Re-expression of fetal antigens may be important for dis- ease induction. In support of thi s concept, carcinoem- bryonic antigen (CEA) has been isolated from diseased glomeruli in pa tients with adenocarcinoma. Various cytokines that exhibit antitumor activity (e.g. IL-6) have also been implicated. Clinical features Glomerulonephritis is an intrinsic renal disease. The fol- lowing feature s are commonly encountered with glomeru- lar disorders. \200 Nephrotic range proteinuria and the classical features of nephrotic syndrome (NS) may be the primary manifesta- tion of the associated GN. However, non-nephrotic range proteinuria may also occur. 102 de novo cancers were found in 1958 patients. These cancer rates represent a two- to thr ee-fold excess of the expected number at <1 and 1 \200\2234 but not \211 5 years after a b iopsy. Non-Hodgkin \200\231s lymphomas were observed six to eight times more than expected. Microscopic hematuria (in the absence of bladder pathology) with erythrocyte casts and dysm orphic red cells indicates the presence of glomerulonephritis. Macroscopic nonglomerular hematuria is of particular significance because it is much more l ikely than CHAPTER 3.12 Malignancy-associated glomerular disease 135 microscopic hematuria to be associated with a urological malignancy. A bland urinary sediment (absent proteinuria, hematuria, erythrocyte casts) argues strongly against the diagno- sis of glomerulonephritis. In the context of renal func- tion impairme nt, alternative explanations such as obstructive uropathy and tubulointerstitial disease sh ould be considered. Acute renal failure is more likely to occur with crescen- tic and membranoproliferative glo merulonephritis. The former may present with extrarenal symptoms such as skin rash or hemop tysis. An elevated ESR is not uncommon in NS and by itself is not an indication to investigate for occult malignancy. Immunological testing for ANCA and anti-GBM antibodies is indicated whe n there is a reasonable suspicion of rapidly progressive glomerulonephritis with the releva nt features such as the characteristic vasculitic rash and active urinary sediment. Without such features, positive immunological testing carries little signi \201 cance. False-posi tive ANCA has been reported with several malignancies such as lympho- mas and lung cancer. Ultimately the con \201 rmation of the diagnosis and identi \201 ca- tion of the underlyi ng glomerulonephritis requires a renal biopsy. Renal biopsy is an invasive test, with poten tially serious complications. The decision to carry out such a test is affected by the prog nosis of the associated cancer. Although essential for diagnostic purposes, it may not alwa ys be technically possible due to concurrent coagu- lopathy and/or thrombocytopenia. Speci \201 c glomerular disorders Membranous nephropathy (MN) This is the commonest malign ancy-associated glomeru- lopathy. Up to 20% of patients, particularly those aged >60 years, who have MN are reported to have a malignancy. Age, smoking, and the presence of glomerula r leukocytic in \201 ltrates strongly increase the likelihood of malignancy in MN patients . Secondary MN will present with nephrotic syndrome with or without renal impairment. It is associated with solid tumors particularly cancers of the lung, breast stomach and colon. Fig. 3.12.1 Membranous nephropathy (MN). (Upper) Methana- mine-silver stain showing extensi ve \200\230spikes \200\231 in a case of advanced MN. The \200\230spikes \200\231 represen t basement membrane material laid down between the subepithelial immune complexes. The latt er are eventually incorporated into the basement membrane and are resorbed. (Lower) Global coarsely granular positivity for IgG highlighting the capillary walls in a case of \200 \230idiopathic \200\231 MN, which also showed a similar pattern of \202 uorescence with I gG and C3. IgG1 and IgG2 subtypes have been found to be more often associ- ated with malign ancy-associated MN, but these antibodies are not typically used in routine diagnostic pract ice. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leice ster, UK.) Histological \201 ndings in MN The renal biopsy appearances, particularly the immuno \202 u- orescence and electron micro scopy \201 ndings, will help dif- ferentiate idiopathic from secondary membranous nephrop athy. Diffuse thickening of the glomerular basement membrane without any hypercellularity i s typical on light microscopy (Fig. 3.12.1). In malignancy-associated MN, immuno \202 uore scence shows a diffuse granular pattern of IgG1 and IgG2 rather than IgG4 (which is charact eristic of idiopathic membranous nephropathy). Tubular basement membrane positivity on IF i s rare with idiopathic MN, but common in secondary forms of MN. Minimal change disease (MCD) This is the commonest glomerulonephritis encountered with Hodg kin \200\231s lymphoma. MCD has also been reported less frequently with leuke- mias, other lymphomas, and rarely with mesothelioma, and prostate and pancreatic cancer. In a review of 21 cases of MCD associated with Hodgkin \200\231s lymphomas: \200 nephrotic syndrome appeared before the diagnosis of lymphoma in 38% of patients; nephrotic syndrome was frequently steroid resistant (50%) or steroid dependent (12.5%); curative trea tment of the lymphoma resulted in remis- sion of the nephrotic syndrome. H. EL SHAZLY 136 It has been reported that nephrotic syndrome due to MCD may be diagnosed up to a median of 2 years prior to the diagnosis of malignancy. In the absence of features suggestive of an u nderlying neoplasm (e.g. fever, weight loss, lymphadenopathy), exhaustive investigation is not indicated. Light, immuno \202 uorescence and electron microscopy revealed \201 brin deposition in a ll cases and no evidence of anti-GBM or immune complex disease. Three patients experienced a rapidly progressive course while renal function improved in four patients following treat ment of the underlying malignancy. Treatment of crescentic GN requires immunosupression with steroids and other agents such as cyclophosphamide. In addition plasma exchange may be required to alleviate both the renal and nonrenal manifestations of the vasculi- tis. However, this may increase the neoplastic burden. Focal segmental glomerulosclerosis (FSGS) This has been observed primarily with hematologic al malignancies although with a lower frequency than the association of MCD and Hodgkin \200\231s lymphoma. It has also been reported with non small-cell lung cancer. In that case it presented with nephrotic syndrome and the proteinuria reduced dramatically during radio therapy for the lung cancer. Mesangiocapillary GN (MCGN) When nephrotic syndrome presents in association with lung cance r, MCGN tends to be the most common glomerulonephritis. Chronic hepatitis C virus infection has been linked to cryoglobulinemia, mesangiocapillary glomerulonephritis, and malignant B -cell lymphoproliferation. However, this proposed linkage has been challenged in a case rep ort where this clinical triad has occurred in the absence of hepatitis C infection. This fo rm of glomerulonephritis has a progressive nature and is usually associated with renal impa irment. Amyloidosis Both primary and secondary amyloidosis may be associ- ated with malignancies. P rimary amyloidosis (AL) occurs as a result of deposition of light chain fragments and may o ccur in association with multiple myeloma; these \201 brils are derived from light cha ins in the majority of cases. Secondary amyloidosis (AA) has been described in associ- atio n with a number of malignancies, particularly renal cell carcinoma, Hodgkin \200\231s lymph oma and CLL. \200 IgA nephropathy IgA nephropathy has been reported with small cell lung carcinoma, and lymph omas such as Hodgkin \200\231s disease. Presentation will typically be of nephrotic syndrome and less commonly renal failure. Extra renal manifestations are not uncommon especially in primary amyloidosis (AL). Serum parapro tein and monoclonal urinary light chain may be detected in AL. This should be assessed furt her using serum free light chain assays. Tissue diagnosis can be obtained by biopsy of the abdominal fat pad, rectum, or the affected organ, e.g. liver or kidney (most sensitive and most speci \201 c). Thrombotic microangiopathy Thrombotic microangiopathy is characterized by the triad of acut e renal failure, idiopathic thrombocytopenia and microangiopathic hemolysis. Hemolytic urem ic syndrome (HUS) commonly causes acute renal failure due to microthrombi formation within the glomerular capillaries and renal arterioles (Fig. 3.12.2). Histological \201 nding in amyloidosis The renal biopsy will show the typical \201 bril lar arrangement on electron microscopy. These amyloid \201 brils are charac- terized by t heir ability to bind Congo Red. This gives the typical apple green birefringence under pola rized light. Immunohistochemical staining for or light chains, or serum amyloid A, ca n de \201 ne the type of amyloidosis. Crescentic glomerulonephritis Crescentic GN commonly presents with acute renal failure. Ext ra-renal manifestations such as pulmonary hemorrhage may be the initial manifestation of th e vasculitic process. Serological testing may demonstrate positive ANCA serology. Patients with ANCA-positive vasculitis have an increased risk of simultanous malignancy. Crescentic GN has been reported with a number of cancers: \200 Fig. 3.12.2 Hemolytic uremic syndrome. H&E stain showing glomerular and arteriolar thrombos is. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leices ter, UK.) Renal cell carcinoma (and following immunotherapy for renal cell carcinoma). Gastric adenoc arcinoma. Carcinoma of the hypopharynx. Non-Hodgkin lymphoma. \200 \200 A review of 80 patients with a renal biopsy diagnosis of crescentic GN revealed seven cases with a coexistent non renal malignancy. \200 Patients with disseminated malignancy are at risk for devel- oping HUS. The diagnosis must be differentiated from DIC, which may also be encountered in the context of malignancy. All of the malignancies occurred in patients aged >40 years. CHAPTER 3.12 Malignancy-associated glomerular disease 137 HUS has been reported with mucin-producing gastric ade- nocarcinomas, and adenocarcinomas o f the prostate, pan- creas and breast. It may present in its acute form with acute kidney i njury or may have a more chronic indolent presentation. Rarely occult disseminated malignan cy may mimic TTP. This should be suspected when plasma exchange, the mainstay of treatment, is ineffective. In such situations the search for an underlying malignancy should be consi dered. The treatment should be aimed at the underlying malignancy. Immunosuppression for selected glomerulonephritides increases the cancer burden and should be considered on an individual basis. The prognosis of the GN is strongly linked to the natural history of the associated cancer. Further reading Birkeland SA, Storm HH. Glomerulonephritis and malignancy: Treatment Most of the common glomerulonephritides and the associ- ated renal failure if pre sent will respond to treatment of the associated malignancy. However, conventional therapie s, such as steroids for MCD and immunosuppression and plasma exchange in crescen- tic glome rulonephritis, have been shown to be effective. a population based analysis. Kidney Int 2003; 63: 716 \200\223721. Brueggemayer CD, et al. Membranous nephropathy; a concern for malignancy. Am J Kidney Dis 1987; 9: 23 \200\22326. Burstein DM, et al. Membranous glomerulonephritis and malig- nancy. Am J Kidney Dis 1993; 22: 5 \200\22310. Cathen R, et al. Etiology of membranous glomerulonephritis: a prospective study of 82 adult patients. Nephrol Dialysis Transpl 1989; 4: 172 \200\223180. Couser WG, et al. Glomerular deposition of tumor antigen in membranous nephropathy associat ed with colonic carcinoma. Am J Med 1974; 57: 962 \200\223970. Screening for malignancy To date there is no consensus on cancer screening for patients wit h newly diagnosed secondary glomerulone- phritides. This is certainly true when clinical fe atures such anemia, fever, and weight loss are absent. In cases of secondary MN and in the presence of the high- risk indicators, e.g. age >50 years and a heavy smoking his- tory, fo llowing a detailed history and physical examination for evidence of neoplastic disease, rel evant screening strat- egies may be employed. In general there is a paucity of evidence and further research is needed to address the most appropriate screening strategies, if any, i n such patients. A reasonable approach would include CXR, occult blood testing of the stool s, mammography (in women), measurement of tumor markers (e.g. CEA and prostate-speci \201 c antigen (PSA)), and possibly colonoscopy and abdominal CT scanning if abdominal symptoms are present. Helin M, et al. Glomerular electron-dense deposits and circulating immune complexes in pati ents with malignant tumors. Clin Nephrol 1980; 14: 23 \200\22330. Kincaid-Smith P. The investigation of hemturia. Semin Nephrol 2005; 25: 127 \200\223135. Lefaucheur C, et al. Epidemiologic evidence and determinants of high-risk cancer associatio n. Kidney Int 2006; 70: 1510 \200\2231517. Muthia P. New lung lesion in immunocompromised h ost-correct diagnosis despite a false positive ANCA. Southern Med J 2006; 99: 701 \200\2237 02. Ohtani H, et al. Distribution of IgG subclass deposits in malignancy- associated membranous nephropathy. Nephrol Dialysis Transpl 2004; 19: 74 \200\223579. Rihova Z, et al. Secondary membranous nephropathy \200\223 one center experience. Renal Failure 2005; 27: 397 \200\223402. Sawyer, N, Wadsworth J, et al. Prevalence, concentration and prog- nostic importance of pro teinuria in patients with malignancies. Br Med J 1988; 296: 295 \200\223298. Conclusions Urinary abnormalities are common in patients with malig- nant disease. Malignan cy-associated glomerulonephritis is rare but should be considered in the context of the app ropriate clinical clues. The con \201 rmation of the diagnosis requires a renal biopsy. See also Membranous nephropathy, p. 106 Minimal change disease, p. 86 Amyloid or immunotact oid glomerulopathy, p. 150 Plasma cell dyscrasias, p. 158 S. AJAYI 138 Glomerular disease in the tropics IgG rheumatoid factor initiating an autoimmune reaction Glomerulonephritis (GN) accounts for 30 \200\22360% of all end- stage renal disease (ESRD) in the tropics. Infection is the commonest cause of glomerular disease in this setting with hypertension and diabetes mellitus accounting for the majority of the remainder. Infectiou s causes of glomerular disease in the tropics are listed in Table 3.13.1. Human immunode \201 ciency virus (HIV)-associated disease is becoming increasingly common. Renal biopsy co n \201 rmation of the diagnosis is often dif \201 cult due to lack of diagnostic faciliti es and to late presentation when, in the face of advanced disease, renal biopsies become di f \201 cult to interpret. in the glomerulus. Table 3.13.1. Infections associated with glomerulonephritis in the tropics Bacterial Streptococus pyogenes E. coli 0157 :H7 (HUS) Salmonella typhi Mycobacterium lepra e Mycobacterium tuberculosis Staphylococcus epidermidis/aureus Treponema pallidum Streptoco ccus pneumoniae Epidemiology There is variability in the etiology of glomerular disease in different parts of the tropics due to differences in the epi- demiology of infections, standards of living, and infrastruc- ture development. The high prevalence of chronic GN points to variety of e tiological agents. GN usually presents in one of four ways in the tropics: acute nephritic syndrome, nephrotic syndrome, asympto- matic urinary abnormalities, and ESRD. This chapter focuses on causes of the nephrotic and nephritic syndromes, and incorporates asymptomatic u ri- nary abnormalities and ESRD where appropriate. Protozoal Plasmodium falciparum Plasmodium malariae Leishmania donovani Toxoplasma gondii T rypanosoma cruzei Viral Hepatitis B Hepatitis C HIV Epstein \200\223Barr virus Helminthic Schistosoma mansoni Schistosoma haematobium Wuchereria bancrofti Brugia malayi L oa loa Onchocerca volvulus Acute nephritic syndrome Etiology Post-streptococcal GN (PSGN) is the commonest cause of ra pidly progressive renal failure in the tropics. It is most common in children. It may occur during epidemics of post-streptococcal skin (impetigo, pyoderma) and throat infections. Di fferent nephritogenic serotypes have been identi \201 ed: \200 skin: M types 47, 49, 55, and 57; \200 throat: M types 1, 2, 4, and 12. The risk of nephritis is 5% with throat in fection and up to 25% for pyoderma. GN occurs 1 \200\2233 weeks after the onset of a strept ococcal infection. Clinical course Most children (>90%) recover completely. Approximately 5% develop progressi ve acute kidney injury or acute GN. In acute GN, there is rapid deterioration of renal func tion, oliguria, \202 uid overload from sodium and water retention, hypertension (80%), ed ema (80 \200\22390%), and pulmonary edema. Approximately 20% have long-term sequelae with a symp- tomatic urinary abnormalities, nephrotic syndrome, hyper- tension, or very rarely pro gressive renal dysfunction. Examination of renal histology of the nephrotic syndrome in non malarious parts of the tropical world would suggest that PSGN may be a cause in some patien ts. It may be the reason why minimal change disease is rarely seen in Black African childre n with nephrotic syndrome. Chronic GN leading to progressive chronic kidney disease is more likely in adolescents than in children, especially in those with persistent proteinuria. E lderly patients do less well (70% have azotemia, 40% heart failure, 25% early mortality). L onger-term prognosis is also less good than in children with up to 25% being left with abno rmal renal function. Pathogenesis PSGN is generally assumed to be due to deposition of cir- culating immune comp lexes in the glomeruli. However, this should result in activation of the classical compleme nt pathway (with C3 and C4 activation), but C4 levels are normal and only C3 is found in th e glomerular immune deposits (suggesting alternative pathway activation). The following pos sibly contribute to in \202 ammation and injury: \200 activation of the alternative comp lement pathway by glyceraldehyde-3-phosphate dehydrogenase (GAPDH); \200 cationic strepto coccal antigen promoting development Diagnosis This is usually easy to make from the clinical features and simple laboratory tes ts. Oliguria may not be obvious in children, but \200\230coca-cola \200\231- colored urine , due to macroscopic hematuria, is usually apparent. of subepithelial immune deposits ( \200\230humps \200\231); cytokines IL-6, TNF-A and vasoactive mediators such as platelet activating factors; in situ deposition of antigen followed by antibody formation; CHAPTER 3.13 Glomerular disease in the tropics 139 Urinalysis \200 Red blood cells and red cell casts. \200 Variable degree of proteinuria . \200 Some may have nephrotic range proteinuria. \200 Leukocytes. Serology A positive antistreptolysin O (ASO) titer is seen in only 30% of patients (perhaps because of early a ntibiotic use). Serum C3 levels are reduced in >90% of patients in the \201 rst week, but return to normal within 2 months. Serum C4 is typically normal. Serum IgG and IgM are elev ated in 75 \200\22380% of patients. A low level of anti-DNA antibodies and ANCA may be seen . It has recently been reported that NS accounts for 38% of nephrological admissions in the D emocratic Republic of Congo. Etiology Even within the tropics, there are interracial differences. For example: In South Africa minimal change disease is more common in Indian children than in Black children who have a prepon- derance of mesangiocapillary GN (MCGN). Minimal change disease is also commo n in India, suggesting a genetic predisposition. MCGN predominates in Nigerian and Kuwaiti children. The disparities in histological features may suggest that NS may be a complicatio n of PSGN and other forms of glomerular diseases. This may account for the rarity of minima l change disease as a cause of NS in African children. The three main primary causes of NS are: \200 MCGN. \200 membranous GN. \200 focal segmental glomerulosclerosis. The most common secondary form of GN causing NS in the tropics is Quartan malarial nephrotic syndro me. Because this is peculiar to the tropics, it is discussed in more detail. Renal biopsy This is rarely needed to con \201 rm the diagnosis. Indications: \200 Nephr otic-range proteinuria. \200 Acute kidney injury. \200 Patients with sickle-cell anemia (a recognized cause of hematuria). Light microscopy: \200 Diffuse endocapillary, mesangial and endothelial proli f- eration. Neutrophil in \201 ltration in glomeruli. Quartan malarial nephrotic syndrome (QMNS) Plasmodium malariae is the most important cause of sec- ondary GN causing NS in children and adolescents. QMNS is probably due to depositio n of soluble immune complexes in the glomerulus but it is characterized by the absence of s peci \201 c antibody and antigen. This has raised questions about the exact pathogenetic m echanism. Pathology: The characteristic appearance is of MCGN with progressive mesangial sc lerosis leading to obliteration of glomerular capillaries with eventual involvement of tubu les. Immuno \202 uorescence microscopy demonstrates coarse granular deposits of IgG, IgM a nd C3 mainly within the glomerular capillary walls. Electron microscopy shows subendothelia l electron-dense deposits and thickened GBM. Clinical features: Fever peaking once every 72 h is the earliest feature. Gross edema and ascites are the main symptoms which develop sev eral weeks after the onset of fever. This may easily be confused with protein-energy malnut rition (kwashiorkor). Other features are nonselective proteinuria, micro- scopic hematuria, normal blood pressure, anemia, and hepatomegaly. Hypoalbuminemia may be severe (10 \200 \22320 g/L). Due to associated malnutrition in the majority of cases, the serum cholesterol is characteristically normal. P. malariae may be detected in 69 \200\22370% of cases. The pres- ence of parasites even when glomerular changes are present does not necessarily indic ate cause and effect. Detection of a speci \201 c antigen has been demonstrated in only a few cases. Interstitial in \201 ltration by monocytes and lymphocytes. Immuno \202 uorescence micros copy: \200 C3, IgG, IgM deposition in capillary loops and the mesangium is invariable. Electron microscopy: \200 Classic subepithelial electron-dense deposits ( \200\230humps \200\231). Differential diagnosis Protein-energy malnutrition and nephrotic syndrome due to other causes. Treatment Treat ongoing streptococcal infection with appropriate antibiotics, e.g. benzathi ne penicillin (1.2 million U intra- muscularly as a single dose). Restrict salt and water i ntake. Diuretics (e.g. furosemide) for volume overload. Antihypertensive agents which may a lso prevent hyper- tensive encephalopathy: nifedipine, hydrallazine, Na nitroprusside. Dial ysis, although rarely needed in children, is a challenge in many tropical countries due to lack of dialysis infra- structure. Prognosis This is excellent in children who recover, but poor in ado- lescents who may prog ress to chronic GN. Proteinuria may persist for months, and sometimes years. Follow-up It may be necessary to screen other family members \200\223 especially young chi ldren, who may have subclinical disease in epidemics of PSGN. Nephrotic syndrome (NS) NS is 2 \200\22310 times more common in the tropical countries than in Western Europe or North America. S. AJAYI 140 Clinical course: Prognosis is poor, and spontaneous remission is rare. QMNS causes end-stag e renal failure in <4 years. Treatment: There is a uniformly a poor response to corticoster oids, and to antimalarials. There are reports of remission of ster- oid-resistant patients with cyclophosphamide but this leads to no improvement in overall survival. Giving a therap eutic trial of corticosteroids before biopsy is therefore a prac- tice that is increasingly being called into question. Hepatitis B virus (HBV)-associated GN HBV infection is prevalent in certain tropical countr ies, and the kidneys may be affected by immune-complex-mediated disease. Acute HBV infectio n is associated with a serum sickness- like syndrome characterized by fever, arthralgias/ar thritis, hepatitis, rash (urticaria/maculopapular) and renal involve- ment (microscopic hem aturia, sterile pyuria, and proteinuria) Renal biopsy, if performed, shows mesangial prolif era- tive GN. GN resolves with remission of the acute phase of the disease. Approximately 1 0% of patients acutely infected with HBV become chronic carriers and are at risk for other renal manifestations of HBV. These include membranous nephropathy, polyarteritis nodosa, MC GN, and IgA nephropathy. This topic is covered in detail in Chapter 3.11. The treatment of HBV-related renal disease is more effec- tive for membranous GN than for MCGN. Treatment re gimens that have shown benefit usually include interferon- and lamivudine. However, since these agents are not widely available in the tropics, the management of HBV-mediated renal disease (and the other manifestations of HBV infection) can be suboptimal. Steroids and cy totoxics are contraindicated since they enhance viral replication and may precipitate hepat itic \202 ares. Falciparum malaria P. falciparum infection is mainly a disease of children in the tropics. Unlike QMNS, it is not progressive, and it resolves following eradication of P. falciparum. Indeed, GN may pass unnoticed especially with the widespread use of antimalarials. There i s nonselective proteinuria, microscopic hematuria and casts. The typical pathological abnor malities are mesangial hyper- cellularity with mild matrix expansion changes without baseme nt membrane involvement. IgG, IgM and C3 can be identified in the mesangium. Immune deposit s can be identi \201 ed by EM in the mesangial and subendothelial areas. The renal lesions recover with conventional antimalarial treatment. Schistosoma mansoni-associated nephropat hy (see Chapter 7.4 for more detail) This is common in Brazil and Egypt, and patients often present with the nephrotic syndrome. Glomerulonephritis is most common when there are hepa tosplenic manifestations and chronic salmonella infection. Males are twice more affected th an females, probably due to outdoor activities in rivers and pools. Clinical features inclu de: \200 \200 \200 \200 Hepatitis C virus (HCV)-associated GN Glomerular disease associated with HCV has not been w ell-described in the tropics, even though the pathological changes and clinical course are not expected to be differ- ent from those described in the Western world. These include var iable degrees of proteinuria, microscopic hematuria, and renal impairment. Mesangiocapillar y GN has been described. overt peripheral edema and ascites; poorly selective proteinuria and, rarely, hematuria; lo w serum C3 with hypergammaglobulinemia; normal cholesterol. HIV-associated renal disease The tropical regions, especially sub-Saharan Africa cur- rentl y bear the brunt of the HIV/AIDS pandemic. Therefore, occurrence of renal disease associate d with HIV is on the increase, and impacting negatively on the outcome of HIV disease. HIV is immunocytopathic, and it therefore can cause a vari- ety of renal syndromes such as: \200 Pathology: Several patterns of glomerular pathology have been observed: \200 \200 \200 \200 \200 class I mesangioproliferative lesions; class II diffuse proliferative GN; class III MCGN ty pes I and III; class IV focal and segmental glomerulosclerosis (FSGS); class V amyloidosis. HIV nephropathy (HIVAN) (in >60% it occurs with advanced disease). Immune complex GN ( \200 \230lupus-like syndrome \200\231). Thrombotic microangiopathy. \200 In addition, chemotherapy can present a challenge because some antiretroviral (ARV) and adj unct medications can cause nephrotoxicity (pentamidine) or nephrolithiasis (indinavir). HIV AN: Occurs in about 60% of patients with advanced disease, but may be subclinical in the ma jority of cases. It is rapidly progressive and may reach ESRD within 5 months. HIVAN is a d iagnosis of exclusion, and therefore other treatable causes such as hypovolemia from diarrh ea should be excluded. In the tropics, a signi \201 cant number of patients use herbal pre parations for recurrent febrile illness, and this may cause nephrotoxicity. Treatment: Praziquantel 20 mg/kg body weight is effective in eradicat- ing the parasites bu t this does not result in resolution of glomerular disease that has progressed beyond class II. The treatment of chronic salmonella infection may cause resolution of glomerular disea se (usually class II changes), suggesting a critical role for salmonella antigens in the pa thogenesis of disease. A good response to oxamniquine has been observed in class II disease . The role of immunosuppression is unclear. CHAPTER 3.13 Glomerular disease in the tropics 141 Pathogenesis: HIV infects tubular and glomerular epithelial cells and podocytes. This may e xplain the occurrence of NS in affected individuals. Pathology: This typically shows a pres erved Bowman \200\231s space with col- lapsed/shrunken glomeruli ( \200\230collapsing glome rulopathy \200\231), and focal dilatations of tubules presenting a \200\230microcystic \200\231 appearance. Treatment: RAS blockade can slow progression in those with moder- ate CKD (creat <176 mol/L (2 mg/dL)). HAART (highly active antiretroviral therapy) may cause remission of glomerulopathy. Prednisolone may be bene \201 cial in high risk patients. Treatment: Early treatment of leprosy may prevent occurrence of renal involvement. Treatmen t with rifampicin and occur- rence of erythema nodosum leprosum (ENL) may exacer- bate glom erular lesions. Steroids have no proven bene \201 t. Other forms of secondary GN The following organisms can cause GN, even though the prevalenc e varies from region to region depending on the level of preventive measures: \201 larial worms, helminths, protozoas, and fungi. They induce various forms of GN, e.g. MCGN, membra nous GN. Patients often present with asymptomatic proteinuria or hematuria, and sometimes n ephrotic syndrome. Generally, glomerular lesions do not respond to treatment of causa- tive organisms. Further reading Akinkugbe OO. Tropical nephropathy \200\223 an overview. Afr J Med Med Sickle cell-associated renal disease Sickle cell disease is common in certain population gr oups in the tropics, particularly Black Africans and Africans in the Caribbean. It causes r enal disease by one or all of the fol- lowing mechanisms: \200 \200 \200 Sci 1992; 21: 3 \200\2237. Asinobi AO, Gbadegesin, R. The predominance of membranoprolif- erative glomerulonephritis i n childhood nephrotic syndrome in Ibadan, Nigeria. W Afr J Med 1999; 18: 203 \200\223206. Barsoum RS. Schistosomal glomerulopathies. Kidney Int 1993; hypoperfusion/ischemia; iron overload and deposition; intracapillary fragmentation and phag ocytosis of sickled cells; immune complex formation; hyper \201 ltration and subsequent gl omerular sclerosis. 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 