SLE \200 Renal involvement in SLE is characterized by immune complex deposition. Immune complexes ar e composed of DNA-anti-DNA and may include composites of nucleosomes, C1q, chromatin, and o ther nuclear antigens. The pattern of deposition of immune complexes largely determines the phenotype of the renal disease. Large and anionic immune complexes deposit in the subendot helial and mesangial compartments of the glomerulus, and subsequent activation of the immun e systems provokes a proliferative glomerular lesion the severity of which is determined by the amount deposited. Severe proliferative lesions are char- acterized by dysmorphic haema turia, red blood cell casts, proteinuria, hypertensions, and eventually renal dysfunction. Kidney involvement in SLE may be due to specific subclasses of IgG in speci \201 c patient s. IgG1 and IgG3 autoantibodies more avidly fix complement, and are more commonly associate d with severe renal lesions. Rheumatological diseases associated with the nephritic syndrome include proliferative lupus nephritis, anti-neutrophil cytoplasm antibody associated vasculitis [(AAV), which include Wegener \200\231s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg \200\223Str auss syndrome [CSS]), Henoch \200\223Sch nlein purpura (HSP), cryoglobulinemic vasculitis and, rarely, RA or Beh et \200\231s disease. The nephritic syndrome results from immunolog ical lesions of the glomerulus in these diseases. Epidemiology \200 75% of patients with SLE will have abnormalities of urinalysis at some point. 16% of patien ts in large European cohorts have signi \201 - cant proteinuria at diagnosis of SLE and 35 % will develop proteinuria within 10 years of diagnosis. Renal involvement in drug-induced lupus is rare. ANCA associated vasculitis (AAV) has a an overall inci- dence of 10 \200\223 14 per million in Europe and 80% will have some form of renal involvement but this may vary from isolated urinary abnormalities to rapidly progressive glomerulonephritis and end-stag e renal disease The incidence of AAV peaks in the 6 \200\2237th decade of life. ANCA determ ined by immuno \202 uorescence is manifest by either a cytoplasmic pattern (C-ANCA), assoc iated with reactivity to proteinase 3 (PR3-ANCA) by ELISA, or a peri-nuclear pattern (P-ANC A) associated with reactivity to myeloperoxidase (MPO-ANCA). Approximately 90% of patients with WG will have a detectable ANCA (the majority are PR3-ANCA posi- tive), while approxima tely 70 \200\22380% of patients with MPA will have a detectable ANCA (usually MPO-ANCA posi - tive). Less than 50% of patients with CSS are ANCA positive (usually MPO-ANCA). AAV \200 \200 The pathogenicity of ANCA is debated. Murine models of MPO-induced glomerulonephritis provi de the strongest evidence that ANCA are patho- genic. This evidence is supported in humans by a case report of in utero transfer of ANCA causing a pulmo- nary-renal syndrome. However , ANCA alone may be insuf \201 cient in humans to cause disease and other abnor- malities, such as a neutrophil priming event (an infection or environmental exposure), endothelial d ysfunction, B cell dysfunction, and Fc-RIIIB polymorphisms are impli- cated in the pathogen esis. Whether these abnormalities are required to initiate vasculitis or are a consequence of the vasculitic damage are unclear. \200 \200 HSP \200 Renal damage is mediated by the deposition of immune complexes, primarily immunoglobulin A1 . IgA deposition may result from increased IgA secretion following a mucosal infection and/ or abnormal glycosyla- tion of IgA. CHAPTER 3 Organ involvement in rheumatological disease 75 Cryoglobulinaemia \200 Special investigations \200 Antigen-antibody complexes are deposited in small and medium arteries including glomerular capillaries. Hepatitis C virus (HCV) is a common cause. Serum creatinine should be performed in all patients suspected of having nephritis, but are not sensitive even in cases of severe disease, as abnormalities of renal function tend to occur late in the disease course. Urinalysis demonstrating dysmorphic haematuria with prote inuria and/or cellular casts support the presence of glomerulonephritis. Quantification of proteinuria \200\223 either a 24-h urine collection or a spot morning urine protein to cre atinine ratio should be performed in patients with suspected nephritis and dipstick positiv e proteinuria. Blood tests aim to determine the cause of nephritis and should include hepat itis B, hepatitis C, HIV, ANCA, anti-glomerular basement membrane antibodies, ANA, anti-DNA antibodies, extractable nuclear antigens, APL antibodies, RF, complement levels, protein e lectrophoresis, and cryoglobulins. Anti-double stranded DNA antibodies and hypocomple- ment emia occur frequently in patients with SLE. ANCA indirect immunofluorescence, and an ELISA for PR3 and MPO antibodies should be done in all cases. A negative test does not exclude a diagnosis of vasculitis. A renal biopsy should be used to con \201 rm the diagnosis whenev er possible, since no serological or urine labora- tory work are suf \201 ciently sensitiv e and speci \201 c. A renal biopsy will also provide prognostic information and is used to stratify treatment (see color plates). Risk factors \200 Patients of black African or Hispanic descent are more likely to have lupus nephritis, and it is more likely to follow a severe course. AAV patients with nasal Staphylococcus aureus carriage are at higher risk of relapse. A1-antitrypsin de \201 ciency is associated with a more severe course. The NA1 polymorphism of the FcG-RIIIB allele also appears over- repres ented in patients with severe AAV. AAV may result as a complication of medications used in hyperthyroidism, such as propylthiouracil or more rarely with the use of hydralazine or min ocycline. Exposure to silica has also been associated with the development of AAV. HSP occu rs rarely in the summer and is commonly preceded by an upper respiratory tract infection. Key features in the history Features associated with the nephritic syndrome. \200 New onset hypertension or hypertension that has become increasingly dif \201 cult to contr ol. Hypertension may be severe and present as an emer- gency (headache, visual changes, che st pain, dyspnoea). Advanced and chronic renal failure is associated with fatigue, anorexia , and pruritis. Abnormalities of the urinalysis: haematuria and cellular casts and sub-neph rotic levels of proteinuria. Cellular casts are often missed in routine urine samples, but are quite speci \201 c for a nephritic process. The protean manifestations of renal dysfun ction or a systemic immunological process are often mistaken for an infection. Patients com monly report being treated with antibiotics for upper respiratory or urinary tract infectio ns repeatedly with no improvement in their symptoms. This is particularly true of patients with abnormalities of the urinalysis, but without a docu- mented microbiologic diagnosis. E xtra-renal manifestations of systemic diseases are often more pronounced during periods whe n the kidneys are also involved. Treatment Supportive treatment for all patients with nephritis includes the management of v olume status, electrolyte abnormalities, and hypertension. Renal replacement ther- apy in t he form of dialysis or renal transplantation may be required for patients with advanced ren al failure. The treat- ment of lupus nephritis is usually predicated by renal biopsy \201 ndings. \200 Class I and II lesions typically have an excellent renal prognosis even without treatment a nd are not speci \201 - cally treated. Proliferative lupus nephritis (Class III and IV) is treated with a combination of an immunosuppressive and a tapering course of glucocorticoid s (GCs). The immunosuppressive of choice has been intravenous cyclophosphamide for 3 \200 \2236 months on the basis of data demonstrating a longer time to the doubling of creati- ni ne in landmark NIH studies. More recently, there is accumulating data for the use of mycoph enolate mofetil. Mycophenolate mofetil or azathioprine (AZA) are most frequently used to ma intain remission. Consideration of prophylaxis against osteoporosis should be given to pati ents on GCs and to Pneumocystis jirovecii for patients on immunosuppressants. The treatment of AAV with renal involvement includes the use of an immunosuppressive agent and a taperin g course of GCs. As with proliferative lupus nephritis, immunosuppressive medications are a dministered sequentially with cyclophosphamide used to induce a remission followed by AZA t o maintain remission. Cyclophosphamide has been administered orally with frequent monitorin g for the induction of leukopenias, but there is mounting evidence that intravenous pulse c yclophosphamide may be equally ef \201 cacious with fewer toxicities due to its lower cumu lative dose. Table 3.6 International Society of Nephrologists/Renal Pathology Society classi \201 catio n of glomerulonephritis due to SLE. Classes III and IV are proliferative Class Major pathological \201 ndings Glomeruli normal by light microscopy (LM), but immune complex deposits seen by immuno \202 uorescence (IF) I Light microscopy reveals expansion of mesangial cell or the mesangial matrix II <50% of glomeruli demonstrate endocapillary or extracapillary glomerulonephritis in additio n to mesangial expansion III \211 50% of glomeruli demonstrate endocapillary or extracapillary glomerulonephritis in ad dition to mesangial expansion IV Subepithelial immune complex deposits are seen on LM, electron microscopy or IF. Class V ca n occur with other classes. V At least 90% of glomeruli are sclerosed VI THE KIDNEY 76 AZA is used after 3 \200\2236 months of treatment with cyclo- phosphamide once a clinical r emission has been induced. The optimal duration of AZA is unknown. Plasma exchange should b e considered for those patients who present with severe renal dysfunction due to AAV or who have a lung hemorrhage. The optimal duration of GC therapy is unknown, but longer duration s of low-dose therapy has been associated with fewer relapses of disease. The treatment of HSP is supportive and includes adequate hydration, rest, and symptomatic relief of pain. Ho spitalization may be required for renal insuf \201 ciency. The role of GCs in HSP in child ren is controversial, but may decrease the likelihood of renal involvement. Children with H SP who present with renal involvement have a poorer renal prognosis, but no therapy has bee n shown efficacious in randomized controlled trials. Consideration of GCs, immunosuppressio n, IVIG, or plasma exchange should be given to these patients. Treatment of cryoglobulinaem ia with renal involvement includes plasma exchange, GCs and immunosuppres- sants. Treatment of the underlying disease (e.g. HCV or non-Hodgkin \200\231s lymphoma) can result in remis sion. There \200\231s some evidence that B cell depletion can be effective in the treatment of cryoglobulinaemic vasculitis. Monitoring \200 Monitor for neutropaenia (the nadir after cyclophospha- mide is between 10 and 14 days) and infections. In the longer term, particularly in patients who receive multiple or extended courses of immunosuppression, the development of pre-malignant or malignant skin lesions, a nd solid organ malignancies, in particular, bladder cancer, should be excluded. Patients wi th nephritis should have their renal function, urinalysis and proteinuria monitored regular ly. Additional monitoring should be disease speci \201 c. In lupus nephritis, monitoring o f complement levels is warranted as persistent hypocomplementemia portends a poor prognosis . In lupus nephritis repeating the renal biopsy should be considered for patients with pers istent serological or urinary abnormalities after a year of treatment. Persistent immunolog ical activity in repeat renal biopsies may require escalating or prolonged immunosuppressio n. In AAV, monitoring of ANCA is of uncertain signi \201 cance. Patients may relapse, whil e ANCA negative or fail to relapse after signi \201 cant rises in ANCA. Nephrotic syndromes De \201 nition The nephrotic syndrome is characterized by peripheral e dema, hypoalbuminema, hyperlipidemia, lipiduria, and nephrotic range proteinuria ( \211 3.5 g/day). Lower levels of proteinuria do not exclude the nephrotic syndrome, but the urinaly sis is generally dominated by proteinuria. \200 Prognosis \200 The prognosis of proliferative lupus nephritis before the use of immunosuppressants/GCs was poor \200\223 the majority of patients developing end-stage renal failure in <5 years. Th ose treated have 5-year renal survival rate of 90%. Despite advancements in preventing end- stage renal disease, patients who develop proliferative lupus nephri- tis are at a 5-fold h igher risk of death over 10 years compared with patients without nephritis. Untreated, AAV has a dismal prognosis (1-year mortality >90%). End-stage renal disease is a common complic ation of late diagnosis \200\223 also a poor prognosis. With treatment, the prognosis of A AV has improved dramatically. Patients with very poor renal function at diagnosis (serum cr eatinine >500 mol/l) still have a 1-year mortality of 25% with an additional 25% develop- ing end-stage renal disease in randomized clinical trials. Patients with AAV, but a serum creatinine <500 mol/l have a 1-year mortality of 10% or less. Some cohorts of unselected patients with AAV report 5-year mortality rates of <20%, but many of the patients in these cohorts do not have renal involvement. The short-term prognosis of HSP in most patients is favorable with 94% of children and 89% of adults com- pletely recovered by 18 months. One-t hird of patients will, however, have a relapse of HSP, and this is more common in adolescen t or adult patients. Persistent and progressive HSP can be poorly responsive to treatment a nd up to 18% of adults will require dialysis, while only 7% of children will become dialysi s depend- ent. Prognosis is worse among patients presenting with nephrotic syndrome, renal insuf \201 ciency, hypertension, tubulointerstitial nephritis, or crescentic glomerulone- phritis on biopsy. The prognosis of patients with cryoglobulinemic vasculi- tis is not yet well documented due to relatively recent changes in the standard of care of HCV. Rheumatological diseases associated with the nephrotic syndrome include membranous lupus ne phritis, RA (either due to its treatment or AA amyloidosis) and AL amyloidosis. The nephrot ic syndrome can also result as a rare complication of non-steroidal anti-in \202 ammatory drug (NSAID) or pamidronate use. Other very rare causes of the nephrotic syndrome include d ermatomyositis, mixed connective tissue disease, mixed cryoglobulinemia, Sj gren \200\231s syndrome, Takayasu arteritis, sarcoidosis, Fabry \200\231s disease, and AAV The nephrotic syndrome is thought to result from a loss of plasma proteins and a subsequent derangement o f renal sodium handling. Several speci \201 c pathologic lesions arising from rheumatologi cal diseases result in the nephrotic syndrome and include membranous neph- ropathy, minimal change disease, and focal and segmental glomerulosclerosis. Epidemiology \200 Membranous lupus nephritis affects 10 \200\22320% of patients with SLE and renal involvemen t. Membranous lupus nephritis often occurs in conjunction with a proliferative lesion (e.g. Class III + V). Gold and D-penicillamine are known to induce membra- nous lesions. Inciden ce, respectively, 3% and 7%. Secondary AA amyloidosis is a rare complication of RA or Beh et \200\231s disease and may affect the kidneys. Although this complication is usually thou ght of as a result of long- standing disease, there are few data to support this. Secondary amyloidosis may occur in up to 10% of RA patients, but is only rarely clinically evident. Primary AL amyloidosis commonly affects the kidneys and up to 75% of patients will present with proteinuria. NSAIDs can induce a minimal change lesion or membra- nous lesion that cau ses nephrotic syndrome rarely. CHAPTER 3 Organ involvement in rheumatological disease 77 Blood tests to exclude other causes of the nephrotic syndrome should include tests for hepa titis B, HCV, HIV, ANA, anti-DNA antibodies, extractable nuclear antigens, RF, complement l evels, protein electrophoresis, and cryoglobulins. Anti-double stranded DNA antibodies and hypocomple- mentemia are frequently in lupus nephritis. A renal biopsy can con \201 rm the diagnosis possible since no serologic or urine laboratory work are suf \201 ciently sensi tive or speci \201 c. A renal biopsy will provide prognostic information and is used to st ratify treatment. Case series \200\231 of patients with a severe form of focal and segmental glomeruloscleros is due to the use of IV bisphosphonates exist, but the incidence is unknown Etiology The pathogenic mechanisms responsible for the nephrotic syndrome vary according th e speci \201 c pathologic lesion. In all cases, there appears to be excess \201 ltration of plasma proteins (notably albumin) and reduced tubular reabsorp- tion. The excess \201 ltration of albumin increases tubular sodium reabsorption. This excess sodium reabsorption and concomitant excess water reabsorption combined with the reduced intravascular oncotic pressure is thought to cause peripheral oedema. \200 Treatment Treatment of nephrotic syndrome can be divided into treatment of symptoms due to the syndrome and treat- ment of the underlying cause. In some cases, treating the underlyin g cause results in relatively rapid resolution of the syndrome and, therefore, treatment of the symptoms may be less important as they are short lived. Central to the excess \201 ltration of plasma proteins has been the identi \201 cation o f widespread podocyte efface- ment. Podocytes form an important component of the \201 ltr ation barrier to the urinary space and effacement may result in loss of both the mechanical barrier and/or the electrostatic barrier to protein \201 ltration. In SLE, small or cati onic immune complexes deposit in the subepithelial space or may be directed against subepit helial antigens and provoke a membranous lesion. A similar process is thought to happen in medication related membranous lesions. In amyloidosis, abnormal proteins are generated eith er at an increased rate, or a decreased rate of clearance. These abnormal proteins are depo sited in the glomerular basement membrane disrupting the \201 ltration barrier and in the tubules and interstitium disrupting normal plasma protein reabsorption. General management \200 Symptomatic control of peripheral oedema using diuretics. Loop diuretics are likely the mos t effective. The ef \201 cacy of loop diuretics will be reduced by intratu- bular binding with albumin. Large doses of diuretic may be needed. Combining a loop diuretic with a non-l oop diuretic may improve the diuresis. Treatment of hypertension. Hypertension usually occu rs only after some reduction in renal function. Hypertension in these cases may be volume d ependent and resolve with effective dieresis. Angiotensin blockade may effectively reduce p roteinuria, as well as control blood pressure and is an important therapy. Lipid lowering m edication can be used to control cholesterol in high-risk patients, but cholesterol levels usually respond rapidly to reductions in proteinuria. If a lipid lowering medication is use d, its necessity needs reviewing after a signi \201 cant reduction in proteinuria. Prophyl actic anticoagulation is highly debated. Data on the relative risk of thrombosis is lacking . Most experts agree that the risk of thrombosis is minimal when serum albumin levels are > 20 g/l. The decision to use anti-platelet or anti-coagulant therapy must be weighed for eac h individual patient. There are no data to suggest prophylactic antibiotics are necessary. If patients progress to end-stage renal disease, renal replacement therapy may be necessary . This is particularly relevant for patients with amyloidosis. Key features in the history and on examination In nephrotic syndromes, renal failure may al so occur as a result of the underlying immunologic insult, but nephrotic syndromes tend to have a slower course than nephritic syndromes except in the case of NSAID induced injuries. \200 Peripheral oedema including oedema of the hands and periorbital \200\223 can be reported a s \200\230tightness \200\231 or \200\230swelling \200\231. Excessive frothing of the urin e may indicate proteinuria, but is not always noticed by the patient. Patients may report f atigue (non-speci \201 c), weight gain, repeated bacterial infections, and reduced appetit e. The development of hypothyroidism or marked hyperli- pidemia by the patient \200\231s Pr imary Care doctor, that is dif \201 cult to treat with standard antihyperlipidemic agents, is a pointer toward the diagnosis. A recent history of venous thromboembolic disease may b e relevant. Lipemic blood samples may be noticed. Treatment of speci \201 c causes of the nephrotic syndrome \200 The treatment membranous lupus is controversial owing to its frequent overlap with prolifer ative lesions in epide- miological cohorts. The treatment approach to this variant is dispu ted because the prognosis of pure Class V disease is not well understood. A common approach for membranous lupus is to use GCs in severe cases and to add immunosuppression if the nep hrotic syndrome persists despite 3 \200\2236 months of treatment. Non-lupus-related membran ous nephropathy is frequently treated with 6 months of alternating GCs and cyclophos- phami de, an approach shown to reduce end-stage renal disease, but has not been validated in a lu pus population. Ciclosporin has been advocated by some for primary or secondary membranous nephropathy, but lacks rand- omized control trial evidence as a \201 rst line agent. Special investigations \200 Serum creatinine should be checked in all patients with the nephrotic syndrome, but the mea sure is not a sensi- tive measure, even of severe disease, as abnormalities of renal functi on can occur late in the disease course. Urinalysis demonstrating fatty casts or fat drople ts supports the diagnosis of a nephrotic syndrome. Renal ultrasound (US) and Doppler US stu dies to exclude renal vein thrombosis, a complication of severe nephrotic syndromes, especi ally membranous lesions, and in preparation for kidney biopsy. Quanti \201 cation of prote inuria by either a 24-h urine collection or a spot morning urine protein:creatinine ratio s hould be checked. THE KIDNEY 78 with the development of TIN, including Sj gren \200\231s syndrome, NSAID or allopurinol us e, sarcoidosis, uveitis (TINU), or rarely Beh et \200\231s disease. Discontinuation of the causative drug in drug-induced nephrotic syndromes is essential. Tre atment with GCs may still be used to reduce the duration of the nephrotic syndrome in sever e or prolonged cases, particularly in those with associated renal dysfunction. Primary amyl oidosis is a plasma cell dyscrasia and as such, therapies are similar to those for multiple myeloma. Treatment options include melphalan with or without GCs, thalidomide and dexameth asone with or without cyclophosphamide, lenalidomide with dexamethasone, and haematopoietic stem cell transfer. The treatment of secondary amyloidosis is to control the underlying di sease with or without adjunctive therapy. Adjunctive therapies have included colchicine and cyclo- phosphamide, but the data supporting these approaches is limited. New products such as eprodisate have shown promise in reducing poor renal outcomes in patients with secondar y amyloidosis Epidemiology \200 Sj gren \200\231s syndrome can involve the kidneys rarely but there are no precise estimat es of frequency. The most common lesion is TIN, but there can also be isolated metabolic ab normalities (type 1 renal tubular acidosis or isolated hypokalemia), nephrogenic diabetes i nsipidus, or very rarely a glomerular lesion. Granulomatous interstitial nephritis is commo n in sar- coidosis, but it rarely results in clinically apparent disease. Additionally, sar coidosis can result in nephro- lithiasis due to related hypercalciuria, nephrotic syndrome due to membranous lesions or urinary obstruction due to retroperitoneal \201 brosis. Sarc oidosis may also be related to the tubulointerstitial nephritis and uveitis syndrome (TINU) . NSAID-related TIN was seen most commonly with fenoprofen, but is probably equally likely with all non- selective NSAIDs. There are reports of COX-2 selective NSAIDs also causing TI N. Prognosis \200 The prognosis of Class V lupus is variable in the reported literature, but this may be due to classi \201 cation systems that overlap membranous variants with proliferative variants . Pure Class V cases appear to have a good prog- nosis for renal function, but may have dif \201 cult to control nephrotic syndrome. Nephrotic syndrome resolves after stopping causa tive gold, D-penicillamine or NSAIDs in virtually all cases. The prognosis of patients with secondary amyloidosis is poor with a median survival of about 5 years and a mean time to d eveloping end-stage renal disease of 18 months. More recent epidemiological data suggests t hat the median survival in the UK is closer to 10 years. The prognosis of patients with pri mary amyloidosis appears worse in patients with higher peripheral blood plasma cell counts (>0.5/ l or >1%), higher serum B2- microglobulin (>2.7 g/ml), higher bone marrow plasma cell percentage (>10%) and/or dominant cardiac involve- ment. Survival on haemodialysis is 68% at 1 year and 30% at 5 years. Etiology \200 TIN in Sj gren \200\231s syndrome is characterized by a lym- phocytic in \201 ltrate inva ding and damaging the tubules. In some cases, granuloma formation is seen. Granulomatous in \202 ammation is common in sarcoidosis. The etiology is unclear. The interstitial in \201 ltrate in NSAID-induced TIN is prima- rily composed of T cells. It is postulated that cyclooxygen- ase inhibition results in the conversion of arachidonic acid to leukotrienes, which activate Th cells. TIN is complicated in NSAID use by a concomitant haemodynamic inju ry. Key clinical features \200 Isolated renal manifestations of Sj gren \200\231s syndrome or sarcoidosis are rare. A his tory should include a detailed search for extra-renal disease activity. Patients with Sj g ren \200\231s syndrome may have hypokalemia causing general muscle weakness or nephrogenic diabetes insipidus causing hypotension, low volume status and fatigue. Patients with sarcoi dosis may have a history of nephro- lithiasis due to persistent hypercalciuria. Patients wi th drug-related TIN may develop a rash (15%), fever (27%), eosinophilia (23%), or all 3 (10 %). Other causes of TIN should be excluded (e.g. antibiotic or infection-related (legionell a, cytomegalovirus). Owing to the often-insidious nature of the renal injury, advanced rena l failure may be present at the time of diagnosis. Advanced renal failure may present as fa tigue, anorexia, pruritis, or peripheral oedema. Monitoring Patients with nephrotic syndrome should have their renal function, urinalysis, a nd proteinuria monitored regularly. Additional monitoring should be disease-speci \201 c. \200 In SLE, monitoring complement levels is prudent as persistent hypocomplementemia suggests a poor prog- nosis. Consideration to a repeat renal biopsy should be given to patients with persistent serologic or urinary abnormalities after a year of treatment. Persistent immunol ogical activity or class switching (the addition of a proliferative lesion) in repeat renal biopsies may require escalating or prolonged immunosuppres- sion in SLE. Monitoring of ser um amyloid protein in secondary amy- loid may be a useful way of tracking disease progressi on and response to therapy. Investigations TIN is classically characterized by the presence of white blood cell casts i n the urinalysis. Haematuria and protein- uria are also commonly found, although red blood cell casts would be very uncommon. \200 Tubulointerstitial nephritis Tubulointerstitial nephritis (TIN) refers to in \202 ammation of the interstitial compartment of the kidney. It may present very subtly with few abnorma lities of the urinalysis and slowly progressive renal failure. It is classically character- ized by white blood cell casts in the urine sediment with or without non-nephrotic range p roteinuria and renal dys- function. Several rheumatological diseases are associated Blood biochemistry may reveal an acidosis or hypokalemia in Sj gren \200\231s syndrome. Ur ine biochemistry is helpful in con \201 rming a type 4 renal tubular acidosis. Urine eosin ophils are commonly associated with drug induced TIN, but are not usually found in NSAID re lated TIN. CHAPTER 3 Organ involvement in rheumatological disease 79 Gallium scanning has been advocated in drug-induced interstitial nephritis, but its role is incompletely de \201 ned. A renal biopsy should be used to con \201 rm the diagnosis if the cause of the renal dysfunction is unclear. A renal biopsy will also provide prognostic information and is used to stratify treatment. Renal involvement from APLS can occur in up to 25% of patients \200\223 affecting blood ve ssels of all sizes. Renal disease in APLS associated with SLE is found in only 10% of renal biopsies from patients with SLE. Accelerated vasculopathy influences the long-term prognos is of many patients with rheumatological diseases and can result in chronic kidney disease. Treatment \200 There is little evidence for the treatment of renal Sj gren \200\231s syndrome or sarcoido sis. In general, patients with clinically apparent renal manifestations of these diseases a re treated with GCs, often for a prolonged period. Hydroxychloroquine is often an effective treatment for patients with isolated hypercalciuria due to sarcoidosis. The primary treatm ent for drug-induced TIN is with- drawal of the offending agent. The value of a course of G Cs is debated, but several weeks of therapy may decrease the time to renal recovery in pati ents not recovering quickly. Etiology \200 SSc results in intimal proliferation and thickening of the small arcuate and interlobular a rteries. This \201 nding is commonly referred to as onion-skin hypertrophy. SSc renal c rises result from a thrombotic microangiopathy. Endothelial damage in small vessels causes \201 brin clots and renal hypoxia/ischemia. This results in rapidly increasing blood pres sure through activation of the renin-angiotensin that worsens the endothelial damage. APLS with renal damage is also a thrombotic microangi- opathy and may be clinically indistinguis hable from a SSc renal crisis (aside from the presence of SSc) or other causes of thromboti c microangiopathy. In APLS affected arteries demonstrate thrombotic lesions with intimal mu coid thickening, subendothelial \201 brosis and medial hyperplasia. Delayed diagnosis/tre atment in either SSc renal crisis or APLS may result in sclerotic lesions forming and a bio psy would thus show focal and segmental glomerulosclerosis, rather than the primary \201 ndings of a thrombotic micro- angiopathy. Accelerated vascular disease in any rheumatologic al disease can be caused by prolonged periods of in \202 am- mation causing endothelial dy sfunction, exposure to GCs (direct effects, and effects on blood pressure and serum lipids) , and exposure to immunosuppressants that adversely affect vascular function. Prognosis \200 The prognosis of TIN in Sj gren \200\231s syndrome is good with few cases progressing to e nd-stage renal disease. GCs often arrest the progression of TIN in sarcoidosis, but there i s often incomplete renal recovery due to chronic scarring. Relapses appear more likely in p atients who receive less than 20 mg/day of prednisolone for the \201 rst 3 months of trea tment. End-stage renal disease from acute TIN secondary to medications is uncommon, but chr onic TIN from NSAID use or from chronic analgesic nephropathy is common and there is only l imited recovery of renal function after discontinuing the offending agent. Monitoring \200 Patients with any form of TIN should have their renal function monitored closely. Urine cal cium is thought to be a sensitive measure of sarcoidosis activity due to increased vitamin D activity in active granulomata. Patients on prolonged courses of GCs require monitoring f or the development of diabetes mellitus and glaucoma. Adequate calcium and vitamin D3 suppl ements and, if necessary speci \201 c osteoporosis therapy needs to be given as per guidel ines [e.g. American College of Rheumatology Guidelines or Royal College of Physicians (RCP) (UK)]. Risk factors \200 Diffuse skin involvement, GC use, ciclosporin, and joint contractures are associated with a n increased risk of SSc renal crisis. SSc renal crisis is associated with autoantibodies to RNA polymerase III and is less frequent in the presence of anti-centromere antibodies. In APLS, presence of coagulation factor mutations such as factor V Leiden, are associated with an increased risk of clinical activity including renal disease. There is an association be tween APLS and HLA-DR7 in several ethnic groups and HLA-DQ7 in some groups. Acute renal failure Acute renal failure, renal dysfunction developing and/or worsening over a period of days, can complicate several rheumatological disorders in the absence of abnor malities of the urinalysis. This presentation occurs in systemic scle- rosis (SSc; see also p. 264 \200\223272, the antiphospholipid syndrome (APLS; see also p. 274 \200\223280 and v ascular disease, and also, following diagnoses, commonly considered to have a nephritic, ne phrotic or TIN presentation when they have a benign or non-diagnostic urine sediment. Key clinical features \200 Thrombotic microangiopathies are characterized by haemolytic anemia and thrombocytopaenia. Both SSc renal crisis and APLS may result in dramatic elevations in blood pressure and acut e retinal changes, proteinuria and haematuria and pulmonary oedema. Not all patients with S Sc renal crisis will have typical skin manifestations of SSc. Other causes of microangiopat hy must be excluded: haemolytic-uraemic syndrome/thrombotic thrombocy- topaenic purpura and malignant hypertension. Use of medications known to increase the risk of SSc renal crisis, such as GCs or ciclosporin. Ciclosporin and other calcineurin inhibitors may induce thromb otic thrombocytopaenic purpura independent of SSc. Epidemiology \200 Autopsy studies indicate up to 80% of patients with diffuse cutaneous SSc have renal damage , although only 50% will have a clinical manifestation. Severe renal crisis can develop in a substantial minority of patients with SSc (mainly diffuse cutaneous disease). THE KIDNEY 80 renal dysfunction is associated with hyperparathyroidism that can cause bone pain and arthr algia or haemodialysis may be associated with the accumulation of B2 microglobulin leading to a secondary amyloidosis. Investigations \200 Clinical details are of primary importance in the rapid and accurate diagnosis of these con ditions. The underlying medical condition must be established. Renal biopsy con \201 rms a microscopic angiopathy, but will not distinguish between causes. The vast majority of patients with CKD do not progress to end stage renal failure but die o f cardiovascular disease. The management of cardiovascular risk is a important in managing these patients. Epidemiology and etiology \200 Treatment \200 Angiotensin conver ting enzyme inhibitor-based anti-hypertensive treatments are the mainsta y of treat- ing SSc renal crisis. Serum creatinine may rise initially, but the relaxation o f the efferent arteriole will reduce intra- glomerular pressure and reduce scarring, as wel l as increase interstitial blood \202 ow. Control of blood pressure with other agents may also be required. Intravenous prostacyclin can help improve microvascular lesions in SSc r enal crisis, but experience remains largely anecdotal. Rapidly progressive renal failure in APLS may respond to plasma exchange. Chronic anticoagulation in patients with APLS with a significant thrombotic complication, such as renal involvement, should be considered. Chronic glomerulopathy is an uncommon complication of RA. The most common pathologic lesion in this disorder is a mesangial proliferative lesion. Chronic urate nephropathy is now unc ommon. The decrease in urate nephropathy may be partially attributed to the decline in chro nic lead exposure, an important aetiological agent in saturnine gout in which lead was a ma jor contributor to renal dysfunction. Urate nephropathy is characterized by an elevation in serum urate out of keeping with the degree of renal dys- function (urate >535 mol/l in p atients with mild renal disease and >700 mol/l in patients with a creatinine >176 mol/l ). Up to 80% of patients with diffuse cutaneous SSc will have renal damage and up to 50% wi ll have chronic hypertension, mild proteinuria, or CKD. Although hyperparathyroidism is com mon in advanced CKD, clinically apparent bone disease is rare outside the dialysis populati on. Within the dialysis population, disor- ders of parathyroid hormone (PTH) that can resul t in fractures and bone pain include osteitis \201 brosa (due to excess PTH), osteomalaci a (due to inadequate mineralization), and adynamic bone disease (due to over suppression of PTH). See Chapter 14, p. 426. Haemodialysis related amyloidosis is a rare complication tha t is more common with increasing years on dialysis. This disorder is related to the increas ed generation of B2 microglobulin due to increased levels of in \202 ammation (perhaps due to contact of blood with the dialysis appa- ratus) and decreased clearance due to poor tra nsportation across the dialysis membrane. Atherosclerotic renal disease may affect any size blood vessels, but is most common in small vessels. The excess of atherosclerotic disease may be due to chronic in \202 am- mation causing endothelial dysfunction and/or the effect s of commonly used medications, such as non-NSAIDs, which cause hypertension, or GCs, which cause hyper- tension and hyperglycaemia. Prognosis Left untreated, SSc renal crisis may result in rapid loss of renal function and e nd-stage renal disease in <8 weeks. Monitoring \200 \200 Regular blood pressure monitoring is essential. Full blood count, \201 brin degradation p roducts, and blood smear are useful in monitoring microangiopathy. Antiphospholipid antibod y binding levels are of uncer- tain signi \201 cance. Chronic kidney disease (CKD) Some patients will present with a chronic elevation in serum c reatinine re \202 ecting a reduced glomerular \201 ltration rate (GFR). This reduction i n kidney function may be stable or slowly progressive, and is usually associated with a bla nd urine sediment. In patients with rheumatological diseases, the chronic glomerulopathy of RA, SSc, amyloidosis, chronic urate nephropathy/saturine gout results from chronic in \202 ammation, and is associated with micro-vascu- lar arteriopathy and interstitial \201 brosis in the kidney. Chronic NSAID use may exacerbate this chronic injury by promoting hy pertension and hyperglycaemia. The severity of chronic kidney disease is classi \201 ed on the basis of the patient \200\231s GFR (or estimate of glomerular \201 ltration rate on the basis of a stable serum creatinine).