Edema Nephrotic edema is managed using a combination of sodium restriction (50 \200\22380 m mol/day (this also potentiates the anti- proteinuric effect of RAS inhibition)), and loop d iuretics. Nephrotic patients are relatively diuretic resistant because: \200 Diuretics ar e protein-bound. Hypoalbuminemia increases the proportion of unbound drug which increases i ts vol- ume of distribution. Plasma concentrations are therefore reduced. Diuretic that ent ers into the renal tubules becomes bound to the urinary proteins, limiting its effectivenes s. The loop of Henle is relatively resistant to loop diuretics. Absorption of oral diuretic may be delayed in severely nephrotic patients due to intestinal edema. Renal dysfunction Acute kidney injury Patients with nephrotic syndrome are at risk of devel oping acute renal insuf \201 ciency. This is most common in adults with minimal change/FSG S. It is usually present at the time of the initial presentation with the nephrotic syndrom e and only unusually develops after diagnosis. The potential causes of this are listed in T able 3.2.3. Table 3.2.3. Causes of acute kidney injury in nephrotic syndrome Diuretics should be administered in a stepwise fashion until an appropriate response is ach ieved (e.g. Fig. 3.2.1). If high-dose loop diuretic fails to induce a diuresis, the additio n of a thiazide may be effective. Spironolactone is rarely effective in this setting and sh ould not be used. If there is concern about drug absorption, IV administra- tion (either as bolus or infusion) should be considered. Infusion of salt-poor albumin prior to IV loop di uretic can induce a diuresis in some resistant cases. Caution needs to be exhibited since p ulmonary edema can be precipitated if a diuresis is not induced. Finally, patients resistan t to these measures may require mechanical ultra \201 ltration although this may precipita te acute kidney injury as a result of intravascular volume depletion. In any patient and wi th any treatment the rate of \202 uid loss should be limited to <2 kg per day, to avoid s evere volume depletion and the risk of precipitating acute kidney injury. Close monitoring of electrolytes is required. If hypokale- mia develops, potassium supplements or a potassiu m- sparing diuretic should be added. Pre-renal failure due to volume depletion/sepsis (potentially compounded by the use of ACEIs, ARBs, and NSAIDs). \200 Acute tubular necrosis due to vol ume depletion/sepsis. \200 Acute interstitial nephritis. Usually due to drugs including diuretics. Intrarenal edema causing tubular (and vascular) compression. Transformation of underlying glomerulopathy, e.g. crescentic glomerulonephritis in patient with membranous nephropathy. Renal vein thrombosis. Chronic kidney disease (CKD) With the exception of minimal change disease, nephrotic range proteinuria is associated with an increased risk of progressive renal dysfunction and CKD. The risk is proportional to the degree of proteinuria and is largely independent of the und erlying cause. While the link between proteinuria and progressive renal disease may be due to the severity of the underlying glomer- ular disorder, there is increasing evidence that proteinuria is a mediator of tubulointerstitial in \202 ammation and \201 brosis. In sup port of this, strategies that reduce proteinuria also limit the development of tubulointers titial \201 brosis and renal impairment. Proteinuria Given the evidence that persistent heavy proteinuria pre- dicts progressive ren al dysfunction, reduction of proteinu- ria is an important therapeutic goal. In the absence of disease-speci \201 c therapy, a number of approaches are available. CHAPTER 3.2 Nephrotic syndrome 83 Low protein diet Dietary protein restriction reduces intraglomerular pres- sure (via constr iction of afferent arterioles). However, in nephrotic patients dietary protein restriction risks making the negative nitrogen balance worse. It is therefore recommended that dietary protein intake should be 0.8 g/kg/day plus 1 g of protein per gram of proteinuria. Antiproteinuria therapy works mainly by altering glomeru- lar hemodynamics to reduce intrag lomerular hydrostatic pressure. RAS inhibition The most commonly used drugs are inhibitors of the renin \200\223angiotensin system. These result in efferent arteri- olar dilatation. There is accumulating evidence t hat a combination of ACEIs and ARBs provides an additional antiproteinuric effect, and furt her slows renal function decline when com- pared with either agent alone. Therefore both an ACEI and an ARB at the maximum dose tolerated may be used in nephrotic patients. The serum potassium concentration needs to be carefully monitored. Hyperkalemia can usually be manag ed with dietary measures. Excessive sodium intake can eliminate the bene \201 t of RAS blo ckade. Therefore, the dietary sodium intake should be limited to 50 \200\22370 mmol/day. Other pharmacological approaches NSAIDs and ciclosporin both cause afferent arteriolar cons triction, and dipyridamole causes efferent arteriolar dilatation. They have all been used i n nephrotic patients but the clear bene \201 t (and safety) of RAS inhibition has led to o ther agents being used less commonly. In morbidly nephrotic patients with an inadequate res ponse to RAS inhibition, NSAIDs can be very effective. They may, however, precipitate AKI, particularly in volume- depleted patients, and therefore need to be used very cautiously. Nephrectomy Rarely, the nephrotic syndrome can be very severe and resistant to treatment. I n such patients the complications of nephrotic syndrome can become potentially life-threat- ening; nephrectomy, dialysis and intensive nutrition may be the preferred treatment. Nephr ectomy can be achieved surgically, radiologically by renal artery embolization, or medicall y using high dose diu- retics, RAS inhibitors, and NSAIDs. Oral loop diuretic eg furosemide 40mg bd or bumetanide 1mg bd No response Sequentially double the dose until diuresis is induced Maximum dose furosemide 250mg bd bum etanide 5mg bd Hyperlipidemia The severity of hyperlipidemia is proportional to the degree of proteinuria. Therefore successful disease-speci \201 c treatment or antiproteinuria treatment usually leads to an improvement in the lipid pro \201 le. Dietary fat restriction has only a modes t effect on hyperli- pidemia in nephrotic patients. Statins (HMG CoA reductase inhibitors) are the most commonly used agents for the treatment for nephrotic hyperlipidemia. LDL chole sterol can be reduced by 35 \200\22340% and triglycer- ides by 15 \200\22330%. Lipoprotein (a) concentrations are not affected. Statins are generally safe and indeed there is some ev i- dence to suggest that statins may reduce proteinuria and slow renal function decline. Re versible myopathy can complicate statin use. Rarely this can lead to rhabdomyolysis and AKI . Serum creatine kinase levels should be monitored after initiation of a statin. Fibrates h ave a less potent effect on LDL-cholesterol than statins, and since lowering LDL is the mai n aim in nephrotic patients, \201 brates are uncommonly used. Fibrate-induced muscle inju ry is also more common in patients with renal impairment. No response Add oral thiazide diuretic eg hydrochlorthiazide 25 - 50mg bd or metolazone 2.5 - 5mg od No response Administer loop diuretic intravenously either as bolus injection twice daily or as infusion No response Add intravenous 20% albumin (50 - 100ml) followed by IV diuretic Hypercoagulability Prophylactic anticoagulation The role of anticoagulation in nephrotic pa tients without evidence of thrombosis is unclear. Relatively immobile patients, e.g. during hospitalization, with a serum albumin <25 g/L should be given low-dose No response Mechanical ultrafiltration Fig. 3.2.1 An approach to the management of edema in the nephrotic syndrome. P. TOPHAM 84 anticoagulation (e.g. heparin 5000 U bd SC) until normal mobility has returned. Many clinic ians would also administer full-dose anticoagu- lation to those at particularly high risk o f thromboembolic events, i.e. serum albumin <20 g/L, underlying membra- nous nephropathy, s ubstantial proteinuria (>10 g/day), par- ticularly when additional risk factors are present , e.g. reduced mobility, massive edema, heart failure, substantial diuresis. However, the e vidence base to support this approach is weak. The response to heparin may be blunted due t o reduced levels of antithrombin III, therefore higher doses may be necessary. In contrast, the response to warfarin is enhanced because of reduced protein binding. This is of partic ular relevance during remission of proteinuria, when the anticoagulant effect of a stable d ose of warfarin decreases. An alternative approach is treatment with aspirin and dipy- rida mole, which may also be bene \201 cial given the associated cardiovascular risk. Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatm ent. Clin Nephrol 2004; 62: 245 \200\223259. Glassock RJ. Prophylactic anticoagulation in n ephrotic syndrome: a clinical conundrum. J Am Soc Nephrol 2007; 18: 2221 \200\2232225. Koomans HA. Pathophysiology of oedema in idiopathic nephrotic syndrome. Nephrol Dial Transpl 2003; 18(Suppl 6): vi30 \200\22332. Internet resources Nephrotic syndrome information: http://www.kidney.org.uk/Medical-Info/kidney- disease/nephsyn_adult.html Patient informatio n about childhood nephrotic syndrome: http://www.ich.ucl.ac.uk/factsheets/families/ F040225/ Overview of nephrotic syndrome \200 \223 suitable for patient information: http://www.merck.com/mmhe/sec11/ch144/ch144c. html See also History and clinical examination of patients with renal disease, p. 2 Urinalysis a nd microscopy, p. 8 Renal biopsy, p. 32 Immunological investigation of renal disease, p. 36 Proteinuria and/or hematuria, p. 76 Minimal change disease, p. 86 Focal segmental glomerul osclerosis, p. 92 Membranous nephropathy, p. 106 Therapeutic anticoagulation Patients with clinically apparent thromboembolic disease should be anticoagulated with hepa rin followed by warfarin. Treatment should be continued for the duration of the nephrotic s yndrome (or at least until serum albumin rises to >25 g/L) unless the risks of anticoagulat ion become excessive. The optimal treatment of clinically silent thromboembo- lism is less clear-cut. Asymptomatic pulmonary emboli should prompt full anti- coagulation, and most cli nicians would fully anticoagulate those with silent deep venous thrombosis. Diabetes mellitus, p. 144 Further reading Charlesworth JA, Gracey DM, Pussell BA. Adult nephrotic syndrome: Non-speci \201 c strategies for treatment. Nephrology (Carlton) 2008; 13: 45 \200\22350. This page intentionally left blank P. TOPHAM 86 Minimal change disease Thromboembolism This can involve conventional sites; however, in children cerebral venous t hrombosis and arterial thrombosis are rare but devastating consequences of nephrosis. Minimal change disease (MCD) is the cause of nephrotic syndrome in 90% of children, 50% of postpubertal children, and 10 \200\22315% of adults. Epidemiology MCD is most common in children but can be seen in adults of all ages. There is geographical variation in incidence: \200 \200 Peritonitis This remains a significant problem, particularly in the developing world. It occurs mainly in children and is caused by encapsulated organisms. 1 pmp in the UK; 27 pmp in USA. Table 3.3.1 Causes of minimal change disease It is more common in South Asians and Native Americans and less common in Africans. Before puberty, the male:female ratio is 2:1; the gender difference disappears after puberty. Drugs NSAIDs \200 Interferon- \200 Lithium (rare) \200 Gold (rare, usually causes membran ous nephropathy) \200 Pamidronate (rare, usually causes FSGS) Etiology This is unknown but a disorder of T-lymphocytes has been proposed. This is support ed by: \200 Allergy Pollens \200 House dust \200 Insect stings \200 Immunizations the association with lymphoma (particularly Hodgkin \200\231s disease); the association wit h HLA-DR7; the association with atopy (up to 30% of children in some series); MCD relapse f ollowing allergen exposure in sensitive individuals; remission of nephrotic syndrome with i ntercurrent mea- sles infection. \200 Malignancy Hodgkin \200\231s disease \200 Mycosis fungoides \200 Chronic lymphocytic leukemia (unc ommon) Others Associations with lupus nephritis and IgA nephropathy (uncommon) In addition, a circulating factor of T-cell origin has also been postulated: \200 Chronic graft-versus-host disease supernatants from patient-derived T-cell hybridomas induce proteinuria and podocyte foot pr ocess efface- ment in rats; a single report of proteinuria resolution after a renal transpl ant from a donor with MCD. Laboratory investigations Urinalysis Nephrotic range proteinuria is invariably found in MCD : \200 \200 >50 mg/kg/day or >40 mg/h/m2 in children; >3.5 g/day in adults. Although most cases of MCD are idiopathic, infre- quent cases have an identi \201 able cau se. These are listed in Table 3.3.1. The proteinuria in MCD is highly selective (i.e. mainly involves loss of albumin and low mo lecular weight proteins). Protein selectivity can be determined from the ratio of IgG to al bumin or transferrin clearance. A ratio of <0.1 indicates highly selective proteinuria. Val ues >0.15 \200\2230.2 imply loss of higher molecular weight proteins and raise doubt about a diagnosis of MCD. Glycosuria can result from transient proteinuria-induced tubular dysfun ction. Clinical presentation The typical presentation is with edema of rapid onset. Up to two-thir ds present after an infective episode (typically infection of the upper respiratory tract). Symptoms and signs are the same as for any cause of the nephrotic syndrome (see Chapter 3. 2). Microscopic hematuria is rare in MCD: its presence is more typical of focal segmental g lomerulosclerosis (FSGS). Hypertension occurs in 30 \200\22389% of adults and 14 \200\22321 % of children. Blood chemistry The albumin concentration is reduced often to <20 g/L. Serum IgG is also co nsiderably reduced. By contrast, IgM is increased and IgA tends to be unchanged. Electrolyt es are usually normal. Hyponatremia may result from volume-depletion-induced ADH release. I onized calcium may be reduced in prolonged nephrosis due to 25-(OH) vitamin D3 loss in the urine. Hypokalemia can result from transient proteinuria-induced tubular dysfunction. Complications of nephrotic syndrome These occur uncommonly in patients with MCD: Acute kidney injury This usually occurs following aggressive diuresis but other causes incl ude: \200 \200 \200 renal vein thrombosis; drug-induced interstitial nephritis; interstitial edema leading to t ubular compression. CHAPTER 3.3 Minimal change disease 87 Diagnosis In children aged between 1 year and puberty, nephrotic syndrome is assumed to be due to MCD. Renal biopsy is reserved for those children with an atypical presentation: \200 \200 \200 \200 \200 Increased urea and creatinine may be seen as the result of AKI. Hematology Hemoglobin concentrations can be increased acutely due to intravascular volume c ontraction. Chronic nephrosis can be associated with microcytic ane- mia due to urinary tra nsferrin loss. microscopic hematuria; reduced complement levels; impaired renal function; marked hypertens ion; absence of steroid response. Pathology By de \201 nition MCD is associated with completely normal light microscopic and immunohistological appearances (Fig. 3.3.1). By electron microscopy the abnormalities are limited to podocyte effacement. This appearance is not speci \201 c and can be seen in non sclerosed glomeruli in primary FSGS. It is accepted that small numbers of patients with cli nical courses compatible with MCD may have: \200 mild mesangial hypercellularity (3 \200 \2235%); \200 small amounts of mesangial IgG, complement C3, and occasionally IgA deposit ion. In addition, if ciclosporin treatment is being contemplated, a baseline renal biopsy should be performed so that an assessment of nephrotoxicity can be made on later biopsies. In adu lts and older children without systemic disease there is no reliable way to predict the glo merular pathology with con \201 dence by noninvasive criteria alone, therefore a renal bio psy should be performed. The biopsy is not always able to discriminate between MCD and FSGS . The latter diagnosis relies upon the identi \201 cation of seg- mental sclerosing lesion s. Since these are focal, they may be missed through sampling error. Sampling the corticome dullary junction improves the chances of identifying FSGS if it is present. Mesangial IgM deposition (often with mild mesangial hyper- cellularity) can be seen but man y regard this as a separate entity (IgM nephropathy). IgM deposition is associated with red uced steroid respon- siveness (50% vs 90%). Natural history In adults 5 \200\22310% of patients will have a spontaneous remis- sion wit hin a few months. By 18 and 36 months the spontaneous remission rate increases to 50% and 7 0% respectively. This has to be bal- anced against the signi \201 cant morbidity and morta lity that accompanies untreated nephrosis. MCD tends to run a relapsing \200\223remitting c ourse. The length of the disease course is determined by the age at onset: onset at a young age predicts a longer course before long-term remission is achieved: \200 \200 1 two-thirds of children have at least one relapse; 50% of children have more than four relap ses. Long-term remission occurs in 75% of responders who remain in remission for >6 months. Rela psers tend to achieve long-term remission after an average of 3 years. Fewer than 5% of chi ldren have further relapses after entering adulthood. MCD does not progress to renal failur e. If renal failure develops, a repeat biopsy will usually dem- onstrate FSGS. Whether this represents evolution of MCD into FSGS, or a missed diagnosis of FSGS on the initial biopsy , is unknown. 2 Treatment Corticosteroids are the treatment of choice in MCD and are effective in most pati ents. Complete remission occurs in >90% of patients. Children tend to respond rapidly with >80% remission within 4 weeks and almost all within 8 weeks. Adults respond more slowly wit h >25% taking as long as 16 weeks to remit. Fig. 3.3.1 (1) Light micrograph of H&E-stained renal biopsy section showing normal glomerul ar morphology. (2) Electron micrograph demonstrates extensive effacement of podocyte foot p rocesses (arrowheads) but otherwise normal glomerular ultrastructure. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leicester, UK.) P. TOPHAM 88 \200 \200 cataracts; osteoporosis; Suppression of the hypothalamic \200\223pituitary \200\223adrenal axis. To avoid serious side-effects of steroids with prolonged or repeated use, \200\230se cond-line agents \200\231 are often used in this circumstance. (1) Cyclophosphamide (2 \200 \2232.5 mg/kg/day orally) for 8 \200\22312 weeks or chlorambucil (0.2 mg/kg orally) for 8 w eeks. These induce sustained remission at 2 years in 67% treated for 12 weeks versus 30% tr eated for 8 weeks (others have not shown this difference). Frequent relapsers are more like ly to respond than ster- oid-dependent children (70% versus 30%). Cyclophosphamide has pote ntially serious side-effects including: \200 \200 \200 \200 \200 Initial approach General measures to deal with consequences of nephrotic syndrome are descr ibed the Chapter 3.2. Children 1. Treatment of the \201 rst episode Prednisolone 60 mg/m2 (maximum 60 mg) per d ay: \200 \200 \200 75% respond within 2 weeks; 80 \200\22385% respond within 4 weeks; >90% respond within 8 we eks. Continue steroids at the initial dose for 4 weeks after the urine becomes protein-free. Swi tch to alternate day dosing for 8 weeks, then taper every 2 weeks by 15 mg/m2 on alternate days until stopped. The relapse rate is lower if steroids are maintained for 3 \200\2234 mo nths rather than for 2 months. Treatment failure may be due to poor compliance or poor abso rption from an edematous gut. If proteinuria persists at 4 weeks consider increasing the do se of oral steroids or giving three pulses of methylpred- nisolone (1 g/1.73 m2) on alterna te days. Failure to respond to this is de \201 ned as steroid resistance. Potential outcom es: \200 \200 infection; alopecia; gonadal toxicity; hemorrhagic cystitis; longer-term risks of hematolog ical malignancy. The risks are probably minor given the doses used in an 8 or 12 week regimen but nonetheles s need to be weighed against the fact that MCD is usually self-limiting. (2) Levamisole (2. 5 mg/kg on alternate days for 3 months) can induce remission in just under 50% of patients but most relapse within 3 months of stopping the drug. However, it is a relatively safe ste roid-sparing alternative that may be used until spontaneous remission occurs. The most seri ous side-effect is reversible neutro- penia. (3) Ciclosporin 150 mg/m2 per day in two doses (aiming for trough levels of 100 \200\223200 ng/ml) leads to remission in 85% of frequentl y relapsing or steroid-dependent patients. However, relapse usually occurs within several m onths of stopping treatment. Prolonged treatment may therefore be necessary which runs the risk of nephrotoxicity. Some advocate renal biopsy after 18 months of treatment to identify evidence of subclinical nephrotoxicity. The optimal length of treatment is unclear but man y advocate 1 year of treatment followed by slow withdrawal. (4) Mycophenolate mofetil. Ther e are only limited data for its use in children. A small number of retrospective series hav e been described which suggest bene \201 t in preventing relapse once remission is achieve d; however, well-designed trials need to be performed before it can be recommended for use in childhood MCD. 30% of children have only one episode and no relapses. 10 \200\22320% relapse several month s after treatment is discontinued. Most have three or four steroid- responsive episodes bef ore prolonged remission is achieved. 40 \200\22350% relapse rapidly after stopping steroids and relapse frequently (four or more relapses per year), or relapse while still on steroid s (frequent relapsing and steroid-dependent disease respectively). 2. Treatment of \201 rst relapse Following remission, patients should monitor their weigh t frequently and test their urine daily. A \201 nding of 3+ protein for 3 consecutive day s indicates relapse and should be treated promptly to avoid nephrotic complica- tions. The \201 rst relapse is treated with a second course of pred- nisolone as indicated above alt hough a shorter course may be appropriate (dose reduction 3 \200\2235 days after proteinuri a has resolved). 3. Treatment of frequently relapsing or steroid-dependent disease A number of treatment opt ions are available: (1) Prednisolone 60 mg/m2 per day until the urine has been protein-free for 3 days, then 40 mg/m2 on alter- nate days for 4 weeks. 4. Steroid-resistant nephrotic syndrome in children 10% of children will not respond to ste roid treatment. In this setting a renal biopsy should be performed and genetic screening sh ould be undertaken to guide further treatment. 10 \200\22330% of patients with sporadic ste roid-resistant neph- rotic syndrome will have mutations of NPHS2, the gene encoding the pod ocyte protein, podocin. Such patients tend to have early onset of disease and a high risk o f progressive renal dysfunction. Treatment with steroids or \200\230second-line \200\231 a gents is ineffective. A further 10% of patients with sporadic steroid-resistant nephrotic s yndrome will have mutations of WT1 (the Wilms \200\231 tumor suppressor gene). Such patient s are also resistant to treatment. (2) Prednisolone 40 \200\22360 mg/m2 per day until the urine has been protein-free for 4 \200\2235 days. Alternate day therapy is then begun and the dose tapered to 15 \200\22320 m g/m2 on alternate days (depending on the steroid dose at which relapse has occurred). This dose is continued for 6 \200\22312 months. Option (2) may be better since the duration of high dose steroid therapy is shorter, theref ore steroid side-effects may be minimized. Repeated or prolonged courses of steroids may be compli- cated by signi \201 cant steroid side-effects: \200 \200 growth impairment; weight gain; CHAPTER 3.3 Minimal change disease 89 0 \200\22320% will have persistent heavy proteinuria after 16 weeks of steroid treatment an d are classi \201 ed as ster- oid-resistant. In the absence of an identi \201 able genetic cause, further treatment options need to be considered: \200 Alkylating agents. There is no evidence to support the use of cyclophosphamide or chlorambu cil in this setting. Ciclosporin. Remission rates of 40 \200\22350% can be achieved with 15 0 \200\223200 mg/m2/day of cyclosporin A. Remission is seen within 1 month in 50% of these patients. Subsequent relapses can also become steroid-sensitive and the risk of developing progressive renal impairment is also reduced. Mycophenolate. There is insuf \201 cient evi dence about its effectiveness in this setting. Methylprednisolone. Aggressive regimens usin g pulse methylprednisolone (30 mg/kg given IV every other day for 2 weeks, weekly for 8 wee ks, every other week for 8 weeks, monthly for 9 months, and then every other month for 6 mo nths), oral prednisone (2 mg/kg every other day), and cyclophosphamide (2 \200\2232.5 mg/kg /day) if no response is observed after 2 weeks of pulse therapy, have been shown to induce remission in 60% of patients. The presence of segmental sclerosis on the renal biopsy reduc es the ef \201 cacy of this regimen. Renin \200\223angiotensin system blockade. There are few data about the use of ACEIs and ARBs in children. Nonetheless by extrapolation from adu lt data, they should be used in children with persistent nephrotic- level proteinuria. Obvi ously they should be discontinued if refractory hyperkalemia or progressive renal dysfunc- tion ensues. 2. Treatment of the \201 rst relapse The \201 rst relapse is treated with a further cou rse of pred- nisolone identical to that described above. 3. Treatment of frequently relapsing and steroid-dependent disease Oral cyclophosphamide 2 mg/kg/day for 8 weeks. 75% and 66% of frequent relapsers will be relapse-free at 2 and 5 ye ars respectively with this regimen. The success rate is lower in steroid-dependent disease but the success rate may be enhanced by increasing the dura- tion of therapy to 12 weeks al though the bene \201 t of this approach has not been universally noted. Ciclosporin. Furth er relapses or steroid-dependent disease after cyclophosphamide treatment can be treated wi th ciclosporin 4 \200\2236 mg/kg/day. 70 \200\22390% of patients will completely or partial ly remit. However, 60 \200\22390% will relapse after therapy is withdrawn (usually within 6 months). There is some evidence that if ciclosporin is continued for 1 year and then gradu ally withdrawn, prolonged remission can be achieved. Evidence suggests that ciclosporin dos es of <5.5 mg/kg/day do not produce nephrotoxicity even after 20 months of treatment. Other treatment options: \200 Adults 1. Treatment of the \201 rst episode There is no consensus about the optimal stero id regimen to be used in the treatment of adult MCD. However, a typical treatment regimen i s: Oral prednisolone 1 mg/kg/day (maximum dose 80 mg/ day) for 8 weeks even if remission is induced before this. If remission is not achieved by 8 weeks, prednisolone is continued un til 1 week after remission has been induced, to a maximum of 16 weeks. Alternatively IV met hylpred- nisolone can be considered in those without remission at 8 weeks. Gastric protecti on with an H2 blocker or proton pump inhibitor should be commenced. Bone protection with ca lcium/vitamin D or bisphosphonates should also be considered. On remission reduce to half d ose for 4 \200\2236 weeks, then gradually reduce the dose over next 4 \200\2236 weeks, then stop. Several outcomes can be observed: \200 80 \200\22395% of patients will remit. \200 <50% remit within 4 weeks; 10 \200\22325% will only remit after 3 \200\2234 months of treatment. Older patients in general take longer to remit. 50 \200\22375% will relapse aft er remission is achieved. This usu- ally occurs within 1 year of steroid cessation although occasionally relapses can develop after years of remis- sion. Relapses can be triggered by infection or allergy. 10 \200\22325% of patients will have frequent relapses. 25 \200\2233 0% will relapse while still taking steroids ( \200\230steroid- dependent \200\231). Mycophenolate mofetil (MMF). There is limited pub- lished experience with MMF suggesting po tential bene \201 t in patients with steroid-dependent and -resistant dis- ease. Further s tudies are required before the role of MMF in MCD can be determined. Azathioprine, levamiso le and rituximab have been shown to be effective in very small studies. However, the data a re so limited that their use cannot be recommended. 4. Treatment of steroid-resistant disease Steroid-resistant MCD is uncommon and often repre sents: \200 \200 a missed diagnosis of FSGS; the presence of another MCD variant such as mesangial hypercell ularity; inadequate treatment (<8 weeks treatment, <1 mg/kg/ day of prednisolone, or altern ate day treatment). For truly steroid-resistant MCD the options are: \200 Cyclophosphamide (2 mg/kg/day for 8 \200\22312 weeks), usually started while the patient is taking steroids, induces remission in many patients. Relapses can occur but these are ofte n steroid responsive. Ciclosporin (4 \200\2236 mg/kg/day). This regimen will induce partial or complete remission in 50% of patients. Since early withdrawal will often lead to early relapse, continu- ation of full-dose treatment for 12 months followed by slow tapering of the dose is recommended and will often maintain prolonged remission. \200 Follow-up Once remission is achieved patients should monitor their weight and dipstick test the urine regularly. \200 P. TOPHAM 90 Weight gain, edema, and 3+ proteinuria on dipstick on at least 3 consecutive days should be treated as a relapse and medical attention should be sought immediately. Regular nephrolog y follow-up is not essential for those who stay in remission for at least 1 year. Frequent relapsers or steroid-dependent or -resistant patients should continue with regular nephrolo gy follow-up. Korbet SM. Management of idiopathic nephrosis in adults, including steroid-resistant nephro sis. Curr Opin Nephrol Hypertens 1995; 4: 169 \200\223176. Niaudet P. Nephrotic syndrome in children. Curr Opin Pediatr 1993; 5: 174 \200\223179. Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change disease: clinical characteristics , treatment, and outcomes. Clin J Am Soc Nephrol 2007; 2: 445 \200\223453. See also Urinalysis and microscopy, p. 8 Renal biopsy, p. 32 Nephrotic syndrome, p. 80 Foca l segmental glomerulosclerosis, p. 92 Internet resources Nephrotic syndrome in children support group: http://www.nephrotic.co.uk/ National Kidney Federation: http://www.kidney.org.uk/ Further reading Brodehl J. The treatment of minimal change nephrotic syndrome: lessons lear ned from multicentre co-operative studies. Eur J Pediatr 1991; 150: 380 \200\223387. This page intentionally left blank P. TOPHAM 92 Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is not a single disease entity but rather a group of clinicopathological syn- dromes that present with similar histological appearances on r enal biopsy. Usually FSGS presents with proteinuria or nephrotic syn- drome. It accounts fo r up to 35% of nephrotic syndrome in adults but is uncommon in children. It is associated w ith progressive renal dysfunction with a risk that is proportional to the level of proteinu ria. FSGS can be classi \201 ed as primary (idiopathic) or secondary (to a wide variety of disease processes). Table 3.4.1 Causes of FSGS Primary (idiopathic) FSGS Secondary FSGS Familial FSGS due to mutations in: -Actinin 4 (autosomal dominant) \200 Podocin (autosomal recessive) \200 TRPC6 (autoso mal dominant) Virus-associated: HIV (HIV-associated nephropathy) \200 Parvovirus B19 Drugs: Pamidronate \200 Lithium \200 Interferon- \200 Heroin Epidemiology The prevalence of FSGS is increasing in both adults and children. Primary FSGS is marginally more common in males. The risk of progressing to ESRD is two times higher in males than in females. It is two to three times more common in Blacks than in Caucasians ( it accounts for up to 50% of nephrotic syndrome in adult Blacks in the USA). Progression to ESRD is also four times more likely in Blacks than in Caucasians. There is geographic vari ation in prevalence. For example: \200 in the USA, FSGS is the commonest cause of nephrot ic syndrome in adults (35 \200\22350%) and is the commonest pri- mary glomerular cause of E SRD (2.3% of all ESRD patients); Secondary FSGS due to adaptive responses: Reduced renal mass Oligomeganephronia \200 Unilateral renal agenesis \200 Renal dysplasia \200 Re \202 ux nephropathy \200 Chronic allograft nephropathy Normal renal mass \200 Hypertension \200 Obesity \200 Sickle cell anemia \200 Cyano tic congenital heart disease by contrast, in Spain FSGS accounts for 12% of adult Secondary FSGS Genetic disease -Actinin 4 \200 \200 nephrotic syndrome. Etiology The causes of FSGS are listed in Table 3.4.1. This is inherited in an autosomal dominant pattern. -Actinin 4 is an actin cross-linking protein the mutant form of which binds to actin with higher af \201 nity. It is postu- lat ed that this causes alterations to the podocyte cytoskeleton and dysfunction. It characteri stically causes subnephrotic proteinuria. Primary FSGS By de \201 nition the etiology of primary FSGS is unknown. The focus of injur y is the podocyte although the mediators of this injury are unknown. Some argue that primar y FSGS and minimal change dis- ease (MCD) may be part of the same disease spectrum and ther efore share a common etiology. This is sup- ported by: \200 the morphological similarity of MCD glomeruli with Podocin \200 \200 This is inherited in an autosomal recessive pattern. It characteristically causes steroid-r esistant disease in childhood. Sporadic cases have also been described in both children and adults. This is more common in children and 20 \200\22330% of sporadic FSGS in children ha ve podocin (NPHS2 gene) mutations. Podocin is an integral membrane protein that interacts w ith nephrin and CD2-associated protein (CD2-AP) and therefore has a critical role in mainta ining glomerular permselectivity. nonsclerosed glomeruli in FSGS; the observation in a small number of cases of MCD of apparent evolution with time into FSGS; the presence of a circulating factor in some patients with FSGS. This factor is thought to be responsible for the early recurrence of proteinuria after transplanta- tion in some pati ents. This factor has not yet been characterized. TRPC6 \200 This view is not universally held, however. The differential expression of cyclin-dependent kinase inhibitors, dystro- glycans, TGF- , and cytotoxic T-lymphocyte effectors in MCD an d FSGS argue that MCD and FSGS have divergent etiologies. Mutations of the transient receptor potential cation 6 channel cause autosomal dominant FSG S. TRPC6 localizes to the slit-diaphragm in association with podocin and nephrin. Alteratio ns in calcium \202 uxes caused by the TRPC6 muta- tions probably underlie the development of FSGS through alteration of podocyte cytoskeletal structure. CHAPTER 3.4 Focal segmental glomerulosclerosis 93 Complement levels and other soluble immunological investigations are normal. Tubular dysfun ction (aminoaciduria, phosphaturia, glycosuria) may develop as a consequence of proteinuria - induced injury. CD2-AP \200 CD2-AP interacts with nephrin and podocin and is prob- ably important for the maintenance o f slit-diaphragm integrity. CD2-AP mutations have been identi \201 ed in a small number of cases of FSGS, although causality has not been established. Pathology FSGS is classi \201 ed into a number of histological variants based on their lig ht microscopic appearances. This classi \201 cation is used for both primary and secondary forms but first requires exclusion of other glomeru- lopathies that may result in an FSGS pattern of injury (e.g. hereditary nephritis, healed in \202 ammatory GN) by immuno \202 uorescence and electron microscopy, and clinical correlation. In this classi \201 cation \201 ve variants have been descri bed (Table 3.4.2). In addition, other variants have been proposed to fall within the FSGS spectrum (e.g. C1q nephropathy, FSGS with diffuse mesangi al hypercellularity). It should be understood that these variants are simply pathological d escriptions and their clinical implications have not yet been tested prospectively. Viral-mediated FSGS Parvovirus B19 \200 This has been detected in 80% of biopsies and >85% of serum samples from patients with coll apsing FSGS. It is highly prevalent in the general population, and there- fore causality ha s not yet been established. Human immunode \201 ciency virus (HIV) \200 There is robust evidence that HIV causes collapsing FSGS. HIV can directly infect podocytes . A number of HIV gene products have been shown to disrupt podocytes: Nef induces dediffere ntiation and proliferation of podocytes and also disrupts the cytoskeleton; Tat suppresses nephrin expression; vpr synergizes with nef and enhances podocyte injury. \200 Drug-induced FSGS \200 Table 3.4.2 Morphologic variants of FSGS Heroin, pamidronate, lithium, and -interferon have been associated with FSGS. The mechani sm of injury is unclear but direct podocyte toxicity is likely. FSGS can remit following dr ug withdrawal. FSGS, not otherwise speci \201 ed (NOS) (classic FSGS) FSGS, perihilar variant FSGS, cellu lar variant FSGS, collapsing variant (collapsing glomerulopathy) FSGS, tip variant Structural maladaptive FSGS \200 Common forms of secondary FSGS are caused by adaptive glomerular responses. These usually r elate to: congenital renal mass reduction (renal dysplasia, oligomeganephronia, unilateral renal agenesis); acquired renal mass reduction (reflux nephropathy, surgical resection, chr onic allograft nephropathy); hemodynamic stress (obesity, hypertension, sickle cell disease ).