Prognosis Very poor outlook without treatment \200\224 usually progressive and fatal withi n 1 \200\223 2 years. Cardiac involvement is a particularly poor prognostic indicator. Dia gnosis of renal AL amyloid is associated with a median time to RRT of 7 1 year (with median time to death within a further year). Happily, the prognosis is greatly improved with effective therapy of the underlying plasma cell dyscrasia \200\224 with amyloid regression in many cases. For renal involvement, reso lution of the nephrotic syndrome, with stabi- lization of renal function and retarded progr ession to ESRD, is the goal of treatment. Management Treatment aims to decrease, or eliminate, the culpable plasma cell clone. Patien ts are often elderly, so therapy must be tailored accord- ingly. Regimens include cyclophos phamide, thalidomide, and dexametha- sone (CTD), or melphalan plus dexamethasone (M/Dex). R esponses in 7 30 \200\223 50%. Lenalidomide and bortezomib are increasingly used, based on experiences in myeloma. High-dose chemotherapy with autologous stem cell transplantation i n selected patients. Dialysis for standard indications. Renal transplantation is only possible if the plasma cel l dyscrasia is in complete remission (recurrence in the graft is inevitable otherwise) and cardiac function remains acceptable. CHAPTER 8 The kidney in systemic disease 630 Renal amyloid: AA amyloidosis AA amyloidosis AA amyloidosis results from the sustained elev ation of the acute phase reactant serum amyloid A protein (SAA). In developing countries, c hronic infections account for the majority of cases. In developed nations, chronic in \202 ammatory autoimmune conditions, particularly rheumatoid arthritis, are now much more impor tant. Prevalence is linked to that of underlying conditions, which vary accord- ing to geography. The overall post-mortem incidence of AA amyloidosis in western nations is 0.5 \200\223 0. 86%. Pathogenesis There are several isoforms of SAA: SAA1 and SAA2 appear to be most important f or acute phase responses. They are HDL-bound apolipopro- teins that i macrophage HDL uptake during in \202 ammation (through the displacement of apolipoprotein A1). The persistence of SAA is probably s to pro-in \202 ammatory cytokines, such as IL-1, IL-6, and TNF- A . P roteolytic cleavage of SAA then generates peptide fragments that aggregate into mis- folded AA \201 brils via an interaction with the glycosaminoglycan heparan sulfate. It remains unknown why only 7 5% of patients with persistent in \202 ammation develop AA amyloidosis; other factors (e.g. genetic, includ- ing SAA1 polymorphisms) are clearly important. Causes \200 Chronic in \202 ammatory disease: Rheumatoid arthritis and juvenile rheumatoid arthritis ( 7 40%). \200 Psoriatic arthropat hy, ankylosing spondylitis ( 7 30%). \200 Reiter \200\231 s syndrome. \200 Beh et \200\231 s syndrome. \200 In \202 ammatory bowel disease. Chronic infections: \200 TB, leprosy. \200 Osteomyelitis. \200 Cystic \201 brosis, bronchiectasis. \200 Chronic ulceration. Malignancies: Renal cell carcinoma. \200 Lymphoma, Castleman \200\231 s disease. Familial: Familial Mediterranean fever (FMF). Clinical features \200 Renal: unlike AL amyloid, renal involvement is universal. Proteinu ria (often nephrotic range) is typical, although a minority (<10%) present with progressive CKD , with no proteinuria (predominantly vascular amyloid deposition). Renal biopsy demonstrate s both glomerular and tubulointerstitial involvement. Note: microscopic haematuria is prese nt in 7 30% so is a much more common feature than in AL amyloid. Spleen: always involved ( l hyposplenism l infection). \200 Adrenals: abnormal adrenal fu nction in 7 50%. RENAL AMYLOID: AA AMYLOIDOSIS 631 Liver: hepatomegaly. \200 GI tract: present in more advanced disease ( l motility disorde rs, malabsorption, bleeding). Cardiac ( 7 10%), skin, tongue, and nerve: much less common than in AL. Investigations \200 Tissue biopsy is necessary to con \201 rm diagnosis. This is often a renal biopsy, but less invasive alternatives include salivary gland, subcutaneous abdominal fat, or rectum (positive in >80%). Immunostaining tissue for SAA protein differentiates AA from other forms of amyloidosis in virtually all cases. CRP and ESR were used to monitor disease and response to treatment, but SAA is increasingly used for this purpose. 123 I SAP scintigraphy ( b p. 629). Prognosis Outcomes depend heavily on the control of und erlying disease processes. Prognosis is better than AL amyloid but still guarded: 7 40% sur vival at 3 years, overall. Infection is the major cause of death. SAA concentration helps p redict outcomes, as risk of death rises with the median SAA (10-year survival 7 90% if medi an SAA <10mg/L and only 7 40% if >10mg/dL). Outcomes have improved for those with ESRD (previously a signi \201 cant cause of death), although patients still have worse dialysis outcomes than those with unrelated conditions. Renal transplantation can be considered if underlying disease is consistently controlled, a s recurrent amyloid is surprisingly uncommon in this context. However, 3-year patient survi val post-transplant is reduced (principally s to infectious and CV causes). Treatment Treat the underlying in \202 ammatory or infectious condition to prevent further amyloid deposi tion. Existing amyloid appears to regress in 7 50%, especially if SAA is maintained <10mg/L . \200 Infectious disease: antimicrobials and or surgical intervention, as indicated. Chronic in \202 ammatory disease: several treatments have shown ef \201 cacy in the in \202 ammatory arthritides and may be applicable to other situations. \200 Alkylating agen ts, such as cyclophosphamide and chlorambucil, have been shown to improve survival. Anti-TNF therapy, with in \202 iximab, etanercept, and adalimumab, are effective at lowering SAA production. Experience is growing with the anti-IL6 receptor antibody tocilizumab. Colchicine has demonstrable ef \201 cacy in FMF, reducing febrile episodes and renal involvement. Mechanism of action is unclear but appears related to suppr ession of in \202 ammatory responses. X It has also been used, with variable success, in n on-FMF patients with renal disease. Novel approaches: there is increasing interest in therapies that can interfere with \201 bril aggregation and deposition, e.g. agents that disrupt the int eraction of SAA with glycosaminoglycan or induce dimerization of SAP to provoke improved sy stemic clearance. CHAPTER 8 The kidney in systemic disease 632 Renal amyloid: other forms Other forms of amyloidosis with renal involvement Inherited fever syndromes Familial Mediterranean fever (FMF): causes AA amyloidosis and is the most common inherited form. Inheritance is autosomal recessive, most commonly affecting Sephardic Jews, Armenians, and Turks. It is caused by a mutation in the MEFV gene encoding pyrin, a regulator of transcription for in \202 ammatory mediators, including IL-1. Perio dic acute attacks (of variable frequency) pre- sent before the age of 20, with fever ( 7 25 % have fever alone) and serositis ( l peritonitis, pleurisy, synovitis) lasting 48 \200 \223 72 hours before spontaneous reso- lution. During the \202 are: i WCC and i CRP. AA a myloid complicates 7 60% (Turks are at highest risk), and renal involvement is common. Colc hicine 1 \200\223 2mg/day is highly successful at reducing both \202 are frequency and A A amy- loidosis risk. It may also stabilize already established renal disease. Others: TNF receptor-associated periodic syndrome (TRAPS) is autoso- mal dominant, with onset in childh ood. Colchicine is less effective. Muckle Wells syndrome presents soon after birth, with da ily episodes of rash, red eyes, and fever. Hereditary amyloidosis These are much less common than the AL or AA types. The inheritance of an abnormal gene leads to lifelong production of a potentially amy- loidogenic protein. Most forms do not present until middle age or later. They can be dif \201 cult to identify and may potentially be mislabelled as AL amyloid, particularly if there is a concomitant M GUS (common in this age group). Characterization of the amyloid type with immunohistochemis try is helpful, but genetic testing at specialist centers is diagnostic. Familial amyloid p olyneuropathy: the commonest. Caused by mutations in transthyretin. Multiple mutations have been identi \201 ed, producing differ- ent clinical phenotypes. Predominantly a neurologi cal disorder, but renal involvement is described. Fibrinogen A A -chain: the hereditary for m with most renal involvement (almost exclusively glomerular). Presents >age 50. Combined l iver \200\223 renal transplantation is a potential treatment option. Apolipoprotein AI: ma y present with hypertension and CKD in middle age ( 9 cardiac and nerve involvement). Again , combined liver \200\223 renal transplan- tation is a potential treatment option. B 2 mic roglobulin-related dialysis amyloid \200 B 2 microglobulin ( B 2-M) is a component of the MHC class I complex and is produced by all cells that express MHC I. It is freely \201 l tered at the glomerulus and reabsorbed (and metabolized) in the proximal tubule. Consequent ly, it accumulates in patients with ESRD, and these accumulations are amyloidogenic. B 2-M is incompletely cleared by dialysis treatments ( 7 1,500mg is produced each week, only 7 1/3 of which is removed). B 2-M clearance on dialysis depends on several factors: RENAL AMYLOID: OTHER FORMS 633 Residual renal function. \200 Modality (clearance on HD < PD < daily HD < nocturnal HD). \200 Characteristics of the dialysis membrane (high \202 ux is better than standard. Biocompatible is better than bioincompatible). Duration of treatment and ultra \201 ltration volumes. A degree of deposition is universal and begins early after reaching ESRD. However, clinical presentation takes much longer; usually occurring after >5 years \200\231 dialysis treatm ent. Clinical features: \200 Generally, a disorder of soft tissue and joints. \200 Carp al tunnel (very common in patients on dialysis >10 years). \200 Chronic tenosynovitis of \201 nger \202 exors. Generalized joint pain, stiffness, and restricted movement (parti cularly shoulders, but also hands, feet, and spine). Progresses to destructive arthropathy. Contributes to an increased fracture risk. Organ deposits occur (esp. GI), but clinical issues are rare. Diagnosis: Generally made on clinical grounds. Radiological appearances (bone cysts and periarticular lucency) are characteristic (see Fig. 8.2). If tissue is available (e.g. after joint replac ement), it will stain with Congo red. Speci \201 c anti- B 2-M immunostains are available. Treatment: Modify dialysis prescription ( b p. 288): increase treatment hours; use a high- \202 ux, biocompatible dialyser; consider HDF. Analgesia and orthopedic intervention, as needed. \200 Renal transplantation is the treat ment of choice but is often not possible in the group of long-standing, often elderly, dialysis patients who are most sever ely affected. Deposits are slow to resolve post-transplant, but symptoms often signi \201 cantly improve. Fig. 8.2 Amyloid \201 brils on electron micrograph of renal biopsy tissue. Reproduced wit h permission from Davison AMA, Cameron JS, Grunfeld J-P et al . (eds) (2005). Oxford Textbo ok of Clinical Nephrology , 3rd edn. Oxford: Oxford University Press. CHAPTER 8 The kidney in systemic disease 634 Cryoglobulinaemia Introduction Cryoglobulins are single or mixed immunoglobulins that preci pitate below 37 * C and re-dissolve on warming. Several types have been described and may b e encountered in different clinical scenarios \200\224 and with different clinical consequ ences. Cryoglobulinaemia implies that circulating cryoglobulins are causing tis- sue damage. This may be s to hyperviscosity, immune complex deposi- tion (with complement activation), or pr ecipitation in small vessels, with thrombosis and downstream ischaemia (typically in cooler extremities). The overall prevalence of cryoglobulinaemia is unknown but strongly tied to that of hepatitis C (HCV) ( b p. 686). It is more common in \231\200 . Cryoglobulins may be present in otherwise healthy individuals, so prog- nosis will depend o n both disease activity and disease associations. Renal manifestations are associated with a worse outcome. Classi \201 cation Classi \201 ed according to their constituents. Type I cryoglobulinaemia (<20%) The result of a monoclonal immunoglobulin (usually IgM, the n IgG > IgA > light chain) and often associated with lymphoproliferative disease (mye- loma , lymphoma, CLL, Waldenstr m macroglobulinaemia). Type II (or mixed essential) cryoglobulinaemia Usually monoclonal IgM, complexed with the F c portion of polyclonal IgG. This monoclonal IgM autoantibody is a type of rheumatoid facto r (any antibody directed against another antibody is termed anti-idiotypic and possesses rh eumatoid factor activity). Associated with HCV ( b p. 686) and other infections (including HIV, HBV, and syphilis) as well as autoim- mune disease (e.g. SLE, Sj gren \200\231 s s yndrome). Also described with B cell non-Hodgkin \200\231 s lymphoma. HCV enters host cells (hepatocytes and CD5+ B cells) via the LDL receptor \200\224 infecte d B cells are resistant to apoptosis and exhibit increased production of autoantibodies. Type III cryoglobulinaemia Similar to type II, but this time polyclonal IgM is directed aga inst IgG. Type III is also associated with viral infections and autoimmune disease and may evolve into type II over time. Clinical features Type I cryoglobulins do not \201 x complement so may present with a hyp er- viscosity syndrome (acrocyanosis, retinal occlusions, Raynaud \200\231 s, digital ulce ration, livedo reticularis, purpura, arterial and venous thrombosis). Type II and III cryoglobulins cause systemic in \202 ammation. Consider cryo- globulinaemi a in any patient with unexplained renal disease and a rash (skin involvement is virtually u niversal \200\224 often a cutaneous vasculitis, with infarcts and ulceration), particularl y if systemic symptoms, such as fatigue and myalgia, are present. Also neuropathy, arthralg ia, GI involvement, and lung involvement (pulmonary in \201 ltrates and hemorrhage). CRYOGLOBULINAEMIA 635 Renal involvement occurs early in up to 60% cases, usually presenting as the nephritic synd rome with AKI. Renal biopsy reveals an MCGN-type pattern of injury ( b p. 550). Investigation \200 Complement components ( b p. 41). \200 2 Screening test for types II and III: high titre of rheumatoid factor plus low C4. Cryoglobulins: the blood sample needs to be transported at 37 * C, ideally in a water bath. Speak to your laboratory. \200 Type I cryoglobulins may precipit ate within 24 \200\223 48h, but II and III can take up to 7 days. Result is generally reported as \200\230 cryocrit \200\231 (the volume of precipitate as a percentage of original serum volume) and can be helpful for disease monitoring. The speci \201 c constituents of the cryoglobulin can be con \201 rmed by immunochemistry. Tissue biopsy, e.g. renal. \200 Investigate for underlying condition, particularly hepati tis serology, HIV testing, autoimmune serology (ANA, dsDNA, ENAs, etc.), FBC, blood \201 lm, serum and protein electrophoresis, SFLC, appropriate imaging 9 bone marrow examination for hematological disease. Treatment 2 Treat underlying condition, e.g. pegylated IFN- A and ribavirin for HCV. \200 Immune suppression, typically corticosteroids and cyclophosphamide, but increasing interest in rituximab (trials in progress). Plasma exchange: for hyperviscosity or severe disease, e.g. rapidly progressive AKI. Waldenstr m \200\231 s macroglobulinaemia \200 A clonal lymphoid and plasma cell diso rder with overproduction of IgM monoclonal protein. Multiple presentations: systemic symptoms (fever, weight loss, night sweats), anemia, lymph adenopathy, hepatosplenomegaly, neuropathy, hyperviscosity syndrome ( b p. 634), and cryogl obulinaemia. Renal involvement is uncommon but is glomerular (not cast nephropathy) when it occurs (microscopic haematuria, proteinuria, i SCr). Histologically: G N with intracapillary thrombi and deposits from IgM aggregation. These stain for and chains. Cryoglobulinaemic features, MCGN, and amyloid may also be seen. Diagnosis rests on \201 nding a monoclonal IgM protein and >10% lymphoplasmacytic cell in \201 ltration of bone marrow. Treatment: plasma exchange for hyperviscosity, rituximab, alkylating agents (cyclophosphami de, chlorambucil), purine analogs (e.g. \202 udarabine), and stem cell transplantation ar e all possibilities. CHAPTER 8 The kidney in systemic disease 636 Sickle cell nephropathy Introduction Renal involvement occurs in 7 60% of patients with sic kle cell disease (HbSS) at some point during their life, although only 10 \200\223 15% of these patients will develop ESRD. These \201 gures are halved in individuals with the HbS C form of the disease. Heterozygous patients (HbSA) may develop tubular defects later in li fe, although they do not appear to be at a greater risk of developing CKD. Pathophysiology The relatively hypoxic and hyperosmolar environment of the inner medulla pr omotes polymerization of deoxygenated hemoglobin S and subsequent sickling of erythrocytes. This results in impaired renal medul- lary blood \202 ow, microinfarcts, and papillary n ecrosis. Alongside this, per- sistent anemia and high cardiac output lead to glomerular hyp ertrophy and hyper \201 ltration. Over time, the \201 ne network of vasa recta is destro yed; the enlarged glomeruli become sclerosed, and CKD ensues. Clinical presentation (and underlying cause) \200 Polyuria and nocturia: Hyper \201 ltration and poor medullary perfusion l hyposthenuria (inability to concentrate urine under water-deprived conditions). This is reversible (with blood transfusions) until age 10 but becomes irreversible in later life, causing polyuria a nd dehydration. Metabolic abnormalities: SCN patients often have a partial form of distal RTA and a primary defect in the tubular se cretion of K + , resulting in a hyperchloraemic metabolic acidosis and i K + . In contrast, proximal tubular function appears to be supranormal, associated with i PO 4 an d B 2 microglobulin reabsorption and i uric acid and creatinine secretion. Proteinuria: In the majority of patients, prolonged hyper \201 ltration leads to microalbuminuria, prog ressing to overt proteinuria over time. \200 Although proteinuria is rare in individuals with HbSS disease aged <20, 7 60% aged >40 have an elevated uACR or uPCR. CKD: GFR begins to fall from the 3rd decade onwards, leading to CKD in a signi \201 cant number of patients (ESRD in 7 5 \200\223 10%). Haematuria and renal colic: Medullary infarction and papillary necrosis can cause visible haematuria. This is usually self-limiting but can be painful and persistent. Hypertension: Uncommon in most patients with SCD (presumably the result of persistent vasodilation and dehydration). However, in patients with SCN and CKD, i BP is more prevalent and may contribute to a rapid decline in renal function. AKI: Occurs in 7 10% of those hospitalized with crises. SICKLE CELL NEPHROPATHY 637 Renal medullary carcinoma This aggressive malignancy is extremely rare but is found exclusi vely in patients with sickle cell disease or, more commonly, sickle cell trait. It can occu r at any age from childhood onwards and presents with loin pain, haematuria, and weight los s. Although patients are treated with surgery and chemotherapy, these are essentially palli ative, as the disease is usually metastatic at presentation and fatal within a year. Investigations Although SCN is relatively common in patients with SCD, it is not the only c ause of haematuria, proteinuria, or CKD in these patients. Other conditions, such as lupus nephritis, HIVAN, or hepatitis B- or C \200\223 associated nephropathy, need to be exclude d. \200 Routine, outpatient investigations: U&Es, SCr, urinalysis and uACR/uPCR, FBC, reticulocytes, LFTs. New-onset haematuria: renal tract USS, urine cytology; and consider CT-IVU. Cystoscopy may be necessary in older patients as in the general population ( b p. 67). Heavy proteinuria or new-onset nephrotic syndrome: immunological and serological screen ( b p. 40). Parvovirus serology (may cause nephrotic syndrome after the acute infection). Rena l biopsy may be necessary (particularly if rapid onset). Management There is no speci \201 c management for SCN, so treatment can be divided into t he management of SCD and the management of proteinuric CKD. \200 SCD. Many of the complic ations of SCD, such as frequent crisis and severe anemia, can be improved with regular hydroxycarbamide (HC) (also known as hydroxyure a). There is limited evidence from studies in children that early signs of SCN can be impro ved with HC therapy. Similarly, regular transfusion ( 9 exchange transfusion) can help miti gate many complications of the disease, although evidence for impact on renal disease is la cking. Bone marrow transplantation in childhood will cure SCD but carries signi \201 cant risks (not currently widely available). \200 CKD. Patients with proteinuria (uACR >50mg/m mol) should be treated with an ACE-I or ARB. Start at low dose because of the risks of i K + and d BP in this grou p. When taken at night, these drugs often also reduce nocturia. EPO can improve Hb and redu ce transfusion requirement in some patients (target Hb 80 \200\223 100g/L), although high doses are often necessary. Heavy, visible haematuria should be treated with analgesia and I V hydration. It is usually self-limiting, but embolization may be considered for persistent , heavy bleeding. Dialysis and transplantation should be considered for all patients with ESRD. There appears to be a survival disadvantage on dialysis for sickle patients (when age-matched to non-sic kle patients). USRDS data show comparable graft function at 1 year but reduced patient surv ival ( 7 60% at 3 years). Recurrent transfusions may lead to sensitization with anti-HLA an tibodies. Recurrent disease is common but usually mild. CHAPTER 8 The kidney in systemic disease 638 The kidney in systemic vasculitis Introduction The term \200\230 vasculitis \200\231 re \202 ects the underlying process: in \202 ammation and leucocyte in \201 ltration of bloo d vessel walls. This may lead to local in \202 am- mation (e.g. purpura), vessel wall dama ge ( l aneurysm formation or hemorrhage), or vessel occlusion ( l ischaemia and infarction) . It is an autoimmune condition, but the precise causes are unclear. Both genetic (e.g. assoc iation with A 1-antitrypsin de \201 ciency and certain tyrosine phosphatase polymorphisms) and environmental factors (nasal S. aureus carriage, silica exposure, and certain drugs, e .g. propylthiouracil) appear important. The systemic vasculitides are classi \201 ed as small, medium, and/or vessel, according to the size of the smallest vessel affected (see Fig. 8.3). The forms that most commonly invo lve the kidneys are discussed here (or elsewhere as indicated). Vasculitis: classi \201 ed according to the smallest vessel involved \200 Large vessel: Takayasu \200\231 s arteritis affects the thoracic aorta and its branches, presenting with i BP, pulse de \201 cits, and ischaemic limbs or viscera (brain, heart, lungs, gut). Giant cell arteritis (temporal arteritis) presents in older patients with headache, jaw cla udication, visual symptoms, and myalgia. Medium vessel: Polyarteritis nodosa ( b p. 652). \200 Kawasaki disease affects children, presenting as a febrile illness with lymphadenopathy, skin rash, conjunctivitis, and mucositis (lips, tong ue). Small vessel: Without immune complex deposition: ANCA-associated vasculitis ( b p. 640). \200 Eosinophilic granulomatosis with polyangiiti s (Churg \200\223 Strauss). With immune complex deposition: Henoch \200\223 Sch nlein purpura ( b p. 650). \200 Cryoglobulinaemia ( b p. 634). \200 Cutaneous leucocytoclastic vasculitis. Other forms of vasculitis may be associated with autoimmune diseases, such as SLE, RA, Sj gren \200\231 s, and Beh et \200\231 s.