44: 1 \200\22312. Barsoum RS. Malarial nephropathies. Nephrol Dial Transpl 1998; 13: 1588 \200\2231597. Browne SG. Epidemioloogy and prevention of kidney disease \200 in Africa. Trans R Soc Trop Med 1980; 74: 8 \200\22316. Hendrickse RG, Adeniyi A. Quartan malarial nephrotic syndrome in children. Kidney Int 1979; 16: 64 \200\22374. Pathology: The following appearances may be observed: \200 \200 \200 \200 \200 Hutt MSR. Renal disease in a tropical environment. Trans R Soc Trop Med 1980; 74: 17 \200\22321. congestion of capillary loops with sickled cells; FSGS ; MCGN ; tubular atrophy ; iron pigm ent deposits. Jha V, Chugh KS. Glomerular disease in the tropics. In: Davison AM, Cameron JS, Grun \201 eld JP (eds), Oxford textbook of clinical nephrology, 3rd edn. New York: Oxford University Press; 2005. Rodriguez-Iturbe B, Burdman EA, Ophascharoensuk V, Barsoum RS. Glomerular dise ases associated with infections. In: Johnson RJ, Feehally J (eds), Comprehensive clinical n ephrology, 2nd edn. Philadelphia: Mosby, Elsevier; 2003. Clinical features: \200 \200 Pham PT, Pham PT, Wilkinson AH, et al. Renal abnormalities in gross hematuria; acute kidney injury from renal papillary necrosis, preg- nancy, multiple o rgan failure; nephrotic syndrome. ESRD. Treatment: RAS blockade improves proteinuria by red ucing intra- glomerular pressure, but large-scale studies are required to prove their long- term bene \201 t for prevention/resolution of glomerular sclerosis. NSAIDs and immunosuppr essive drugs (steroids and cyclophosphamide) are not of proven bene \201 t. sickle cell disease. Kidney Int 2000; 57: 1 \200\2238. Internet resources Information on schistosomiasis: \200 www.who.int/ctd/schisto See also Infection-related glomerulonephritis, p. 128 Acute endocapillary glomerulonephriti s, p. 116 Mesangiocapillary glomerulonephritis, p. 112 Mixed cryoglobulinemia and hepatitis C infection, p. 176 Sickle cell disease, p. 192 Renal tuberculosis and other mycobacterial infections, p. 256 Schistosomiasis, p. 260 Fungal infections and the kidney, p. 264 Leprosy-associated GN Mycobacterium leprae may cause immune complex disease, secondary amyl oidosis, interstitial nephritis, and renal tubular disorders. Glomerular lesions occur more commonly in the leproma- tous form, and the histological lesions include: mesangio- prolif erative, mesangiocapillary, and crescentic GN, especially when patient is being treated wit h rifampicin. Clinical features: Only a few patients present with nephrotic syndrome, nephr itic syndrome and rapidly progressive GN. Most patients are asymptomatic with a variety of urinary abnor- malities. This page intentionally left blank 143 Chapter 4 The kidney in systemic disease Chapter contents Diabetes mellitus 144 Amyloid and immunotactoid glomerulopathy 150 Plasma cell dyscrasias 158 Sarcoidosis 164 Systemic vasculitis 168 Mixed cryoglobulinemia and hepa titis C infection 176 Systemic lupus erythematosus 180 Scleroderma \200\223systemic scleros is 186 Rheumatoid arthritis, connective tissue diseases, and Sj gren \200\231s syndrome 18 8 Sickle cell nephropathy 192 Cancer and the kidney 196 C. COMBE AND V. RIGALLEAU 144 Diabetes mellitus Diabetic renal disease is the commonest cause of end- stage renal disease (ESRD) in the Wes tern world and is rapidly becoming the leading cause in developing countries. Diabetes mell itus (mainly type 2) is present in 25 \200\22350% of new patients with ESRD. The developmen t of diabetic renal disease occurs both in type 1 and type 2 diabetes, with a similar evolu tion over time for both types of diabetes. The quality of care of diabetes and its complica tions directly in \202 uences the occurrence and development of dia- betic nephropathy. In most cases, chronic kidney disease in diabetics results from diabetic nephropathy (diabeti c kidney disease in the K/DOQI Guidelines) and does not require a renal biopsy for diagnosi s. >30% reduction in GFR within 2 \200\2233 months after initiation of an angiotensin-conver t ing enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Epidemiology Type 1 diabetes Microalbuminuria develops in 20 \200\22330% of patients after 15 years. Overt DN develops in 50% of patients with microalbu- minuria. Intensive monitorin g and treatment of diabetes prevents microalbuminuria and halts its progression to overt ne ph- ropathy. After 30 years of type 1 diabetes, the prevalence of ESRD used to be >15%. Wit h intensive monitoring and treatment regimens, this proportion may be reduced to <9%. De \201 nitions Microalbuminuria Albumin excretion of 30 \200\223300 mg/24 h or 20 \200 \223200 g/min, (Table 4.1.1) is the \201 rst detectable sign of renal injury asso- ciat ed with diabetes. Type 2 diabetes The renal risk in patients with type 2 diabetes is the same as for type 1, whatever stage of DN (see below) is consid- ered. The bene \201 ts of tight glycemic and b lood pressure control are identical to those shown in type 1 diabetes. They have been demon strated in the UKPDS (UK Prospective Diabetes Study) that included >5000 patients. More tha n 90% of diabetic patients who enter dialysis pro- grams have type 2 diabetes. This proport ion has steadily increased over the last decade. However, a trend towards stabilization of the number of diabetics who reach ESRD is observed in countries with programs of aggressive diabetes management such as Denmark. Diabetic nephropathy (DN) Typically presents with the constellation of: \200 \200 \200 albuminuria (>300 mg/24 h or >200 g/min, Table 4.1.1); high blood pressure; progressive r enal failure. In most patients with diabetes, CKD can be attributable to diabetes if: \200 \200 macroalbuminuria is present; microalbuminuria is associated with the presence of diabetic r etinopathy in patients with type 1 diabetes of \211 10 years duration. Genetic and environmental factors A higher incidence of DN is observed in countries of Nort hern Europe and in the USA than in Southern Europe. This may be the consequence of genetic and/or environ- mental factors. DN occurs with a higher frequency in certain ethnic groups (e.g. African-Americans, Indo-Asians in the UK, Pima Indians). DN is more likely to develop in diabetic patients who have relatives with DN. The incidence of DN peaks 15 years after the onset of type 1 diabetes. By contrast with other microangiopathic complications such a s proliferative retinopathy, new cases then become rare, which suggests that some patients are protected from the development of nephropathy. Diabetes and other forms of renal disease Alternative presentations of renal disease may oc cur: \200 ischemic nephropathy with little or no proteinuria; \200 diabetes may also be associated with other causes of CKD (glomerulonephritis, polycystic kidney disease, etc.) and may worsen their evolution. Other cause(s) of CKD should be considered in diabetic patients in the following circumstan ces: \200 absence of diabetic retinopathy, particularly in type 1 diabetes; low or rapidly decreasing GFR; rapidly increasing proteinuria or nephrotic syndrome; refractory hypertension; presen ce of an active urinary sediment; symptoms or signs of other systemic disease; \200 \200 \200 \200 Table 4.1.1 De \201 nitions of abnormalities in albumin excretion (from the K/DOQI guideli nes) Category Spot collection (mg/mmol creatinine) 24 h collection (mg/24 h) Timed collection ( g/min) Normoalbuminuria <3 <30 <20 Microalbuminuria 3 \200\22330 30 \200\223300 20 \200\223200 Macroalbuminuria >30 >300 >200 Because of variability in urinary albumin excretion, at least two specimens, preferably \201 rst morning void, collected within a 3 \200\2236 month period should be abnormal. CHAPTER 4.1 Diabetes mellitus 145 Pathology DN is characterized by three cardinal pathological glomer- ular features: \200 \200 \200 Hyperglycemia favors the formation of advanced glycation end-products (AGEs): glucose combi nes with free amino acids on circulating and tissue proteins to form AGEs. These products, which are normally excreted by the kidney, accu- mulate in diabetic patients, particularly in arteries and the kidneys where they promote matrix accumulation. mesangial expansion; glomerular (and tubular) basement membrane thickening; nodular glomeru lar sclerosis. Glomerular hemodynamics Glomerular hypertension and hyper \201 ltration are early events i n the course of DN: a GFR 25 \200\22350% above normal is observed in 50% of patients with t ype 1 diabetes of <5 years duration. Systemic hypertension leads to glomerular hypertension . These glomerular hemodynamic alterations lead to arteri- olar and glomerular sclerosis. Thickening of glomerular and tubular basement mem- branes leads to the typical nodular glom erular intercapil- lary lesions described by Kimmelstiel and Wilson in 1936, in type 2 diab etic patients with heavy proteinuria and renal failure accompanied by arterial hypertension (Fig. 4.1.1). Progressive mesangial matrix expansion leading to glomer- ular sclerosis. Ot her features include: \200 Activation of the renin \200\223angiotensin \200\223aldosterone system (RAAS) Activation of components of the local renal RAAS in diabe- tes has been demonstrated in animal models an d in humans, even though circulating levels of components of the RAAS may be low or normal. Local RAAS activation promotes cell growth and matrix accumulation in all compartments of the kidney. RAAS inhibition has been shown to be protective against the development and pro gression of DN. This is true at each level of the RAAS: renin inhibitors, ACEIs, ARBs, and antialdosterone agents have all been shown to be protec- tive against the development of DN at some stage, either in humans or in experimental models. arteriolar sclerosis with early afferent and efferent glomerular arteriolar hyalinosis; tub ular atrophy and interstitial \201 brosis; nonspeci \201 c linear staining for IgG in th e glomerular and tubular basement membranes, and in Bowman \200\231s capsule on immuno \202 uorescence microscopy. \200 Nephrosclerosis may be the predominant feature, particu- larly in older patients with type 2 diabetes who have arte- riosclerotic vascular lesions, and little proteinuria. Nephroscle rosis includes arteriolar injury, focal and seg- mental glomerular sclerosis (with much les ser matrix expansion than in DN), and interstitial injury. Proteinuria Initially, microalbuminuria arises from glomerular injury and evolves towards m acroproteinuria. As in other types of chronic kidney diseases, proteinuria has deleterious effects per se, inducing tubular injury and interstitial \201 brosis. Nephroprotection ma y be obtained by reducing proteinu- ria through lowering blood pressure (and therefore intr a- glomerular pressure) and antagonizing the RAAS. a b Role of podocytes Podocyte function is altered in diabetic patients, with reduced expressio n of nephrin, a glomerular slit-diaphragm protein which has a central role in the permeabil ity of the glomerulus to proteins. c Natural history of diabetic nephropathy Overview Progressive renal injury from diabetes has been classi \201 ed by Mogensen into \201 ve stages (summarized in Table 4.1.2). In the early stages, glomerular hyper \201 ltration and kidney hypertrophy result from hyperglyc emia. Renal lesions develop during a clinically and biologically silent phase of several ye ars. Microalbuminuria and high blood pressure are the conse- quences of the glomerular and arterial lesions that develop during 10 \200\22320 years of diabetes-induced injury. The ev olution of DN with typical pathological features leads to macroalbuminuria and high blood p ressure which result in decreasing GFR. This evolution is observed preferentially in type 1 diabetes. The evolution of DN in type 2 diabetes is less predictable, partly because DN de velops later in life after a hypertensive Fig. 4.1.1 Typical lesions of DN with (a) diffuse and nodular glomerulosclerosis, (b) inter stitial \201 brosis with tubular atrophy, and (c) arteriolar sclerosis with lumen narrowi ng. Pathogenesis The development of diabetic renal disease is a multifacto- rial process involv ing several mechanisms. Metabolic consequences of diabetes The magnitude of hyperglycemia correlates with the func- tional and structural changes of diabetic nephropathy. Kidney enlargement, with glomerular enlargement is an early event in the course of diabetes-mediated renal injury. In animal m odels, it occurs as soon as 4 days after the ini- tiation of diabetes. Hyperglycemia stimul ates mesangial cell matrix production and cell growth. C. COMBE AND V. RIGALLEAU 146 \200 male gender; ethnicity (more frequent in Indo-Asians, African Americans and Pima Indians in the USA); familial clustering; socioeconomic factors (poverty) may compound ethnic factors , and lead to poor control of glycemia, blood pressure, and other determinants of the occur rence of microalbuminuria and DN. Table 4.1.2 Stages of diabetic nephropathy according to Mogensen Stage Duration Clinical, biological and pathological signs related to renal disease \200 of diabetes At diagnosis No clinical or biological signs of renal injury Hypertrophy of the kidneys Glo merular hyper \201 ltration 1 Renal pathologic changes in microalbuminuric patients can range from relatively normal hist ologic \201 ndings to clear evidence of diabetic nephropathy. 2 \200\2235 years Clinically and biologically \200\230silent \200\231 nephropathy 2 5 \200\22310 years Early nephropathy: \200 Microalbuminuria \200 High blood pressure \200 Normal GFR 3 Evolution of established diabetic nephropathy: from macroalbuminuria to CKD stage 5 Once es tablished (i.e. at macroproteinuric stages), DN may progress with increasing proteinuria an d a median GFR loss as great as 1 mL/min/month. All factors cited as favoring the developme nt and pro- gression of microalbuminuria may contribute to a steeper progression of DN. Mos t important factors are: \200 blood pressure control; \200 the magnitude of proteinuria ; \200 glycemic control (HbA1C). 10 \200\22320 years Established diabetic nephropathy: \200 Macroalbuminuria \200 High blood pressure \200 Decreasing GFR \200 Pathology: mesangial expansion; GBM thickening; and glomerular scler osis 4 >20 years End-stage renal disease \200 Pathology: advanced \201 brosis of the 5 kidneys Need for: \200 Renal transplant ( pancreas) \200 Peritoneal dialysis \200 H emodialysis Therapeutic interventions may slow or even halt the pro- gression of DN (see below). Diagnosis Detection of renal injury in diabetics In all patients with diabetes, dipstick ur inalysis for protein should be performed yearly: \200 phase and in association with exposure to other cardiovas- cular risk factors, which are de leterious in themselves. if no protein is detected in the urine by dipstick, micro- albuminuria should be measured; if proteinuria is present, the potential diagnosis of DN should be investigated. From microalbuminuria to macroalbuminuria Type 1 diabetes The prevalence of microalbuminuri a ranges from 30 to 50%. The evolution from microalbuminuria to overt nephropa- thy is vari able. If microalbuminuria develops within the \201 rst 10 years of type 1 diabetes, progr ession to macroalbuminuria is very likely. If microalbuminuria develops later in the course of type 1 diabetes, progression may occur in only 20 \200\22350% of patients. Patients wh o progress from normoalbuminuria to micro- albuminuria or microalbuminuria to macroalbuminu ria are more likely to have higher hemoglobin A1C (HbA1C) values and higher blood pressure than nonprogressors. Regression of microalbuminuria may be achieved in 50% of patients with good control of glycemia, blood pressure, and cholesterol levels, and in those with microa lbuminuria of short duration. Positive diagnosis of microalbuminuria Microalbuminuria should be measured in at least two out of three consecutive sterile urine samples. Use of the albu- min:creatinine ratio in an untimed urine sample is the pre- ferred screening strategy (Table 4.1.1). The magnitude of microalbuminuria can be variable in an individual because of confounding factors such as: \200 \200 \200 \200 \200 \200 exercise; infection; fever; marked hyperglycemia; pregnancy and menstruation; urinary tract infection. These should all be excluded before interpretation of microalbuminuria is attempted. Diagnosis of DN The diagnosis of DN relies on clinical and simple bio- logical criteria and does not require a renal biopsy in most cases. Type 2 diabetes The evolution from microalbuminuria to overt nephropa- thy occurs in 20 \200\22340% of patients over 10 years. In both type 1 and 2 diabetes Several factors favor the development and progression of micr oalbuminuria: \200 hyperglycemia; \200 onset of type 1 diabetes before the age of 20 ye ars; \200 hypertension; \200 cigarette smoking; Patients with type 1 diabetes A diagnosis of DN can be made in the presence of: \200 \200 \200 proteinuria; retinopathy; diabetes of >10 years duration. If these criteria are not ful \201 lled, a renal biopsy may be necessary. CHAPTER 4.1 Diabetes mellitus 147 Patients with type 2 diabetes A diagnosis of DN can be made if the above criteria are prese nt. However, retinopathy may be absent, and the date of onset of type 2 diabetes is often u ncertain. Nephrosclerosis may present with the same clinical and biological features as DN. However, the distinction between these 2 types of renal insult has no signi \201 cant in \202 uence on therapeutic goals (see below). meglitinides may be used in patients with impaired renal function, because of their hepatic elimination; thiazolidinediones may be used if the GFR is <30 mL/ min, but there are limit ed data about their safety; insulin is often necessary to achieve optimal glycemic control. Blood pressure control Aim for \211 130/80 mmHg. Avoid a systolic BP of <110 mmHg. In type 1 diabetes, ACEIs should be used \201 rst. In type 2 diabetes, ARBs should be used \201 rst. If the target of 130/80 mmHg is not achieved, a combina- tion of ACEIs and ARBs s hould be considered. In all cases, start with a low dose (e.g. enalapril 2.5 mg/day, ramipr il 1.25 mg/day for ACEIs, losartan 25 mg/day, irbe- sartan 75 mg/day for ARB), monitor rena l function and serum K+ after 5 \200\22310 days, and increase treatment progres- sively wit h monitoring. Diuretics should be used as third-line therapy, either thi- azides (if GFR >3 0 mL/min) or loop diuretics (if GFR <30 mL/min). Other antihypertensive agents may be used, including cal- cium antagonists and B-blockers. In some patients drugs from four to \201 ve different thera- peutic classes will be required to achieve the target BP. Indications for renal biopsy Renal biopsy should be considered in the following circum- sta nces: \200 absence of retinopathy in patients with type 1 diabetes (type 2 diabetics can have DN witho ut retinopathy); clinical and/or paraclinical signs which may suggest another cause of seco ndary glomerular disease (e.g. in \202 ammatory joint disease, monoclonal gammapathy, posi tive lupus antibodies, etc.); rapidly progressing glomerular disease; active urine sediment containing red cells and cellular casts; massive proteinuria or proteinuria of rapid onset , as may be seen in amyloidosis or glomerular diseases such as minimal change disease and m embranous nephropathy; increase of serum creatinine after administration of ACEI or ARB, af ter exclusion of renovascular disease; in proteinuric patients with type 1 diabetes of shor t duration (<10 years), renal biopsy might be discussed. \200 Reduction of proteinuria In patients with microalbuminuria, the lowest albumin excretion ra te is the best. In patients with DN, aim for <0.5 g/24 h or 50 mg/mmol creatinine. The magn itude of proteinuria is dependent on the level of blood pressure. At similar levels of bloo d pressure reduction, inhibitors of the RAAS have a greater impact on proteinuria. Moderate salt restriction (4 \200\2236 g/24 h (Na+ <100 mmol/day)) increases the antiproteinuric ef fect of RAAS inhibitors. Future therapies: additional inhibition of the RAAS using renin an d aldosterone antagonists (aliskiren and eplerenone respectively) may be recommended in the near future depending on the results of ongoing clinical trials. Special investigations Ocular fundus examination This should be performed in all diabetic p atients with renal disease, since the presence of retinopathy demonstrates the presence of diabetes-related microangiopathy, and, therefore, supports a diagnosis of DN. Duplex Doppler ultrasonography Renal artery stenosis may be present in patients with dia- b etes, particularly type 2. It should be screened by Doppler ultrasonography or MR angiograp hy if: \200 serum creatinine increases by >20 \200\22330% after administra- tion of ACEIs or ARBs. hype rtension resolves dramatically after administration of ACEIs or ARBs. Therapeutic management Goals In diabetics without albuminuria, glycemic control is the main therapeutic target In patients with overt DN, blood pressure control and pro- teinuria red uction are the most important goals. Cardiovascular risk Diabetic patients with DN are at very high cardiovascular risk. Aim for LDL-cholesterol of \211 3 mmol/L ( \211 100 mg/dL). Dietary advice is necessary. Statins need to be used in many patients to reach the tar- get LDL-cholesterol. Glycemic control Aim for HbA1C of 6.5%. In type 1 diabetes, intensive insulin treatment is necessary when microalbuminuria or DN are present. In type 2 diabetes: \200 Lifestyle modi \201 cations and diet Smoking cessation should be strongly encouraged: The del- eterious effect of active smoking on the progression of DN has been demonstrated in ty pe 2 diabetes. Moderate protein restriction (0.8 g/kg body weight/day) is recommended, alth ough the effect of low protein diets to slow the progression of CKD and to decrease protein uria is debated. Moderate salt restriction (4 \200\2236 g/24 h (<100 mmol/day)) as stated a bove. the bene \201 ts of intensive therapy are independent of the type of treatment administere d; metformin should be discontinued when the GFR falls to <40 mL/min, because of the increa sed risk of metabolic acidosis; discontinuation of sulfonylureas should be considered when the GFR falls to <30 mL/min, because of the risk of hypoglycemia; C. COMBE AND V. RIGALLEAU 148 Increase dietary fruit and vegetable intake (at least \201 ve portions of either type per day). Avoid malnutrition: The diet should provide \211 30 kcal/kg/ day, unless weight red uction is needed. Weight reduction should be encouraged in obese type 2 diabetics. Regular exercise should be encouraged. http://www.kidney.org/patients/ American Diabetes Association: http://www.diabetes.org/ Further reading Brenner BM, Cooper ME, et al. Effects of losartan on renal and cardiovascul ar outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861 \200\223869. Genuth S, Eastman R, et al. Implications of the United kingdom pro- spective diabetes study . Diabetes Care 2003; 6(Suppl 1): S28 \200\22332 K/DOQI Clinical Practice Guidelines and Cl inical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 20 07; 49: S1 \200\223S179. Follow-up Patients with DN and CKD 1 \200\2233 can be followed up in pri- mary care. Patien ts with progressive renal decline and CKD 4/5 require ongoing nephrological review on a 2 \200\2236-monthly basis dependent upon their eGFR. Lewis EJ, Hunsicker LG, et al. The effect of angiotensin-converting- enzyme inhibition on d iabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329: 1456 \200\22314 62. Lewis EJ, Hunsicker LG, et al. Renoprotective effect of the angi- otensin-receptor antagoni st irbesartan in patients with nephrop- athy due to type 2 diabetes. N Engl J Med 2001; 345 : 851 \200\223860. Nathan DM, Cleary PA, et al. Intensive diabetes treatment and car- diova scular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643 \200\2232653. Pregnancy As with other chronic glomerular diseases, pregnancy- related complications in di abetic nephropathy are increased when there is: \200 \200 \200 renal impairment; proteinuria (>1 g/24 h); hypertension. Internet resources National Diabetes Support Team, UK, guidelines: The risk of rapidly progressing retinopathy is a particular concern. Patients with high ris k clinical pro \201 les should be offered preconception counseling and when pregnant caref ul monitoring in a combined renal \200\223obstetric clinic. http://www.diabetes.nhs.uk/downloads/NICE_and_ Diabetes.pdf Canadian diabetes guidelines: http://www.diabetes.ca/ UK Renal Association guidelines contain guidelines for dia- betic p atients with CKD: Patient advice General As with all causes of chronic kidney disease patients with diabetic nephropathy and CKD 3 \200\2235 must pay close atten- tion to cardiovascular risk and: \200 h t t p : / / w w w . r e n a l . o r g / C K D g u i d e / f u l l / CKDprintedfullguide.p df United States National Kidney Foundation KDOQI guide- lines: monitor blood sugar and adapt insulin therapy as needed; stop smoking; eat a healthy and ba lanced diet (see above); take regular exercise. http://www.kidney.org/professionals/kdoqi/ guideline_diabetes/ Association de Langue Fran aise pour l tude du Diab te et des Maladies Metaboliques (in French): \200 \200 Information and support Resources and information for patients with diabetic neph- ropathy may be found at the following web sites: UK Renal Association: http://www.alfediam.org http://www.renal.org/ Diabetes UK: http://www.diabetes.org.uk/ National Kidney Foundation (US): This page intentionally left blank J. GILLMORE AND P. HAWKINS 150 Amyloid and immunotactoid glomerulopathy Amyloidosis is a multisystem clinical disorder caused by extracellular deposition of insolu ble abnormal fibrils, derived from the aggregation of a misfolded, normally soluble, protei n. Amyloid is diagnosed on the basis of its pathognomonic red- green birefringence when an affected tissue biopsy is viewed under cross polarized light after staining with Congo Red. Amyloid \201 brils of all types are 8 \200\22312 nm in diameter and always express a lig and that binds the normal plasma pro- tein, serum amyloid P component (SAP). Renal amyloido sis can result from a number of amyloid precursors, most commonly: \200 \200 Etiology The \201 brils in AL amyloid deposits and the microtubules in ITG deposits are d erived from monoclonal immunoglobu- lins or fragments thereof. The B-cell dyscrasias that u nderlie AL amyloidosis and ITG are frequently very subtle. In contrast, minor clinically in signi \201 cant AL amyloid deposits occur in 15% of patients with symptomatic myeloma. AL amyloid may be deposited in almost any organ in the body, whereas the deposits in ITG are g enerally limited to the kidneys. The propensity for certain monoclonal immunoglobulins to f orm either amyloid \201 brils or microtubules is deter- mined by their intrinsic physicoc hemical properties. The pattern of organ involvement in AL amyloidosis is also, in part, go verned by intrinsic properties of the particular monoclonal amyloidogenic light chain. monoclonal Ig light chains (AL amyloidosis); serum amyloid A protein (SAA) (AA amyloidosis) ; and less commonly: \200 \200 \200 \200 \200 \200 \201 brinogen AA chain; transthyretin; lysozyme; apolipoprotein AI; apolipoprotein AII; g elsolin. Clinical features AL amyloidosis Symptoms in AL amyloidosis depend on which organs are invo lved, and this varies enormously. Weight loss and general malaise are common. Involvement o f the heart, liver, peripheral nerves and tongue causes restrictive cardiomyopathy, hepatom egaly, peripheral sensorimotor neuropathy, and macroglossia respectively. There may be auto nomic nerve involvement causing pos- tural hypotension, gastrointestinal disturbances and e rec- tile dysfunction. Gut involvement may cause bleeding and occasionally bowel obstructio n. Approximately 50% of patients with AL amyloidosis have renal manifestations, usually nep hrotic syndrome, which may be accompanied by varying degrees of chronic kidney disease (CKD ). Proteinuria can be >20 g/24 h and microscopic hematuria is not infrequent. Occasionally, patients with predominantly tubulo-intersti- tial amyloid deposits progress to advanced CK D in the absence of heavy proteinuria. The clinical signs of systemic AL amyloidosis are pr otean and the majority are not speci \201 c for the disease, including those of restrictiv e cardiomyopathy, nephrotic syndrome, hepatomegaly, splenomegaly and peripheral neuropathy. Certain signs are almost pathognomonic of AL amy- loidosis such as macroglossia and recurr ent periorbital purpurae. The organized deposition of immunoglobulin components can also result in Congo Red-negative organized deposits that display two characteristic patterns on EM: \200 \201 brils that are randomly arranged ( \201 brillary glomeru- lopathy (FGN)); microtubu les that are usually larger, have a hollow core, and are ordered in parallel arrays (immuno tactoid glomerulopathy (ITG)). In ITG the microtubules are usually >30 nm in diameter and the glomerular Ig deposits are m onoclonal, whereas in FGN the \201 brils are usually 12 \200\22330 nm in diameter and are derived from polyclonal, subclass restricted IgG. An overt B-cell proliferative disorder i s evident in up to 50% of ITG cases. Immunoglobulin-associated glomerulopathies The recognized spectrum of renal diseases charac terized by deposition or precipitation of monoclonal immunoglob- ulin (Ig) and related mate rial has expanded dramatically in recent years. The precise diagnosis can only be determine d after detailed examination of renal tissue by both light and electron microscopy (EM), th e latter de \201 ning two broad disease cat- egories: Organized deposits which include: \200 \200 \200 systemic AL ( \200\230light chain \200\231) amyloidosis; \201 brillary glomerulonephritis (FGN); immunotactoid glomerulopathy (ITG). Immunotactoid glomerulopathy and \201 brillary glomerulonephritis ITG and FGN usually pre sent with nephrotic syndrome and CKD. Extra-renal involvement is rare but microtubular depo sits have been reported in the skin, peripheral nerve, lung, liver, and in the cytoplasm of circulating or bone marrow lym- phocytes in ITG associated with chronic lymphocytic leukem ia or non-Hodgkin B-cell lymphomas. Nonorganized deposits referred to as: \200 monoclonal immunoglobulin deposition diseases (MIDD) (discussed further in Chapter 4.3). Epidemiology AL amyloid deposits are identi \201 ed in 2% of native adult kidney biopsies compared to ITG which comprises <0.1%. The peak age of diagnosis of AL amyloidosis and ITG is 60 years. CHAPTER 4.2 Amyloid and immunotactoid glomerulopathy 151 Table 4.2.1 Comparison of histological features in immunoglobulin deposition diseases of th e kidney Fibrillary GN Immunotactoid glomerulopathy AL (light chain) amyloid Monoclonal immunoglobulin deposition diseases (MIDD) Negative Negative Positive Negative Red-green birefringence with Congo Red staining MCGN Atypical membranous GN Predominant mesangial deposits Nodular glomeruloscerosis Light microscopy Mesangial proliferation Lobular MCGN Tubular basement membrane deposits Monotypic light or heavy chain deposits, > Nonorganized granular electron-dense depos its Monotypic light or heavy chain deposits, > Organized but randomly arranged \201 bri ls, 8 \200\22312 nm in diameter Polyclonal IgG deposits of 4 isotype Coarse granular mono- typic IgG (IgG1, or IgG2, or IgG3) and C3 deposits Immunohistochemistry Hollow microtubules, usually >30 nm in diameter, ordered in parallel Organized but randomly arranged \201 brils, usually 20 nm in diameter Electron microscopy GN, glomerulonephritis; MCGN, mesangiocapillary GN. The signs of ITG and FGN are usually those of the neph- rotic syndrome. generally yield de \201 nitive results, but AL deposits are stained with standard antisera to or light chains in only 50% of \201 xed biopsies. Confirmation of AL amyloidos is therefore commonly requires exclusion of other types through an immunohisto- chemical pa nel and sequencing of the genes associated with hereditary systemic amyloidosis. Differenti ating between the various immunoglobulin- related glomerulopathies can be dif \201 cult (T able 4.2.1). Renal biopsy Histological diagnosis of amyloid requires staining of the tissue deposits wit h Congo Red and demonstration of pathognomonic red \200\223green dichroism when viewed in c ross-polarized light. The lesions of ITG and FGN are Congo Red negative. A renal biopsy is the most frequent diagnostic test. Renal AL amyloid deposits are typically found in the mes an- gium, along the glomerular basement membrane (GBM) and in the blood vessels but are als o often present in the tubules and interstitium. However, there is a signi \201 cant rate of false-positive and false-negative diagnoses, owing to sampling errors and inadequate pre paration, staining and interpretation. The presence of SAP within deposits, identified by i mmunohistochemistry (optimally using frozen sections) and/or immunogold labeling, also dist inguishes amyloid (including AA and hereditary forms) from ITG and MIDD. The basis of a rep ort of SAP within the deposits of FGN is unclear. Amyloid deposits identi \201 ed histolog ically must be further characterized immunohistochemically to identify the par- ticular amy loid \201 bril type, of which there are 20. Renal involvement by amyloid occurs in amylo idosis associ- ated with the following amyloid \201 brils: \200 \200 \200 \200 \200 \200 \200 \200 Light microscopy ITG and FGN are characterized by atypical mem- branous GN lesions or lobul ar mesangiocapillary GN but there may be mesangial proliferation, crescents or sclerosing G N. MIDD is characterized by Congo Red-negative nodular glomerulosclerosis and deposition of periodic acid \200\223Schiff (PAS) positive material in the tubular basement mem- brane. Immuno \202 uorescence (IF) microscopy Immuno \202 uorescence in ITG should include not o nly stand- ard antisera to and light chains, but also antisera to IgG subclasses, in order to demonstrate clonality. IF will reveal coarse granular staining for IgG (IgG1, or I gG2, or IgG3) and C3 along the capillary basement membranes and in the mesangium. In both I TG and AL amyloidosis the Ig deposits are clonal and therefore always have a monotypic ligh t chain ( or ), although this is not always demonstrable by immunohistochemistry. In FG N, polyclonal IgG deposits of the 4 isotype are typical. In MIDD, IF reveals monotypic li ght or heavy chain deposits along glomerular and/or tubular basement membranes, more common ly than isotype. Electron microscopy In ITG there are typically large (>30 nm) (Fig. 4.2.1C) thick- walled microtubular (hollow) \201 brils with hollow, lucent centers arrang ed in parallel arrays, compared with small (8 \200\22312 nm) organized solid \201 brils w ithout a lucent core in amyloidosis (Fig. 4.2.1A) and organized but randomly arranged \201 brils of 12 \200\22330 nm in FGN (Fig. 4.2.1B). AL; AA; \201 brinogen AA chain; transthyretin; lysozyme; apolipoprotein AI; apolipoprotei n AII; gelsolin. Commercially available antibodies to serum amyloid A protein (SAA), transthyretin (TTR) and B2-micro-globulin J. GILLMORE AND P. HAWKINS 152 Electron microscopy in MIDD shows nonorganized granu- lar electron-dense deposits in the gl omerulus and along tubular basement membranes. Tests for cryoglobulins should be undertaken in all cases in which microtubular renal deposits are identi \201 ed. (a) General investigations Discovery of AL amyloid deposits should be followed by a careful ass essment of renal, hepatic, cardiac and peripheral and autonomic nerve function. ITG and FGN almost always have renal-limited manifestations. Imaging for soft tissue or lymph node inv olvement by amy- loid may be indicated by the clinical features. Special investigations All patients with AL amyloidosis or ITG should undergo comprehensive investigation for an underlying clonal B-cell dyscrasia, which may be extremely subtle. El ectrophoresis and immuno \201 xation of blood and urine are mandatory. (b) Serum free light chain assay A high sensitivity serum free light chain assay has recently b een developed which can quantify circulating free immu- noglobulin light chains with a rema rkable sensitivity of <5 mg/L. The serum free light chain assay has increased identi \201 ca- tion of an underlying clonal B-cell dyscrasia from 80% to >95% in patients with system ic AL amyloidosis, and it is frequently the only quantitative measure of clonal response to treatment. [123I]SAP scintigraphy This was developed and is routinely available at the Nat ional Amyloidosis Center, UK. The scan identi \201 es the presence, distribution and exten t of amyloid deposits in systemic amyloidosis. Serial SAP scans monitor progress, and have shown that amyloid deposits often regress when the supply of the respective amyloid \201 bril precursor protein is suf \201 ciently reduced (Fig. 4.2.2). SAP scans are negative in Congo Red-negative \201 brillary glomerulopathies and nonorganized MIDD, providing valu- able corroborative support of this diagnosis. (c) Natural history Without treatment, AL amyloidosis is inexorably progres- sive and almost al ways fatal with a median survival of only 6 \200\22315 months. Diagnosis of renal AL amyloi dosis is associated with a median time to renal replacement therapy (RRT) of 1 year in the absence of effective chemotherapy, and median survival on dialysis is only 8 months. ITG a nd FGN are generally renal-limited and more slowly progressive diseases, with the median ti me from diagnosis to RRT >2 years and with a markedly better overall prog- nosis than AL am yloidosis. Approximately 20% of patients with kidney dysfunction due to renal AL amyloid de posits eventually develop ESRD. The outcome of AL amyloidosis can be dramatically improved by chemotherapy that suppresses monoclonal Ig production. This can halt disease progression and may facilitate regression of amyloid. There may be complete resolution of the nephroti c syndrome following effective chemotherapy in AL Fig. 4.2.1 Electron micrographs demonstrating the \201 brils of (a) amyloidosis (randomly arranged 8 \200\22312 nm in diameter), (b) \201 brillary glomerulonephritis (randomly ar ranged 12 \200\22330 nm in diameter), and (c) immunotactoid glomerulopathy (parallel arrays , hollow centered microtubules (arrowheads) >30 nm in diameter). amyloidosis, and progression of CKD may be substantially retarded. 50% of patients with ITG or FGN reach ESRD. However, marked improvement in nephrotic-range proteinuria and renal ex cretory function have been reported following chemotherapy in patients with ITG (or FGN). Recurrence after renal transplantation Amyloid deposits may recur in the renal allograft. S uppression of monoclonal light chain production by chemotherapy reduces the risk of graft a myloid. CHAPTER 4.2 Amyloid and immunotactoid glomerulopathy 153