Renal replacement, as per standard indications ( b p. 172). Shunt nephritis Originally coined to describe the GN associated with a chronically infected ventriculoatrial or ventriculojugular shunt used to treat hydro- cephalus. In the modern e ra, bacterial bio \201 lms on an indwelling central venous cannula or cardiac pacing appar atus are more likely to be the source of low-grade infection ( l immune complex formation a nd glo- merular deposition). Clinical features in such scenarios include: Fever. \200 Haematuria, proteinuria, and i SCr. \200 Splenomegaly. \200 i ESR, CRP, d Hb, and d C3. \200 Histology is similar to PIGN. Removal of the foreign body is essential for resolution. CHAPTER 7 Diseases of the kidney 550 Mesangiocapillary glomerulonephritis Confusingly, also called membranoproliferative glomeru lonephritis (MPGN). Introduction MCGN is a histological term used to describe a pattern of injury, rather than a distinct GN. Can be idiopathic but commonly secondary to a variety of causes. MCGN associations With cryoglobulins \200 Hepatitis C (less commonly B) ( b p. 686). \200 Mixed cryoglobu linaemia unrelated to HCV ( b p. 634). Without cryoglobulins \200 Shunt nephritis and oth er chronic infections, including endocarditis and visceral abscesses ( b p. 692). SLE, Sj gren \200\231 s syndrome. \200 HBV, HCV, HIV, parvovirus B19. \200 TB, lepr osy. \200 Malaria, schistosomiasis. \200 Complement de \201 ciencies (e.g. factor H). \200 TMA. \200 Plasma cell dyscrasia (e.g. myeloma), lymphoma. \200 Transplant glomer ulopathy ( b p. 415). Classi \201 cation and histology The subendothelial and mesangial deposition of immune com plexes implies a common pathogenic mechanism (see Fig. 7.5 ). All subtypes have a character istic \200\230 double contour \200\231 or \200\230 basement membrane splitting \200\231 appearance of the GBM s to the interposition of mesangial cell cytoplasm between the endot helium and GBM. Type I MCGN \200 Characterized by mesangial hypercellularity and discrete immune deposits in the mesangium and subendothelial space. Monocyte in \201 ltration causes a lobular pat tern to the glomerular tufts. Crescentic change can occur. Immuno \202 uorescence shows gr anular IgG and C3 deposition within capillaries and mesangium. Commonly associated with cryoglobulinaemia (with HCV). \200 Also associated with SLE, end ocarditis, plasma cell dyscrasias (e.g. MIDD and AL amyloid), and HBV infection. Less commonly, a primary idiopathic MCGN (consider this a diagnosis of exclusion). MESANGIOCAPILLARY GLOMERULONEPHRITIS 551 Dense deposit disease (type II MCGN) \200 Continuous, dense, ribbon-like intramembranous deposits along the GBM, tubule, and Bowman \200\231 s capsule. These contain C3 but no immunoglobulin. Related to de \201 ciency in complement factor H (often with partial lipodystrophy and retinal abnormalities). Type III MCGN \200 Immune deposits, as in type I, but complete disruption of the GBM with membranous change. Three distinct varieties of type III MCGN have been described. \200 An inherited form is associated with chromosome 1q32. C3 glomerulopathy \200 Isolated deposition of C3, often with similar features to type I, but with no immunoglobulin deposition. Associated with genetic or acquired abnormalities of complement regulation. Serum C3 nephritic factor is positive (see b p. 552). \200 Probably part of the spectrum of dense deposit disease. Subendothelial deposit Capillary lumen GBM Mesangial hypercellularity Endothelial cell Podocyte Fig. 7.5 Cartoon of subendothelial deposits in MCGN. CHAPTER 7 Diseases of the kidney 552 MCGN: presentation and management Presentation Idiopathic MCGN tends to affect \231\202 = \231\200 aged 8 \200\223 30. It carries a relatively poor prognosis: 7 50% ESRD at 10 yea rs. Symptoms and signs All may present as asymptomatic urinary abnormalities, acute nephritis, nephrotic syndrome, or progressive renal failure. i BP is particularly common. For presenta tion of cryoglobulinaemia, see b p. 634. MCGN type II may be associated with partial lipody strophy (absent sub- cutaneous issue in the face and upper limbs) and retinal abnormalities (pigmentation and visual \201 eld de \201 cits). Investigations \200 SCr, eGFR, U&E, albumin, LFTs, uPCR (or uACR), microscopy for red cell casts. 2 Consider potential underlying causes: immunoglobulins, serum and urinary protein electrop horesis ( 9 serum free light chains), hepatitis serology (for HCV and MCGN, see b p. 686), rheumatoid factor, cryoglobulins, complement components, and C3 nephritic factor ( b p. 41) . Complement in MCGN \200 Type I MCGN: Classical pathway is activated by immune complexes l normal/ d C3 and d C4). Type II MCGN (dense deposit disease): Alternate pathway is activated l d C3, normal C4. \200 A stabilizing IgG binding a C3 con vertase (C3Bb) occurs in dense deposit disease l persistent cleavage of C3. This is termed the C3 nephritic factor. Type III MCGN: Findings similar to type II but without the C3 nephritic factor. Management \200 2 Exclude s causes of MCGN prior to treatment. \200 For treatment of HC V-related MCGN, see b p. 688. \200 (cid:2) Evidence-based treatment strategies are lackin g for primary MCGN. Many early studies almost certainly (inadvertently) included patients w ith s MCGN. General measures \200 Stop smoking (as in all progressive nephropathies). \200 Treat i BP vigorously. \200 Reduce proteinuria: use ACE-I or ARB. \200 Restrict s alt intake 9 diuretic ( b p. 538). \200 Dual antiplatelet therapy with aspirin and dipyri damole is no longer widely advocated. MCGN: PRESENTATION AND MANAGEMENT 553 Immune suppression The following strategies may offer bene \201 t. They are generally rese rved for patients with the nephrotic syndrome and progressive renal impairment. \200 Cort icosteroids (tapering prednisolone started at 1mg/kg/day). An alternate day, long-term corticosteroid regimen has been common in pediatric practice. Corticosteroids 9 cyclophosphamide 1.5 \200\223 2mg/kg/day for \211 6 months. \200 Cor ticosteroids 9 MMF for \211 6 months is a potentially less toxic alternative. MCGN: towards a new classi \201 cation Until recently, MCGN was generally classi \201 ed as described on b p. 550; i.e. either p (idiopathic) or s if an underlying cause could be i denti \201 ed. p MCGN was further classi \201 ed into I \200\223III based on ultrastructu ral appear- ances and distribution of electron-dense deposits. More recently, a bet- ter un derstanding of the pathogenetic role of complement in MCGN has informed a new view of the l esion, with categorization into either Ig-mediated disease (driven by the classical complem ent pathway) or non-Ig-mediated disease (driven by the alternative complement path- way) (s ee Fig. 7.6). The non-Ig-mediated group, referred to as C3 glo- merulopathy, includes dense deposit disease and C3 glomerulonephritis. C3 glomerulopathy is a proliferative lesion, us ually with a MCGN-type appearance on light microscopy. C3 alone on immunostaining suggests overactivity of the alternative complement pathway. Historically, clinical trials within MCGN have selected patients with comparable histology on light microscopy \200\223 meaning that many different etiologies were probably represen ted. It is hoped that advances in clin- icopathological understanding will foster diagnosti c clarity and generate disease-speci \201 c therapies. MCGN or other proliferative GN (e.g. mesangioproliferative GN or crescentic GN) on LM C3 + Immunoglobulin on IF C3 alone on IF C3 glomerulopathy: complement alternative pathway-mediated GN Immune-complex-mediated GN Mesangial and intramembranous highly election-dense deposits on EM Mesangial, subendothelial, subepithelial, and/or intramembranous deposits on EM DDD C3GN Fig. 7.6 Reclassi \201 cation of MCGN has promoted a new group of diseases called C3 glome rulopathies. The classi \201 cation may also be usefully extended to other forms of prolif erative GN, even if they do not have an MCGN pattern on light microscopy. An Ig-mediated GN should prompt an investigation into infectious, malignant, or autoimmune causes (immune-co mplex formation). A GN with C3 staining alone suggests overactivity of the alternative comp lement pathway; i.e. a complement-mediated GN. Such diseases, including C3GN and Dense Depo sit Disease, have been termed C3 glomerulopathies and should suggest investigation of the a lternative complement pathway (e.g. functional assays, genetic mutation analysis, and autoa ntibody screening). From Bomback, A.S. and Appel, G.B. Nat. Rev. Nephrol. 8, 634 \200\22364 2 (2012), with permission from Macmillan Publishers. CHAPTER 7 Diseases of the kidney 554 The nephrotic syndrome Introduction A clinical syndrome de \201 ned as proteinuria >3.5g/1 .73m 2 /day that is asso- ciated with hypoalbuminaemia, oedema, hyperlipidaemia, lipiduria (and thrombotic tendency). The syndrome arises as a result of a failure of the glomerular \201 ltration barrier to r estrict the passage of proteins into Bowman \200\231 s space. It implies structural abnorm alities within the glomerular \201 lter. Primer: the glomerular \201 lter (see b p. 916) \200 Comprises: Charged endothelial cell glycocalyx layer. \200 Endothelium and its fenestrations. \200 The glomerular basement membrane (GBM). \200 Interdigitating podocytes that form a slit diaphragm. The passage of albumin, with its net negative charge, through the glomerular \201 lter is prevented by size-speci \201 c factors (e.g. the slit diaphragm) and charge-speci \201 c factors (e.g. the anionic endothelial glycocalyx and GBM). Any albumin that escapes into Bowman \200\231 s space is ef \201 ciently reabsorbed in th e proximal tubule via receptor-mediated endocytosis. It is then degraded and returned to th e circulation as peptide fragments. Many primary and secondary causes of the nephrotic syndrome are now thought to be due to ab normalities of, or injury to, podocytes and the slit diaphragm ( \200\230 podocytopathies \200\231 ). How does proteinuria cause the clinical syndrome? \200 The cause of hypoalbuminaemia is n ot as straightforward as one might think. The liver is actually capable of synthesizing 25g albumin/ day: much higher th an urinary losses. Potential explanations: Larger quantities of albumin pass through the glomerular \201 lter but are reabsorbed and catabolized within the renal tubules (i.e. the degree of proteinuria underestimates protei n losses). Other circulating factors alter the production of albumin by the liver in response to protein losses. Hypoalbuminaemia itself is not usually severe enough to directly explain the profound oedema of the nephrotic syndrome. Potential explanations: The (classical) \200\230 under \201 ll \200\231 hypothesis: low plasma oncotic pressure l d circulating volume l Na + and water retention. The \200\230 over \201 ll \200\231 hypothesis: proteinuria directly causes i tubular Na + reabsorption. THE NEPHROTIC SYNDROME 555 Hyperlipidaemia is caused by i hepatic lipoprotein synthesis s to reduced plasma oncotic pressure. Thrombotic tendency is caused by i hepatic synthesis of procoagulant factors, i platelet ag gregation, and i urinary losses of anticoagulant factors. Causes of the nephrotic syndrome In descending order of frequency in adults: \200 Membran ous nephropathy. \200 Minimal change nephropathy. \200 SLE. \200 Focal and segmental glomerulosclerosis. \200 Mesangiocapillary (or membranoproliferative) glomerulonephritis (MCGN). Renal amyloidosis. \200 IgAN. \200 Light chain deposition disease. 2 Diabetic nephropathy may also present with nephrotic range proteinu- ria and the nephroti c syndrome. Investigation of the nephrotic syndrome \200 SCr, eGFR, U&E, albumin and total protein, L FT, bone pro \201 le. \200 Lipid pro \201 le (preferably fasting). \200 Urine microsc opy for casts or lipid bodies ( b p. 25). \200 uPCR (or uACR). \200 Urinary selectivity index (particularly in children). Calculated as the transferrin:IgG ratio. Selective proteinuria refers to loss of proteins of lower MW (<100kD a), such as albumin or transferrin. Non-selective proteinuria includes proteins of higher M W, such as Igs ( b p. 60). Consider full immunological and serological screen ( b p. 40). \200 USS kidneys. \200 R enal biopsy ( b p. 80). CHAPTER 7 Diseases of the kidney 556 The nephrotic syndrome: general management principles Salt and \202 uid restriction \200 i Na + retention and i blood volume l dependent oedema. 2 Monitor volume status carefully. Include regular measurement of weight, aiming for 0.5 \200\223 1kg loss/day. Chart intake and output wherever possible (however, urinary tract ca theterization is rarely necessary). Salt-restrict to \211 2g/day. \200 Diuretics: a loop diuretic, such as furosemide, e.g. 40mg/day PO, increasing, as necessary, to 250mg daily. In massive oedema, IV diuretics may be requir ed to overcome impaired oral drug absorption ( s to gut oedema). Many clinicians use IV furosemide in combination with salt-poor albumin (e.g. 50 \200\223 100mg furosemide in 100mL 20% human albumin solution over 1h) to augment natriuresis and diuresis; however, the enhanced effect may simply be due to volume expansion. \200 Add-on thiazide-type diuretics (e.g. metolazone 2.5 \200\223 5mg PO od) may help to promote diuresis through a synergistic effect with high-dose loop diuretics ( (cid:2) requires regular (often daily) measurement of Na + and K + to prevent profound elec trolyte imbalances \200\224 use with caution, especially in an outpatient setting). Reduction of proteinuria \200 Proteinuria will itself aggravate tubulointerstitial in \202 ammation ( l \201 brosis) and 6 accelerate renal damage and functional decline. \200 Heavy proteinuria exposes nephrotic patients to infection and malnutrition. \200 Use ACE-I or ARB for their anti-proteinuric effect. Titrate carefully toward full dose (consider night-time administration if hypotension). May reduce proteinuria by up to 50% at 8 weeks and 6 prevent progression. Treat i BP, aiming for \211 125/75mmHg. \200 Protein restriction to 0.8g/kg/day. (cid:2) This requires careful nutritional assessment and dietetic supervision. Hypercoagulability \200 Risk factors for thrombosis in nephrotic syndrome: Duration of syndrome. \200 Degree of proteinuria. \200 Serum albumin <20g/L. \200 Und erlying membranous nephropathy ( b p. 564). 2 Up to 20% of patients with nephrotic syndrome s to membranous nephropathy will develop a DVT. 3 Breathlessness in a nephrotic patient may not always be s to volume overload; it may indi cate pulmonary thromboembolism. THE NEPHROTIC SYNDROME: GENERAL MANAGEMENT PRINCIPLES 557 Flank pain and haematuria suggest renal vein thrombosis ( b p. 590). \200 Prophylactic an ticoagulation with SC heparin (and sometimes warfarin) in high-risk patients ( b p. 892). Formally anticoagulate those with proven DVT or thromboembolic episode. Treat for the duration of the nephrotic syndrome; aim INR 2 \200\223 3. Infection \200 Low IgG levels predispose to infection. \200 Treat infections promptly, with appropriate cover for polysaccharide encapsulated organisms: Strep pneumoniae, Neisser ia meningitidis, Klebsiella pneumoniae, Haemophilus in \202 uenzae, Salmonella typhi, Cryp tocoocus neoformans, Pseudomonas aeruginosa (mnemonic: Some Nasty Killers Have Some Capsule Protection). Offer persistently nephrotic patients vaccination against pneumococcal disease. Infection may also complicate immune suppressive treatment of the nephrotic syndrome ( b p. 540). Dyslipidaemia \200 Nephrotic syndrome l i hepatic synthesis and d catabolism of LDL chole sterol (possibly in response to d plasma oncotic pressure). \200 Successful treatment of elevated LDL cholesterol may prevent CV morbidity and slow decline in renal function. Dietary restriction is usually insuf \201 cient and drug treatment with statins is often appropriate. Treatment of underlying nephrotic syndrome will lead to resolution of dyslipidaemia. CHAPTER 7 Diseases of the kidney 558 Minimal change disease Introduction MCD is less common in adults ( 7 25% of cases of the ne phrotic syndrome) than in children. It generally carries an excellent prognosis. The pathogenesis of minimal change nephropathy (MCD) is uncertain, but altered T lymphocyte activity and production of a glomerular perme- ability factor ( l podocyte dysfunction) ar e suspected. Albuminuria essen- tially results from a failure of the glomerular \201 lter . Etiology May be idiopathic ( p ) or s to: \200 Drugs: NSAIDs (most common), antimicrobial s, lithium, bisphosphonates, and penicillamine (many others). Cancer: hematological malignancies (most common), solid organ malignancies (rare: more comm only associated with membranous nephropathy). Infections (rarely): esp. TB, syphilis, HIV, mycoplasma, HCV. \200 Atopy: 30% of MCD pati ents. \200 Immunizations. Symptoms and signs \200 Oedema, often massive, with facial and periorbital swelling, asci tes, pleural and pericardial effusions. Proteinuria and, rarely, microscopic haematuria on urinalysis. \200 Urine may be foamy (p rotein has a detergent effect). \200 Lipiduria may be visible on microscopy as fat bodies . \200 May present with infections (esp. skin and soft tissue) or hypotension ( s to hypovolaemia). Abdominal pain s to spontaneous peritonitis. \200 Venous thrombosis (e.g. renal or deep v ein). \200 AKI ( s to ATI). Investigations \200 SCr, eGFR, U&E, d albumin, LFT, bone pro \201 le, i cholesterol. \200 uPCR or uACR (tests for selective proteinuria may be helpful) ( b p. 60). Urine microscopy (may show lipid bodies, hyaline or granular casts). \200 Renal biopsy in adults. Histology \200 Normal on light microscopy (hence \200\230 minimal change \200\231 ). \200 Negative immunohistochemistry or immuno \202 uorescence. \200 EM reveals diffuse e ffacement of podocyte foot processes. Treatment \200 Symptomatic treatment, as outlined on b p. 556. \200 MCD remits rapidly with corticosteroids therapy; 80 \200\223 90% of adults will be in remission after 12 weeks of therapy. MINIMAL CHANGE DISEASE 559 Prednisolone 1mg/kg daily (to maximum of 80mg/day) until remission achieved. Taper prednisolone fortnightly, then weekly, until discontinued. \200 2 Ensure treatment is continued for at least 12 weeks at \201 rst presentation to minimize risk of relapse. Taper slowly, e.g. over 6 months. \200 See initiating immunosuppression ( b p. 540). Relapse can be expected in 30 \200\223 70% of cases. First relapse and infrequent relapses should be treated as described earlier. If relapses are more frequent and respond quickly to steroids, then taper immediat ely on remission, aiming for a shorter course. Certain subgroups will be more dif \201 cult to treat. Recurrent relapses occur despite initial response to treatment. \200\230 Frequent relapse \200\231 is generally de \201 ned as two relapses inside 6 months. Relapse occurs during steroid treatment or within 2 weeks of steroid withdrawal ( \200\230 steroid-dependent \200\231 ). No response to steroids at all, i.e. no remission within 12 weeks of treatment ( \200\230 steroid-resistant \200\231 ). 2 In these situations, it is important to review the histology to ensure diagnosis is de \201 nitely MCD, rather than a potentially less steroid-responsive alternative, such as FSGS ( b p. 560). In some cases, this may necessitate a repeat kidney biopsy to ensure that glomerular sampling has been adequate. See initiating immunosuppression ( b p. 540). \200 Consider: Ciclosporin 3 \200\223 5mg/kg/day in two divided doses for 12 months. (cid:2) Monitor GFR carefully ( 51 Cr-EDTA GFR is the most accurate method for monitoring any subtle decline in GFR, e.g. annually) to avoid or limit ciclosporin nephrotoxicity. Tacrolimus 0.05 \200\223 0.1mg/kg/day in divided doses is an alternative. \200 CNIs can be cautiously tapered to the minimum dose required to sustain remission once this has been achieved for 3 months. Consider stopping therapy at 1 \200\223 2 years. Cyclophosphamide 2 \200\223 2.5mg/kg/day for 8 \200\223 12 weeks, then stop. \200 If re mission not achieved with one regimen, consider the other. CNIs may be preferred in \231\200 of childbearing age. MMF has been used as a steroid-sparing agent in children, and small studies suggest modest bene \201 t in adults. Rituximab: several case reports suggest bene \201 t. Further clinical trials are awaited. CHAPTER 7 Diseases of the kidney 560 Focal and segmental glomerulosclerosis (FSGS) Background FSGS is used primarily as a histol ogical description, but also to refer to a particular disease entity. 2 FSGS occurs in the context of glomerular damage and \200\230 dropout \200\231 in an a lready injured kidney where haemodynamic stresses damage remaining nephrons (so-called \200\230 hyper \201 ltration injury \200\231 ). 1 or idiopathic FSGS refers to a de novo glomerulopathy, rather than the result of associated disease. Primary FSGS Introduction \200 \231\202 > \231\200 (with an additional higher risk of p rogressive CKD in \231\202 ). \200 It is 3 x more common in black patients (where p FSGS causes 7 2/3 of the nephrotic syndrome). Black patients are more likely to have mutations in the apolipoprotein L1 ( APOL1 ) gene. Cause remains uncertain, however podocyte injury with subsequent abnormal podocyte responses is characteristic of the disease. As p FSGS disease recurs after transplantation (often immediately), a circulating factor ca pable of disturbing glomerular permeability has been implicated in some patients. This has not yet been fully characterized, but candidates include the soluble form of the urokinase receptor (suPAR) and VEGF. Symptoms and signs \200 Proteinuria (often very heavy); nephrotic syndrome 7 80%. \200 Microscopic haematuria ( 7 50%). \200 i BP ( 7 40%). \200 Impaired renal function ( 7 2 5% at presentation). Young black men presenting with heavy proteinuria (>10g/day), profound hypoalbuminaemia (albumin <20g/L), and renal impairment tend to follow a more severe cours e, often resulting in ESRD. Investigations \200 SCr, eGFR, U&E, d albumin, LFT, i total and LDL cholesterol. \200 U rinalysis, uPCR, or uACR (tests for non-selective proteinuria may be helpful) ( b p. 60). Urine microscopy (may show lipid bodies, hyaline or granular casts). \200 Renal biopsy. Histology \200 A focal (affecting some, but not all, glomeruli) and segmental (affecting part, but not all, of the glomerular tuft) process (see Fig. 7.7). \200 Mesangial matrix expansion, glomerular sclerosis, endocapillary hypercellularity (including foam cells) and hyalinosis (hyaline deposits in the permeable c apillary wall) are all variably present. FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 561 No abnormalities may be apparent if the sample size is small, re \202 ecting the focal nat ure of the disease. Such cases may then be mislabelled as minimal change disease. Biopsies that include juxtaglomerular glomeruli from the corticomedullary junction (affected early i n the course of the disease) have a greater chance of detecting sclerotic lesions. ATN and tubulointerstitial \201 brosis are not uncommon. \200 Immunostaining: no immune deposits, but IgM and C3 may be trapped in sclerotic lesions. EM: foot process effacement and podocyte degeneration. Sub-classi \201 cation Sub-classi \201 cation of both p and, to a lesser extent, s FSGS i nto several histological variants may have prognostic signi \201 cance: \200 Classic FSG S: the prototype. \200 Cellular variant: at least one glomerulus has segmental endocapill ary hypercellularity with capillary occlusion. Tip variant: at least one segmental sclerosis affects the outer \200\230 tip \200\231 of the glomerulus alongside the proximal tubule. Potentially more steroid-responsive with a better prognosis. Collapsing variant: collapsing FSGS is characterized by collapse and sclerosis of the entire glomerular tuft, with GBM wrinkling, cystic tubular changes, and in terstitial \201 brosis. There is no endocapillary proliferation. 2 Often due to HIVAN ( b p. 676), but occurs with other viral diseases (esp. parvovirus B19). Also described in oth er situations, e.g. following high-dose bisphosphonates. Collapsing FSGS typically presents with torrential nephrotic syndrome and rapidly declining renal function. Perihilar variant: perihilar hyalinosis and sclerosis in >50% of the glomeruli with sclerotic lesions. Often seen with the hyper \201 ltration injury of s FSGS . Fig. 7.7 FSGS: a segmental sclerosis in an affected tuft. CHAPTER 7 Diseases of the kidney 562 Secondary FSGS A less speci \201 c histological \201 nding, usually resulting from glome rular hyper \201 ltration (an adaptive response to maintain GFR). Histologically, glo- mer ulomegaly and perihilar sclerosis may be more prominent, with less marked podocyte hyperpla sia and, on EM, less widespread foot process effacement. Secondary FSGS tends to present with less proteinuria and hypoalbumi- naemia than the prima ry variant; however, progressive CKD is relatively common. It is associated with the follow ing conditions: \200 Familial (see below). \200 Infection (podocyte invasion): HIV-associated nephropathy (HIVAN), parvovirus B19. Drugs (podocyte toxicity): Pamidronate, lithium, A interferon, and heroin. \200 Congenital or acquired nephron mass reduction: Renal dysplasia, re \202 ux nephropathy, renovasular disease, partial or unilateral nephrectomy. Hyper \201 ltration as part of a disease process: Morbid obesity, diabetic nephropathy, pre-eclampsia, sickle cell disease. Any cause of glomerular disease with progressive scarring: E.g. membranous GN, IgAN, Alport syndrome, thrombotic microangiopathy, vasculitis. Inherited FSGS Genetic diseases may lead to FSGS through the mutation of genes respon- sibl e for podocyte differentiation and function. These provide useful insights into podocyte fu nction and podocytopathies. However, genetic testing is unnecessary in adults, unless there is a family history, as muta- tions are found in a small minority only and do not in \202 uence treatment. Transient receptor potential cation 6 channel (TRPC6) AD inheritance. A non-selective catio n channel that localizes to the slit diaphragm where it associates with podocin and nephrin . Mutations cause childhood nephrotic syndrome. -actinin 4 AD inheritance. ACTN4 is an a ctin-bound cross-linking protein impor- tant for podocyte cytoskeletal integrity. Presents with low-grade pro- teinuria and slowly progressive CKD. Podocin (NPHS2) AR inheritance. NPHS2 encodes podocin, an integral membrane protein that is localized to the slit diaphragm where it interacts with nephrin. Almost 50 mutations have now been identi \201 ed. May be responsible for 7 1/3 of steroid-resistant nephrotic syndr ome in children. FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 563 FSGS management Overview \200 Symptomatic treatment, as outlined on b p. 556. \200 2 Fo r s FSGS, treat the underlying cause where possible. \200 For p FSGS, the initiation of i mmune suppression is based on estimates of renal prognosis and likely response. For non-nep hrotic proteinuria, symptomatic treatment and watchful waiting are generally advocated. Poor prognostic factors \200 Severe proteinuria (e.g. >10g/day). \200 Progressive CKD. \200 Interstitial \201 brosis on histology. \200 Black race. \200 No response to tr eatment. \200 Histology: presence of collapsing variant (bad) or tip lesion (good). If nephrotic, spontaneous remission is uncommon. Progression to ESRD in 7 50% at 5 years if untreated. Some have a more protracted course, with slow decline in kidney function over d ecades. Disease-modifying treatment. \200 2 See initiation of immune suppression on b p. 540. \200 Prednisolone 1mg/kg/day (max 80mg) (or alternate day 2mg/kg) for a minimum of 4 weeks . Continue, as tolerated, for 16 weeks or until remission is achieved. (cid:2) FSGS is slow to respond, and shorter courses of steroids are unlikely to be of bene \201 t. If response, taper steroids to cessation over 6 months. \200 Unlike minimal change, a deg ree of proteinuria often persists: remission may be complete (<0.3g/day urinary protein + s erum albumin >35g/L + normal renal function) or partial (<3.5g/day urinary protein + 50% re duction from peak + stabilization of renal function). Expect complete or partial remission in 7 40 \200\22360%. \200 Those that relapse whilst on (tapering) steroids or <2 weeks after cessation (on x 2 occasions) are \200\230 steroid-dependent \200\231 , and those with no reduction in proteinuria at 16 weeks are \200\230 steroid-resistant \200\231 . In these groups: Continue low-dose (0.15mg/kg/day) prednisolone. \200 Add ciclosporin 3 \200\223 5mg/kg/d ay in two divided doses. Treat for 6 months. Aim for trough levels 125 \200\223 225ng/mL. Consider measuring accurate iso topic GFR at baseline. If response (expect in 7 70%): continue for 12 months, then taper dose, and stop. Ciclospor in dependence, with relapse on drug withdrawal, is not uncommon. Tacrolimus 0.1 \200\223 0.2mg/kg/day in two divided doses is an alternative, \200 MMF or cyclophosphamide (both with corticosteroids) have been used in this situation but do not e njoy a robust evidence base. \200 X Plasma exchange is sometimes used as adjunctive thera py in severe disease unresponsive to other measures, with the aim of removing a pathogenic circulating factor in some cases. Relapse after treatment is common. PEX is an important pa rt of the treatment of recurrent FSGS post-transplantation ( b p. 418). CHAPTER 7 Diseases of the kidney 564 Membranous nephropathy (MN) Introduction Membranous nephropathy (MN) is one of the commones t causes of the nephrotic syndrome worldwide, with a peak incidence in the 4th to 6th decad es, 2 \231\202 :1 \231\200 . May be idiopathic (IMN) (75%) or secondary (25%) ( b p. 565). Pathogenesis Animal models of MN suggest in situ formation of immune deposits on the outer surface of the GBM (see Fig. 7.8). These deposits activate comple- ment, leading to podocyt e injury. Several proteins have been implicated in the development of MN. \200 The phosph olipase A2 receptor: a transmembrane receptor present in podocytes. Autoantibodies to this receptor (anti-PLA2) have been demonstrated in 7 70% of \200\230 idiopathic \200\231 MN. Neutral endopeptidase: anti-neutral endopeptidase antibodies have been implicated in a rare antenatal form of MN. Cationic bovine serum albumin (cBSA): antibodies to cBSA have been demonstrated in a small number of MN in childhood cases. This protein may be absorbed through the immature GI tract and subsequently lodge in the glomerular capillary wall. Capillary lumen GBM Endothelial cell Mesangium Subepithelial deposits Podocyte Fig. 7.8 Cartoon of subepithelial deposits in MN. Symptoms and signs \200 Proteinuria, occasionally sub-nephrotic or asymptomatic, but ofte n heavy and associated with the nephrotic syndrome ( 7 80%). Microscopic haematuria is relatively common. \200 i BP. \200 Venous thromboembolism ( 2 up to 20% of patients with nephrotic syndrome s to membranous nephropathy will develop a D VT). MEMBRANOUS NEPHROPATHY (MN) 565 Secondary MN \200 More common worldwide than IMN. Presentation with nephrotic syndrome may not coincide with presentation of underlying disease. MN may precede the prese ntation of malignancy by many years. Development of nephrotic syndrome in a patient with a known malignancy may herald a relapse of their cancer. Infections: HBV, HCV, HIV, malaria, syphilis, leprosy, schistosomiasis. \200 Neoplasms: s olid tumors (including lung, colon, breast, kidney, stomach, oesophageal, ovarian, prostate ), lymphoma, leukemia, mesothelioma. Autoimmune disease: SLE, thyroiditis, dermatitis herpetiformis, sarcoidosis, in \202 ammat ory bowel disease, myasthenia gravis. Drugs and toxins: NSAIDs, captopril, gold, penicillamine, lithium, clopidogrel. Investigations \200 SCr, eGFR, U&E, d albumin, LFT, bone pro \201 le, i total and LDL cholesterol, d Igs common (IgG > IgA), HBV and HCV serology, ANA. uPCR or uACR (tests for non-selective proteinuria may be helpful) ( b p. 60). Urine microscopy (may show lipid bodies, hyaline or granular casts). \200 Renal biopsy. \200 Consider investigations for s causes of MN. Approaching MN Careful history and examination are essential. Focus on: \200 Drug history . \200 Risk factors for hepatitis viruses or other infections (travel, sexual history, blood transfusions, etc.). Malignancy? <10% of cases, but proportion increases with age. \200 Check for recent weight loss and a ny localizing symptoms. \200 If history and physical examination alone do not suggest an associated neoplasm, extensive investigation is unwarranted and unlikely to reveal a tumor. X Some clinicians advocate additional imaging (e.g. CT chest, abdomen, pelvis, mammography in \231\200 ) + upper and lower GI endoscopy in patients aged >50. Histology \200 Light microscopy: often normal, but, in more advanced cases, diffuse GBM thickening, with \200\230 spikes \200\231 of GBM extending around subepithelial depos its, are usually evident (best seen on silver stains). Variable degrees of ATI and tubuloin terstitial \201 brosis may also be seen \200 Immunostaining: granular IgG 9 C3 deposits within capillary wall. Presence of the IgG4 subclass may be a pointer toward s MN. \200 EM: subepithelial electron dense deposits. Foot process effacement. CHAPTER 7 Diseases of the kidney 566 Idiopathic MN: treatment Treatment General measures Symptomatic treatment of the nephrotic syndrome ( b p. 556). Treatment of secondary MN Treating the underlying condition (e.g. treatment of HBV or resec tion of tumor) may lead to remission of the MN and the nephrotic syndrome in many cases. Th ere is rarely, if ever, a role for immune suppression. Natural history and risk strati \201 cation The natural history of IMN is variable, with 2 0 \200\223 30% progressing to ESRD and about 25 \200\223 40% remitting spontaneously. It has 6 traditionally been referred to as a \200\230 disease of thirds \200\231 : 7 1/3 spo ntaneously remit, 7 1/3 continue to exhibit low-grade proteinuria with normal renal functio n, and 7 1/3 have progressive CKD, eventually leading to ESRD. Remission may be complete (<0.3g/day urinary protein, with normal serum albumin and normal renal function) or partial (<3.5g/day urinary protein and 50% reduction from peak protein e xcretion, with an improve- ment in serum albumin and stabilization of renal function). Aim to predict the course of the disease. Low risk \200 Normal renal function. \200 Age <50 . \200 \231\200 . \200 Proteinuria <4g/day or spontaneously declining proteinuria. \200 Management: Symptomatic treatment ( b p. 556). \200 Expect remission (may occur up to 2 years after d iagnosis; mean 7 15 months), but regularly reassess risk. High risk \200 Progressive renal impairment. \200 Age >50. \200 \231\202 . \200 Pr oteinuria >8g/day. \200 Persistent proteinuria >4g/day for >6 months, with no evidence of decline (despite ACE-I/ARB). Management: consider disease-modifying treatment with immune suppression, unless renal biopsy demonstrates excessive interstitial scarring ( 6 likely to be irretrievable) or kidneys are small on USS. Most clinicians will wait for 6 months to s ee if spontaneous remission occurs, but treat earlier if severe, symptomatic nephrotic synd rome, or early decline in renal function. IDIOPATHIC MN: TREATMENT 567 Immune suppression \200 Disease-modifying therapy: the aim of immunosuppression is to red uce proteinuria, spare renal function, and induce complete, or partial, remission. Achievement of either complete or partial remission, either spontaneously or after treatment, is associated with a much improved prognosis. 2 See initiation of immune suppression on b p. 540. \200 Alternating monthly steroids and alkylating agents for 6 months \200\224 the \200\230 Ponticelli regimen \200\231 : \200 Month 1: IV methylprednisolone 1g x 3, then oral methylprednisolone (0.5mg/kg/day) for the remainder of the month. Month 2: oral cyclophosphamide 2.0mg/kg/day (or chlorambucil 0.15 \200\223 0.2mg/kg/day). Month 3: repeat month 1. \200 Month 4: repeat month 2. \200 Month 5: repeat month 1. \200 Month 6: repeat month 2. For practical reasons, many clinicians adapt this to a non-cyclical regimen, giving prednis olone 1mg/kg/day PO daily (max 60 mg) (with or without 3 x pulses of IV methylprednisolone at the outset) + cyclophosphamide 1.5 \200\223 2.0mg/kg/day PO, tapering steroids against response. X Whilst this is common practice, it does not have the evidence base available fo r the cyclical regimen. Most clinicians are less familiar with chlorambucil so prefer to use cyclophosphamide. CNIs are an alternative, particularly where alkylating agents are undesirable (or have been unsuccessful). \200 Ciclosporin 3.5 \200\223 5mg/kg/day in two divided doses, with low prednisolone (0.15mg/kg/day) for at least 6 months. Tacrolimus 0.05 \200\223 0.075mg/kg/day in two divided doses may also be used. Start at lower dose, and titrate up, as tolerated. (cid:2) Watch GFR closely. CNI levels sh ould be monitored, particularly during the initial stages. If no response, stop at 6 months. In those that respond, aim to reduce to the minimum dose that maintains remission, and continue for at least 12 months. MMF may have a role (in combination with steroids), but supporting evidence is currently la cking, and there appears to be a higher risk of relapse. Rituximab (e.g. 375mg/m 2 weekly x 4 doses) has been used, with encouraging success in observational studies. Long-term follow-up is currently lacking, so relapse rates are unknown. Relapse \200 Treat with the same regimen that was successful initially, although an alkylating agent should, in general, only be used once more. CHAPTER 7 Diseases of the kidney 568 Hereditary nephropathies Alport syndrome Classically presents as a triad of: \200 Family history of progressive nephropathy. \200 Sensorineural deafness. \200 Ocular abnormalit ies. Defective basement membrane formation in the glomerulus, cochlea, and eye accounts for thes e \201 ndings. Although inheritance is varied, an X-linked inherited mutation in the COL4 A5 gene (>200 described) that encodes A 5 type IV collagen accounts for 80% of cases. This leads to af \202 icted \231\202 , with \231\200 carriers. Autosomal recessive (AR) forms account for 7 15% and auto- somal dominant (AD) for 7 5% (gene: COL4A3 / COL4A4 on chromos ome 2). Affects 7 1 in 5,000 live births.