Staging Bladder TCC is staged using the 2002 TNM system (Table 17.4.1). About 70% of bladde r carcinomas present as nonmuscle- invasive disease (Ta/T1), 25% as muscle-invasive disease (T2+) and 5% as CIS. Muscle-invasive TCC Patients found to have muscle-invasive disease (T2 \200\223T4a, N0 \200 \223Nx, M0) or those with high risk nonmuscle-invasive disease in whom conservative treatme nt fails may be can- didates for radical treatment in the form of either radical cystectomy or radical external beam radiotherapy. Treatment Accurate staging is a prerequisite to the correct manage- ment of bladder TCC, as the management of nonmuscle- invasive versus muscle-invasive tumors differs signi \201 ca ntly. Management of all but the lowest risk bladder transitional cell carcinomas should be discussed within multidiscipli- nary teams. Radical cystectomy with urinary diversion This is currently regarded as the gold standard t reatment. It also includes bilateral lymph node dissection, the limits of which are current ly debated with recent evidence sug- gesting that a more radical lymph node dissection lead s to a better outcome. Three main options exist for the urinary diversion: \200 Nonmuscle-invasive TCC Initial management is by transurethral resection (TURBT). Small tumo rs can often be resected in one chip which includes detrusor muscle; larger tumors may requ ire more extensive resection followed by a separate deep muscle biopsy. For large tumors, t he tumor edge should be resected separately to allow thorough pathological exami- nation fo r CIS. Bladder biopsies should also be taken of any abnormal areas within the bladder, or r andom biopsies taken from throughout an otherwise normal bladder if cytology is positive. I f tumor is found at the bladder neck, or CIS is suspected, the prostatic urethra should als o be biopsied in males. Within 24 h of the initial TURBT, a single dose of an intra- vesica l chemotherapy agent (commonly mitomycin-C, but epirubicin and doxorubicin are also used) s hould be given to reduce the risk of recurrence. Subsequent management depends on a variety of factors related to the initial tumor and is based on the likelihood of the tumor either recurring or progressing. Re-resection should be performed, usually within 6 weeks, if res idual tumor is known to have been left, if no detrusor muscle is present in the TURBT speci men, or if high grade disease is reported. Re-resection decreases the risk of ileal conduit using a segment of exteriorized ileum to form a stoma; orthotopic neobladder using a pouch formed from detu- bularized bowel segments anastomosed to the urethra; contin ent cutaneous pouches, similar to neobladders, but which are connected to the skin via the appendix or a bowel segment to allow catheterization for drainage. Urethrectomy should be p erformed when tumor has been identi \201 ed in the prostatic urethra in males or the bladd er neck in females. This then precludes the creation of an orthotopic neobladder. Radical c ystectomy has an operative mortality rate of 3%. Perioperative morbidity is between 20% an d 56% and long- term morbidity is between 28% and 94%, mainly being due to the method of ur inary diversion. Five year survival rates are 40 \200\22360%. Radical external beam radiotherapy Radiotherapy traditionally has been reserved for patient s who are less \201 t or have poorer outlooks. A dose of 60 \200\22366 J.K. MELLON, R.F.J. STANFORD AND J.F. THORPE 682 Prognosis 60 \200\22370% of nonmuscle-invasive bladder cancers recur, 10 \200\22320% progre ss in stage or grade. Risk factors that correlate with recurrence and progres- sion of supe r \201 cial disease are: \200 lamina propria invasion (T1); \200 grade; \200 presenc e of CIS; \200 >3 tumors; \200 tumor >3 cm; \200 previous recurrence. Gy with a subsequent boost can be given within a 6 \200\2237 week course, to give a 5 year survival rate of 40 \200\22360%. Patients who relapse or fail to respond to radiotherapy ca n be considered for salvage cystectomy. Neoadjuvant chemotherapy Chemotherapy has a role in managing muscle-invasive tumors. Good q uality evidence supports the use of neoad- juvant rather than adjuvant chemotherapy, using regimes such as MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) or newer ones s uch as GC (gemcitabine and cis- platin), along with radical cystectomy and radiotherapy to improve survival. Approximately half of patients with muscle-invasive blad- der carcinoma have occult metasta ses at presentation, which become overt within 5 years. Metastatic disease MVAC and GC chemotherapy regimes can prolong life, although outcome with metastatic disease is invariably poor. External beam radiotherapy can also be used in the pallia- tive setting to manage symptoms such as recurrent hema- turia, urinary urgency and pain. Future prospects For nonmuscle-invasive disease, urinary biomarkers have the potential to r educe the need for follow-up cystoscopy and newer methods of administering intravesical age nts (e.g. hyperthermia, electromotive drug administration) and photodynamic therapy are gai ning in popularity. For inva- sive tumors, laparoscopic and robotic cystectomy are being pe rformed increasingly and new chemotherapeutic agents are being tested in clinical trials fo r this type of aggressive cancer. Squamous cell carcinoma Both pure squamous cell carcinoma and bilharzial squa- mous cell ca rcinoma have poor long-term outcomes. The treatment of choice is radical cystectomy, althou gh there is limited evidence for neoadjuvant chemotherapy and radio- therapy in bilharzial squamous cell carcinoma. Further reading Jakse G, Algaba F, Fossa S, Stenzl A, Sternberg C. Guidelines on Bladder Ca ncer (Muscle-invasive and Metastatic). European Association of Urology Guidelines; 2006. Adenocarcinoma The treatment of choice for primary adenocarcinoma is radical cystectomy. Pa tients with urachal adenocarcinoma should be treated with en bloc resection of the urachus and umbilicus combined with partial cystectomy, or radical cys- tectomy for larger tumors. Oosterlinck W, van der Meijden A, Sylvester R, et al. Guidelines on TaT1 (Non-muscle-invasi ve) Bladder Cancer. European Association of Urology Guidelines; 2006. Parekh DJ, Bochner BH, Dalbagni G. Super \201 cial and muscle-invasive bladder cancer: pri nciples of management for outcomes assess- ments. J Clin Oncol 2006; 24: 5519 \200\2235527. Follow-up Nonmuscle-invasive TCC \200\223 low risk tumors Patients with low risk tumors (G 1pTa) should have check \202 exible cystoscopies at 3, 12, 24, 36, 48 and 60 months, or u ntil they develop a recurrence. Recurrences may be dealed with by repeat TURBT or cystodiat hermy (electrocautery or laser) depending on size and equipment availability. Table 17.4.1 TNM classi \201 cation of transitional cell carcinoma Stage Description Non muscle-invasive TCC \200\223 intermediate risk tumors The follow-up cystoscopy protoco l for these patients is often intermediate to that of low and high risk patients and allows for patient factors and local availability. Ta Papillary tumor con \201 ned to the urothelium T1 Invasion into the lamina propria T2a Invasion into the inner half of the muscularis propria Non muscle-invasive TCC \200\223 high risk tumors Cystoscopic follow-up for these patients is 3-monthly for two years, then 4-monthly for 1 year, 6-monthly until 5 years and then ye arly after, or until recurrence or pro- gression intervenes. T2b Invasion into the deeper half of the muscularis propria T3a Microscopic invasion into the perivesical fat T3b Macroscopic invasion into the perivesical fat T4a Invasion into prostate, uterus or vagina T4b Invasion into pelvic or abdominal wall Muscle-invasive TCC In muscle-invasive disease, follow-up of patients after cys- tectomy or bladder preservation is recommended to detect local recurrence or distant metastasis as ea rly as possible. Following cystectomy regular outpatient review is neces- sary. Early asses sment of upper tract drainage with IVU or USS is necessary and annual urethroscopy when the ure- thra is left. In cases of node-positive disease, additional reg- ular CT scans and bo ne scans are necessary. Patients treated with radiotherapy should undergo an early CT scan of the pelvis and regular cystoscopic examination. NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Single lymph node metastasis <2 cm N2 Single lymph node metastasis 2 \200\2235 cm or multiple lymph nodes <5 cm N3 Lymph node metastasis >5 cm M0 No evidence of distant metastasis M1 Distant metastasis present CHAPTER 17.4 Tumors of the bladder 683 Internet resources A useful online calculator for recurrence and progression probabilities: http://www.eortc.be/tools/bladdercalculator/ Hematuria referral guidelines: h t t p : / / w w w . e m r n . o r g . u k / d o c u m e n t s / HaematuriaGuidelines_25_4 .pdf European Association of Urology: http://www.uroweb.org/ Cancerbackup: http://www.cancerbackup.org.uk/home See also Tumors of the renal pelvis and ureter, p. 676 Figure 17.4.2 MRI demonstrating large right-sided invasive bladder cancer with right hydron ephrosis (arrow). Figure 17.4.1 IVU demonstrating a \201 lling defect consistent with a bladder tumor. R. KOCKELBERGH 684 Tumors of the prostate Introduction Prostate cancer is the commonest solid organ malignancy diagnosed in men in Eu rope and the USA and is the second most frequent cause of cancer-related death in men. The age-adjusted incidence has increased from 21 per 100 000 in 1980 to 98 per 100 000 in 2004 in the UK, an almost four- fold increase. This is partly due to the increasing use of trans urethral surgery leading to diagnosis, but mainly due to increasing levels of awareness cau sed by prostate- speci \201 c antigen (PSA) testing. In many patients the disease has an i ndolent course, hence surveillance is commonly recommended in localized disease. Prostate cancer is very rare at ages <50 years and becomes the commonest malignancy in olde r men. Ethnic origin is important as the incidence worldwide is highly variable. Asian men have the lowest incidence whereas the Afro-Carribean population in the UK and African-Ameri can men have a high incidence. The low incidence seen in the Japanese is increased if they move to Hawaii and rises to near that of the US population if they move to California, sugg esting an environmental cause. There is mounting evidence that exposure to sunlight and con sumption of vegetables is protective. Conversely red meat and animal fat consumption may co ntribute to its development. De \201 nition Prostate cancer is most commonly an adenocarcinoma arising in the periphera l zone of the prostate, classically in a posterior location, making it readily palpable on digital rectal examination. Prostate cancer usually develops in a multifocal pattern; howev er, by the time symptoms develop, one or more focus will have grown to substantially replac e the prostate. It is dif \201 cult to de \201 ne \200\230clinically relevant \200\231 p rostate cancer. Histological (microscopic) prostate cancer is common in the asymptomatic po pulation. Furthermore, advanced dis- ease may not cause symptoms and as prostate cancer is a disease of old age, when there are many competing causes of morbidity and mortality, it i s dif \201 cult to establish the true impact of histological prostate cancer. Genetics A family history is a strong predisposing factor. If one \201 rst-degree relativ e has prostate cancer then the risk is doubled, but rises to 5 \200\22310-fold if two \201 rst-degree relatives have the disease. A small proportion (9%) of patients are thought to have genetically linked prostate cancer. For the majority of these the predisposing gen etic abnor- malities are unknown. This is the subject of the \200\230UK genetic prostate c ancer study \200\231 which is recruiting young patients and those with a family history, ai ming to discover a shared germline mutation. In a small proportion of these men, with a his tory of breast cancer in the female line, genetic linkage of the disease is established and linked to the BCRA-2 gene. Epidemiology Since the introduction of PSA testing in 1990 the incidence of prostate cancer has been rising due to detection of asymptomatic disease. In parallel there has been a sim ilar increase in the rates of prostate surgery. Incidental disease Postmortem studies reveal that 30% of men aged >50 years have microscopi c prostate cancer. Only a small number of these will become clinically relevant. Healthy me n in the prostate cancer prevention trial had a prostate biopsy at the end of the study. In the placebo arm 15% of men with a normal PSA were found to have pros- tate cancer. Clinical features Symptoms Localized disease \200 Asymptomatic. \200 Lower urinary trac t symptoms. Locally advanced disease \200 \200 \200 \200 \200 Hematuria. Erectile dysfunction. Perineal or suprapubic pain. Uremic symptoms (from obstruc tive renal failure). Rectal obstruction. Prostate cancer In 2004 there were 34 986 new cases of prostate cancer reported in the UK. In 2005 there were 10 000 deaths from prostate cancer in the UK. 70% of patients with meta stases die from prostate cancer. Metastatic disease \200 Bone pain. \200 Paraplegia due to spinal cord compression. \200 Cachexia. Screening for prostate cancer Screening presents a dilemma. Localized disease has a good pr ognosis and PSA is effective in its detection. Screening detects many cases which may not p rogress and may miss cases destined to progress. No adequate study has shown a bene \201 t from screening. Physical examination \200 \200 \200 Abnormal rectal examination (Table 17.5.1). Palpable bladder. Lymphadenopathy which may cau se lower limb. Edema due to venous or lymphatic obstruction. Investigations \200 \200 Predisposing factors The main predisposing factor is age. PSA. Transrectal ultrasound (TRUS) and biopsy. CHAPTER 17.5 Tumors of the prostate 685 suitable treatment for the elderly and those with comorbidity. It is inferior to surgery an d so is little used in young \201 t men. Prostate-speci \201 c antigen (PSA) Is a serine protease. Is prostate speci \201 c, not p rostate cancer speci \201 c. Rises with age and increasing prostate volume. May be raised in: \200 \200 \200 \200 \200 Active monitoring De \201 ned as monitoring with subsequent radical treatment on disease p rogression. This may be an effective means of selecting patients for radical treatment. The results of the ProtecT study (Prostate testing for cancer and Treatment) will con \201 rm if this approach is comparable to surgery or radiotherapy. prostate cancer; benign prostatic hyperplasia; urinary tract infection; prostatitis; follow ing instrumentation. Radical prostatectomy This produces very good results in terms of cancer survival but at th e expense of signi \201 cant treatment-related morbid- ity including erectile dysfunction and incontinence. It has been shown to be superior to watchful waiting although the surviva l difference is relatively small currently. The real chal- lenge is in de \201 ning which patients will bene \201 t, since some will not be cured while many others will be overtrea ted. Around 30% of patients with a raised PSA will have prostate cancer. 15% of men with a norma l PSA will have prostate cancer on biopsy. The rate of rise is a strong predictor of tumor progression. Is a valuable marker in follow-up where clinical relapse is usually preceded b y a rise in PSA. There are age-related reference ranges (Table 17.5.2). Radical radiotherapy The dilemma of who to treat is very similar to that with surgery. Ther e is no proof that this is a better treatment than monitoring. Treatment-related morbidity includes lower uri- nary tract and rectal symptoms and erectile dysfunction. TRUS and biopsy The commonest de \201 nitive diagnostic test. Local anesthetic procedure. Brachytherapy The insertion of radioactive seeds into the prostate. 15 year survival data s hows this to be effective but there is no randomized controlled trial evidence. It can be d eliv- ered in a single day-case procedure. Treatment-related morbidity mainly involves the lower urinary tract. Other investigations In patients with localized or locally advanced disease, staging invest igations may include a bone scan and prostate MRI. For those with advanced disease, alkalin e phosphatase may indicate bone metastases. Hypercalcemia is surprisingly rare despite bone metas- tases. Renal failure and anemia, particularly a leukoerythroblastic anemia, are com monly seen in symptomatic advanced disease. Locally advanced disease Radical radiotherapy This is a commonly offered treatment for pati ents with a long life expectancy. We know that survival is improved by the addition of horm one therapy. It remains unclear whether this treatment is more effective than hormone thera py alone. Pathology The vast majority of prostate cancers are adenocarcino- mas which may be multifoc al in origin but at symptomatic presentation have usually coalesced. Rarer types include tr ansitional cell carcinoma of the prostate ducts, epider- moid carcinoma and adenoid cystic carcinoma. Tumor differentiation (grade) is measured by the Gleason score which ranges from 2 (well-differentiated) to 10 (poorly differentiated). The score is based on the degree of glandular differentiation and growth pattern of the tumor in relation to the stroma. The G leason score correlates closely with the staging and prognosis. Hormone therapy This provides effective palliation and delays progression. There is mountin g but incomplete evidence that it improves survival. Radical prostatectomy This may have a role in \201 t young patients with limited disease. A signi \201 cant proportion of selected patients will have a pathologically complete exc ision. It is not known if surgery improves survival in this group. Table 17.5.1 Prostate cancer staging by digital rectal examination Staging The TNM stage classi \201 cation system is recommended (Table 17.5.3). T staging i s most commonly decided using rectal examina- tion (Table 17.5.1). A small proportion of pa tients undergo cross-sectional imaging, which can determine T and N stage with reasona- ble accuracy. Digital rectal examination staging Rectal examination \201 ndings Tumor clinically inapparent/not palpable. Normal texture prostate. Symmetrical. T1 Tumor con \201 ned to prostate. No distortion of capsule. T2 Treatment Localized disease Watchful waiting De \201 ned as monitoring and subsequent trea tment with hor- mone therapy on disease progression. This is a particularly Tumor extends through capsule. Tumor mobile. Distortion of capsule. T3 Tumor invades other organs locally. Immobile as other structures are involved. T4 R. KOCKELBERGH 686 Table 17.5.2 Age-related reference ranges for PSA Table 17.5.3 TNM staging classi \201 cation for prostate cancer Age (years) PSA (ng/mL) Stage Description 40 \200\22349 \211 2.5 Primary tumor cannot be assessed TX 50 \200\22359 \211 3.5 No evidence of primary tumor T0 60 \200\22369 \211 4.5 Clinically inapparent tumor not palpable or visible by imaging T1 >70 \211 6.5 Tumor incidental histological \201 nding in \211 5% of tissue resected T1a Metastatic disease Hormone therapy Early hormone therapy is superior to delayed therapy in terms of complications and mortality. However, the differences are small and need to be bal anced against long-term cardiovascular and bone dem- ineralization risks. Tumor incidental histological \201 nding in >5% of tissue resected T1b Tumor identi \201 ed by needle biopsy (e.g. because of elevated PSA) T1c Palpable tumor con \201 ned within prostate T2 Tumor involves half of a lobe or less T2a Hormone therapy Hormone therapy decreases androgenic stimulation of the prostate cancer whi ch in turn leads to tumor regression and delayed progression in most patients. Side-effects of hormone therapy include hot \202 ushes, gyne- comastia and loss of male characteristi cs. Includes the following equivalent therapies: Tumor involves more than half of a lobe, but not both lobes T2b Tumor involves both lobes T2c Tumor extends through the prostatic capsule T3 Extracapsular extention (unilateral or bilateral) T3a Tumor invades seminal vesicle(s) T3b Tumor is \201 xed or invades adjacent structures other than seminal vesicles (bladder nec k, external sphincter, rectum, levator muscles or pelvic wall) T4 Surgical orchidectomy \200 Effective but unfashionable. Medical orchidectomy \200 Regional lymph nodes cannot be assessed NX Luteinizing hormone-releasing hormone (LHRH) agonists. No regional lymph node metastasis N0 Regional lymph node metastasis N1 Antiandrogens. Estrogens. Distant metastasis cannot be assessed MX No evidence of distant metastasis M0 LHRH agonists are used with antiandrogens to prevent tumor \202 are. Antiandrogens are or al drugs occasionally used alone for primary treatment. Estrogen is commonly used second li ne or in combination therapy. It is effective but is used second line due to the risk of ca rdiovascular complications. Distant metastasis present M1 Nonregional lymph nodes M1a Bone metastasis present M1b Other metastasis present M1c offer nephrostomy in those well enough to receive chemotherapy. Palliative care Common problems in those with progressive disease include: Follow-up Follow-up is heavily reliant on PSA as a tumor marker. Following radical surgery any rise in PSA is indicative of recurrent disease, while following radical radio- therapy a rise of 2 ng/mL above the nadir de \201 nes treat- ment failure. A rising PSA over time suggests disease progression; the rate of rise has important prognostic value. However, dis ease progression can take place without a PSA rise, particularly in poorly differentiated d isease. Follow-up intervals are determined by the risk of progres- sion, generally 3 \200 \2236-monthly. The upcoming NICE guideline is likely to recommend that the majority of foll ow-up takes place in primary care. Bladder out \202 ow obstruction Often managed by TURP. Pelvic and bone pain Treated with radiotherapy, chemotherapy (docetaxel) or bisphosphonates . Renal failure Prostate cancer causes renal failure by two mechanisms: \200 Bladder outflow obstruction: usually high pressure chronic retention caused by locally adva nced disease. Ureteric obstruction: caused by locally advanced disease or pelvic/retroperit oneal lymphadenopathy. Renal failure has a poor prognosis but can occur in two settings: \200 Hormone-naive patients in whom aggressive therapy for renal failure including nephrostomy i s justi \201 ed. Hormone-relapsed disease: patients are reaching the end of their lives. P atients and carers need to be involved in the decision-making process. It may be justi \201 ed to Prognosis Localized disease 90% 10 year survival. CHAPTER 17.5 Tumors of the prostate 687 Further reading Bhatnagtar V, Kaplan RM. Treatment options for prostate cancer: Evaluating the evidence. Am Fam Physician 2005; 15: 1915 \200\2231922. Downes MR, Byrne JC, Pennington SR, Dunn MJ, Fitzpatrick JM, Watson RW. Urinary markers for prostate cancer. BJU Int 2007; 99: 263 \200\223268. Tumor differentiation, clinical stage and PSA level are the important factors. It is rare t o diagnose prostate cancer with a Gleason score of \211 5 on needle biopsy and so in moder n practice Gleason score 6 has a good prognosis, scores 8 \200\22310 a poor progno- sis and score 7 an intermediate prognosis. Hamdy FC, Basler JW, Neal DE, Catalona WJ. Management of uro- Metastatic disease 2 \200\2233 years median survival. Hormone-relapsed metastatic disease 6 months median survival if symptomatic. logical malignancy. Edinburgh: Churchill Livingstone; 2002. Kirby RS, Brawer MK. Fast facts \200\223 prostate cancer. Health Press; 2004. Internet resources Age-standardized incidence and mortality rates for pros- tate cancer: Great Britain 1971 \200\223 2004. Available at Cancer Research UK: Future prospects New diagnostic tests, including the PCA3 urine test, may be more speci \201 c than those currently available. There is clearly a need to develop a test which iden ti \201 es disease likely to progress and not indolent disease. Genomic stud- ies may lead to such a development. The ProtecT study, randomizing patients with localized dis- ease be tween surgery, radiotherapy and active monitoring, should determine which of these is most effective, but will require 10 \200\22315 years of follow-up. New technology is being used to manage prostate cancer in the form of cryotherapy, high-intensity-focused ultra- sound ( HIFU), laparoscopic surgery and intensity-modu- lated radiotherapy. These may replace curre nt therapy as they promise treatment with low levels of morbidity. Future developments in a dvanced disease will include combinations of treatments including chemotherapy and hormones . Vaccines and manipulation of androgen signal- ing appear promising for advanced disease. http://info.cancerresearchuk.org/cancerstats/ European Association of Urology: www.uroweb.org National Cancer Institute \200\223 Prostate cancer: http://www.cancer.gov/cancertopics/types/pros- tate ProtecT Study: http://www.epi.tris.ac.uk/protect See also Tumors of the bladder, p. 680 Urinary tract obstruction, p. 652 This page intentionally left blank 689 Chapter 18 Pharmacology and drug use in kidney disease Chapter Contents Handling of drugs in kidney disease 690 Drug-induced nephropathies 698 Clinical use of diur etics 708 Systemic cancer therapies and the kidney 714 S. MAXWELL 690 Handling of drugs in kidney disease Introduction The handling of drugs in the body (pharmacokinetics) is signi \201 cantly alt ered in renal disease and also by the reduction in renal function with advancing age. Many drugs, and some active metabolites, are eliminated by the kidney, either by glomerular \201 ltration or tubular secretion. Patients with kidney disease, and especially those who require dial- ysis, are often on multiple drugs. There is the potential for the accumulatio n of many drugs even with modest decreases in renal function. In these circumstances, patie nts may be much more sensitive to their adverse effects. In everyday clinical practice, the number of drugs for which changes in dose or interval are required is small and lim- ited to those with a narrow therapeutic index or those that are associated with serious adverse effects. Important factors that may reduce the risk of serious med- ication adverse effects in patients with kidney disease are: \200 awareness of the presence or possibility of re nal impair- ment; recognition that some medicines may be reliant on renal clearance; abilit y to monitor the therapeutic and adverse effects. The main factor that determines the need for and the extent of the dose reduction is the glomerular \201 ltration rate (GFR) and i ts impact on drug clearance. In practice, GFR is usually estimated from serum creatinine co ncentration and may be unreliable in patients with AKI. In some cases the GFR does not corr elate well with the change in renal elimination. As a general guide, alteration of drug dos age is only necessary if renal clearance exceeds 25% of total body clearance. Distribution The build-up of acidic compounds in renal failure creates competition with var ious drugs for binding sites on albumin and other proteins. Serum albumin levels are signif icantly reduced in the nephrotic syndrome. This means that, for a given amount of drug, the ratio of free to bound drug is increased and the \202 uctuation of free drug after each dose may be greater. Importantly, the drug concentration reported by most assays includes b oth bound and free drug and these may not re \202 ect increased tissue exposure. Drugs whe re reduction in protein binding may be important include: \200 \200 \200 warfarin; diazepam; phenytoin. Increases in doses of drugs such as phenytoin should be small. Fluid retention may lead to an expansion of both the intra- vascular and extracellular fluid compartments, which result s in an increased volume of distribution (Vd) for many drugs. This decreases the plasma dru g concentration resulting from a given dose of drug that is mainly distributed within those compartments. Conversely, the tissue binding of some drugs (notably digoxin) is reduced an d hence Vd decreases. This increases the plasma drug concentration resulting from a given d ose. Renal impairment is also associated with changes in body composition such as a reducti on in the proportion of fat and reduced muscle mass. The former, in particular, may reduce the Vd of nonpolar (lipid-soluble) drugs. Metabolism Most drugs are excreted unchanged or as more polar (water-soluble) compounds pro duced after metabolism in the liver. Plasma drug assays must be interpreted with cau- tion, not only because of the increase in free fraction noted above, but because some may pick u p active or inactive metabolites making interpretation dif \201 cult. The kidney itself is a site of metabolism of some drugs. The most notable example is the conversion of 25-(OH) vita- min D3 to its active form 1,25-(OH)2 vitamin D3 which is reduced in renal impairment. The synthetic analog 1A- (OH) vitamin D3 is converted to the active form and is used thera peutically. Pharmacokinetic alterations in kidney disease The main effect of renal disease is to alter the rate of drug excretion but all phases of pharmacokinetics may be affected: \200 \200 \200 \200 absorption; distribution; metabolism; elimination. In addition to its effects on pharmacokinetic handling, renal impairment may alter the sens itivity of target tissues to the therapeutic and adverse effects of drugs (pharmacody- nami cs). For example, antiplatelet drugs may have an exaggerated effect in uremic patients (who already have impaired platelet aggregation), and there is a signi \201 cantly increased r isk of statin-induced myopathy. Some speci \201 c examples of pharmacokinetic variations a re given in Table 18.1.1. Elimination The rate of renal excretion of drugs depends on: \200 \200 \200 \200 glomerular \201 ltration; active tubular secretion; active tubular reabsorption; passive diffusion. This can be expressed mathematically by the equation: \200 Absorption Increased ammonia production in the stomach from urea hydrolysis buffers hydroch loric acid and raises pH. This may reduce absorption of ferrous sulfate and folic acid. Alu minum hydroxide is occasionally used as a phosphate binding agent and may bind several drug s including aspirin, ferrous sulfate and cipro \202 oxacin. Clearance = (Funbnd \227 GFR) + Secretion \200\223 Reabsorption where Funbnd is the fract ion of drug unbound in the plasma. Clearance < (Funbnd \227 GFR) means that active reabsor ption is taking place. Compounds with a molecular mass of <60 000 Da are \201 ltered to a n extent dependent on molecular size unless they are protein-bound when only the nonbound p ortion is \201 ltered. CHAPTER 18.1 Handling of drugs in kidney disease 691 Table 18.1.1 Mechanisms of altered pharmacokinetics in renal disease Pharmacokinetic phase Pharmacokinetic change Examples ferrous sulfate, folic acid aspirin, ferrous sulfate, cipro \202 oxacin Raised stomach pH can reduce absorption of some drugs. Phosphate-binding agents such as alu minum hydroxide may Absorption interfere with the absorption of other drug. Other factors in \202 uencing absorption: \200 prolonged gastric emptying \200 gut edema \200 nausea. reduced activity of intestinal drug transporters Protein concentration or protein binding reduced (more unbound (active) drug). warfarin, diazepam, phenytoin Distribution Fluid volume expansion (increased volume of distribution of water-soluble drugs). atenolol Tissue binding reduced (decreased volume of distribution). digoxin Reduced proportion of body fat (decreased volume of distribution of fat-soluble drugs). Reduced liver metabolism for many drugs due to: impaired transportation into hepatocytes im paired liver metabolic pathways. aciclovir, cimetidine, metoclopramide, codeine, imipenem Metabolism \200 Reduced renal metabolism. insulin Reduced GFR leading to the retention of: Renal excretion unaltered drug \200 active metabolites. digoxin, gentamicin, morphine-6-glucuronide Renal blood \202 ow Renal blood \202 ow can become an important independent in \202 ue nce on drug excretion when GFR has declined sig- ni \201 cantly. In these circumstances, d rug clearance may be adversely affected by hypovolemia or other drugs that impact on perfus ion, e.g. NSAIDs (impair cortical blood \202 ow by inter- fering with prostaglandin synth esis). All aspects of renal elimination including glomerular \201 ltration, reabsorption and sec retion are altered in renal failure. Nonpolar drugs easily diffuse across membranes while p olar ones do not. As the urine is progressively concentrated during its passage through the renal tubule, nonpolar drugs tend to be reabsorbed passively down their concentration grad ient while polar drugs or the polar derivatives of nonpolar drugs produced in the liver are not. Some polar drugs are actively excreted by the same mech- anisms as organic acids and bases: \200 Assessing renal function before prescribing The most important measure of renal function th at might in \202 uence prescribing is the GFR. Serum creatinine has been a widely used sur rogate of renal function but is dependent not only on GFR but also on creatinine production and may signi \201 cantly overestimate GFR in some groups (e.g. the elderly, those with l ow body mass). Estimation of GFR from single creatinine measurements can be made by adjustm ent for body weight, age and gender using mathematical formulas (e.g. the Cockcroft \200 \223Gault formula). The modi \201 ed MDRD formula is now commonly used to calculate \200 \230eGFR \200\231. The advantage is that it requires only the serum creatinine, age and gen der (not height or weight). However, when using eGFR to make assessments of renal function that may in \202 uence decisions about thera- peutic dose, there are important caveats: \200 organic acids (e.g. penicillins, cephalosporins, salicylates, furosemide and thiazides); or ganic bases (e.g. amiloride, procainamide and quinidine). Some drugs interfere with the excretion of others: \200 \200 \200 probenecid with penicillins; cephalosporins and furosemide; aspirin and paracetamol reduce the excretion of meth- otrexate. A low protein diet reduces the acidity of the urine which may alter the ionization of drugs . There is some evidence that \201 ltration and secretion of drugs may fall in parallel a nd in proportion to the GFR. Some drugs are eliminated unchanged by the kidneys and are par ticularly vulnerable to accumulation in renal disorders. More commonly drugs are cleared by transformation into more water-soluble metabolites that can be eliminated in the urine. Fo r most drugs the development of renal failure has a modest impact but, in some cases, the m etabolite retains much of the activity of the parent drug and has the potential to cause ad verse effects. the eGFR is increasingly unreliable at the extremes of body weight and might lead to overdo sing of small patients and underdosing of large patients; rises in serum creatinine (and he nce reductions in eGFR) may lag behind the actual deterioration of GFR in AKI which is espe cially important in the intensive care setting; it is not valid in pregnant women or in chi ldren. S. MAXWELL 692 Concentration \200\223time relationship Most drugs eliminated by the kidneys exhibit \201 rst-order kinetics, i.e. the rate of removal is proportionate to the drug concentration. U nder these circumstances a plot of concentration (C) versus time (t) displays an exponentia l decline (Fig. 18.1.1a) described by the equation Most drugs are given repeatedly at regular intervals and their concentration increases to r each a steady state (after \210 5 \227 t ) when the rate of intake matches the rate of e xcretion (Fig. 18.1.1b). Increases in the dose or frequency will result in a new, higher, s teady state concen- tration pro \201 le producing the required elimination rate. If renal function is impaired the clearance rate is reduced at any given concentration and the drug t is increased. If the dose and frequency remain the same, a higher steady state concentr ation (and hence drug exposure) will be required to produce the necessary elimination (Fig. 18.1.1b). The increased steady state plasma concentration and drug exposure can be avoided by either a reduction in the drug dose or frequency (dose interval). It should be noted th at these two strategies are not equivalent. C(t) = C0 e \200\223kt where C0 is the concentration at time zero and k is the elimination rate constant. Drugs that exhibit such kinetics can be described by their half-life (t ), the time taken for the concentration to halve (after absorption and distribution are comple te). This has a major in \202 uence on the best dosing interval, the time required to achi eve \200\230steady state \200\231 and the persistence of the drug effect after treatment i s stopped (all are proportional to t ). 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 m ( 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 (a) Plasma drug concentration Repeat dosing Renal failure 97% Trough level 94% 87.5% 75% Normal 50% 1 2 Time (days) 3 (b) Fig. 18.1.1 Dose \200\223response curves following (a) single dose administration or (b) re peated dosing in the presence and absence of renal impairment. Note the effect of reduced r enal clearance on the half-life, time to steady state, and the steady state plasma concentr ation. CHAPTER 18.1 Handling of drugs in kidney disease 693 Dose reductions result in lower peak concentrations but maintained trough levels, which is ideal if a constant exposure is required. Increased dose intervals preserve peak concentrat ions but allow lower trough levels to be reached. The former strategy may be more suited to antihypertensive drugs while the latter is more suitable for aminoglycoside antibiotics wh ere high peak concentration is required for bactericidal activity with low troughs to help avoid toxicity. Single or \200\230loading \200\231 doses do not usually need to be altered in renal failure, even if the drug has a narrow therapeutic index. This is because, althou gh drug exposure time may be increased, accumulation to high concentration will not occur. The dose should take into account the diminished intrinsic renal function.