose modi \201 cation. Cimetidine is best avoided: it interacts with cytochrome P450 enzymes, c ausing drug interactions, and falsely elevates SCr through the inhibition of active urinary creatinine secretion. Constipation GI motility is affected by renal failure: uraemia disturbs colonic innerva- ti on; diet is often suboptimal, and polypharmacy is common. Both HD and CAPD patients should avoid constipation \200\224 the former because of increased enteric K + absorption, and th e latter as it impairs in \202 ow and out \202 ow of dialysis and 6 dialysis ef \201 cie ncy. Dietary intervention Can be effective. Dose modi \201 cations of bulking agents (e.g. ispaghula), stimulating agents (e.g. senna, bisacodyl), and osmotic agents (e.g. lactulose ) are generally not required. Bowel cleansing solutions Should be used with caution in advanced CKD and AKI due to the po tential risk of hypovolaemia as well as their high phosphate or magnesium content. Psychotropic drugs Mostly lipid-soluble and liver-metabolized. However, caution is prudent, as side effects may be more common in advanced CKD. Slow dose titra- tion is advisable. Of ten non-dialysed. Serotonin-speci \201 c reuptake inhibitors (SSRIs) Are widely prescribed at normal doses, with cautious titration (e.g. citalopram, paroxetine, sertraline). Tricyclic antidepressants Are predominantly hepatically metabolized and may be used with ca reful titration. However, patients with advanced CKD may be more prone to anticholinergic s ide effects, such as postural hypotension. Benzodiazepines Are liver-metabolized, but heightened CNS toxicity, particularly sedation, is a concern. Short-acting agents are 6 preferred. Protein binding of midazolam is reduced, so it should be used with caution in advanced CKD. Antipsychotics Such as clozapine, olanzapine, and quetiapine, are generally well tolerated. Risperidone and its active metabolites are renally excreted, so initiation and titration a re cautious. Lithium is discussed on b p. 904. PRESCRIBING IN SPECIFIC SITUATIONS 897 Haloperidol Is often used in acute agitation as well as an antiemetic. Smaller initial dose s should be used in advanced CKD because of increased CNS sensitivity. Anticonvulsants Carbamazepine Is dosed as normal. However, it is a potent enzyme inducer wi th multiple interactions, so particular care must be taken post-transplantation. (cid:2) Ga bapentin and pregabalin require signi \201 cant dose reduction, according to GFR, as well as clinical vigilance for evidence of toxicity (confusion, dizziness, ataxia, drowsiness). Both are dialysable (useful in overdose). The pharmacokinetic behavior of phenytoin is signi \201 cantly altered in renal insuf \201 ciency ( l variable absorption, d protein binding, and i V d ). Modest dose changes ma y 6 result in disproportionate side effects. Therapeutic drug monitoring is also more compl icated. Many laboratories measure total drug (i.e. protein-bound and unbound). However, the pro- portion of free drug may be higher, so total levels are often misleading. Cautious do se titration and clinical correlation are required. Measurement of free drug levels may be available. (cid:2) Phenytoin is also a potent enzyme inducer, with several important drug i nteractions. Valproate is not signi \201 cantly renally excreted and has fewer interactions. However, c hanges to the protein binding may cause increased sensitivity. Levetiracetam, topiramate and vigabatrin undergo signi \201 cant renal excretion, and dose modi \201 cation is required. Lamotrigine has metabolites that are renally excreted and s hould be used with caution. Opioid analgesics ( 3 see also b p. 271) \200 Opioid analgesics have metabolites with var iable activity and dependence on renal excretion. Cautious titration is necessary. 2 However, this should be an excuse for the habitual undertreatment of pain in patients with CKD. Metabolite accumulation l prolonged action and potential CNS toxicity ( (cid:2) confusion, sedation, respiratory depression, hallucinations, seizure s). \200 Morphine metabolism l active and renally cleared metabolites (morphine-3-glucuronide and morphine-6-glucuronide), accumulation of which can be problemat ic, so morphine is best avoided. Hydromorphone l hydromorphone-3-glucuronide, which does not accumulate signi \201 cantly. Buprenorphine l relatively inactive biliary excreted metabolites. \200 Codeine l morphine -6-glucuronide accumulation with the inherent problems above. Alfentanil, fentanyl, and oxycodone are relatively safe choices, as they do not have active metabolites. Tramadol l O-desmethyltramadol, which can accumulate in CKD. 2 Naloxone is used for opiate reversal in standard doses. Dialysis may also be helpful in overdose situations. CHAPTER 12 Drugs and the kidney 898 Drug-related nephrotoxicity Introduction The kidneys \200\231 role in the excretion of man y drugs means that they are particularly vulnerable to drug-related toxicity. High renal bl ood \202 ow and 6 high renal drug delivery intensify this. The concentration of a drug in tubular \202 uid and the medullary interstitium may be many times higher than that in pl asma or other tissues. A variety of renal presentations and syndromes may result from drug toxicity ( b see Chapte r 1, p. 7). This means that the drug history is an absolutely fundamental component of rena l medicine. Antifungals Amphotericin Is associated with frequent and severe toxicity (>50%). Risk facto rs: cumulative dose, infusion rate (continuous infusion appears less toxic), pre-existing r enal disease, older age, concomitant diuretic use, electrolyte disturbances. Usually causes reversible AKI during treatment. Mechanisms: afferent vasoconstriction and increased tubul ar permeability. Prevention: adequate hydration, continuous infusion, correct electrolyte i mbalances. Liposomal formulations appear less nephrotoxic (if signi \201 cantly more expen sive). Distal renal tubular acidosis and urinary Mg 2+ and K + wasting may also occur. d K + is common and often signi \201 cant, requiring replacement. Note: beware the difference in doses across the different formulations. Antiviral therapy Aciclovir, valaciclovir, famciclovir, ganciclovir and valganciclovir May crys- tallize in renal tubules, causing reversible AKI, particularly in the setting of volu me depletion and after IV bolus administration. Urine microscopy reveals birefringent cryst als under polarized light (and haematuria). (cid:2) All require signi \201 cant dose reduc tion in renal impairment and are freely dia- lysed ( b Table 12.2). Cidofovir Causes revers ible dose-dependent the induction of proximal tubular apoptosis ( l proteinuria, d GFR, int erstitial nephritis, Fanconi syndrome, nephrogenic DI). Administer with hydration. Co-admin istration of probenecid has been used to slow renal tubular excretion and ameliorate toxici ty. toxicity through Foscarnet Frequently causes AKI, especially if given to volume-depleted patients. Pre-hydra te. Indinavir Is only poorly soluble at urine pH 5.5 \200\223 7.0. Precipitation causes crysta lluria and tubular obstruction ( l dysuria, haematuria, renal colic, \202 ank pain, and s igni \201 cant renal impairment). Stones (radiolucent) may form. Pre-hydrate. Ritonavir Can cause reversible AKI, particularly pre-existing renal insuf \201 ciency. in patients with Tenofovir A reverse transcriptase inhibitor, has been associated with a proximal tubulopath y. DRUG-RELATED NEPHROTOXICITY 899 Chemotherapeutic drugs Anti-cancer drugs are often given at high dose and have a relatively narrow therapeutic index. Toxic effects include AKI, CKD, tubular dysfunction, and thrombo tic microangiopathy. Methotrexate Is primarily renally excreted and requires a dose reduction, according to GFR. Renal toxicity is rare with chronic low-dose administration (e.g. rheumatoid arthritis) bu t more common with high-dose regimens (e.g. cancer treatment). Best avoided if GFR <30mL/ m in. Removed by HD ( (cid:2) but not CAPD). Intrarenal drug precipitation causes tubular obs truction ( l ATN and AKI). The administration of the recombinant bacterial enzyme carboxype ptidase (glucarpidase) can reduce toxic serum levels when renal impairment compromises clea rance. Cisplatin Toxicity can restrict its clinical utility. Multiple mechanisms are involved ( l vasoconstriction, i proin \202 ammatory cytokines, tubular cell necrosis and apoptosis). R enal impairment may persist and progress despite cessation of therapy. Usually avoided if p re-existing renal disease. Other presentations: d Mg 2+ , d Ca 2+ , tubular proteinuria, an d (rarely) TTP. Prevention: hydration; maintain good urine output; use modi \201 ed daily dosing regimens, and restrict cumulative dose. Carboplatin is considered less nephrotoxic a nd may be preferred in many situations. Cyclophosphamide and ifosfamide May cause haemorrhagic cystitis (prevention: hydration and concomitant Mesna administration). Also: irreversible tubular toxicity (including Fanconi s yndrome). Mitomycin and gemcitabine Have been associated with severe thrombotic microangiopathy. Immunomodulation therapy Intravenous immunoglobulin (IVIg) Is generally well tolerated, but AKI can result from toxic tubular effects of carbohydrates in many formula- tions ( l cell vacuolization and swelling l progressive luminal obstruc- tion). Diabetes and pre-existing renal disease appear to be risk factors. Prevention: avoid sucrose-containing products, sl ow infusion rate, ade- quate hydration. Interferon alfa Causes proteinuria ( 7 25%) and i S Cr ( 7 10%). A variety of glomerular lesions, including minimal change disease and crescent ic GN, have been described. TTP also reported. (cid:2) In addition, interferons can upregul ate the expression of class II histocompatibility antigens, provoking rejection of transpla nted organs. Calcineurin inhibitors (CNIs) Ciclosporin and tacrolimus are widely used in transplantation , glomerular disease, and in \202 ammatory disorders. Both are associated with important n ephrotoxicity. CHAPTER 12 Drugs and the kidney 900 Acute toxicity \200 Haemodynamically mediated and reversible. \200 Often no structural damage. \200 Responds to dose adjustment or drug withdrawal. \200 Presents as an asympt omatic i SCr (even where serum level is in the desired therapeutic range). This can mimic rejection in transplant recipients, triggeri ng further investigation, e.g. a transplant biopsy ( b p. 416). Histology may be normal or reveal indicative tubular changes, such as vacuolization, tubular microcalci \201 cation, or giant mitochondria. \200 AKI is relati vely common in post-heart, lung, and bone marrow transplantation (although is not exclusively s to CNIs in this situation). CNI-induced thrombotic microangiopathy is an uncommon, but important, syndrome post-transplantation ( b p. 412). Chronic toxicity \200 Characterized by irreversible and progressive tubulointerstitial \201 brosis. \200 Fibrosis typically a \200\230 striped \200\231 pattern from the medul la to the cortical medullary rays. Degenerative afferent arteriolar changes may be present. In non-renal transplantation, CNIs are linked to the development of CKD, e.g. ESRD occurs i n 7 1 \200\223 8% of cardiac transplant recipients. Nephrotoxicity may increase with concurrent use of mTOR inhibitors, e.g. sirolimus, everolimus. Prevention: Therapeutic drug monitoring. Tacrolimus trough concentrations (C 0 ) correlate well with overall drug exposure (AUC) and are used to monitor therapy. X Debate remains surrounding the optimal way of monitoring ciclosporin levels. C 0 , C 2 (2 hours post-dose), and AUC 0 \200\223 4 (multipoint testing from 0 \200\223 4 hours) are all in clinical use. Avoid concomitant nephrotoxins. \200 Be cautious with drugs that inhibit cytochrome P450 liver microsomal enzymes and i CNI levels (e.g. ketoconazole, \202 uconazole, erythromyci n, clarithromycin, verapamil, diltiazem). Drugs that induce cytochrome P450 and d CNI levels include carbamazepine and rifampicin. DRUG-RELATED NEPHROTOXICITY 901 Herbal medicines Herbal medicines, often dispensed in an unregulated manner, are a ubiquito us part of healthcare provision in many developing countries, and their use in the develope d world has expanded considerably (see Table 12.3). The kidney is the primary route of excr etion for many such compounds, and their potential for nephrotoxicity is increasingly recog nized. The true global incidence of CKD related to the ingestion of herbal remedies is curr ently unknown but could be very signi \201 cant. When suspected, reporting is desirable. Causes of toxicity \200 Consumption of herbs known to have toxic potential. \200 Consum ption of herbs with unknown, or underappreciated, toxicity. \200 Incorrect identi \201 c ation l inadvertent ingestion of a toxic herb. \200 Deliberate or accidental contaminatio n of herbal products, e.g. NSAIDs or heavy metals (such as cadmium). Interaction with prescribed drugs. Table 12.3 Clinical syndromes and associated herbal medicines Clinical syndrome Example Securida longe pedunculata , Euphoria matabelensis , Callilepsis laureola (African medicine s) Taxus celebica (yew tree) Tung Sheuh pills (containing mefenamic acid) Aristolochia spp. ( b p. 583), Fucus vesiculosis (bladder wrack), Larrea tridentate (chapparal) Aristolochia spp. ( b p. 583), cadmium contamination d K + : Glycyrrhiza glabra (liquorice) AKI CKD Tubular dysfunction Electrolyte disturbances i K + : Medicago sativa (alfala), Taraxacum of \201 cinale (dandelion) Glycyrrhiza glabra (liquorice) Hypertension Ephedra sinica (ma-huang) Renal stone disease Vaccinium macrocarpon (cranberry l oxalate) Salix daphnoides (willow bark l salicylate) Aristolochia spp. ( b p. 583) Papillary necrosis Urothelial cancer CHAPTER 12 Drugs and the kidney 902 NSAIDs and the kidney Mechanism of action NSAIDs inhibit the cyclo-oxygenases (COX), an enz yme family critical for prostaglandin synthesis. There are at least two COX isoforms: most NSAIDs inhibit both, but COX-2 inhibitors (the \200\230 -coxib \200\231 family) are selec - tive for COX-2 ( X and 6 possibly cause fewer GI side effects). Side effects Potent anti-in \202 ammatory and analgesic properties make these drugs amongs t the most ubiquitous in the world. Adverse effects include: \200 Renal toxicity ( b see below). \200 GI side effects: dyspepsia, ulceration, and small and large bowel toxicity. Cardiovascular: i risk of CV disease and i BP ( X COX-2 > non-selective NSAIDs). Bronchospasm. \200 Liver toxicity: abnormal LFTs (although serious liver failure is rare) . \200 Antiplatelet effects ( d thromboxane A 2 production). Bene \201 cial when aspirin is given to modify CV risk but a potential adverse effect in other situations. Renal toxicity \200 2 NSAIDs should generally be avoided in the presence of either AKI or CKD, except in very select and carefully monitored situations. (cid:2) NSAIDs are a very signi \201 cant cause of hospital-based AKI. \200 NSAIDs and r enal haemodynamics: NSAIDs have only a marginal effect on renal haemodynamics when kidney function is normal. However, when renal blood \202 ow is impaired, they abolish prostacyclin- and prostaglandin E 2 -mediated compensatory afferent arteriolar vasodilation , causing reduced glomerular perfusion. Clinically relevant situations include: pre-existing CKD, CCF, sepsis, nephrotic syndrome, hypovolaemia, concomitant ACE-I/ARB use, concomitant gentamicin or other nephrotoxin use, i ncreasing age. NSAIDs also ameliorate the antagonistic effect of prostaglandins on ADH action. This antidiuretic effect can cause salt and water retention, i BP, and blunt th e action of diuretics. Many of the renal effects of NSAIDs are mediated by COX-2, so COX-2 inhibitors appear equally nephrotoxic. (cid:2) In general, always beware claims of more \200\230 renal friendly \200\231 NSAIDs, as there is limited supporting evidence. \200 Other NSAID-induced renal lesions: Important cause of acute interstitial nephritis ( b p. 580). \200 Chronic interstitial ne phritis (and 6 CKD) with long-term use. \200 Analgesic nephropathy ( b p. 584). \200 Ne phrotic syndrome: particularly minimal change disease and membranous GN ( b p. 564). \200 Papillary necrosis ( b p. 585). \200 Electrolyte disord ers d Na + , i K + , acidosis. NSAIDS AND THE KIDNEY 903 Sulfasalazines \200 Sulfasalazine is 5-aminosalicylic acid (5-ASA) coupled to a carrier sulfapyridine molecule that assists GI absorption. \200 5-ASA shares structural similarit ies with aspirin. \200 Second-generation sulfasalazines (e.g. mesalazine) were designed t o minimize troublesome hematological side effects. Such agents are effective and important treatments for in \202 ammatory bowel disease (IBD). There has been signi \201 cant historical concern regarding an association with acute interstitial nephritis. However, available data suggest this is actually relatively uncommon. Case control data fro m a UK primary care database suggested an adjusted odds ratio for renal disease of 0.86 for current 5-ASA users and 2.48 for recent users. Mesalazine and sulfasalazine appeared to ca rry comparable risks. Causality was unclear in the majority of cases. What is more important is to keep in mind that patients with IBD are at increased risk of renal disease, in general. In addition to 5-ASA toxicity, the diff erential of renal impairment in patients with IBD includes: \200 Glomerulonephritis (e.g. membranous GN). \200 Amyloidosis. \200 Oxalate stone disease. If suspected, acute interstitial nephritis usually requires a diagnostic renal biopsy for con \201 rmation.