An interaction between advanced glycation end-products (AGE) and B2M has been reported resu lting in activation of the receptor for AGE (RAGE) and a variety of intracel- lular signali ng processes. This occurs prior to the histologi- cal detection of AB2M. If pathophysiologi cally relevant processes are active before clinical disease becomes apparent, new therapies may be able to interrupt the long term effects of AB2M. Epidemiology This is markedly dependent upon the time spent on dialysis. Post-mortem studie s indicate a prevalence of 20% after 1 year on dialysis rising to >90% after 9 years. Clin ical or radiological features are unlikely before 5 years on dialysis but then rise to 50% at 15 years. Histological detection is much greater than that found on clinical or radiolo gical grounds. Changes in practice would imply that greater clearances of B2M will result i n a falling prevalence. Pathogenesis B2M is a nonglycosylated polypeptide of 11.8 kDa. It is a component of the cla ss I major histocompatibility complex and is present on the cell surface of virtually all n ucleated cells. Clearance occurs by glomerular \201 ltration followed by proximal tubular cell (PTC) uptake and catabolism. A raised serum level of B2M is a prerequisite for AB2M f ormation. This can result from increased production or decreased clearance of the molecule. Causes of increased B2M production include: \200 Clinical features The major clinical features of AB2M relate to the muscu- loskeletal syste m. Carpal tunnel syndrome (CTS) This is one of most frequently encountered manifestations of A B2M. On the basis of neurological involvement it is clinically indistinguishable from other causes of CTS. It is, however, more likely to be exacerbated by dialysis ses- sions and at night. A high index of suspicion should remain for other causes of CTS in renal patients ( diabetes mellitus, myeloma and AL-amyloid). lymphoid cell activation (clonal B-cell disorders, various viral infections, rheumatoid art hritis, Crohn \200\231s disease and systemic lupus erythematosus); interferon-A therapy; \200 \200 metabolic acidosis; \200 bioincompatibility of HD membranes. Factors affecti ng clearance of B2M include: \200 \200 falling GFR; the mode of dialysis in ESRD. Scapulohumeral periarthritis The most commonly affected joint in AB2M is the shoulder. Amyl oid deposits are found in the synovial tissue and sub- acromial bursa. A seemingly trivial residual GFR in ESRD can signi \201 cantly increase renal clearance of B2M. Although raised serum B2M levels are a prerequisite this alone is insuf \201 cient t o initiate AB2M. Generation of amyloid \201 brils Although it is well-documented that B2M can spontane- ously assemble into amyloid \201 brils in vitro there is discord- ance bet ween the physicochemical conditions required for this and those that would occur pathophysi ologically. It is unclear how \201 bril seeds form in vivo although transient unfolding o f the native protein under mildly acidic condi- tions has been suggested. Once formed, \201 bril seeds can be stabilized by biologically relevant molecules (serum amyloid protein , apolipoprotein E, glycosaminoglycans, collagen and prostaglandins). Such seeds then provi de a focus for further elongation into \201 brils using B2M. This process may be enhanced by the addition of uremic serum. At a histological level these deposits will eventually di srupt tissue architecture and have a deleterious effect on func- tion. There is also eviden ce that amyloid-derived \201 brils are able to modify cell function at a much earlier poi nt in the natural history, before clinical disease becomes apparent. Effusive arthropathy This is commonly bilateral and affects the knees and shoulders. It is characterized by restricted movement and pain. It is exacerbated during dialysis and is wor se at night. Amyloid deposits may be found in the synovial \202 uid. Bone cysts These occur at the ends of long bones and contain amyloid deposits. They may cau se pathological fractures. Spondyloarthropathy This is radiologically characterized by cysts and narrowing of the inte rvertebral space. Osteophytes are not a feature. It can be compounded by coexistent hyperpa rathyroidism and aluminum overload. It is associated with back pain of variable severity. CHAPTER 11.10 b2-Microglobulin amyloidosis in chronic kidney disease 437 Scintigraphy Serum amyloid P (SAP) is a liver synthesized glycoprotein that binds noncovale ntly and in a calcium-dependent man- ner to virtually all forms of amyloid \201 brils. Us e of radiolabelled SAP for the detection of AB2M has been limited largely by the poor sensi tivity and speci \201 city of the investigation. Use of [131I]B2M has produced mixed resul ts. Generally the sensitivity and speci \201 city are better than the combined use of clin ical and radiological evidence. The high cost of the investigation precludes its widespread use in clinical practice. Rarely encroachment on the spinal cord may result in paralysis or a cauda equine syndrome. Visceral involvement Visceral involvement at postmortem is well-described though the functi onal consequences of such in \201 ltration are less clear. GI tract Involvement is serosal rather than mucosal and at post- mortem this gives a ripple d appearance to the entire GI tract. It can cause bleeding, pseudo-obstruction, perforation , infarction and diarrhea. Cardiovascular system The literature is not extensive but the predominant sites of involvem ent are the walls of the small blood vessels sup- plying the myocardium. These changes have been reported at postmortem but there is no information on any func- tional correlation. R isk factors for cardiac involvement are age at onset of dialysis and the duration of dialys is treatment. Treatment Medical management Simple analgesia Intra-articular corticosteroid injections are useful when a single joint is affected. As with all joint injections their effect is trans itory and carries a de \201 nite risk of septic arthritis. Oral prednisolone (0.1 mg/kg/da y) may be helpful. Respiratory system It is a rare cause of pulmonary hypertension but has been described as a cause of exudative pleural effusions in long- term hemodialysis patients. Surgical management The natural history is for nerve entrapment syndromes to be progressive and therefore early intervention is war- ranted to prevent permanent neurological de \201 cit. Arthroscopic or open surgery for affected shoulder joints and removal of affected syn ovium has a marked analgesic effect. Curettage of cysts within the femoral head and subsequ ent bone grafting has been reported to reduce hip pain. Prosthetic replacement of affected joints may be consid- ered on an individual basis and may result in bene \201 cial effects on pain and mobility. Skin Cutaneous involvement has been described although it is rare. Investigations Histology The \200\230gold standard \200\231 remains the histological exami nation of affected tissue. In common with other forms of amyloid, AB2M stains with Congo Re d and there is apple-green birefringence under polarized light. Joint aspiration may yield AB2M in synovial tissue fragments. Biopsy of rectal mucosa is of low yield and may re \202 ect the serosal rather than mucosal pattern of involvement. Renal transplantation Renal transplantation results in the most significant improvement in symptoms and may arrest disease progression. B2M levels fall to the normal range. Pain from affected joints is reduced. This has been attributed in the short term to the bene \201 c ial effects of steroids but the effect continues despite steroid dose reduction. Regression of AB2M deposits following transplantation is dif \201 cult to assess. Radiological lesio ns including bone cysts remain for 15 years post transplantation suggesting that pre-existi ng lesions may not regress. Measures to reduce AB2M in patients with ESRD Guidelines to red uce the risk of AB2M have been pub- lished (Table 11.10.1). The use of high \202 ux HD me mbranes reduces B2M levels probably by a combination of diffusion/convective mass transport ation and adsorption. Hemodia \201 ltration also results in a substantially higher clearan ce of B2M as a result of convective removal. Increased frequency and duration of dialysis w ill also reduce levels of B2M. Whether lowering B2M levels equates to an improved clinical outcome has not been clearly established. Radiology Plain radiography Features include: \200 \200 swelling of the soft tissues around the joint; preserved or widened joint space with juxta- articular cystic bone lesions. Typical joints affected are the wrist, shoulder and hip. Over time the size and number of c ysts increases ( \211 30% per year). For a diagnosis of AB2M changes must be present in at least two joints. CT and MRI Useful when lesions are too small to see with plain radiography. Particularly us eful for investigating potential involvement of the nonaxial skeleton. MRI is useful for th e diagnosis of AB2M spondyloarthropa- thy and spondylodiscitis. Ultrasonography May be of use in detecting synovial sheath thickening or rotator cuff enlar gement. R. BAINES 438 Trials of high \202 ux dialysis, B2M and survival A systematic review of 27 randomized tr ials comparing cellulose, modi \201 ed cellulose and synthetic membranes showed a signi \201 cant reduction in end-of-study B2M values when high \202 ux synthetic membranes were used and one small study showed that dialysis-related amyloid occurred less frequently wit h this treatment. The potential bene \201 t of high \202 ux membranes was exam- ined pro spectively in the HEMO study. No differences in overall mortality or secondary endpoints we re observed between the groups that received high- or low- \202 ux treat- ment. A 10-fold increase in B2M clearance was observed in the high \202 ux group (B2M clearance of \211 20 mL/min) versus the low \202 ux group. Secondary analysis of those that had been on dia lysis for >3.7 years suggested that there may be an advantage to high \202 ux dialysis on overall mortality. The impact of high flux dialysis on outcome in HD is currently being as sessed in the Membrane Permeability Outcome study (MPO) which has now \201 nished recruit ment. In animal studies megalin-expressing cells implanted under the skin have been shown to bind and endocytose B2M. Megalin is a member of the low-density lipoprotein recep- tor superfam ily that is expressed on a variety of secretory epithelia including the PTC and mediates up take of a large number of ligands. Further reading Cheung AK, Rocco MV, Yan G, et al. for HEMO Study Group. Serum B-2 microglo bulin levels predict mortality in dialysis patients: results of the HEMO Study. J Am Soc Ne ph 2006; 17: 546 \200\223555. Dember LM, Jaber BL. Dialysis-related amyloidosis: late \201 nding or hidden epidemic? Semin Dial 2006; 19: 105 \200\223109. Grovender EA, Kellogg B, Singh J, et al. Single-chain antibody frag- ment-based adsorbent f or the extracorporeal removal of B2- microglobulin. Kid Int 2004; 65: 310 \200\223322. Jadoul M, van Ypersele C. B2M Amyloidosis. In: Davidson et al. (ed.), Oxford Textbook of Ne phrology. Oxford: Oxford University Press; 2005. pp. 1861 \200\2231867. Saito A, Geyjo F. Current clinical aspects of dialysis-related amy- loidosis in chronic dia lysis patients. Ther Apheresis Dial 2006; 10: 316 \200\223320. Prognosis Over time there is an inevitable increase in the deposition of B2M. The rate of d eposition is altered by reducing the produc- tion or clearance of B2M. Transplantation arre sts disease progression. No other intervention achieves this effect. There is no clear rela tionship between deposition of B2M and function of the affected organ. Individual prognosis is dif \201 cult to assess. Genetic variability is important: polymorphisms in various cy tokines, including transforming growth factor-B (TGF-B), are important in modifying disease progression. Prognosis is affected by the clearance of other \200\230middle molecules \200\231 that have neutrophil inhibitory effects. This is thought to underly the susceptibi lity to infection of those with elevated serum B2M levels. Winchester JF, Salsberg JA, Levin NW. Beta-2 microglobulin in ESRD: an in-depth review. Adv Renal Replacement Therapy 2003; 10: 279 \200\223309. Internet resources Renal Association Clinical Practice Guidelines for Hemodialysis: http://www.renal.org/guidelines/module3a.html The Renal Registry: http://www.renalreg.org National Kidney Federation Dialysis Outcomes Quality Initiative: http://www.kidney.org/professionals/kdoqi/ European Best Practice Guidelines: http://www.ndt-educational.org/guidelines.asp Future prospects See also Hemodialysis, hemo \201 ltration and hemodia \201 ltration, p. 494 Adequacy of d ialysis, p. 518 Medical management of dialysis patients, p. 528 Extra- and intracorporeal techniques are being developed to facilitate removal of B2M altho ugh these are not cur- rently in clinical use. Immunoabsorbent technology using membrane- \201 xed anti- bodies against B2M has been developed and under labora- tory conditions is c apable of removing B2M. CHAPTER 11.10 b2-Microglobulin amyloidosis in chronic kidney disease 439 Table 11.10.1 Guidelines for the management of B2-microglobulin amyloidosis (AB2M) UK Renal Association (2007) Ultrapure water is easily available and should be regarded as standard. \200 The use of h igh \202 ux synthetic and modi \201 ed cellulose dialysers can be justi \201 ed on the basis of potentially bene \201 cial biological effects and equivalent cost. The balance of evidence supports the use of a dialysis regimen that promotes the clearance of middle molecules in either incident patients predicted to stay on dialysis for several y ears (personal choice, age, HLA sensitization, risk of recurrent disease, rare tissue type or other contraindications), or prevalent patients that have been on dialysis for >3.7 year s. At the current time there is no evidence to support the routine use of hemo \201 ltration or hemodia \201 ltration in the management of ESRD. K/DOQI (2003) Screening for AB2M, including measurement of serum levels of B2M, is not recommended. \200 No currently available therapy (except kidney transplantation) can stop disease progressi on or provide symptomatic relief. \200 Kidney transplantation should be considered to sto p disease progression or provide symptomatic relief in patients with AB2M. \200 In patien ts with or at risk for AB2M, noncuprophane, high \202 ux dialysers should be used. S. J. DICKINSON 440 Immune function in chronic kidney disease Introduction The effect of failing renal function on the immune system is insidious and far reaching. Both innate and adaptive immune responses are affected and this leads to a numbe r of clini- cally important consequences. All patients with CKD stage 5, whether they are a pproach- ing ESRD or already on dialysis, share the common immu- nologic defects caused by the uremic milieu. Epidemiological studies have consistently shown that infection is the se cond commonest cause of morbidity and mortality in patients on dialysis after cardiovascula r disease. Innate immune system: monocyte/macrophage function Uremia is associated with changes in cel l surface expres- sion of a number of costimulatory molecules necessary for effective antig en presentation and T-cell activation. In parallel there are defects in phagocytosis furthe r com- pounding antigen presentation. Activation of monocytes by advanced glycation end-pro d- ucts is thought to be an important factor in the develop- ment of the syndrome of malnut rition, in \202 ammation, and atherosclerosis (MIA). Effects of the underlying renal condition In the UK and other developed countries diabetes is the most common cause of ESRD requiring RRT. The World Health Organization lists diabete s as a cause of secondary immunode \201 ciency. Hyperglycemia has been shown to impair bot h the innate and adaptive immune systems with defects being reported in chemotaxis, phagocy tosis and cidal activity of lym- phocytes and neutrophils. Other causes of CKD and ESRD ass ociated with signi \201 cant immune dysfunction include amyloidosis, multiple myeloma and the multisystem autoimmune diseases where many abnormalities have been described in T-cell and antibody function. Abnormalities of immune function Abnormalities of immune function arise as a conse- quence of: \200 \200 \200 \200 direct effects of uremic toxins on immune cell function; underlying renal condition; treatm ent of the underlying renal condition; effects of proteinuria. Effects of uremia There is an increasing body of evidence supporting the role of uremia in abnormalities of the innate and adaptive immune systems in CKD and ESRD. Uremia is associat ed with hypermethylation of a number of genes associated with in \202 ammation, atheroscle rosis and aging. Hypermethylation of gene promoter regions will result in changes in gene e xpression and ultimately cell function. Effects of treatment of the underlying renal condition Immunosuppression Immunosuppression with steroids, cytotoxic agents, cal- cineurin inhibitors and biologics will invariably acc e- ntuate the immunosuppressive effect of the uremic syndrome. Different immunosuppressive regimens will have variable effects on T-cell (calcineurin inhibitors) and/or B-cell (myc- ophenolate mofetil, rituximab) function. It is clearly important when commencing immunosupp res- sive therapy in a patient with CKD or ESRD that the risks of further immunosuppression are discussed with the patient; that appropriate monitoring is in place to assess the leuk ocyte count; and that antibiotic prophylaxis is com- menced when necessary. Adaptive immune system: T- and B-cell function The exact mechanisms underlying lymphocyte d ysfunction in vivo remain unknown. Transfer of lymphocytes from a uremic to nonuremic envi- ronment in vitro results in a return to normal lymphocyte function implying that the effec ts of uremia are potentially reversible. Uremia has been shown to affect: \200 \200 \200 T-cell maturation; T-helper (CD4) cell function; T-cell activation through defective costim ulatory signaling. Plasma exchange There are theoretical concerns that the removal of immu- noglobulin and com plement during plasma exchange increases the risk of infection. There are no data to suppor t an increase in infection spe- ci \201 cally due to the institution of plasma exchange al though these patients invariably have AKI and will be receiving immunosuppression. Innate immune system: neutrophil function A number of peptides have been identi \201 ed in both hemo- dialysis ultra \201 ltrate and peritoneal dialysis ef \202 uent that inhibit neutrophil function. These include: \200 \200 granulocyte inhibitory proteins (GIP); degranulation inhibitory proteins (DIP). Effects of proteinuria Proteins lost in the urine by the nephrotic patient with nonselectiv e proteinuria include immunoglobulins (princi- pally IgG) and complement components. Nephro tic range proteinuria may therefore lead to impair- ment of both the innate (complement) an d adaptive (IgG) immune systems. In practice this increases the risks of infection, particu larly with encapsulated bacteria such as Pneumococcus spp. These proteins inhibit all stages of the neutrophil response including: \200 \200 \200 chemotaxis; phagocytosis; degranulation. This inhibition of neutrophil function is believed partly to explain the increased suscepti bility to bacterial infections in CKD and ESRD. CHAPTER 11.11 Immune function in chronic kidney disease 441 The risk of infection is further increased when there is a breakdown in skin integrity that may develop in patients with severe edema. Cancer and uremia Despite the theoretical risk of an increased incidence of cancer in uremi c patients this has not been con \201 rmed in a number of retrospective studies. A retrosp ective case note study of 834 patients with CKD failed to demonstrate an increased incidenc e of cancer. A separate study of 28 000 patients on dialysis found no statistically signi \201 cant increase in cancer incidence (excluding nonmelanoma skin cancer, multiple myeloma , kidney cancer, and uterine cervix cancer). There is some evidence for a slight increase i n cancer of the kidney and urinary tract in patients on dialysis and transplant recipients. Vaccination In an attempt to reduce the risk of infection most guide- lines advocate the fo llowing vaccinations in patients with CKD and ESRD: \200 hepatitis B; \200 pneumococcus ; \200 in \202 uenza; \200 tetanus; \200 meningococcus (serogroup B). As one might expect, however, patients with CKD and ESRD are less likely to respond to thes e vaccinations. Cancer and primary renal disease von Hippel \200\223Lindau disease is a familial, autosomal domi- nant, multisystem cancer syndrome. Patients develop multiple benign and malignant tu mors in many organs. The CNS, kidneys, adrenal glands and pancreas are most commonly affect ed. An association between analgesic nephropathy and transi- tional cell carcinoma has been described; perhaps related to a common toxic insult. Similarly, Balkan nephropathy may be associated with the development of transitional cell carcinoma. There is no evidence for an increased risk of renal cell car- cinoma in the ADPKD population. However, if renal cancer is present it is more likely to be bilateral, multicentric and sarcomatous. Hepatitis B It is recommended that all patients approaching ESRD should be vaccinated again st hepatitis B in order to avoid the potential for transmission among patients and between patients and staff. Hepatitis B outbreaks continue to occur in hemodialysis centers and vac cination is the most effective measure to prevent infection. The response to hepatitis B va ccination reduces as serum creatinine and age rise. Vaccination is more likely to be succes sful in patients with mild \200\223moderate CKD, and is successful in only 37% of patients on hemodialysis. Furthermore, patients with CKD require larger doses of vaccine than patie nts with normal renal function. The immune defects leading to the reduction in response to hepatitis B vaccination has been the focus of much research. Impaired T-helper cell functio n is thought to be important and arises due to abnormal cytokine signaling and reduced expr ession of HLA class II molecules by antigen-presenting cells in CKD and ESRD. A typical hep atitis B vaccine schedule would be a 40 g vaccination repeated at 1, 2 and 6 months. Sero conversion is conventionally said to have occurred when the hepatitis B surface antibody is >10 IU three months after the last vaccination. Cancer and the treatment of renal disease There is an increasing body of evidence that cyto toxic agents such as cyclophosphamide used in the treatment of a number of glomerulonephrit ides and vasculitides are associated with an increased incidence of neoplasia. This increas e may not become apparent until many years or decades after treatment, often making it dif \201 cult to directly link the two. It is clearly important when commencing immunosuppres- sion in a patient with CKD or ESRD that the risks of fur- ther immunosuppression, includin g neoplasia, are discussed with the patient Cancer in renal transplant recipients It is unclear whether the incidence of cancer is incr eased or decreased in transplant recipients when compared with uremic patients both on and off dialysis. Certain cancers are more common in transplant recipients: nonmelanoma skin ca ncer, post-transplant lymphoprolifer- ative disease. The risk of neoplasia is linked to the immunosuppressive regimen used and there is some evidence that mTOR inhibitors such as rap amycin may in fact have an antiprolif- erative effect and reduce the risk of neoplasia. Other vaccinations Each year in \202 uenza viruses cause signi \201 cant morbidity and mo rtality, particularly in immunocompromised patients, including those with CKD. In the UK as part of the national NHS Influenza Immunization program all patients with ESRD and CKD sho uld be offered the in \202 uenza vaccine. In \202 uenza vaccination is associated with a signi \201 cant reduc- tion in hospitalization and death in patients with ESRD but uptake of the vaccination is variable. Other factors in \202 uencing immune function Parathyroid hormone Parathyroid hormone (PTH ) mobilizes calcium from bone and increases urinary phosphate excretion. Uremic patients in variably develop secondary hyperpar- athyroidism with raised levels of circulating PTH. PTH is also a potent modulator of immune function. Cancer Immune surveillance is an important mechanism for the early detection and deletion o f potentially cancerous cells. Immune dysfunction in kidney disease may therefore increase the risk of cancer in a number of ways: \200 \200 \200 direct effect of uremic toxins on immune cell function; underlying renal condition; treatme nt of the underlying renal condition. S. J. DICKINSON 442 Lymphocytes bear PTH receptors and there is evi- dence that B-lymphocyte proliferation and T-lymphocyte activation are reduced in uremic patients with hyperpar- athyroidism. Changes in polymorphonuclear cell function have also been reported. Skin integrity Repeated breaches of the skin and mucosal surfaces pre- dispose patients wit h CKD to the development of bacterial infection. This includes the formation of hemodialysi s and peritoneal access and its repeated use for dialysis. In particular, vascular and peri toneal catheters (both tun- neled and nontunneled) are a common portal of entry for micro-o rganisms. Gram-positive organisms account for two-thirds of dialysis access-related infecti ons. Methicillin-sensitive (MSSA) and -resistant (MRSA) Staphylococcus aureus infections ca n be associated with serious metastatic complications including endocarditis, discitis and abscess formation. UK Department of Health initiatives (High Impact Interventions) have bee n developed to reduce healthcare- associated infections (HCAIs). These have particularly fo cused on MRSA as a surrogate marker of all HCAIs. In the UK, renal departments typically ac count for 10% of all hospital-acquired MRSA infections. Iron and erythropoiesis-stimulating agents Patients with CKD stages 4 and 5 commonly develo p anemia. Erythropoiesis-stimulating agents (ESAs) are most effective when iron stores are replete, prompting the frequent pre- scription of IV iron to patients receiving ESA. It has been recognized for some time that chronic iron overload (hemochromatosis and B-thalassemi a) is associ- ated with impaired immune function. High circulating levels of iron in the ur emic patient may interfere with normal immune function in a number of ways: \200 \200 \200 reduction of macrophage cytotoxic effector function; impairment of the complement system; i mpairment of T-helper-1 cell function. Body temperature In a signi \201 cant proportion of hemodialysis patients intradi- alytic body temperature is 1 C lower than normal. This can make identi \201 cation of infection more dif \201 cult due to the apparent absence of pyrexia. As a consequence of these effects there is a theoretical concern that high levels of iron c ould further increase susceptibility to infection and neoplasia. The effects of ESAs on the immune system are uncertain with con \202 icting studies reporting: \200 \200 \200 \200 \200 an antineoplastic effect; B-cell-stimulating properties; reduced cell-mediated immune respo nses; immunosuppression in patients on dialysis; enhanced tumor growth. Malnutrition in \202 ammation and atherosclerosis (MIA) Malnutrition, in \202 ammation and atherosclerosis (MIA) syn- drome describes wasting as p art of an in \202 ammatory state associated with cardiovascular disease. It is not respons ive to increasing dietary nutrient intake. MIA was proposed to explain the enormously incre ased risk of cardiovascular disease in those with failing renal function and those on dialy sis. The evolution of atherosclerosis is an in \202 ammatory proc- ess, and there is incre asing evidence that C-reactive pro- tein (CRP) enhances this process. Patients with CKD hav e raised circulating levels of CRP and a number of proin \202 ammatory cytokines including IL-6. The low serum albumin levels seen in MIA rather than re \202 ecting poor nutritiona l intake instead re \202 ect ongoing in \202 ammation, as well as cytokine action on the GI tract. It remains unclear at present whether tumor cells express erythropoietin receptors that can be stimulated by ESAs. Mood disorders There is increasing evidence to support the theory that depression and mood disorders impact negatively on immune function. These \201 ndings are most marked in the elderly and those who are hospitalized. Depression may affect as many as one-third of all d ialysis patients. Recent studies suggest that chronic inflammation and immune activation ma y lead to mood disorders. Recognition and treatment of psychiatric disorders in patients wi th failing renal function and those on dialysis may also have a positive impact on immune f unction. Children with failing renal function In contrast to adult patients with failing renal funct ion, rela- tively few studies have investigated immune function in children with CKD. Most studies have found that children with uremia are not overtly immunocompromised, but do have detectable abnormalities in many areas of immune function. Nutrition Intake of essential nutrients is integral to maintaining a healthy immune system. Patients with failing renal function may have a decreased appetite due to uremia, altered taste sensation, dyspepsia and other comorbid conditions. Metabolic acidosis increases prot ein catabolism. Malnutrition affects up to 50 \200\22370% of hemodialysis patients. It has been shown in hemodialysis patients that peripheral blood lymphocyte counts correlate with serum albumin and cholesterol levels. Further reading Bush A, Gabriel R. Cancer in uremic patients. Clin Nephrol 1984; 22: 77 \200\22381. Fraser GM, Ochana N, Fenyves D, et al. Increasing serum creatinine and age reduce the respo nse to hepatitis B vaccine in renal failure patients. J Hepatol 1994; 21: 450 \200\223454. Gilbertson DT, Unruh M, et al. In \202 uenza vaccine delivery and effectiveness in end-sta ge renal disease. Kidney Int 2003; 63: 738 \200\223743. CHAPTER 11.11 Immune function in chronic kidney disease 443 UK Department of Health High Impact Interventions: Kantor AF, Hoover RN, et al. Cancer in patients receiving long-term dialysis treatment. Am J Epidemiol 1987; 126: 370 \200\223376. http://www.dh.gov.uk/en/Publichealth/ Healthprotection/Healthcareacquiredinfection/ Healthc areacquiredgeneralinformation/index.htm Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, in \202 am- mation, and ather osclerosis (MIA) syndrome \200\223 the heart of the matter. Nephrol Dial Transplant 2002; 17(Suppl 11): 28 \200\22331. Stenvinkel P, Karimi M, et al. Impact of in \202 ammation on epigenetic DNA methylation \200\223 a novel risk factor for cardiovascular disease? J Intern Med 2007; 261: 488 \200 \223499. See also Hematological disorders in CKD, p. 426 Nephrotic syndrome, p. 80 Medical managemen t of dialysis patients, p. 528 Internet resources European Best Practice Guidelines: http://www.ndt-educational.org/guidelines.asp Renal Association Clinical Practice Guideline s: http://www.renal.org/guidelines/ S. PAVORD 444 Coagulation disorders in chronic kidney diesase Introduction Disturbances in blood coagulation mechanisms are com- monly seen in patients w ith failing renal function. The nature of these changes depends on the underlying cause of the renal disease but complex situations involving both hypo- and hypercoaguable states can arise, leading to a precarious balance of bleeding and thrombotic risk. In order to unders tand the effects of renal failure a basic appreciation of normal hemostasis is required. Deficiencies in the latter two are associated with an increase in thrombotic risk, whereas the clinical signi \201 - cance of TFPI de \201 ciency is not yet clear. TFPI is responsi ble for the inactivation of FVIIa bound to tissue factor. Antithrombin neutralizes several of the activated coag- ulation factors, including thrombin. Its action is catalyzed by hepa rin-like proteoglycans synthesized by the endothe- lial cell. Protein C is activated by the binding of thrombin to throm- bomodulin on the endothelial cell surface. The activated pro tein C, with protein S as a cofactor, inactivates Va and VIIIa. Normal hemostasis Hemostasis is the process of repair to damaged vessels. Highly developed coagulation and fibrinolytic systems coordinate to form a thrombus which is localized to th e site of injury, whilst avoiding unwanted systemic changes and physiological disturbance a t critical sites. Three simultanous mechanisms are triggered at the moment of vascular dama ge: \200 \200 Relationship between coagulation and in \202 ammation The coagulation system is strongly r elated to in \202 ammation. In inflammatory states, prothrombotic potential is increased, with risk of disseminated intravascular coagula- tion or systemic thrombosis in extreme cir cumstances. In \202 ammatory cytokines enhance platelet numbers and reac- tivity and stimu late monocytes to synthesize tissue factor. The change in shape of platelets and monocytes and release of microparticles provide increased phospholipid surfaces to support hemostatic reactions. Leukocyte adhesion molecules such as P-selectin and E- selectin, synthesized by the endothelial cell, enhance bind- ing of activated platelets to circulating microparticl es. C-reactive protein facilitates endothelial cell \200\223monocyte interactions and furth er promotes tissue factor expression. It also activates complement, thereby increasing plat elet activation and available procoagulant membrane surfaces. Anticoagulant function is dow nregulated by the disappear- ance of thrombomodulin from the endothelial cell surface, redu cing the ability of thrombin to activate the protein C system. Antithrombin inhibitory acti vity is also reduced. The \201 brinolytic system is impaired and \201 brinogen, being a n acute phase reactant, is increased in in \202 ammatory states. platelet adhesion and activation; initiation and propagation of coagulation pathways, cul- minating in the formation of \201 brin; vasoconstriction, to reduce blood \202 ow to th e damaged area and to bring circulating platelets and leukocytes in contact with the broken endothelium. Primary hemostasis Involves platelet adhesion, mediated by the binding of von Willebrand fa ctor (vWF) to both exposed subendothelial collagen and platelets through their glycoprotein 1b (GP1b) receptor. On activation platelets change shape from disks to tiny spheres with p rojections, to enhance surface area and bring platelet granules to the surface, where they release their contents, of pro- and anticoagulants, into the micro- environment. Platelet a ggregation accelerates. Microparticles bleb from the activated platelet membrane, increasin g phospholipid surfaces to which the activated clotting factors bind. Coagulation disorders secondary to renal disease Uremic bleeding Hemostatic mechanisms, par ticularly those of primary hemostasis, are impaired in patients with CKD. Clinical bleeding , in the form of bruising, bleeding at venepuncture sites, menorrhagia and gastrointestinal blood loss, occurs in up to 50%. Contributing factors include: \200 \200 \200 Secondary hemostasis Involves a highly complicated network of clotting factor reactions tak ing place on cell surfaces. Key reactions include: \200 \200 exposure of tissue factor (TF) which activates factor VII; TF \200\223FVII complex activate s factor X, both directly and indirectly through the intrinsic pathway; the tenase complex, involving activated factor X, acti- vated factor V and prothrombin, generates thrombin; th rombin ampli \201 es its own production in a powerful positive feedback loop, involving th e activation of cofac- tors V and VIII, the intrinsic pathway via factor XI and further act ivation of platelets; the thrombin burst leads to the formation of \201 brin from \201 brinogen and the activation of factor XIII to crosslink the \201 brin monomers and stabil ize the clot. reduced hematocrit; thrombocytopenia; platelet dysfunction (intrinsic platelet abnormalitie s and impaired platelet \200\223vessel wall interaction). Comorbidities and medications such as antiplatelet drugs or anticoagulants may compound the problem. Hematocrit There is an inverse correlation between bleeding time and hematocrit, with a pro longed bleeding time in patients with renal anemia. Platelet adhesion to the subendothelium increases pro- gressively as hematocrit rises. As red cells travel through Natural inhibitors to coagulation There are three major anticoagulation mechanisms: \200 \200 \200 tissue factor pathway inhibitor (TFPI); the protein C system; the antithrombin pathway. CHAPTER 11.12 Coagulation disorders in chronic kidney diesase 445 the blood vessels in the fast stream at the center of the lumen, platelets diffuse radially , increasing the chance of adhesion to sites of injury. Decreases in hematocrit allow fast passage of platelets in the central luminal \202 ow reduc- ing platelet \200\223endotheli al cell interaction. Also, platelet aggregation is affected by lower production of ADP and thromboxane from red cells and reduced availability of hemoglobin to scavenge nitrous oxide . Conversely, disproportionate increases in hematocrit and whole blood viscosity, aggravate d by the use of diuretics, enhance thrombotic risk. Uremic erythrocytes can display increas ed procoagulant activity due to increased phos- phatidylserine exposure on the surface memb rane. Thus a steady hematocrit of 30% should be maintained when managing patients with ren al failure. The test is time-consuming, poorly standardized, subject to interobserver error and results do not correlate with the clinical incidence of bleeding. It has now been largely replaced by PFA-100. The PFA-100 system This is an in vitro system which attempts to reproduce the high shear ci rculation involving vWF binding and the plate- let adhesion, activation and aggregation pro cesses. It deter- mines the time to platelet closure over a tiny aperture in a membrane coa ted with collagen and either ADP or epine- phrine. It is sensitive to abnormalities of vWF and platelet adhesion but certain activation processes and granule secretion defects are no t detected. Closure times have been shown to shorten following DDAVP and dialysis; however, the role of the PFA-100 in therapeutic monitoring of platelet function in patients with re nal failure remains to be established.