plain abdominal X-ray; gastric and small bowel transit tests using either scintig- raphy or manometry. \200 \200 \200 There is no proven treatment other than supportive care: \200 temporary parenteral nutrit ion can be used in severe cases; prokinetic agents (e.g. erythromycin). Practical points: \200 \200 Acute intestinal pseudo-obstruction Predisposing factors: \200 \200 \200 high incidence of angiodysplasia in elderly patients; high incidence of amyloidosis in long -term dialysis patients; consider NSAID enteropathy in patients with rheuma- toid arthritis ; constipation due to phosphate binders or kayexalate exacerbating rectal bleeding; uremia- related coagulation abnormalities \200\223 often primary cause or exacerbating factor. chronic constipation; diabetic autonomic neuropathy; medications (e.g. kayexalate, opioid a nalgesics). The acute abdomen All common causes of an acute abdomen are seen in patients with renal fai lure. Common causes to consider include: \200 small bowel or colon obstruction (particularly if previ- ous PD and risk of intra-abdominal adhesions); visceral perforation; bowel ischemia or necrosis (high incidence of acceler- a ted atherosclerosis in CKD and ESRD); intracyst infection and hemorrhage in patients with p oly- cystic kidney disease; Upper GI tract bleeding The incidence of upper GI bleeding has decreased due to improvement s in dialysis practices and treatment with H2 antagonists/proton pump inhibitors. Neverthel ess, upper GI bleeding accounts for 3 \200\2237% of all deaths in ESRD patients. \200 G. KOSMADAKIS 420 Common causative conditions are listed in Table 11.6.1. Cardiovascular disease, current smo king and increasing debility are associated with a greater risk of upper GI bleeding in pat ients with ESRD. Gastric antral vascular ectasia (watermelon stomach) is an angiodysplastic lesion con \201 ned to the gastric antrum. It is characterized by submucosal capillary di latation and \201 bro- muscular hyperplasia. effects on colonic motility of iron supplements, digoxin, phosphate binders and antihyperte nsive therapy. Clostridium dif \201 cile-associated pseudomembranous colitis is more common, more severe and has a higher recurrence rate in patients with renal failure, due to a reduced thresh- o ld for use of antibiotics in relatively immunocompromised patients with ESRD, in older pati ents, and topical enteral factors (dysmotility, abnormal bile acid pro \201 les). Other pa thogens such as CMV in HIV-positive patients and Strongyloides stercoralis may be the causa tive agents of severe enterocolitis in patients with renal failure. General therapy \200 \200 \200 \200 \200 \200 \200 review need for antiplatelet agents and warfarin; maximize hematocrit (EPO and red cell tra nsfusion); minimize effect of uremia with increased dialysis dose; DDAVP (desmopressin); an ti \201 brinolytic agents (tranexamic acid); cryoprecipitate; recombinant activated factor VII. GI complications in patients on PD The most commonly seen are: \200 \200 \200 \200 gastroparesis; malabsorption; pancreatic dysfunction; protein-losing enteropathy. Tranexamic acid is a potent inhibitor of the \201 brinolytic sys- tem and can be used bot h orally and IV. One suggested protocol is 20 mg IV followed for the next 4 weeks by 10 mg/ kg/48 h orally. Additionally, increased intra-abdominal pressure can result in hernia formation, delayed ga stric emptying and gastro- esophageal re \202 ux. A reduction in supine intraperitoneal \202 uid with adjustment of dialysis prescription to maintain adequate clearance may help g astroesophageal re \202 ux. Oral or intraperitoneal erythromycin may improve gastroparesis . In women, pain on infusion of dialyzate and hemoperito- neum may be seen during menstruat ion and ovulation and can also be seen in endometriosis. Pain during dialyzate infusion is not uncommon and may be due to: \200 \200 \200 Speci \201 c therapy Bleeding peptic ulcer: endoscopic laser therapy, topical injection of adrenaline, ethanol or polidocanol. Esophageal varices: endoscopic sclerotherapy, endoscop ic variceal band ligation, balloon tamponade, somatostatin or octreotide infusion. Hemorrha gic gastritis: antacids, H2 receptor antagonists, proton pump inhibitors, sucralfate. Lower GI tract bleeding Angiodysplasia is the commonest cause (Table 11.6.1). Angiodysplasi a is a vascular abnormality affecting the microcirculation of the GI mucosa and submucosa. It commonly causes GI hemorrhage in the elderly. The incidence is increased in HD patients and responsible for 20% of all GI hemorrhages in HD population. Investigations include: \200 the acidic pH of lactate-buffered dialyzate; catheter malposition; hypertonic dialysis solu tions. Treatment options include: \200 \200 \200 \200 switching to bicarbonate-based PD solutions; catheter repositioning or replacement; slowing the infusion rate; injection of local anesthetic into the PD solution before infusion. endoscopic procedures (colonoscopy, \201 ne \201 bre entero- scopy); selective visceral angiography. Scrotal or labial swelling may be seen due to a patent processus vaginalis or a dissection through the peritoneal General therapy \200 \200 \200 \200 \200 \200 \200 review need for antiplatelet agents and warfarin; maximize hematocrit (EPO and red cell tra nsfusion); minimize effect of uremia with increased dialysis dose; DDAVP; anti \201 brinol ytic agents (tranexamic acid); cryoprecipitate; recombinant activated factor VII. Table 11.6.1 Common causes of GI bleeding in patients with ESRD Upper tract bleeding Esophageal varices Mallory \200\223Weis tear Gastritis/duodenitis Pept ic ulcer Angiodysplasia Gastric antral vascular ectasia Dieulafoy malformation B2-Microglob ulin amyloidosis Lower tract bleeding Angiodysplasia Diverticulae B2-Microglobulin amyloido sis Colorectal polyps Hemorrhoids/anorectal tears Stercoral ulcers Speci \201 c therapy \200 \200 estrogen/progesterone preparations; therapeutic endoscopy (electrocoagulation and laser the rapy); surgical resection. Diarrhea Diarrhea is frequently seen in patients with advanced CKD and ESRD and its cause i s often multifactorial: \200 \200 autonomic neuropathy; nonspeci \201 c antibiotic-induced diarrhea; CHAPTER 11.6 Gastrointestinal disorders in chronic kidney disease 421 membrane. This usually requires surgical repair of the her- nia or patent processus vaginal is. Abdominal wall edema, due to dialyzate leak into the ante- rior abdominal wall, may res olve following a period of rest- ing from PD or transfer onto automated PD. Surgical reposi tioning of the catheter may be required if conserva- tive measures fail. Encapsulating peri toneal sclerosis is a rare complication of PD and is associated with a number of GI complic ations, the most serious of which is malabsorption and conse- quent malnutrition. Diabetic enteropathy This presents with episodic watery and painless diarrhea due to: \200 diabetic autonomic neuropathy (vagal, sympathetic and enteric nervous system damage); and b acterial overgrowth (resulting in bile acid deconjuga- tion and fat malabsorption). Treatment involves both supportive therapy with lopera- mide and octreotide and treatment o f any contributing microbial cause of the diarrhea. Further reading Bossola M, Tazza L, Giungi S, Luciani G. Anorexia in hemodialysis GI complications in patients with diabetes Diabetic gastroparesis This is related to diabet ic autonomic neuropathy of the GI tract. Clinical signs include: \200 abdominal bloating; \200 early satiety; \200 episodic vomiting. patients: an update. Kidney Int 2006; 70: 417 \200\223422. Etemad B. Gastrointestinal complications of renal failure. Gastroenterol Clin North Am 1998; 27: 875 \200\223892. Strid H, Simr n M, Stotzer PO, Abrahamsson H, Bj rnsson ES. Delay in gastric emptying in patients with chronic renal failure. Scand J Gastroenterol 2004; 39: 516 \200\223520. Tsai CJ, Hwang JC. Investigation of upper gastrointestinal hemor- rhage in chronic renal fa ilure. J Clin Gastroenterol 1996; 22: 2 \200\2235. It compromises glycemic control and impairs absorption of orally administered drugs. There are no anatomic alterations of the upper GI tract on imaging studies. Investigation: \200 Internet resources National Library of Guidelines Specialist Library: http://www.library.nhs.uk/guidelinesFinder/ British Society of Gastroenterology: http://www.bsg.org.uk/ American College of Gastroenterology: scintigraphic measurement of gastric emptying. Treatment: \200 \200 \200 http://www.acg.gi.org low fat and low \201 ber diet with frequent small meals; if severe enteral (via jejunosto my) or parenteral nutrition; drug therapy with dopamine antagonists (metoclopra- mide, domp eridone) and motilin receptor stimulants (erythromycin); gastric electric stimulation and p yloric botulinum toxin injection have been successfully used in a small number of cases. See also B2-microglobulin amyloidosis in CKD, p. 436 Chronic kidney disease in diabetic pat ients, p. 472 Autosomal dominant polycystic kidney disease, p. 590 Peritoneal dialysis, p. 506 Coagulation disorders in CKD, p. 444 G. KOSMADAKIS 422 Liver disorders in chronic kidney disease Hepatitis B Hepatitis B virus (HBV) is a dsDNA hepadnavirus. It is rela- tively stable in t he environment and can remain viable for at least 7 days on environmental surfaces. HBV is transmit- ted by percutaneous (i.e. puncture through the skin), per- mucosal (i.e. direct c ontact with mucous membranes) or perinatal exposure to infectious blood. Chronic hepatitis B virus (HBV) infection can be associated with the develop- ment of: \200 \200 \200 In ESRD progression of chronic HBV infection to hepatic cirrhosis and HCC can occur with a less marked hepatic in \202 ammatory response. Investigations Liver function tests Aspartate aminotransferase (AST) and ALT levels may be elevated and re \202 ect hepatocellular injury. Total serum alkaline phosphatase may be el evated but alka- line phosphatase is also produced by the intestine, liver and bone and so may not correlate well with the extent of liver involvement. Measurement of other enzymes, such as 5-nucleotidase and G-glutamyltransferase, may provide some additional information o n extent of liver injury. cirrhosis; hepatocellular carcinoma (HCC); hepatic failure. Patients with renal failure have an increased risk of acquir- ing the virus through blood t ransfusions and contact with contaminated bodily \202 uids during hemodialysis. Liver biopsy This is the \200\230gold standard \200\231 for the assessment of the liver \200\231s functional reserves, the activity and chronicity of liver disease. Epidemiology While the prevalence of HBV hepatitis appears to have decreased in recent time s in Europe and the USA, HBV infection still poses a signi \201 cant public health burden in Asia and South America. Hepatitis B surface antigen (HBsAg) positivity rates among dialy sis patients tend to correlate with rates in the endemic population. A lower prevalence of HBV infection has been reported in patients on PD compared with patients treated with HD. Serological assays \200 A positive result indicates ongoing HBV infection and potential i nfectivity. It appears 30 \200\22360 days after exposure to HBV and persists for variable p eriods) (Fig 11.7.1 & Table 11.7.1). \200 HBeAg This is positive in acute and chronic HBV infection and cor- relates with viral replication and high infectivity. HBeAg-negative pat ients: 1 these are quiescent and were previously known as the HBsAg Predisposing factors The most common risk factors for HBV infection in dialysis patients ar e: \200 \200 \200 \200 multiple transfusions; local levels of hepatitis B carriage; duration of HD; presence of HB sAg+ patients in the dialysis unit and non- separation of infected from noninfected patient s; failing to follow standard infection practices, e.g. sharing multidose vials and IV solu tions or equipment in contact with blood; not periodically screening patients for HBsAg; no t vaccinating susceptible patients; staff members who simultaneously care for both HBV- inf ected and susceptible patients. \200\230healthy \200\231 or \200\230inactive \200\231 carriers; or 2 are actively replicating \200\230pre-core \200\231 mutants. \200\230Pre-core \200\231 m utants have a mutation in the pre-core region of the HBV DNA. They have a worse prognosis a nd poorer response to therapy than HBeAg-positive patients. \200 Antibodies against the H BV core antigen appear in the early stages of infection and persist long term. IgM anti-HBc Ab indicates recent infection and persists for 6 months. \200 Antibodies against the HBV surface antigen indicate immunity from HBV infection, either natural (anti-HBsAb+ and anti -HBcAb+) or after successful vaccination (only anti-HBsAb+). \200 HBeAb Antibodies agains t the HBcAg envelope antigen correlate with nonreplicating virus and with lower levels of v irus. HBcAb \200 \200 HBsAb Clinical features HBV causes both acute and chronic hepatitis. The incubation period ranges from 45 to 160 days. Acute HBV infection in dialysis patients is often mild or asymptomati c and many will become chronic carriers due to impaired uremia-related antiviral immune res ponses. When present, clinical symptoms and signs might include: \200 \200 \200 \200 Nucleic acid detection A quantitative test for HBV DNA copy number is available and measure s hepatitis B viral load (expressed in copies/ ml). It is used: \200 anorexia and malaise; nausea and vomiting; abdominal pain; jaundice. in suspected cases when other tests are inconclusive (e.g. before the HBsAg becomes positiv e, in cases of occult HBV (with a negative HBsAg) or pre-core mutants); prior to initiation of antiviral therapy; to estimate the success of antiviral therapy. Chronic HBV infection is de \201 ned as persistence of HBsAg for >6 months with histologic al changes on liver biopsy and/or persistently elevated alanine aminotransferase (ALT) leve ls. \200 CHAPTER 11.7 Liver disorders in chronic kidney disease 423 no reuse of dialyzers in HBsAg+ patients. Screening for hepatocellular cancer \200 In HBsAg+ patients AFP should be measured every 6 months. It is elevated in 60% of liver cancers. \200 Should be performed every year in HBsAg+ patients. It is diagnostic in 80% of cases of liver cancer. A-Fetoprotein (AFP): When a seroconversion occurs \200 review all patients \200\231 laboratory results to identify addi- tional cases; investigate potential sources of HBV infection; in patients newly infected with HBV, repeat HBsAg and test for HBcAb (including IgM HBcAb) 1 \200\2232 months later; 6 months later, repeat HBsAg testing and test for HBsAb to determine clinical outcome; patients who become HBsAg \200 \223 are no longer infectious and can be removed from isolation. \200 Liver ultrasound: Treatment The goals of therapy are (Fig 11.7.2): \200 suppression of viral replication; \200 prevention of hepatic \201 brosis; \200 seroconversion from HBsAg+ to HBsAb+ and from HBeAg+ to HBeAb+. Commonly used antiviral agents include (Table 11.7.2): Immunization There is no difference in effectiveness between plasma- derived and recombinan t type of vaccines. Success rates of vaccination in HD patients are lower com- pared to the general population due to immunosuppres- sion related to uremia. Vaccine success is invers ely related to the degree of renal dysfunction, therefore early vaccination is recommended. There is no evidence to support the use of alternative vac- cination routes (e.g. intrader mal) or coadministration with other agents (e.g. erythropoietin or IL-2). A three or four d ose recombinant vaccine schedule of 40 g at 0, 1 and 6 months or 0, 1, 2, and 6 months re s pectively is recommended for patients with CKD and ESRD. All vaccinated patients should b e tested for HBsAb 1 \200\223 2 months after the last primary vaccine dose, to determine re sponse. Adequate response: \200 \200 \200 Interferon-a This is an antiviral, antiproliferative and immunomodula- tory agent. Side-eff ects are common and include: \200 \200 \200 \200 \200 Treatment duration for HBeA g+ patients is 16 weeks and for HBeAg \200\223 patients is 12 months. Pegylated interferon- A has improved pharmacokinetics and allows for a weekly dosing schedule. It is associated w ith a 30 \200\22335% HBeAg seroconversion rate, compared to 16 \200\22320% with standard in terferon. \202 u-like symptoms; neutropenia; thrombocytopenia; neuropsychiatric symptoms; exacerbat ion of hepatitis. >10 sample ratio units (SRU); >10 mIU/mL (North America); > 100 IU/L (Europe). Lamivudine A cytosine analog that inhibits HBV reverse tran- scriptase. It is well-tolerate d and safe. Lamivudine-resistant HBV variants have emerged, with a mutation in the YMDD loc us of the HBV DNA polymer- ase. The prevalence of resistance increases with the dura- tion of treatment and HBeAg \200\223 disease. Adefovir dipivoxil This is a phosphonate nucleotid e analog of adenosine that binds competitively to HBV DNA polymerase. It is safe and effect ive in patients with lamivudine-resistant HBV and renal disease. It is cleared by the kidne ys and patients with renal insuf \201 - ciency should receive reduced doses. Responders should be retested annually. Revaccination of nonresponders with three additiona l doses is recommended. No additional doses of vaccine should be given if there is still no response to the second series. In responders whose HBsAb levels decline below protec- tive levels a booster dose is recommended. Patients as peritoneal dialysis should be similarly vaccunated. Hepatitis C Hepatitis C virus (HCV) was discovered in 1989 and causes the majority of cases previously labeled as non-A, non-B hepatitis. HCV is a small RNA hepacivirus of the Flaviv iridae family. At least six different genotypes and >90 subtypes of HCV exist, with genotyp e 1 associated with more severe disease and worse clinical outcomes. Unlike HBV virus, infe ction with one HCV genotype or subtype does not protect against reinfection or superinfec- tion with other HCV strains. There is no correlation between the severity of hepatic lesion s and viral genotype or viral load. HCV infection increases the risk of all cause death in ESRD patients. HCV is transmitted via direct percutaneous exposure to infectious blood. Prophylaxis General measures \200 \200 universal infection control precautions; routine serologic testing for markers of HBV infec tion and prompt review of results; isolation of HBsAg+ patients with dedicated room, machin e, other equipment, supplies and staff members; testing susceptible patients monthly for HB sAg, particu- larly those who have not yet received hepatitis B vaccine, are in the process of being vaccinated, or have not responded to vaccination; dialysis staff should be vaccin ated and wear protective gloves that must be changed before proceeding from one patient to another; G. KOSMADAKIS 424 Fig. 11.7.1 Serologic course of hepatitis B virus infection. Table 11.7.1 Interpretation of the hepatitis B panel Interpretation HBsAg HBsAb HBcAb HBeAg HBeAb + + + + \200\223 \200\223 \200\223 \200\223 IgM IgG + + + \200\223 \200\223 \200\223 Incubation period. Acute hepatitis B or persistent carrier state, high infectivity. Chronic hepatitis B, high infectivity. \200\223 IgG \200\223 + Chronic hepatitis B with low infectivity or \200\230pre-core mutant \200\231 hepatitis B. \200\223 \200\223 \200\223 \200\223 + IgG IgM \200\223 \200\223 \200\223 \200\223 + \200\223 \200\223 Recovery from natural infection. Infection with HBV without detectable HBsAg. Post immunization or recovery from infection with loss of detectable anti-HBcAb. Table 11.7.2 Dosing recommendations in patients with ESRD HBsAg(+) Check HBV DNA HBeAg, HBeAb, AFP, liver USS Drug IFN-A-2b PEG-IFN-A-2a PEG-IFN-A-2b Lamivudine Dosage 3 million units (MU) SC three times per weeka 135 g SC once per weeka 0.5 \200\2231.0 g/kg SC once per weeka HBV DNA <104 c/ml HBV DNA >104 c/ml 35 mg \201 rst dose, then 10 mg PO qds HBeAg(+) No treatment Follow up every 6 \200\22312 months HBeAg( \200\223) Adefovir 10 mg PO every week HBV DNA <104 c/mL HBV DNA >104 c/mL a These drugs should be administered post HD. Liver biopsy Minimal infiltration Delay therapy or pre- transplantation Significant infiltration Give therapy (IFN or LAM+ADE) Cirrhosis Give therapy if HBV detectable (LAM+ADE) Fig. 11.7.2 Diagnostic and therapeutic algorithm for management of hepatitis B infection in patients with renal disease. IFN, interferon-A; LAM, lamivudine; ADE, adefovir; c/mL, copi es/mL. CHAPTER 11.7 Liver disorders in chronic kidney disease 425 National and international recommendations do not include dedicated machines for patients w ith HCV. Despite this, some centers have separate HD machines in dedicated areas (not neces sarily a single room) for HCV infected patients. Screening of all new patients and the HCV \200\223 patient pop- ulation for HCVAb every 3 \200\2236 months. Adherence to infection co ntrol precautions. Epidemiology The prevalence of HCV infection is 8 \200\22320% in HD patients in Europe and North America (10-fold greater than in the general population) and much higher in Asia and South America. Risk factors \200 \200 \200 \200 \200 \200 \200 multiple transfusions; local levels of hepatitis C carriage; duration of HD; prevalence of HCV-positive patients in the unit; failing to follow standard infection practices; not peri odically screening patients for HCV; dialysis modality (greater incidence in in-center than home hemodialysis or peritoneal dialysis); previous organ transplantation; IV drug abuse. HCV-infected patients should be screened for the pres- ence of hepatic cirrhosis and HCC. Hepatitis D Delta hepatitis is caused by the hepatitis delta virus (HDV), a defective virus that causes infection either as a coinfec- tion with HBV or as a superinfection in a perso n with chronic HBV infection. Infection carries a high risk of subsequent hepatic cirrhosis and hepatocellular cancer. HDVAb measurement is only indicated in HBV-infected patients. P revention of HBV infection will prevent HDV infection. Isolation of HDV-infected patients f rom other dialysis patients is recommended, especially those who are HBsAg positive. \200 Clinical features HCV causes both acute and chronic hepatitis. The incu- bation period rang es from 14 to 180 days (average: 6 \200\2237 weeks). HCV-infected ESRD patients are usually either asympto- matic or have a mild clinical illness and rarely show bio- chemical eviden ce of active liver disease, i.e. \202 uctuating ALT levels. ESRD patients with HCVAb are at risk of developing hepatic cirrhosis and HCC. Further reading European Best Practice Guidelines on Hemodialysis. Nephrol Dial Transplant 2002; 7(Suppl 7): 78 \200\22386. Investigations Liver biopsy is the most accurate tool for assessing severity of HCV infecti on. Olsen SK, Brown RS. Hepatitis B treatment: lessons for the neph- rologists. Kidney Int 2006; 70: 1897 \200\2231904. Russo MW, Goldsweig CD, Jacobson IM, Brown RS. Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on ef \201 cacy and safety. Am J Gastroenterol 2003; 98: 1610 \200\2231615. Serological assays \200 There are three generations of tests for antibodies against HCV, with the newer tests having higher sensitivity and speci \201 city. They include the gener al screening enzyme immuno- assays (EIAs) and the recombinant immunoblot assay (RIBA \204 ) which is used to con \201 rm the EIA or clarify incon- clusive tests. HCVAb Sweny PS, Rubin R, Tolkoff-Rubin N (eds). The infectious complica- tions of renal disease. Oxford: Oxford University Press; 2003. Wong P-N ,Fung T-T, Mak S-K, et al. Hepatitis B virus infection in dialysis patients. J Gastroenterol Hepatol 2005; 20: 1641 \200\2231651. Internet resources MMWR Recommendations for Preventing Transmission of Infections Among Chr onic Hemodialysis Patients: Nucleic acid detection A quantitative test for HCV viral copy number is availa- ble and mea sures hepatitis C viral load (expressed in copies/mL). http://www.cdc.gov Clinical Practice Guidelines for the Care of Patients with Chronic Kidne y Disease UK Renal Association. (Guideline CKD 3.3): Treatment Interferon-A and pegylated interferon-A are the only available therapeutic agents for HCV infection in patients with ESRD. HCV genotype is the strongest predictive factor o f response to treatment. Infection with genotypes 2 and 3 have a better response to therapy than patients with genotype 1. Ribavirin is also used for treating HCV infection but is cl eared by the kidneys and cannot be removed by dialysis. It may cause a marked hemolytic ane mia and because of this it is not used in patients with advanced CKD and ESRD. http://www.renal.org/guidelines/ European Best Practice Guidelines: http://www.ndt-educational.org/guidelines.asp Department of Health. Good practice guideline s for renal dialysis/transplantation units: prevention and control of bloodborne virus infe ction: http://www.library.nhs.uk/guidelinesFinder/ European recommendations for the management of healthcare workers occupationally exposed to hepatitis B virus and hepatitis C virus: http://www.eurosurveillance.org Prophylaxis General measures \200 See also Medical management of dialysis patients, p. 528 Polycystic kidney disease in child ren, p. 586 Autosomal dominant polycystic kidney disease, p. 590 Segregation of HCV-infected patients from uninfected patients during dialysis. M. HALL 426 Hematological disorders in chronic kidney disease Decreased red cell survival Circulating erythrocytes have a lifespan of 100 days in health . Uremia can induce chronic hemolysis, reducing red cell half-life by up to 50%. The patient with failing renal function is susceptible to disorders of erythrocyte synthesi s, platelet function and leukocyte function. Anemia Anemia may be de \201 ned as: \200 \200 Overt or occult blood loss May occur as a result of platelet dysfunction, \200\230lost lin es \200\231 during hemodialysis, uremic gastritis or gastric antral vas- cular ectasia. hemoglobin <11.5 g/dL in females; hemoglobin <13.5 g/dL in males. Relative erythropoietin (EPO) de \201 ciency occurs in early CKD although overt anemia is unusual prior to CKD 4 (EPOETIN DARBOPOETIN ERYTHROPOETIN eDER eGFR <30 mL/min/1.73 m2). Th e cause of anemia in patients with renal disease extends beyond a relative de \201 ciency of EPO and is frequently mul- tifactorial. Decreased bone marrow response Absolute or functional iron de \201 ciency is the commonest cause (see below). Aluminum toxicity may contribute but is seen less com- monly than in th e past. Numerous \200\230uremic inhibitors \200\231 of erythropoiesis have been postulated including parathyroid hormone and polyamines such as spermine. Adequate dialysis and contr ol of hyperparathyroidism lead to decreased EPO requirements but a pathogenic role for thes e compounds in impaired erythropoiesis has not been established. Normal erythropoiesis Red cell production in the bone marrow maintains a circu- lating popu lation of >1 \227 1014 erythrocytes. Under the in \202 uence of EPO, burst-forming units \200\223erythroid (BFU-E) multiply and differentiate into proerythrocytes and \201 nally mature red cells. EPO is predominantly secreted from peritubular \201 brob- lasts within the renal cortex. In response to hypoxia, the number of EPO-secreting cells increases. A sm all proportion of circulating EPO originates in the liver. Anemia is the most prominent sti mulus to EPO release. Anemia related to underlying disease Common secondary causes of renal disease may be asso- ciated with anemia such as systemic lupus erythema- tosus (SLE), multiple myeloma, sickle c ell disease or amyloidosis. Treatment of the underlying disease may ameliorate the anemia. Oxygen-sensing mechanisms The rate of secretion of EPO from the renal cortex is determined by the number of functioning nephrons and the difference between parenchymal oxygen supply and demand. EPO gene expression is regulated by the binding of hypoxia- inducible factor (H IF), a transcription factor, to the hypoxia response element (HRE) at the loci of the EPO g ene on chromosome 7q22. HIF is a heterodimer consisting of a constitutively expressed B-sub unit and an A-subunit which, in the kidney, can be induced by hypoxia. In conditions of nor moxia HIF-A undergoes hydroxylation by oxygen-dependent hydroxylases. Hydroxylated HIF-A bi nds to von Hippel \200\223Lindau ubiquitin ligase prompting sub- sequent proteosomal destru ction. In hypoxic conditions hydroxylation of HIF-A does not occur. Heterodimerization with the B-subunit forms the active transcription factor (Fig. 11.8.1). Anemia secondary to treatment of underlying disease Immunosuppressant therapy for vasculiti s or SLE leads to bone marrow suppression. Dose modi \201 cation may be required or altern ative treatment regimes prescribed. Chemotherapy for multiple myeloma and other neoplastic disease is commonly associated with decreased erythro- poiesis. Antiviral therapy for chron ic hepatitis or the human immunode \201 ciency virus may lead to hemolysis or myelo- suppr ession. Anemia secondary to concurrent disease Patients with failing renal function are just as lik ely as the general population to have common unrelated conditions which may lead to anemia such as pernicious anemia, hypothyroidism, celiac disease and primary hematological disease . Treatment There is marked variability in EPO levels between patients and the measurement of serum EPO levels is neither rec- ommended nor useful in diagnosis (Fig. 11.8.2). EPO repla cement therapy for patients with CKD should be considered after investigation for alternati ve causes of ane- mia (Table 11.8.2). Causes of anemia in CKD Common causes of anemia in CKD are listed in Table 11.8.1. Erythropoetin de \201 ciency As renal dysfunction worsens the number of functioning EPO-se creting cells decreases and an appropriate compen- satory response to anemia is not possibl e. The response of the remaining functioning cells to hypoxia is blunted as a consequence o f decreased oxygen use by the damaged parenchyma and the effect of in \202 ammatory cytoki nes. Erythropoiesis-stimulating agents (ESAs) Recombinant human EPO may be administered SC or IV . Patients receiving hemodialysis may prefer the IV route. SC administration offers higher bioavailability and 20% lower dosing. Dosing schedules are summarized in Table 11.8.3. CHAPTER 11.8 Hematological disorders in chronic kidney disease 427 Table 11.8.2 Investigation of anemia in CKD OXYGEN Recommended initial investigations Hemoglobin concentration \200 Mean corpuscular volume and hemoglobin \200 Reticulocyte count \200 Serum ferritin \200 Serum transferrin saturation or reticulocyte hemoglobin HIF prolyl hydroxylase (PHD) content or percentage hypochromic red cells HIF-alpha vHL protein Ubiquitin Ligase C-reactive protein HIF-alpha OH Further investigation in selected patients Serum vitamin B12 and folate concentration \200 Parathyroid hormone concentration \200 Haptoglobin, lactate dehydrogenase, bilirubin, direct HIF-beta Coombs test Serum and urine protein electrophoresis \200 Hemoglobin electrophoresis \200 Serum alum inum \200 Fecal occult blood and/or GI endoscopy Hypoxia HIF-beta HIF-alpha HRE Epo gene Fig. 11.8.1 Oxygen sensing and regulation of the erythropoietin gene. Table 11.8.1 Causes of anemia in CKD Erythropoietin de \201 ciency Decreased red cell survival \200 Chronic uremic hemolysis \200 Gastric antral vascular ectasia or other GI loss \200 Hemodialysis Decreased bone marrow response \200 Absolute iron de \201 ciency \200 Functional iron de \201 ciency \200 \200\230Uremic inhibit ors \200\231 \200 Aluminum toxicity Relating to underlying disease \200 Myeloma \200 SLE \200 Amyloid \200 Sickle cell Relating to treatment \200 Immunosuppressant therap y \200 Idiosyncratic reactions Concurrent unrelated disease \200 Pernicious anemia \200 Hemoglobinopathies \200 Celiac disease \200 Hypothyroidism M. HALL 428 In practice, patients are usually started on a dose of ESA that corresponds as closely as p ossible to one of the avail- able pre \201 lled syringes. Higher initial doses may be appr opriate in severe anemia (hemoglobin <8.0 g/dL). Darbepoetin-A has two additional glycosyla tion chains and eight additional sialic acid residues making it more resistant to metabolic degradation. One microgram of darbepoetin-A is approximately bioequivalent to 200 U of epo etin-A, -B and -D. Mircera (methoxy-polyethylene glycol \200\223epoetin-B) is a continuou s erythropoietin receptor activator which has a longer biological half-life allowing monthl y dosing. Newer ESAs in development include: \200 \200 \200 Serum iron measurement is effectively obsolete as the amounts present are minute and quanti ties are markedly labile. Serum ferritin offers an estimation of reticuloendothelial iron, the predominant source of stored iron. Ferritin may be elevated in infection, in \202 amma tion, malignancy or liver disease, independent of iron stores. A low ferritin is diag- nost ic of iron de \201 ciency Transferrin acts as a binding protein to transportation iron to bone marrow. The percentage of transferrin saturated with iron (TSAT) reveals the balance b etween iron supply and demand. The percentage of red cells which are hypochromic is more se nsitive at con \201 rming iron de \201 ciency but is less available. Reticulocyte hemoglo bin concentration is a more accu- rate assessor of functional iron status but, again, this is not widely available. Oral supplemental iron is rarely adequate to maintain erythropoies is in CKD. Tolerability is limited by gastroin- testinal side-effects. Interaction with pho sphate binders in the gut limits iron bioavailability. IV iron preparations are more effect ive in increasing meas- urements of iron store availability and attaining hemo- globin targ et. Newer preparations have a low incidence of side-effects. biosimilars/generic ESAs (e.g. epoetin-G); erythropoietin-mimetic peptides (hematide); oral agents which inhibit hydroxylation of HIF-A. Clinical bene \201 ts of ESAs include: \200 increased exercise tolerance; \200 decreas ed angina episodes; \200 decreased left ventricular hypertrophy; \200 improved quality of life; \200 improved cognitive function. Inadequate correction of anemia limits these bene \201 ts. Conversely, correction of anemi a to \200\230normal values \200\231 may lead to increased cardiovascular morbidity. ESA resistance An inadequate response to ESA may be caused by: \200 \200 \200 \200 \200 \200 \200 Treatment guidelines There is slight variation between the various national and internation al guidelines for the management of renal ane- mia and these are summarized in Table 11.8.4 . Assessment of response to treatment by hemoglobin concentration measurement is recommende d every 2 weeks until target hemoglobin is reached with a stable ESA dose. Hemoglobin conce ntration should not rise by >2 g/dL/ month. When hemoglobin is stable, hemoglobin concentra tion should be checked every 1 \200\2232 months and ESA dose adjusted accordingly (Fig. 11. 8.3). absolute or relative iron de \201 ciency; in \202 ammation; underdialysis; hyperparathyro idism; malignancy; other hematinic de \201 ciencies; aluminum toxicity. Acute illness in patients with advanced CKD frequently precipitates anemia. Increasing ESA dose is rarely effective and blood transfusion may be required. Side-effects of ESA therapy ESA therapy may be associated with: \200 \200 \200 \200 \200 hypertension; vascular access thrombosis; encephalopathy; in \202 uenza-like symptoms; hyp erkalemia. Iron Erythropoiesis requires 30 \200\22340 mg of iron per day. In the steady state this is available from red cell destruction. During the correction phase of anemia supplemental iro n is required. Insuf \201 cient availability of iron is the most common cause of an inadeq uate response to ESA therapy. Absolute iron de \201 ciency occurs when iron loss, usually as a result of blood loss, exceeds the erythropoietic requirement. Functional iron de \201 ciency is a result of inadequate mobili- zation of iron from stores to bone marrow. Target values for iron stores are higher in CKD than those regarded as normal in the non-CKD popu lation (Table 11.8.4). Measurement of iron stores is challenging (Fig. 11.8.4). Iron staini ng of bone marrow is widely quoted as the \200\230gold standard \200\231 but is invasive. Iatrogenic polycythemia should be avoided. Pure red cell aplasia is a rare complication of ESA therapy characterized by: \200 \200 antibodies against EPO; absent erythropoiesis on bone marrow examination and very low retic ulocyte count; ESA resistance; transfusion-dependent anemia. \200 Immunosuppressive regimes using corticosteroids and cyclophosphamide, ciclosporin and ritux imab have led to the disappearance of anti-EPO antibodies in some patients. Reintroduction of ESA therapy may be successful in those without measurable antibody titers following trea tment. CHAPTER 11.8 Hematological disorders in chronic kidney disease 429 Table 11.8.3 Recommended dosing for ESA therapy ESA Epoetin-A Initiation Maintenance 50 U/kg 3 times per week 1 \200\2233 times/week Epoetin-B 20 U/kg 3 times per week 1 \200\2233 times/week 50 U/kg 3 times per week (IV) 2 times per week (SC) 1 \200\2233 times/week Epoetin- Darbepoetin 450 ng/kg Once per week Weekly or fortnightly (or monthly if predialysis) Mircera Monthly 0.6 g/kg Once per 2 weeks 10000 1000 Serum erythropoietin (mU/ml) 100 10 4 5 6 7 8 10 Hemoglobin (g/dl) 9 11 12 13 14 15 16 Fig. 11.8.2 Relationship between serum erythropoietin levels and hemoglobin in patients wit h normal renal function. Table 11.8.4 Guidelines for target indices in managing renal anemia Hb 11.0 \200\22312.0 g/dLa European Best Practice Guidelines (2004) Ferritin >100 ng/ml TSAT >20% or hypochromic red cells <10% or CHr >29 pg/cell NICE (2006) Hb 10.5 \200\22312.5 g/dL Ferritin 200 \200\223500 ng/mL TSAT >20% or hypochromic red cells <6% Renal Association (2007) Hb 10.5 \200\22312.5 g/dL Ferritin 200 \200\223500 ng/mL (HD) or 100 \200\223500 ng/mL (non-HD) TSAT >20% or hypochro mic red cells <6% NKF-K/DOQI (2007) Hb 11.0 \200\22312.0 g/dL Ferritin >200 ng/mL (HD) or >100 ng/mL (non-HD) TSAT >20% or CHr >29 pg/cell a Target Hb up to 14.0 g/dL for patients with chronic obstructive pulmonary disease. Hb, hemoglobin; TSAT, transferrin saturation; CHr, reticulocyte hemoglobin concentration; H D, hemodialysis. M. HALL 430 Measure Hb Hb <11g/dl Hb 11-12g/dl Hb 12-15g/dl Hb >15g/dl Increase ESA by 25%-50% unless Hb rising by >1g/dl/month Decrease ESA by 25%-50% unless Hb falling by >1g/dl/month No change unless Hb rising by >1g/dl/month Decrease ESA by 50%-100% and repeat Hb in 2 weeks Fig. 11.8.3 Adjusting ESA dosage. Oral intake Total body iron: 4 to 5 g Small bowel absorption Red cells Hemoglobin (65%) Plasma Transferrin (0.1%) Tissue Free iron Ferritin (30%) Heme compounds (0.9%) Myoglobin (4%) Fig. 11.8.4 Iron utilization.