Mild i SCr <125 mol/L (1.4mg/dL) Moderate i SCr 125 \200\223 180 mol/L (1.4 \200\2232.0mg/dL) Severe i SCr >180 mol/L (>2.0mg/dL) Pre-eclampsia 10 \200\223 20% 30 \200\223 50% 60% Preterm delivery 20 \200\223 30% 60% 80 \200\223 90% Permanent deterioration in renal function 0% 20% 50% PRE-EXISTING RENAL DISEASE 857 Speci \201 c renal diseases Diabetic nephropathy Now the commonest renal condition encount ered in pregnancy. It is essential that women with diabetes are educated about the importan ce of good pre-conception diabetic control for reducing the risk of congenital malformation (aim HbA1C \211 6.1% (43mmol/mol)). There is an increased incidence of babies of higher b irthweight. Otherwise, risks relate to both the degree of renal impairment and the degree o f proteinuria, as shown in Table 11.4. Re \202 ux nephropathy Women with re \202 ux nephropathy should be screened for UTI durin g preg- nancy, and, if present, infection should be treated promptly. Acute pyelo- nephriti s is more common. Mothers should also be counseled regarding the potential risk of inherita nce ( 7 25 \200\223 30%) and offered post-natal screen- ing for their children ( b p. 712) . Autosomal dominant polycystic kidney disease (ADPKD) Cyst complications in pregnancy, suc h as hemorrhage or infection, may masquerade as obstetric complications. Patients with a fa mily history of intracranial aneurysms should ideally be screened for aneurysms them- selve s prior to pregnancy. Primary glomerular disease The exact type of glomerular disease does not impact on pregnanc y out- come, but renal impairment, proteinuria, and maternal i BP all can. Relapse of a stable pre-existing glomerular lesion is generally unlikely (and usually very dif \201 cult to differentiate from pre-eclampsia when it occurs) ( b p. 859). Wait until disease is in remission (ideally >6 months) before trying to conceive. The form of treatmen t is also a consideration. If relevant, wait until off cytotoxic agents and on lowest possi ble effec- tive doses of corticosteroids. For other immunosuppressant drugs, see b p. 866. Proteinuria is likely to double during pregnancy. If >3g/24h (PCR >300mg/ mmol), then antic oagulation with low molecular weight heparin (LMWH) should be recommended, as there is an i ncreased thrombotic risk. In addition, signi \201 cant proteinuria (>3g/day) is associated with 7 x 2 increased risk of perinatal loss and preterm delivery, compared to no proteinuria. Lupus nephritis Renal impairment, proteinuria, and maternal i BP can all impact on preg- na ncy outcome. The risk of a disease \202 are increases in pregnancy (30%). Active lupus is associated with increased fetal loss, prematurity, and IUGR. In addition, there is a risk of a transient rash and fetal heart block (requiring pacing) in babies born to anti-Ro posi tive mothers. Those with antiphospholipid antibodies are at increased risk of spontaneous a bortion and should be considered for LMWH from conception. CHAPTER 11 Pregnancy and the kidney 858 Management of renal disease in pregnancy \200 Requires a multidisciplinary approach, incl uding an obstetrician, a nephrologist, and, ideally, an obstetric physician. Pre-pregnancy counseling (including genetic counseling, if relevant) is extremely important. Folic acid 400 micrograms od 3 months before trying to conceive. \200 Alter medications, including antihypertensives, to drugs that are safe in pregnancy ( b p. 849). Recommend aspirin 75mg, particularly from 12 weeks onwards, to reduce the risk of pre-eclampsia. Patients should be booked early to antenatal clinic. \200 Aim to see every 2 \200\223 3 weeks until 28th week, thereafter weekly. \200 BP every visit. Home BP monitoring may be helpful. \200 Urinalysis every visit (MSU for M,C+S in those at particular risk of infection). SCr, U&E, Ca 2+ , LFT, urate, and uPCR or uACR every 2 \200\223 4 weeks. \200 FBC every 4 weeks (IV iron and ESAs are safe). \200 If proteinuria >3g/24h (uPCR >300mg/mmol), then anticoagulation with LMWH should be considered. Monitor disease activity, where possible, e.g. SLE. \200 Serial obstetric scans for those at higher risk ( b p. 853). PRE-EXISTING RENAL DISEASE 859 Case study A 27-year-old primigravid Chinese woman presents to antenatal clinic at 18 weeks \200\231 gestation with progressive oedema. She is found to be nor- motensive, but urinal ysis reveals 3+ proteinuria. Her SCr is 54 mol/L (0.6mg/dL), uPCR 524mg/mmol, and serum al bumin 26g/L. Further investigations included: low C3 and C4, +ve ANA, +ve dsDNA, and +ve antiphospholipid antibody. Renal USS was normal. After discussion, a renal biopsy was undertaken and revealed class V lupus nephritis ( b p. 659). Treatment options Lupus nephritis ( b p. 658) can be treated w ith corticosteroids. Azathioprine is also safe in pregnancy, as is tacrolimus ( b p. 866). However, MMF ( b p. 866) and cyclophosphamide are contraindi- cated. Rituximab may also be considered ( X ) but ideally not in the last 6 months of pregnancy so that fetal B cells ha ve time to reconstitute prior to delivery. This patient should also be offered LMWH treatme nt in view of her proteinuria and antiphospholipid antibody status. If pos- sible, diuretic s should be avoided despite her oedema ( b p. 849). Learning point If new-onset proteinuria ( 9 renal impairment) occurs in early pregnancy (<20 weeks), it is important to attempt to diagnose the underlying renal lesion. Investigation will include immunological and serolog ical test- ing ( b p. 40) and potentially a renal biopsy. A histological diagnosis is likel y to assist management in later pregnancy easier, as differentiating primary renal disease from pre-eclampsia becomes very dif \201 cult (see Table 11.5). Table 11.5 Pre-eclampsia or active lupus nephritis? Pre-eclampsia i i +++ 9 \200\223 i Normal Lupus nephritis i i +++ BP Proteinuria Haematuria +++ Red cell casts ++ ALT Normal d i ++ Complement dsDNA titres Normal Symptoms of lupus \200\223 Response to steroids \200\223 + CHAPTER 11 Pregnancy and the kidney 860 Disorders of the urinary tract in pregnancy Changes to the anatomy of the renal tract durin g pregnancy, particularly dilatation of the collecting system ( b p. 840), need to be consi dered dur- ing the assessment of urinary tract symptoms and signs. Haematuria In the absence of proteinuria, haematuria is usually due to anatomi- cal changes (bleeding from small venules in dilated collecting systems). On microscopy, 2 \200\223 3 RBC/hpf is normal in pregnancy (unlike 1 \200\223 2 in the non-pregnant population). If SC r is normal and no proteinuria, wait until 12 weeks after delivery for further assessment ( b p. 66). Obstruction May occur s to mechanical pressure exerted by the uterus (usually on the right ureter, often where the ureter crosses the iliac artery) or s to pelvic or ureteric stone i mpaction. Renal stones Renal stones are uncommon in pregnancy and usually occur in women known to hav e pre-existing nephrolithiasis. However, collecting system dilatation, coupled with stasis and a 2 \200\223 3-fold increase in urinary calcium excretion, may precipitate new stone f ormation in pregnancy. Ureteric stones are more common than stones in the renal pelvis, and most occur after the \201 rst trimester. The majority will pass spontaneously, but impac ted stones may remain painful, and s urinary infection is a concern. Women with cystinuria should be offered genetic counseling prior to conception, and proactive management of their stone disease should start pre-pregnancy ( b p. 719). 1 The differential diagnosis of ston e-induced colic must include obstetric problems, such as placental abruption Investigation Urine dipstick for haematuria and proteinuria. Microscopy: red cells (+ morph ology), casts, pus cells, and organisms. Urine culture 9 stone analy- sis. FBC, U&E, serum calcium, PTH. USS is the \201 rst-line imaging modality. Ideally, ionizing radiation should be avoided during the 1st and 2nd trimesters. A limited IVU with fetal shielding is recommended in com plex cases. Ureteroscopy may be pre- ferred to CT or multiple irradiations. MRI has limited utility. Management Hydration and analgesia ( 7 75% stones will pass spontaneously). Obstruction, in tractable pain, and urosepsis are indications for more de \201 nitive interven- tion. Stan dard treatment consists of nephrostomy placement and ureteric stent insertion (then changed at intervals until after delivery), but uret- eroscopic methods are increasingly favored. Extracorporeal shockwave lithotripsy should be avoided. DISORDERS OF THE URINARY TRACT IN PREGNANCY 861 CHAPTER 11 Pregnancy and the kidney 862 Pregnancy on dialysis Introduction 5 with ESRD rarely fall pregnant on dialysis: only 0.3 \200\223 2.2% will conceive (reasons are complex, including hyperprolactinaemia, anemia, po lyphar- macy, psychosocial issues, and the uraemic state per se). Nevertheless, contracepti on should be discussed with women who menstruate on dialy- sis ( 7 40%). This is particular ly true in the \201 rst few years after commencing dialysis. B -HCG levels are high in dialysis patients, so if the level is high and pregnancy is a possibility, an USS should be performed. If a pregnancy occurs and progresses beyond the 1st trimester, fetal outcomes have previous ly been poor and associated with signi \201 cant maternal morbidity. However, better mater nal and fetal care, coupled with improvements in dialysis ef \201 ciency and increases in dialysis frequency, have led to more optimism around pregnancy on dialysis. In general, however, transplantation, if feasible, remains the favored means for a patient with ESRD to conceive and undertake a pregnancy ( b p. 864). What dialysis patients of childbearing age should know \200 13 \200\223 45% of pregnanci es result in spontaneous miscarriage before 20 weeks \200\231 gestation. The outcomes of pregnancy on dialysis are improving. Available data suggest 23% of pregnanc ies resulted in a live infant in 1980, whilst this is now in excess of 70%. Maternal morbidity (e.g. hospitalization) remains signi \201 cant, but mortality is rare. Maternal hypertension is very common. \200 Preterm birth (70 \200\223 100%, mean gestati onal age 32 weeks) and low birthweight (virtually 100%) are extremely common. Long-term outcomes for these infants are not yet known. \200 Prolonged admissions to neon atal intensive care are common. \200 Congenital abnormalities occur with the same frequen cy as in the general population. Pregnancy on dialysis is physically and emotionally demanding. \200 Patients should be en couraged to dialyse as much as possible, preferably daily for long hours. It is worth re-exploring options for transplantation. Dialysis prescription There is no overriding reason for a modality switch: HD delivers a hi gher dialysis dose, but CAPD (esp. APD) offers less rapid metabolic changes and allows stea dy \202 uid removal whilst avoiding intradialytic hypotension. Residual renal function is important, as it improves pregnancy outcomes. PREGNANCY ON DIALYSIS 863 Haemodialysis Aim for urea consistently \211 15mmol/L ( 40mg/dL) through daily dialysis f or at least 20h/week) ( 7 6 treatments). Titrate dialysate K + , Ca 2+ , and HCO 3 \200 \223 against serum levels (may require reduction in dialysate HCO 3 \200\223 to prevent ma ternal alkalaemia). Heparin requirements may increase. 1 Avoid hypotension. Allow for addit ional 0.5kg/week weight gains from mid-pregnancy onwards. Peritoneal dialysis As pregnancy progresses and intra-abdominal PD \202 uid volume is les s well-tolerated and automated PD, with more frequent lower vol- ume exchanges, is preferab le. PD-related peritonitis should be treated promptly and assiduously, bearing in mind the potential teratogenicity of many antibiotics. Diet, calcium, and vitamin D Involve your dietetic staff from the outset. i protein intake to 1.2 \200\223 1.4g/ kg pre-pregnant weight + 10g per day. For CAPD, take dialysate prote in losses into account and replace. Offer a daily multivitamin preparation, containing wate r-soluble vitamins. Increase folate to 1.6mg/day. The pla- centa produces calcitriol, so vi tamin D analog doses may require adjust- ment. Supplemental K + may be necessary. Anemia Erythropoietin is not teratogenic. Dose requirements will increase by 50 \200\223 1 00% in pregnancy. IV iron is safe and effective. Labor and delivery \200 Most units will deliver pregnant dialysis patients early (usually prompted by worsening i BP, IUGR, or both). Pregnancies rarely progress beyond 38 weeks. Monitoring of uterine activity should begin as early as the 26th week, as dialysis may induce contractions. Cesarean section is performed for standard obstetric indications. \200 PD patients should be drained out for delivery \200\224 dialysis can resume 24h after delivery, with small-v olume exchanges. Temporary HD may be necessary for a period in cases of PD \202 uid leaka ge. \200 Assess \202 uid status carefully: 1 avoid volume overload. \200 Beware infec tion. \200 Neonates will need specialist input, including regular electrolyte assessment. CHAPTER 11 Pregnancy and the kidney 864 Pregnancy after renal transplantation: introduction Improvement in renal function following successful transplantation, usually restores menstruation and fertility. Post-transplantat ion, 12% of women of childbearing age will become pregnant. Advice regarding contraception should 6 be accessible (key points: avoid estrogen-containin g contraceptives, as they can i BP and they also have an unpredictable effect on CNI metabo lism. Progesterone-only prepara- tions and IUCDs are safe and more effective than barrier m ethods). All renal transplant recipients contemplating pregnancy should be offered appropriate pre-p regnancy counseling (this may include genetic counseling, depending on underlying renal dis ease). Outcomes A number of international registries have recorded the outcomes of preg- nancy in renal transplant patients around the world. A recent meta-analysis of available data from 4 ,706 pregnancies in 3,570 transplant recipients reported a live birth and miscarriage rate of 73% and 14%, respectively. Both these \201 gures are similar to those seen in the gene ral population. In 5 with good graft function, >95% pregnancies that progress beyond 12 wee ks are likely to have a successful outcome. Complications The key renal factors that affect the incidence of complications are: \200 SCr pre-conception. \200 i BP. \200 Degree of proteinuria. Important complications (the incidence range re \202 ects the presence and severity of the above factors) include: \200 i BP (30 \200\223 60%): 7 50% of 5 transplant recipients are taking antihypertensive drugs. \200 i BP is associat ed with premature birth and pre-eclampsia. \200 For safe antihypertensive medications, se e b p. 849. Pre-eclampsia (22 \200\223 45%). \200 IUGR (20 \200\223 40%). \200 Preterm delivery ( 20 \200\223 60%), with associated low birthweight. \200 Gestational diabetes ( 7 8%). Th ere is also an increased incidence of UTI ( 7 40%) (and graft pyelonephri- tis) during preg nancy. Cesarean section rates are increased, re \202 ecting the complex nature of the pregnancies , rather than presence of the transplant itself (which lies in the false pelvis). There is no increase in incidence of congenital abnormalities above that in the general pop ulation. The incidence of longer-term developmental delay is also probably low. TRANSPLANT FUNCTION AND PREGNANCY 865 Transplant function and pregnancy The effect of renal transplant function on outcomes is sh own in Table 11.6. Table 11.6 Pregnancy outcome based on pre-conception SCr SCr ( mol/L) Complicated pregnancy 1 Successful outcome 2 d GFR during pregnancy d GFR persisting post-partum Graft loss within 2 years <125 30% 97% 15% <5% <5% 125 \200\223 159 60% 90% 15% 5% 10% 160 \200\223 199 90% 80% 30% 20% 60% >200 100% 70% 60% 40% 90% Outcome estimates based on literature review (1988 \200\223 2004) from 613 women in 849 pr egnancies that attained at least 24 weeks \200\231 gestation. 1 Complicated pregnancy mean s i BP, pre-eclampsia, IUGR, or premature delivery. 2 Successful outcome means delivery of a live child. Reproduced from Nicholas Torpey et al. (Oxford Specialist Handbook) Renal Tra nsplantation (2010), with permission from Oxford University Press. Pre-pregnancy transplant function predicts the risk of graft dysfunction both during and af ter pregnancy. For 5 with good graft function (SCr \211 125 mol/L (1.4mg/dL)), the risk of deterioration in function due to preg- nancy is low. For those with poor function (SCr > 160 mol/L (1.8mg/dL)), renal function post-pregnancy is likely to be worse than pre-, and there is a signi \201 cant incidence of premature graft loss. Rejection The risk of allograft rejection does not appear to be increased during pregnancy, with a reported rate of 7 4%. However, when it occurs, it is associated with poorer outcom es. Risk factors: shorter interval between transplantation and pregnancy, low CNI levels. 1 Pregnancy enhances CNI metabolism. Diligent therapeutic monitoring is nec essary, often with signi \201 cant dose increases. The cause of graft dysfunction ( b p. 404) can be dif \201 cult to diagnose in pregnancy. Transplant biopsies are often required and are safe in expert hands. CHAPTER 11 Pregnancy and the kidney 866 Pregnancy after renal transplantation: management Transplant drugs during pregnancy In the transplant setting, there is no other choice but to expose the fetus to immunosuppressive a gents, as all the relevant drugs pass through to the fetal circulation to some degree. Reas suringly, however, the incidence of major congenital malformations does not appear differen t from the non-transplant population. 1 There are speci \201 c concerns regarding the use of MMF in pregnancy, and there are too little data on sirolimus to cur- rently recommend it s use (see Table 11.7). Table 11.7 Safety of common immune suppressant agents in pregnancy Immunosuppression Safe Unsafe Mycophenolate Sirolimus (limited data) Ciclosporin Tacrolimus Azathioprine Corticosteroids * Mycophenolate has been shown to cause a speci \201 c pattern of malformation in 20 \200 \223 25% of cases (hypoplastic nails, shortened \201 fth \201 nger, ear defects, includ ing deafness and cleft palate). Neonates should be monitored for adrenal suppression. 1 Pregnancy enhances the metabolism of CNIs. Careful therapeutic mon- itoring is essential, and signi \201 cant dose adjustments are often required. X Breastfeeding is not generally advocated on maintenance immu- nosuppression, but many authorities do not believe it is ab solutely contraindicated. 3 Also unsafe in pregnancy: valganciclovir, co-trimoxazole, stati ns, \202 u- conazole, and other -azole antifungal drugs. Pre-pregnancy and antenatal care \200 Optimize BP management (aim <140/90mmHg). \200 Op timize immune suppression (prior to conception). \200 Folic acid 400 micrograms od (to pr event neural tube defects), and consider aspirin 75mg od (to reduce the incidence of pre-eclampsia). Hepatitis B and C, HSV (cervical cultures if +ve), CMV, HIV, toxoplasmosis, and rubella sta tus, if not already known. Rubella antibodies should ideally be tested prior to transplantation (rubella is a live vaccine, so administration is contraindicated post-transplantation). Rhesus compatibility of the patient and transplant: if the patient is Rh \200\223 ve and the kidney Rh +ve, there is a theoretical risk the patient could be sensit ized to Rh, which could prove problematic for a Rh +ve baby. PREGNANCY AFTER RENAL TRANSPLANTATION: MANAGEMENT 867 Antenatal clinic visit every 2 \200\223 3 weeks. Weekly after 28 weeks. \200 BP check ev ery visit. Home BP monitoring may be helpful. \200 Urinalysis and MSU for M,C+S every vis it. \200 If proteinuria >2g/24h (uPCR >200mg/mmol), then anticoagulation with LMWH should be considered. Check ciclosporin or tacrolimus levels frequently (every 2 \200\223 4 weeks and more frequently if dose adjustments). \200 Glucose tolerance test in each trimester. \200 Monitor for CMV viraemia monthly (risk of congenital infection). \200 SCr, U&E, Ca 2+ , LFT every 2 \200\223 4 weeks. \200 FBC every 2 \200\223 4 weeks (IV iron and ESAs are safe). Delivery \200 Vaginal delivery is safe. Cesarean section for obstetric indications. \200 Perform all VEs with strict aseptic technique. \200 Consider additional hydrocortisone 100mg IVI or IMI (or increase oral prednisolone to 15mg od over labor). Case study A 35-year-old lady with ESRD secondary to membranous nephropathy underwent a liv e related transplant from her husband 9 months ago. At a visit to transplant clinic, she ex presses her desire to try for preg- nancy. She has had one episode of cellular rejection (B anff category 2A) 3 months previously, treated with pulsed corticosteroids. Medications: tacrolimus, mycophenolate, prednisolone, enalapril, amlodipine, simvastatin, alendronic acid. Blood pressure: 140/80mmHg. SCr presently stable at 130 \200\223140 mol/L. What advice would you give her about pregnancy, and what changes to her medications would y ou suggest? Recommendations \200 Offer appropriate detailed counseling and planning, idea lly in a multidisciplinary obstetric-renal clinic. Wait for 1 year post-transplantation (some advocate 18 \200\223 24 months) and, preferably, 6 months after an episode of rejection. \200 Ensure stable graft functio n, and document degree of any proteinuria. Immune suppression: needs to be stable. This patient should be changed to azathioprine under careful supervision and monitored for 3 months. Stop ACE-I (monitor BP, and consider safe alternative), statin, and bisphosphonate. Start folic acid at least 3 months prior to conception to reduce the risk of neural tube defects. Consider aspirin 75mg od once pregnant (particularly after 12 weeks) to reduce the risk of pre-eclampsia. Assess thromboembolic risk (particularly if proteinuria). \200 Give advice regarding appr opriate contraception until safe to conceive. 869 Chapter 12 Drugs and the kidney Prescribing in renal impairment 870 Prescribing for dialysis patients 876 Sepsis and antimi crobials 878 Cardiovascular drugs 892 Prescribing in speci \201 c situations 894 Drug-rela ted nephrotoxicity 898 NSAIDs and the kidney 902 Lithium and the kidney 904 Dialysis treatm ent of poisoning 906 Salicylate poisoning 908 Ethylene glycol poisoning 910 CHAPTER 12 Drugs and the kidney 870 Prescribing in renal impairment 3 Always verify the recommended dose and dosing schedule wh en pre- scribing for a patient with renal impairment. Ask yourself, \200\230 Is the drug s till warranted, given the potential increased risk? \200\231. Principles \200 The kidneys have a fundamental role in the elimination of drugs, even those partially metabolized in the liver. Renal elimination may be either by glomerular \201 ltration or tubular secretion. Renal impairment may necessitate a dose reduction, an extension in the dosing interval, or a combination of both. Such alterations will depend on the degree of renal dysfunction (or form of renal replacement therapy). Impaired renal function is common in elderly patients and those with multiple comorbidities , so the potential effects of polypharmacy and drug interactions are particularly relevant in these groups. Individuals who have been taking a drug at the same dose over a long period may need a dose alteration, as renal function changes with time. In practice, particular care is needed when using those drugs where: \200 There is a narr ow therapeutic index, i.e. the toxic and therapeutic ranges overlap or are close to each ot her (e.g. digoxin, aciclovir). Renal toxicity is a potential effect of the drug. (cid:2) Beware the vicious cycle of worsening renal function, decreasing drug clearance, and rising drug level s (e.g. aminoglycosides). (cid:2) The consequences of accumulation are serious (e.g. metformin, opiates). The monitoring of therapeutic drug levels may be helpful in these situations. If there is a relatively wide therapeutic window, it may be possible to use a drug safely w ith a simple dose reduction (e.g. half the \200\230 standard dose \200\231 ). This is the case with many antibiotics. (cid:2) However, never estimate \200\224 always con \201 rm the appropriate dosing schedule. Pharmacodynamics Renal impairment may alter the sensitivity of target tissue to the effects of drugs. Examples: higher incidence of statin-induced myopathy, more pronounced effect of antiplatelet drugs, increased sensitivity to benzo- diazepines, and increased risk of hype rkalaemia with potassium-sparing diuretics. Pharmacokinetics Renal impairment in \202 uences the pharmacokinetics of most drugs to som e degree. Understanding why can help select drugs, doses, and dosing inter- vals that achie ve therapeutic plasma concentrations but avoiding toxicity. Absorption. Describes the passa ge of drug from site of administration into the plasma volume. Renal impairment may affect oral administration and enteral absorption via alterations in: PRESCRIBING IN RENAL IMPAIRMENT 871 Gastric pH: Passive drug transfer across intestinal epithelial barriers is dependent on ionization. i gastric pH l d ionization l d absorption (e.g. ferrous sulfate, ketoconazole, itraconazole). i gastric pH may be s to drugs (phosphate binders, H 2 antagonists, and proton pump inhibit ors) as well as the excess urea hydrolysis to ammonia (to buffer HCl) present in renal fail ure. Gastric motility: Gastric emptying can be delayed in uraemia (and diabetes mellitus). \200 Vomiting. Drug \200\223drug interaction: Interaction in the GI tract l altered bioavailability (e.g. phosphate binders and ferrous sulfate should not be taken together). \200 Grapefruit juice inhibits the CYP3A4 isoform of the cytochrome P450 enzyme in liver and gut l d \201 rst-pass meta bolism of many drugs, including dihydropyridine calcium channel blockers and ciclosporin. GI tract oedema: Nephrotic syndrome and CCF l d loop diuretic absorption. Distribution. Measures the (theoretical) volume ( V d ) occupied by the total amount ( Q ) of drug, assuming uniform concentration ( C p ) in all body com- partments ( V d = Q / C p ). Several parameters are subject to change in renal insuf \201 ciency. \200 Protein bin ding: Changes in albumin concentration will affect the free (and 6 active) concentration of highly protein-bound drugs. Nephrotic syndrome l hypoalbuminaemia l d albumin binding l i free drug. Competitive binding of acidic uraemic toxins to albumin will also increase free drug. Example: phenytoin is less protein-bound in renal failure, and signs of toxicity may occur at \200\230 therapeutic \200\231 levels. ( (cid:2) Many assays used for therapeutic monit oring will not re \202 ect this, as they measure total drug.) Warfarin and diazepam may al so be affected. 2 Be cautious with dose adjustments. Altered body composition: Impaired renal function is associated with signi \201 cant changes in body water, muscle, and adipose tissue. Fluid overload will increase V d for protein-bound and water-soluble drugs (e.g. atenolol, vancomycin). Reduced muscle and adipose tissue may affect V d for hydrophilic drugs (e.g. statins, morphine, codeine). Altered drug tissue binding: Uraemia reduces tissue binding. Digoxin is the most clinically relevant, with a signi \201 cant reduction in V d . Metabolism. Two important examples of the kidney \200\231 s involvement in drug metabolism are: (i) activation of vitamin D compounds through 1 A -hydroxylation; (ii) metabolism of insulin \200\224 (cid:2) insulin requirements often decrease signi \201 cantly as renal f ailure progresses. CHAPTER 12 Drugs and the kidney 872 Clearance Clearance depends on glomerular \201 ltration, tubular secretion, and tubular r eabsorption. \227 \210\222 Clearance=(F unFF bound GFR)+Secretion GFR)+Secretion Reabsorption where F unbound is the fraction of unbound drug in the plasma. Some drugs are eliminated un changed by the kidney and are 6 particularly susceptible to accumulation in renal failure. A more common scenario is that drugs are cleared via conversion to water-soluble (polar) me tabolites prior to urinary excretion. This initial breakdown to inactive, more polar metabolites usually occurs in the liver via conjugation (to glucuronide or sulfate) or oxidation/ reduction. In general, as GFR falls, drug elimination by all the following mechanisms is reduced. \200 Glomerular \201 ltration. Smaller molecules (MW <60,000) are \201 lt ered at the glomerulus unless protein-bound. Water-soluble (polar) molecules are more freely \201 ltered than lipid-soluble (non-polar) ones. Tubular secretion. Non-polar drugs diffuse more readily across tubular membranes. In additi on, many polar drugs undergo active excretion by the same mechanisms as organic acids and b ases. \200 Organic acids: penicillins, cephalosporins, salicylates, loop and thiazide diuretics. Organic bases: amiloride, quinidine, procainamide. \200 Acidic drugs are more effectively secreted into alkaline urine and vise versa. This can be exploited therapeutically, e.g. urinary alkalinization in salic ylate poisoning. Tubular reabsorption of non-polar drugs may be signi \201 cant. First-order kinetics \200 Most drugs excreted by the kidneys exhibit \201 rst-order kin etics, i.e. the rate of elimination is proportional to the concentration of the drug. \200 Drugs that demonstrate such kinetics can be described by their half-life (t 1/2 ). This i s the time taken for the drug concentration to halve after absorption and distribution. t 1/2 determines steady state concentration, appropriate dosing interval, and persistence after cessation of treatment. The majority of drugs are given at regular intervals and reach steady state after 7 5 x t 1 /2 when rate of intake equals rate of excretion. \200 Increases in dose or dose frequency result in a higher steady state concentration. t 1/2 will itself depend on GFR for drugs excreted by the kidney. \200 d GFR l d clearanc e rate l i t 1/2 l accumulation and increased steady state drug concentration. This necessitates either a d in dose or i in dose interval. Dose reductions l lower peak concentrations but maintained trough levels (ideal when constant exposure required, e.g. many antibiotics, antihypertensi ves). PRESCRIBING IN RENAL IMPAIRMENT 873 Increased dose intervals l maintain peak concentrations but permit lower trough levels (e.g . aminoglycosides \200\224 high peak concentrations are required for bactericidal activity ; low troughs avoid toxicity). See Fig. 12.1 . (a) A constant fraction of drug is cleared in unit time \210\222kt C(t)= C0e C = drug concentration k = rate constant for elimination ) L / g ( n o i t a r t n e c n o c t = 16 h Renal failure t = 8 h g u r D Normal 6 12 Time (h) 18 24 (b) Plasma drug concentration Repeat dosing Renal failure 97% Trough level 94% 87.5% 75% Normal 50% 1 2 Time (days) 3 Fig. 12.1 Dose response curves following (a) single dose administration or (b) repeated dos ing in the presence and absence of renal impairment. Note the effect of reduced renal clear ance on t , time to steady state, and the steady state plasma concentration. Reproduced from Oxford Desk Reference; Nephrology , J. Barratt, K. Harris, P. Topham, with kind permis sion Oxford University Press, p. 692. CHAPTER 12 Drugs and the kidney 874 Assessing kidney function prior to prescribing \200 The most important measure is GFR, no t serum creatinine. \200 A formal creatinine clearance is ideal but cumbersome (requires 24h urine collection) and 6 rarely performed. (cid:2) MDRD eGFR was never intended to guide drug dosing. In particular, it may lead to ov erdosing of small patients and underdosing of large ones. Cockcroft \200\223 Gault estimation of CrCl incorporates body weight and is better suited to this purpose. 2 GFR may be rapidly changing, particularly in AKI or a critical care setting. This makes d rug selection and dosing a key component of management that requires constant attention and review. \200 If in any doubt, discuss with a renal pharmacist \200\224 they are an invaluable resource on all specialist units. PRESCRIBING IN RENAL IMPAIRMENT 875 CHAPTER 12 Drugs and the kidney 876 Prescribing for dialysis patients Patients on renal replacement therapy (RRT) will normally have an insig- ni \201 cant \200\230 native \200\231 GFR, and the removal of drugs usua lly dependent on renal excretion will 6 be negligible. 2 It is vital to know whether such d rugs will be removed by dialysis. Drug clearance will vary, according to modality of dialysis. Clearance by haemodialysis and peritoneal dialysis is contingent on diffusion down a concentration gradient between plasm a and dialysate. Clearance during haemo \201 ltration is reliant on convection alone. Two important factors that may in \202 uence drug removal require consid- eration when prescribing for patients on RRT: \200 Characteristics of the drug. \200 Ch aracteristics of the type of RRT. Drug characteristics \200 Molecular weight (MW): Haemodialysis membranes have relatively small pore sizes and will only clear molecules <500Da. Haemo \201 lters have larger pore sizes and can clear much larger molecules <5,000Da. Protein binding: Heavily protein-bound drugs are not well removed (even if low MW). Volume of distribution: Large volumes of distribution result in low plasma drug concentrations and reduced availability for removal by dialysis. Water solubility: Water-soluble drugs pass through \201 lters more readily than lipid-soluble ones. For patients receiving RRT, GFR cannot be calculated using standard equations. Even though clearance may be higher during treatment, dosing at CrCl <10mL/min is common fo r haemodialysis, as the treatment is generally intermittent. Clearance is higher in continuous techniques, such as continuous veno-venous haemo \201 ltration (CVVHF) or continuous veno-venous haemodia \201 ltration (CVVHDF) where clearances can be in the range 30 \200\223 40mL/min. This allows larger dos es to be prescribed. Generally, the manufacturer of machines and dialysers/ \201 lters will provide an estimate of CrCl by their system. Drugs will have a sieving coef \201 cient that indicates the proportion of drug that will pass through a membrane during treatment. A drug that passes freely has a si eving coef \201 cient of 1, and one does not pass at all will have a coef \201 cient of 0 . It is the knowledge of the system clearance and the drug-sieving coef \201 cient that informs guidance for drug prescription. PRESCRIBING FOR DIALYSIS PATIENTS 877 There are several comprehensive resources, such as renal formularies, that could, and should, be frequently consulted. Clinical decision support alerts within electronic prescribing systems can help reduce errors. Specialist renal and critical care pharmacists are an invaluable source of information and essential members of the relevant clinical teams. RRT characteristics \200 Properties of the dialyser or \201 lter (pore size, surface ar ea). \200 Drug adsorption onto some membrane types. \200 Duration of therapy, e.g. haem odialysis provides ef \201 cient clearance but is only an intermittent treatment. Peritoneal dialysis clears drugs much less ef \201 ciently than either haemodialysis or haemo \201 ltration but is a continuous technique. Dialysate and blood \202 ow rates (determine concentration gradient). \200 For peritone al dialysis: Peritoneal membrane status, e.g. clearance increases during the in \202 ammation caused by peritonitis. \200 Volume and frequency of exchanges. Drugs that are cleared by haemodialysis are usually administered after a treatment session. CHAPTER 12 Drugs and the kidney 878 Sepsis and antimicrobials 3 Sepsis is a relatively common cause and complication of renal f ailure. Presentations may be atypical and non-speci \201 c. Samples for culture and sensit ivity (including blood, urine, sputum, wound swabs, drain \202 uids, and any other releva nt locations) should be obtained (preferably before antibiotic administration) wherever pos sible. See Table 12.1 on choice of antimicrobial treatment and Table 12.2 for antibacterial , antiviral, and antifungal dosing Antimicrobials Choice of antibiotic \200 History and examination may identify the most li kely source of infection and guide initial antibiotic selection. However, prompt empirical treatment to cover all likely pathogens may be necessary in deteriorating patients. 2 Local antibiotic policies, developed with microbiology and drugstore input, should be adh ered to in all, but exceptional, circumstances. \200 Prudent antibiotic prescribing can r educe hospital-related infections, such as MRSA and C. dif \201 cile , and help to prevent antibiotic resistance. Always record indication and intended antibiotic duration or review date. IV antibiotics should be switched to oral equivalents after 48h if T <38 * C for 48h, patie nt is clinically improving, a suitable oral agent is available, and there is no evidence of malabsorption, gastric stasis, or vomiting. There are exceptions (e.g. PD peritonitis, end ocarditis, meningitis) \200\224 your microbiology team will advise. Numerous antimicrobials depend on renal clearance. However, most have a wide therapeutic index, and dose reductions are only necessary once GFR is <20mL/min ( (cid:2) aminoglycosides and vancomycin are important exceptions). High doses of B -lactam antibiotics can accumulate and cause neurological sequelae, including confusion, agitation, and seizures in advanced CKD, includ ing dialysis patients. Cephalosporins and quinolones require dose reductions in more severe renal impairment (see Table 12.2). Vancomycin is extensively used for staphylococcal infections (including dialysis line sepsis and PD-related peritonitis). Monitoring of drug levels is essential ( b p. 882). Aminoglycosides can be used with care ( b p. 880). Haemodialysis patients Central vascular dialysis catheter infection or PTFE access graft sepsis should always be considered ( b p. 297). Even if a PTFE graft has pre- viously been surgically removed, residual material may remain in situ . 2 Always consider immediate removal of any foreign body (particularly dial ysis lines). Do not wait for culture results. Empirical therapy often involves vancomycin a nd gentamicin, which are dosed according to trough drug levels ( b p. 882). Unlike gentamic in ( b p. 881), vancomycin SEPSIS AND ANTIMICROBIALS 879 is not effectively removed by standard HD, so speed of clearance will largely depend on res idual renal function (if any). In practice, doses may be days apart. (cid:2) Beware the com placency this can induce \200\224 it is crucial to proactively measure and respond to drug levels if periods of inadequate antibiotic activity are to be avoided.