www.lupus.org/ Lupus UK: http://www.lupusuk.com/ The lupus site: http://www.uklupus.co.uk/ See also Immunological investigation of renal disease, p. 36 Rheumatoid arthritis, connecti ve tissue diseases and Sj gren \200\231s syndrome, p. 188 Glomerulonephritis, vasculitis, and nephrotic syndrome, p. 340 H. PENN AND C. DENTON 186 Scleroderma \200\223systemic sclerosis Table 4.8.1 Autoantibody associations with scleroderma Systemic sclerosis (SSc) is a heterogeneous autoimmune rheumatic disease of uncertain etiol ogy, characterized by in \202 ammation and \201 brosis in skin and other organs, and vas - cular abnormalities including Raynaud \200\231s phenomenon. It is classi \201 ed into di ffuse cutaneous systemic sclerosis (dcSSc: skin involvement proximal to the elbows and knee s) and limited cutaneous systemic sclerosis (lcSSc: distal skin involvement only). These ha ve distinct associations with organ involvement and outcomes. Autoantibody target % of SSc Clinical association ACAa (anticentromere ab) 30% lcSSc Pulmonary arterial hypertension Scl-70a (topoisomerase-1) RNA polymerasea PM-Scla 20% dcSSc Pulmonary \201 brosis 12% High risk of renal crisis Epidemiology It is more common in women (female:male 5:1). The onset peaks at 40 \200\22360 years of age. There is an association with silica and solvent exposure. The prevalence is estimated to be 3 \200\22324 per 100 000. 4% Overlap with myositis Anti \201 brillarina (U3-RNP) 5% dcSSc PAH Myositis U1-RNP 10% Overlap with SLE, myositis, arthritis Autoantibodies and SSc Autoantibodies associated with SSc are listed in Table 4.8.1. These are valuable for diagnosis and for identifying cases at risk of particular complications. Th/To <5% lcSSc with lung \201 brosis a Scleroderma-de \201 ning antibody. lcSSc, limited cutaneous systemic sclerosis; dcSSc, diffuse cutaneous systemic sclerosis; P AH, pulmonary arterial hypertension. Renal disease in systemic sclerosis This may be divided into: \200 \200 \200 Investigations Urinalysis: non-nephrotic range proteinuria; microscopic hematuria. Blood \201 lm: microangiopathic hemolytic anemia (MAHA) with schistocytes is found in 50%. Renal biopsy shows intimal proliferation, thrombotic microangiopathy, and often fibrinoid necrosi s. It also excludes other pathology (Fig. 4.8.1). Echocardiography commonly demonstrates re duced left ventricular systolic function. This will usually resolve as afterload falls with successful treatment. Pericardial effusions are common, but tamponade occurs infrequently (<5%). Tachy- or bradyarrhythmias may occur and are associated with a poor prognosis. scleroderma renal crisis; other acute presentations; chronic kidney disease. Renal function should be routinely monitored in all cases of SSc with estimated GFR determi nation and urinalysis at least every 6 months, and close home-monitoring of BP in dcSSc cas es. Scleroderma renal crisis De \201 nition Scleroderma renal crisis (SRC) is a clinical syndr ome of acute renal failure and accelerated hypertension in the presence of systemic scleros is. Frequency It occurs in 5% of all SSc patients (15% of dcSSc cases, and 2% of lcSSc cases). Treatment The target for antihypertensive treatment is to bring the systolic BP down by 20 mmHg and the diastolic by 10 mmHg per 24 h, into the normal range, while avoid- ing periods of hypotension. An arterial line and central venous catheter may aid in monitoring the res ponse to treatment. ACEIs must be instituted since they have been shown to reduce mortality . Captopril has a short half-life and may be easiest to titrate to the blood pressure initi ally, but longer-acting ACEI are usually more convenient in the long term. Intravenous pros tacyclin (0.2 \200\2232 ng/kg/min) increases renal perfusion, and also may help to normaliz e blood pressure. ARBs can be safely added if required once ACEIs are at full dose. Alpha-b lockers and calcium antagonists are also help- ful for refractory hypertension. Plasma exch ange may be of use in profound MAHA. Renal support with hemodialysis is required in approxi - mately two-thirds of all cases. Risk factors \200 \200 \200 \200 \200 \200 \200 Recent-onset diffuse scleroderma. Active, progressive skin disease. Tendon friction rubs. A nemia. New cardiac events. Steroid use ( \211 15 mg prednisolone/day). Presence of anti-RNA polymerase III. Clinical features Patients with SRC will typically have an acute or subacute presentation w ith \202 uid overload and/or symptoms of end- organ complications of hypertension. Often nonspeci \201 c systemic symptoms (malaise, exertional breathlessness) are present for wee ks before presentation with: \200 \200 \200 \200 \200 \200 acute kidney injury. new-onset hypertension (>90%). pulmonary edema (>50%). encephalopathy (20%). seizures (10%). hypertensive retinopathy (>60%). CHAPTER 4.8 Scleroderma \200\223systemic sclerosis 187 Prognosis Of the two-thirds of patients who require dialysis, one-half of these will be abl e to discontinue dialysis by 2 years after the onset of SRC. A poor renal outcome is predic ted by low blood pressure at presentation, and the presence of \201 brinoid necrosis and mucoid intimal thickening on renal biopsy. Mortality is signi \201 cant (30% at 3 years) a nd is highest in those requiring permanent dialysis. Renal transplantation may be considere d in patients who still require dialysis at 2 years. Survival rates are similar to transpla nt recipients with other connective tissue diseases. Recurrence of SRC is rare in patients concordant with medication, and uncommon (5%) following transplanta- tion. with high levels of collagen in the interstitium, the mesan- gium, and around blood vessels . Use of drugs such as NSAIDs, cyclosporin and penicilla- mine may also contribute to renal \201 brosis. Follow-up studies of SSc patients with CKD do not dem- onstrate signi \201 cant rates of progression to dialysis how- ever. Table 4.8.2 Practical tips in scleroderma renal crisis Patients may present with normal BP/serum creatinine in the normal range. Fluid balance is dif \201 cult due to the high peripheral vascular resistance \200\223 use small volume \202 uid challenges. BP is often labile initially. ACEIs are \201 rst-line therapy but additional agents often also required. Manage in the HDU/ITU setting with central venous and Prevention There is no evidence that ACEI or ATII receptor blockade is effective in prevent ing SRC. Patients at risk of SRC should avoid doses of steroid >10 mg prednisolone/day. Fur ther practical advice on the management of SRC is described in Table 4.8.2. arterial monitoring. Biopsy is safe when BP is controlled, and excludes alternative diagnoses. Anti-RNA polymerase III antibody is suggested by the presence of \201 ne speckled pattern of ANA in the absence of other routine ENA positivity. Fistula formation is safe in those requiring long-term hemodialysis (despite secondary Raynaud \200\231s phenomenon). \200 Line-related sepsis i s a common complication in these patients due to abnormal skin function. Peritoneal dialysis is well-tolerated in those with suf \201 cient intrinsic renal function. Recovery of renal function can occur up to 2 years after SRC and renal transplantation shou ld only be considered after this time. HDU, high dependency unit; ITU, intensive therapy unit. References Bunn CC, Denton CP, Shiwen X, et al. Anti-RNA polymerases and other autoantibody specificities in systemic sclerosis. Br J Rheumatol 1998; 37: 15 \200\22320. Gibney EM, Parikh CR, Jani A, et al. Kidney transplantation for sys- temic sclerosis improv es survival and may modulate disease activity. Am J Transplant 2004; 4: 2027 \200\2232031. Fig. 4.8.1. Renal biopsy of scleroderma renal crisis artery: smooth muscle actin immunohist ochemistry stain \22710. Note expansion of the vessel media, proliferation of the intima a nd obliteration of the lumen. Penn H, Howie A, Stratton R, et al. Scleroderma renal crisis \200\223 patient characterist ics and long term outcomes in 110 cases. Q J Med 2007; in press. Steen V, Syzd A, Johnson JP, et al. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. 2005; 32: 649 \200\223655. Other renal disease in systemic sclerosis Acute disease SSc patients with SLE overlap featu res can develop glo- merulonephritis \200\223 suspect this in patients with red cell casts , and in those with serological features of SLE in the presence or absence of a scleroderma -de \201 ning antibody (Table 4.8.1). Systemic vasculitis occurs in a small proportion (<2 %) of SSc patients. It often affects the lungs in addition to the kidney, is accompanied by pANCA positivity, and responds to cyclophosphamide. Steen VD, Costantino JP, Shapiro AP, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113: 352 \200\223357. Internet resources The Scleroderma Clinical Trials Consortium: www.sctc-online.org The EULAR scleroderma trials and research group: www.eustar.org Raynaud \200\231s and Scleroderma Association \200\223 for medical informat ion and patient support: Chronic disease CKD is common in patients without SRC. The \201 brotic bur- den in SSc ki dneys is signi \201 cantly greater than in controls, www.raynauds.org.uk A. BARTON 188 Rheumatoid arthritis, connective tissue diseases, and Sj gren \200\231s syndrome Rheumatoid arthritis Clinical Rheumatoid arthritis (RA) is a multisystem autoimmune disorde r characterized by involvement of synovial joints, in which in \202 ammation can lead to j oint erosion. Treatment The treatment choice depends on the pattern of clinical involvement. For example, NSAIDs (Table 4.9.1) and anti- malarials (Table 4.9.1) are used for joint (arthralgia) and skin involvement, corticosteroids for arthritis, and high dose corticosteroids for myositi s and \201 brosing alveolitis. Fibrosing alveolitis may also require more intensive treat - ment with cyclophosphamide (Table 4.9.1). Azathioprine (Table 4.9.1) is often used as a s teroid-sparing agent. Epidemiology The prevalence of RA in the UK has recently been esti- mated to be 0.8% with a female predominance, particularly in younger age groups. Treatment A range of disease-modifying antirheumatic drugs (DMARDs) can be used (Table 4.9. 1) but methotrexate has become the commonest \201 rst-choice DMARD. Recently, the use of biologic drugs in patients resistant to or unable to tolerate treatment with standard DMARD s has become more common. Renal manifestations Clinically overt renal disease is said to be rare but biopsy studies h ave revealed that glomerular disease, particularly membranous nephropathy, does occur in 10 \200\22350% of patients. As the disease evolves, the renal manifestations will also evolve into those of the underlying disease (i.e. lupus nephritis or scleroderma renal disease) a nd should be managed accordingly. Supports diagnosis The presence of rheumatoid factor and/or anti-CCP (cyclic citrullinated peptide) antibodies. Overlap syndromes Clinical Overlap syndromes are de \201 ned as the overlap of clini- cal features of connective tissue diseases such as those listed above, but without anti-U1RNP a ntibody positivity. As in MCTD, patients often evolve features more consist- ent with one c onnective tissue disease over time. Renal manifestations RA per se is rarely associated with clinically overt renal disease alt hough longstanding RA, particularly if poorly controlled, may be associated with the develo pment of amyloidosis (AA amyloid). When renal disease does occur, it most commonly arises a s a result of the treatments used (Table 4.9.1), but mesan- gioproliferative glomerulonephr itis, membranous neph- ropathy and IgA nephropathy have all been reported in association wi th RA. Treatment As above, treatment will depend on the pattern of clinical involvement. Mixed connective tissue disease Clinical Mixed connective tissue disease (MCTD) is characte rized by overlapping features of systemic sclerosis, systemic lupus erythematosus (SLE) and polymyositis and is associated with antibodies to the U1 ribonuclear protein (U1RNP). Clin ical features include a high frequency of Raynaud \200\231s syn- drome, swollen hands, scle rodactyly, polymyositis, \201 brosing alveolitis and pulmonary hypertension. Joint involv ement can range from joint pain (arthralgia) through to an erosive arthritis. Other clinica l features re \202 ect those of the diseases with which it overlaps. Renal manifestations The renal manifestations will depend on the connective tis- sue diseas e features and should be managed as such. For example, a patient with features of SLE and m yositis may well develop lupus nephritis. Polymyositis and dermatomyositis Clinical These conditions are characterized by an in \202 ammatory myositis of skeletal muscles, often presenting as symmetri- cal weakness of proxi mal limb muscles. Dermatomyositis is associated with characteristic skin involvement such a s a heliotrope rash on the eyelids and Gottron \200\231s papules. When it presents in the > 50 year age group, dermatomy- ositis may be associated with underlying neoplasia. Epidemiology Like other connective tissue diseases, it shows a female predominance (9:1) an d has a prevalence of 10/100 000. MCTD often evolves over time into systemic lupus ery- th ematosis (SLE) or systemic sclerosis. Pulmonary hypertension and scleroderma renal crisis a re important causes of death, the former being the most fre- quent. Epidemiology The prevalence of the disease is 50 per 100 000 and women are affected twice a s commonly as men. A bimodal pattern of age at onset is seen with a peak in childhood (5 \200\22315 years) and a second peak in middle age (50 \200\22370 years). The incidence of r enal disease is 20%. Diagnosis This is dependent on the presence of high titer U1RNP antibodies. Supports diagnosis Raised creatine kinase, abnormal electromyography, abnor- mal muscle bio psy, anti-aminoacyl-tRNA synthetase anti- bodies, e.g. anti-Jo-1. CHAPTER 4.9 Rheumatoid arthritis, connective tissue diseases, and Sj gren \200\231s syndro me 189 Table 4.9.1 Potential renal complications of drugs used to treat rheumatoid arthritis Drug therapy Renal manifestation Comment Hemodynamically mediated AKI. Presents with signi \201 cant increases in plasma creatinine and reduced GFR. Potentially reversible on drug withdrawal. Occurs as a result of renal ischemia caused by i nhibition of prostaglandin production, which alters local glomerular arteriolar perfusion. NSAIDs Acute interstitial nephritis. Presents with fever, rash and eosinophilia and is usually the result of an allergic reactio n to the drug. Eosinophils are often present in the urine. Reversible with removal of drug. Reversible on drug withdrawal. Very rare cases of chloroquine toxi- city mimicking the appearance of Fabry disease have be en reported in the literature. Antimalarials (chloroquine/ hydroxychloroquine) None reported in relation to treatment for RA. When used as treatment for in \202 ammatory bowel disease, interstitial nephritis has been reported to occur in 0.29 cases per 100 person-years. Sulphasalazine Decrease in GFR Reversible on drug withdrawal. 90% of dose is cleared via kidneys. Methotrexate Proteinuria in 10% patients, usually mild. Gradual improvement on drug withdrawal. Oral gold (aurano \201 n) Rarely used now for treatment of RA. Usually gradual improvement on drug withdrawal. Can take up to 3.5 years (median 1 year). Affects 10% of patients. Membranous nephropathy most common renal lesion. Presents with pr oteinuria (can be nephrotic range) and hematuria. Parenteral gold (sodium aurothiomalate) Rarely used now for treatment of RA. Usually gradual improvement on drug withdrawal but may persist for up to 1 year. Affects 15% of patients. Membranous nephropathy most common renal lesion. Presents with pr oteinuria (can be nephrotic range). D-Penicillamine Rarely used now for treatment of RA. CsA-induced renal afferent arteriolar constriction. Even at low doses, all patients show so me degree of renal toxicity. Usually reversible on drug withdrawal. Drug is contraindicated in RA patients with renal dysfunction. Hemodynamically mediated AKI. Presents with signi \201 cant increases in plasma creatinine and reduced GFR. Ciclosporin Up to 10% may develop a nephropathy if treated with higher doses of CsA (>5 mg/kg/day). None reported Le \202 unomide None reported Azathioprine None reported Used to treat renal complications of vasculitic disorders. Cyclophosphamide Anti-TNF biologics: In \202 iximab Etanercept Adalimumab None reported None reported None reported None reported In small case series, used to treat renal manifestations of antibody- mediated diseases inc luding Wegener \200\231s granulomatosis and idiopathic membranous nephropathy. Anti-B cell biologic: Rituximab Acute rhabdomyolysis occurs following inflammatory injury to the skeletal muscle with extra vasation of intracel- lular toxic metabolites into the circulatory system. This affects up to 15% of patients with polymyositis/ dermatomyositis. Hemodialysis may be required. It is associated with a high mortality. Treatment Corticosteroids are the mainstay of treatment for the in \202 ammatory manifesta tions of these conditions. Azathioprine (Table 4.9.1) may be used as a steroid-sparing agen t. Renal manifestations They most commonly present with microscopic hematuria and mild \200 \223moderate proteinuria. The commonest patterns of renal involvement are: Chronic glomerulonephritis This affects up to 5% of patients. Membranous nephropathy, mesan gial proliferative glomer- ulonephritis, and IgA nephropathy have been reported. Acute tubular necrosis with renal failure This is related to myoglobinuria, occurring as a result of rhabdomyolysis. A. BARTON 190 Sj gren \200\231s syndrome Clinical Sj gren \200\231s syndrome is a multisystem autoimmun e disorder, which can be classi \201 ed as primary or secondary to another autoimmune dise ase such as RA, SLE or sys- temic sclerosis. The commonest presenting complaints are drynes s of the eyes and mouth which arise as a result of lymphocyte- mediated in \201 ltration o f the exocrine glands, particularly the lachrymal and salivary glands. Schiff MH, Whelton A. Renal toxicity associated with disease-modi- fying antirheumatic drug s used for the treatment of rheumatoid arthritis. Semin Arthritis Rheum 2000; 30: 196 \200 \223208. Suarez-Almazor ME, Belseck E, Shea B, Wells G, Tugwell P. Cyclophosphamide for treating rhe umatoid arthritis. Cochrane Database Syst Rev 2000; (4): CD001157. Guidelines published by the British Society for Rheumatology: Chakravarty K, McDonald H, Pu llar T, et al. on behalf of the British Society for Rheumatology and British Health Profess ionals in Rheumatology Standards, Guidelines and Audit Working Group in association with th e British Association of Dermatologists (BAD). (2006) BSR & BHPR guideline for disease-modi fying anti- rheumatic drug therapy (DMARD) in consultation with the British Association of Dermatologists. Rheumatology (Oxford); 2006(Sep 27). [Epub ahead of print] Epidemiology The prevalence of clinical Sj gren \200\231s syndrome is 3%. Renal involveme nt occurs in up to 20% of patients. Mixed connective tissue disease Venables PJW. Mixed connective tissue disease. Lupus 2006; 15: Supports diagnosis The presence of antibodies to SS-A (anti-Ro) and SS-B (anti-La). 132 \200\223137. Polymyositis and dermatomyositis. Yen TH, Lai PC, Chen CC, Hsueh H, Huang JY. Renal involve ment in patients with polymyositis and dermatomyositis. Int J Clin Pract 2005; 59: 88 \200 \223193. Treatment Treatment is symptomatic as there are no drug therapies with proven ef \201 cacy for the underlying condition. General recommendations include wearing glasses with side pa nels to minimize evaporation from the eyes, chew- ing sugar-free gum, sipping water frequen tly and emphasiz- ing the importance of good dental hygiene. Arti \201 cial tears and sali va replacements may be used. Prednisolone or ciclosporin eye-drops or surgical ablation of the nasolachrymal ducts is sometimes necessary. Sj gren \200\231s syndrome Aasarod K, Haga HJ, Berg KJ, Hammerstrom J, Jorstad S. Renal in volvement in primary Sj gren \200\231s syndrome. Q J Med 2000; 93: 297 \200\223304. Venables PJ. Management of patients presenting with Sjogren \200\231s syn- drome. Best Pract Res Clin Rheumatol 2006; 20: 791 \200\223807. Internet resources Patient information lea \202 ets about various aspects of rheu- matoid arthritis and its management: Renal manifestations Distal renal tubular acidosis This may be complete or incomplete. It i s usually clinically silent but results in a tendency to form stones. The diagnosis is con \201 rmed by an abnormal fasting urine acidi \201 cation test (pH >5.5) and the presence of a meta- bolic acidosis. Ammonium chloride loading may be required to exclude the diagnos is. It is more common in autoantibody-positive patients: ANA, anti-SS-A or -SS-B. http://www.arc.org.uk/arthinfo/patpubs/6033/ 6033.asp - National Rheumatoid Arthritis Socie ty: www.rheumatoid.org.uk Information on the biologics register on which patients treated with a biologic agent should be included. Publications arising from the register are also refere nced: www.medicine.manchester.ac.uk/arc/BSRBR/ MCTD information: http://www.patient.co.uk/showdoc/40001176/ Arthritis Research Campaign information: Hyposthenuria Abnormalities of urine-concentrating ability are reported in up to 30% of cas es. http://www.arc.org.uk/arthinfo/patpubs/6009/ 6009.asp Myositis Support Group: Renal impairment Glomerular disease is rare. Interstitial nephritis is the most commonly re ported lesion on renal biopsy. In patients with interstitial nephritis, high dose corticost er- oids may substantially improve renal function. Renal dysfunction tends to progress slow ly over time but ESRD is rare. http://www.myositis.org.uk/ Sj gren \200\231s patient-based website: http://www.sjogrens.com Information lea \202 et aimed at patients with Sj gren \200\231s: http://www.arc.org.uk/arthinfo/patpubs/6041/6041.asp Arthritis Research Campaign; useful r esource for informa- tion about all the above: Further reading Rheumatoid arthritis Gisbert JP, Gonz lez-Lama Y, Mat J. 5-Aminosalicyla tes and renal function in in \202 ammatory bowel disease: a systematic review. In \202 am m Bowel Dis 2007; 13: 629 \200\223638. http://www.arc.org.uk/ See also Systemic lupus erythematosis, p. 180 Scleroderma \200\223systemic sclerosis, p. 18 6 Membranous nephropathy, p. 106 Renal tubular acidosis, p. 208 Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy \201 ndings and clinicopat hologic correlations in rheumatoid arthri- tis. Arthritis Rheum 1995; 38: 242 \200\223247. Salama AD, Pusey CD. Drug Insight: rituximab in renal disease and transplantation. Nature Clin Pratice 2006; 2: 221 \200\223230. This page intentionally left blank L. BARTON AND C. CHAPMAN 192 Sickle cell nephropathy \200 \200 Introduction Sickle cell hemoglobinopathies (sickle cell anemia (SCA) and sickle cell carri er/trait (SCT)) are a group of genetic disorders characterized by the production of an abno rmal sickle hemoglobin (Hb) that irreversibly polymerizes at low oxygen saturations resulti ng in crescent-shaped red blood cells (sickle cells) which block the microcirculation. Chan ges in both red and white blood cell adherence to vascular endothelium are also found and t ogether these changes result in ischemic damage to organs. Anemia arises due to the prematu re removal of the abnor- mal sickle cells by the reticuloendothelial system. SCA classicall y presents with acute painful crises (e.g. bone pain and acute chest syndrome). Recurrent s plenic infarction is associated with increased susceptibility to infection, particularly wi th encapsulated organisms (e.g. pneumococci). Early vaccination and antibi- otic prophylaxi s are essential to reduce infection and the risk of childhood death. End-organ damage inclu des renal failure, pulmonary hyper- tension, cardiac failure, avascular necrosis, cholelith iasis, leg ulceration, priapism, retinopathy and stroke. SCT patients do not suffer from ac ute, painful crises but are susceptible to sickle cell nephropathy albeit less fre- quently and usually at an older age. proteinuria; anemia; hypertension. Clinical features Glomerular involvement This is manifest by microscopic hematuria, increas ing pro- teinuria and a progressive decline in GFR. This is less common with non-HbSS sickl ing disorders. Sickle cell anemia By age 40 (HbSS): \200 \200 79% have an abnormal ACR; 40% have overt proteinuria. Median age at which ACR is increased is 11 \200\22314 years, but can be as early as 5 years . Nephrotic syndrome is seen in 4 \200\2235% of cases; 2/3 of neph- rotic patients develop ESRD with a 50% mortality at 2 years despite renal replacement therapy. Sickle cell trait Proteinuria and nephrotic syndrome is uncommon. Tubular involvement Hyposthenuria This is associated with childhood enuresis (up to 40% of patients aged 2 \200\22320 years) and nocturia. There is also a risk of rapid dehydration w ith water deprivation, which may precipitate or prolong a sickling crisis. It is reversible with an exchange transfusion program until age 10 years. It is more pronounced in SCA tha n SCT. Genetics of sickle cell disorders SCA arises most frequently from homozygosity for a single point mutation in the B-globin gene (HbSS). Other sickle disorders occur with compound het erozygosity for HbS and other globin mutations and tend to be less severe (SC (most common) , SOarab, SDpunjab, SE and SB-Thal). Considerable variation in severity of disease is also seen between individual patients, in \202 uenced by factors such as associated S gene-clus ter haplotype, HbF concentration, white cell count, level of Hb and the coinheritance of A- thalassemia. SCT occurs when the patient has one normal B-globin gene and one affected gen e generating Hb AS. Impaired potassium excretion and impaired acidi \201 cation of urine This is not normally clinically apparent. Hyperkalemia is more likely to be seen with progressive CKD and when d rugs such as ACEI/ARB and K+-sparing diuretics are used. Patients are rarely acidotic unles s there is concomitant multiple organ dysfunction. Hyperkalemia and acidosis are rarely see n in SCT. De \201 nition Sickle cell nephropathy can affect the whole length of the nephron from the glomerulus to the papillary tip. In particular, the high oxygen demands and relatively slo w blood \202 ow rate within the renal medulla create a hypoxic, hyperosmolar and acidotic environment which predisposes to red blood cell sickling within the vasa recta and the dev elopment of ischemia/infarction. Hematuria This is usually painless micro- or macroscopic hematuria; rarely massive hematuri a may occur. It can be associated with renal \200\230clot \200\231 colic and obstruction ( renal papillary necrosis). Bleeding is mostly unilateral ( 80% arises from the left kidney) . Common causes: \200 \200 \200 Epidemiology Studies in Western populations indicate that: \200 glomerulopathy; renal papillary necrosis; renal medullary carcinoma. 20 \200\22330% of adults with SCA have an eGFR <90 mL/min (28% HbSS and 6% non-HbSS having CKD 3 or worse); ESRD develops in 4 \200\2235% of patients with SCA; mean age at onset 41 14 years; ESRD is rare in SCT. It is commonly seen in SCA, but is less common in SCT (up to 4% admission rate for hematuri a with SCT). Risk factors for ESRD include: \200 \200 Renal papillary necrosis This occurs in both SCA and SCT as a result of sickling and ischem ia in the renal medulla. HbSS (4.2% HbSS vs 2.4% HbSC); S gene-cluster haplotype; CHAPTER 4.10 Sickle cell nephropathy 193 NIH advises introducing antihypertensive treatment if: \200 \200 It is found as an incidental \201 nding in up to two-thirds of patients undergoing urogra phy. It is most commonly asymptomatic but may be associated with hematuria or rarely urinar y tract obstruction due to sloughing of infarcted papillae. systolic/diastolic increases 20/10 mmHg above baseline; >130/85 mmHg and nephropathy/cardio vascular dis- ease; >120/75 mmHg and proteinuria >1 g/24 h. ACEI, ARB, and calcium antagonists are preferred agents; B-blockers and diuretics can be us ed with caution (Table 4.10.1). Acute kidney injury This occurs in 10% of patients hospitalized with acute cri- ses (associ ated with multiple organ failure). No speci \201 c treatment is required and renal recover y is usual with supportive management. Acute crisis can rarely be associated with renal vei n throm- bosis. AKI is also rarely seen with nontraumatic and exertional rhabdomyolysis (SC T). Erythropoiesis stimulating agents (ESAs) Erythropoietin levels are usually lower than expec ted for the degree of anemia. ESAs can be used cautiously in individual patients; precipi- tation of sickle crisis has been reported (Table 4.10.1). ESA requirements are much higher than in other CKD patients. Target Hb is 8 \200\22310 g/dL. Renal medullary carcinoma This is rare (incidence 1.74 per 1000 patient-years). It is almos t exclusively seen in patients with SCT. The average age at diagnosis is 21 years, but it h as also been described in children. The male:female ratio is 2:1. It presents with gross he maturia and \202 ank pain. The majority have metastatic disease at diagnosis therefore th e median survival is 4 months. Renal replacement therapy Hemodialysis and peritoneal dialysis Very few data are available in the literature. There is no evidence for superiority of HD or PD although an increased r isk of dialysis-related septicemia has been reported. There is an increased incidence of he patitis B and C virus infection in some areas of the world due to transfusion requirements. Investigations The assessment of GFR is inaccurate in SCA due to increased proximal tubule secretion of creatinine and low muscle mass leading to overestimation of GFR by both cre- a tinine clearance and derived eGFR. Cockcroft \200\223Gault and MDRD formulas have not been validated in SCA. Therefore, there must be a low threshold for investigation of even a mild increase in creatinine. In SCA patients <25 years, the suggested upper limit of Cr: \200 \200 Transplantation Patients with SCA are less likely to be listed for transplan- tation or be transplanted compared to other ESRD patients (due to coexistent end organ damage). For thos e transplanted (mainly HbSS) 1 year survival is similar to that of the general transplant p opulation. However, at 3 years, when compared to the general trans- plant population, there is: \200 \200 reduced allograft survival (48% vs 60%); signi \201 cantly reduced patient survival (59% v s 81%). males 80 mol/L; females 68 mol/L. Despite this there is a trend to better survival with trans- plantation compared to remaini ng on dialysis and there- fore transplantation should always be considered in patients with SCA and ESRD. The observed morbidity and mortality is largely due to improved post-transpl antation hemopoiesis which increases plasma viscosity and the likelihood of acute crises. R ecurrent sickling is also associated with recurrent sickle cell nephropathy, renal vein thr ombosis and rarely acute allograft loss. Therefore venesection should be considered if Hb i s >10 g/dL. Treatment Glomerular disease Consider ACEI or ARB if the ACR is increased: small, short ter m studies suggest bene \201 t but it is unclear if progression to ESRD is slowed. Tubular disease Ensure adequate hydration particularly during acute crises and have a low t hreshold to check for hyperkalemia and metabolic acidosis during intercurrent illness. Hematuria Conservative management is usually suf \201 cient; exclude UTI; angiography + em bolization/nephrectomy is rarely required; consider renal medullary carcinoma if macro- sco pic hematuria is persistent. Preparation of patients with SCA for surgery A multidisciplinary approach (hematologist, an esthetist surgeon, nephrologist) is essential and a protocol outlining perioperative manage ment should be written in the patient \200\231s notes prior to surgery. Patients may requir e preoperative transfusion (top-up or exchange transfusion). Postoperatively, careful atten tion to \202 uid balance and tis- sue oxygenation is required. Hypertension In SCA the BP is lower than age-/sex-matched African- American controls. The d ifference is most marked in HbSS patients >45 years. \200\230Relative \200\231 hypertensio n (120 \200\223139/70 \200\22389 mmHg) is associ- ated with an increased risk of CKD, strok e, pulmonary hypertension, and all-cause mortality. Little data is available to guide treat ment decisions. Follow-up All patients with SCA require annual review of renal func- tion and measurement o f proteinuria. Once renal disease L. BARTON AND C. CHAPMAN 194 Table 4.10.1 Therapeutic considerations in patients with SCD and CKD Therapy Comment Used to treat sickle cell hemoglobinopathies (increases HbF synthesis and reduces likelihoo d of sickling). Caution in patients with nephropathy as hydroxycarbamide is predominantly c leared by the kidney. Hydroxycarbamide (hydroxyurea) Frequently used during painful acute crises. Analgesics NSAIDs SCA patients more susceptible to glomerular hemodynamic effects of NSAIDs as more dependent on prostaglandins derived from ischemic renal medulla to maintain glomerular blood \202 ow. Avoid in patients with nephropathy. If necessary, carefully monitor renal function and limi t to 5 days of treatment. Opiates Caution in patients with nephropathy as these drugs (e.g. pethidine) are predominantly clea red by kidney. EPO Consider EPO if: Hb <8 g/dL. Cautious escalation of EPO dosing Commence with 100 U/kg twice a week increasing by 100 U/k g/dose every 4 \200\2236 weeks until Hb rises. Stop if Hb >10.5 g/dL, if rise is >1.5 g/dL over 4 weeks or Hct >0.33 Close monitoring is essential FBC, reticulocyte count and BP should be monitored weekly aft er any dose change. Hypertension Diuretics -Blockers ACEIs/ARBs Caution due to tubular dysfunction and susceptibility to dehydration. Caution due to tubular dysfunction and susceptibility to hyperkalaemia particularly in prog ressive CKD. Caution due to tubular dysfunction and susceptibility to hyperkalaemia particu larly in progressive CKD. becomes apparent the frequency of follow-up will be determined by the stage of CKD. Management of Sickle Cell Disease (NIH NHLBI): http://www.nhlbi.nih.gov/health/prof/blood/ sickle/index.htm BCSH Guideline. Management Of Acute Painful Crisis In Sickle Cell Disease: Prognosis The median survival for patients with ESRD is 4 years despite RRT. Poor outcome i s linked to coexistent end- organ damage and refractory anemia. However, survival is simila r to matched ESRD controls when the low transplantation rate is taken into account. http://www.bcshguidelines.com/ Sickle Cell Society: http://www.sicklecellsociety.org/index.htm Sickle Cell Disease Association of America: Further reading Ataga KI, Orringer EP, et al. Renal abnormalities in sickle cell http://www.sicklecelldisease.org/ The Sickle Cell Information Center: disease. Am J Haematol 2000; 63: 205 \200\223211. Guasch A, Navarrete J, et al. Glomerular Involvement in adults with sickle cell haemoglobin opathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006; 17: 2228 \200\2232235. http://www.scinfo.org/ Standards for the clinical care of adults with Sickle Cell disease i n the UK Little JA, McGowan VR, et al. Combination erythropoietin hydrox- yurea therapy in sickle ce ll disease: experience from the National Institutes of Health and a literature review. Haem atologica 2006; 91: 1076 \200\2231083. http://www.sicklecellsociety.org/CareBook.pdf See also Ojo AO, Govaerts TC, et al. Renal transplantation in end stage Tumors of the kidney p. 668 Urinary tract obstruction, p. 652 Hematological disorders in CK D, p. 426 sickle cell nephropathy. Transplantation 1999; 67: 291 \200\223295. Thompson J, Reid M, et al. Albuminuria and renal function in homozygous sickle cell disease . Arch Intern Med 2007; 167: 701 \200\223708. Internet resources Sickle Cell Disease in Childhood: Standards and Guidelines for Clinical Care (NHS): http://www.sickleandthal.org.uk/Documents// DETAILED_CLIN_Oct19.pdf This page intentionally left blank J. FREW, C. McBAIN AND A. ELLIOTT 196 Cancer and the kidney Etiology of renal impairment in cancer patients Renal dysfunction is relatively common in p atients with cancer as a result of complications related to their cancer or treatment (see below) and concomitant comorbidities such as diabetes mellitus and hypertension. The causes include: \200 \200 \200 \200 \200 \200 \200 \200 \200 Coexisting primary hyperparathyroidism A higher incidence of primary hyperparathyroidism is seen in patients with cancer. Calcium levels >3.25 mmol/L are rarely due to primary hyperparathyroidism. Investigations in the hypercalcemic patient Measure serum urea, creatinine, calcium, chlori de, and phosphate. Measure vitamin D and PTH. CXR (for evidence of malignancy or sarcoidosi s). Perform isotope bone scan if not known to have bone metastases. pre-renal failure secondary to \202 uid depletion; anticancer drug-related nephrotoxicity ; metabolic causes, e.g. hypercalcemia; mechanical obstruction; paraneoplastic glomerulonep hropathies; paraprotein-related disease; amyloidosis; radiation nephropathy; renal metastas is. Management of hypercalcemia of malignancy Saline Saline is administered to produce volume e xpansion and increase urinary calcium excretion. Give 3 \200\2234 L of 0.9% saline/day. Adj ust infusion rate to main- tain a urine output of 100 \200\223150 mL/h. This alone rarely n or- malizes serum calcium. Hypercalcemia of malignancy Hypercalcemia is a common metabolic problem occurring in 10 \200\22320% of patients with cancer. In the hospital popula- tion an underlying malignancy is the most frequent cause of hypercalcemia. Cancers of the lung and breast and multiple my eloma are most frequently implicated. Hypercalcemia often develops in the later stages of c ancer, and is not often the isolated presenting feature of malignancy in the absence of oth er symptoms and/or signs. Hypercalcemia is a result of increased bone resorption and releas e of calcium from bone. The mechanisms are dis- cussed below although it is often multifact orial. Bisphosphonates These are nonhydrolyzable analogs of inorganic pyro- phosphate. They inhibit bone resorptio n by adsorbing to the surface of bone hydroxyapatite, thereby interfering with the meta- bo lic activity of osteoclasts. Third-generation bisphosphonates (e.g. zoledronic acid) have b een shown to be superior to second generation bisphosphonates (e.g. pamidronate). Third-gen eration bisphosphonates normalize the corrected calcium level in almost 90% of patients by day 10 with a median duration of calcium control of 32 \200\22343 days. Mechanisms of hypercalcemia Osteolytic metastases Hypercalcemia results from direct inducti on of local oste- olysis by tumor cells. This is common in solid tumors metastatic to bone (espe- cially lung and breast). Cytokines (e.g. IL-1 and TNF) stimulate osteoclast differen tiation and activity. Calcitonin