a number of autoantibodies are associated with GN, their exact role in the

pathogenesis of GN is still unclear.

177

Glomerular damage generally occurs in two phases: acute and chronic. During the

acute phase, immune reactions occur within glomeruli that stimulate the complement

cascade, ultimately resulting in glomerular damage. Nonimmune mechanisms that

occur in response to loss of nephron function and hyperfiltration of remaining

nephrons are characteristic of the chronic phase.

GN often causes acute kidney failure. Patients with damage to more than 50% of

glomeruli in the presence of rapid loss in kidney function (over the course of days to

weeks) are classified as having rapidly progressive glomerulonephritis (RPGN).

178

If

kidney involvement is severe, signs and symptoms of uremia may develop. RPGN

may be classified based on the immunopathogenic etiology of the glomerular damage:

(a) immune complex deposition (e.g., LN); (b) nonimmune deposit-mediated

mechanism (e.g., Wegener granulomatosis); and (c) sclerotic lesions of the

glomerulus (e.g., FSGS).

177 This chapter focuses on the treatment of the more

common forms of chronic GN (i.e., LN, Wegener granulomatosis, FSGS).

LUPUS NEPHRITIS

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease

characterized by abnormalities in cell-mediated immunity, such as B-cell

hyperresponsiveness and defective T-cell–mediated suppressor activity. In certain

predisposed individuals, SLE can lead to the development of LN, a secondary form

of GN. LN is the prototypical immune complex–mediated kidney disease,

characterized by deposition or in situ formation of autoantibody–antigen complexes

along the glomerular capillary network. LN remains an important cause of mortality.

Up to 60% of adults with SLE have some degree of kidney involvement later in the

course of their disease, discernible from clinical evidence of kidney damage: heavy

proteinuria, hematuria, decreased eGFR, and hypertension. Early in the disease,

laboratory abnormalities indicative of kidney involvement are seen in approximately

25% to 50% of patients

177

(see also Chapter 33, Systemic Lupus Erythematosus).

CASE 28-4

QUESTION 1: S.L., a 34-year-old black woman with a 7-year history of SLE, presents to the nephrology

clinic for follow-up of LN. BP of 160/95. Pertinent laboratory values are as follows:

Serum Na, 146 mEq/L

K, 4.2 mEq/L

Cl, 100 mEq/L

CO2

content, 25 mEq/L

SCr, 2.0 mg/dL

BUN, 20 mg/dL

WBC count, 9,600/μL

RBC indices are normal. Platelet count is 175,000/μL. Her 24-hour urine contains 2.3 g of albumin (normal,

<30 mg/day), and her urine analysis shows 12 RBCs/high-power field (HPF) (normal, 0–3). Compared with her

visit of a week ago, S.L.’s kidney function and urinary indices (proteinuria, hematuria) show substantial

worsening of her nephritis. S.L. was hospitalized, and a kidney biopsy showed inflammation of 40% of the

glomeruli. What subjective and objective data in S.L. are consistent with a diagnosis of LN, and what is the

stage of her nephritis?

S.L. has clinical evidence of kidney damage as demonstrated by her proteinuria,

hematuria, and a slightly increased SCr concentration. Glomerular damage is most

evident by the presence of RBC or red cell casts in the urine, a finding observed in

S.L.

Classifications

The International Society of Nephrology and the Renal Pathology Society (ISN/RPS)

classification system was developed in 2003 to replace the previous classification

system published by the World Health Organization (Table 28-11).

179 This

classification scheme provides a reasonable correlation among histopathology,

outcome, and response to treatment. S.L. has proteinuria, hematuria, and inflammation

of less than 50% of her glomeruli, and she is diagnosed as having class III/A (focal

proliferative) GN.

Table 28-11

2003 International Society of Nephrology/Renal Pathology Society Classification

of Lupus Nephritis

177

Class Histologic Characterization Usual Clinical Presentation

I Minimal mesangial lupus nephritis Mild proteinuria

II Mesangial proliferative glomerulonephritis Mild proteinuria and urine sediment abnormalities

III Focal and segmental proliferative

glomerulonephritis

A: active lesions; A/C: active and chronic lesions;

C: chronic lesions

Proteinuria and hematuria

IV Diffuse proliferative segmental (S) or global (G)

glomerulonephritis

A: active lesions; A/C: active and chronic lesions;

C: chronic lesions

Heavy proteinuria; active sediment; hypertension;

renal failure

V Membranous glomerulonephritis Proteinuria; often nephrotic syndrome

VI Advanced sclerosing glomerulonephritis Proteinuria; renal failure; nephrotic syndrome

Data from the 2003 International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis.

Treatment

CASE 28-4, QUESTION 2: Should S.L.’s LN be treated?

Unlike nonkidney manifestations of SLE, serologic markers of disease correlate

poorly with LN. Therefore, elevations in SCr, hypertension, proteinuria and

hematuria, as seen in S.L., are used as primary markers of disease activity.

Treatment of LN must address both management of the acute disease process and

maintenance therapy for the more stable chronic disease process. A general

consensus is that patients, such as S.L., who present with focal or diffuse

proliferative GN (class III or IV) should be treated aggressively, with the primary

goal of preventing irreversible kidney damage. The prognosis of kidney function in

patients with SLE has improved. However, the prognosis is worse in blacks when

compared with the white population treated for SLE.

180 Elevated SCr, heavy

proteinuria, anemia, and disease onset during childhood or in those older than 60

years of age are other predictors of a worse prognosis. Advances in pharmacologic

therapy (i.e., safer immunosuppressive regimens and antihypertensives) have

improved the prognosis for the population as a whole.

The treatment of LN is primarily empiric but is based, to some extent, on

histologic findings. The KDIGO Clinical Practice Guideline for Glomerulonephritis

provides recommendations for treatment based on disease activity.

177 Although

appropriate treatment can improve patient outcomes, vigorous attempts to suppress

SLE activity may lead to serious drug-related complications.

p. 625

p. 626

The primary strategy in the treatment of LN involves suppression of the immune

system with corticosteroids and cytotoxic agents, such as cyclophosphamide (CYC),

azathioprine (AZA), calcineurin inhibitor (CNI) therapy (cyclosporine or tacrolimus)

and mycophenolate mofetil (MMF). Clinicians need to be aware of the potential

complications associated with these therapies and carefully monitor patients to

determine the indication for treatment and improved prognosis. Toxicities associated

with immunosuppressive agents depend on both the dose and the duration of therapy.

Abnormalities in hematopoiesis, such as neutropenia and thrombocytopenia, are the

most common adverse effects associated with cytotoxic agents. Immunosuppression,

in general, increases a patient’s susceptibility to a vast array of infections and to

lymphocytic malignancies. In addition, the alkylating agent CYC can cause nausea

and vomiting, gonadal toxicity, hemorrhagic cystitis, and alopecia. The risk versus

benefit of CYC use has to be seriously weighed in young women who are considering

pregnancy in the future. The antimetabolite AZA can cause pancreatitis and

abnormalities in liver function. The selective inhibitor of inosine monophosphate

dehydrogenase, MMF, although relatively benign compared with the other agents, can

cause GI disturbances.

Induction Therapy

Therapy for LN is usually not indicated in patients with normal kidney function and

proteinuria less than 1 g, because these patients have a good prognosis.

Corticosteroids represent the cornerstone of therapy in patients with a mild form of

LN. Prednisone (1 mg/kg or methylprednisolone) should be initiated for patients with

class II LN with proteinuria >3 g/day or CNI. In patients with a more severe form

(class III and IV), prednisone 1 mg/kg/day combined with either CYC or MMF

should be initiated. For the treatment of acute exacerbations of LN, high-dose pulse

therapy with methylprednisolone may be warranted. Given that S.L.’s LN has

worsened, she should receive pulse methylprednisolone (0.5–1 g IV, not to exceed 1

g) for 3 days in an attempt to reduce the degree of proteinuria and improve kidney

function.

177 Although generally well tolerated, rapid methylprednisolone injections

can cause transient tremor, flushing, and altered taste sensation. To reduce the risk of

adverse effects associated with the rate of injection, S.L. should receive

methylprednisolone for 30 minutes. After a course of pulse methylprednisolone

therapy, oral prednisone at a dose 10 to 20 mg daily may be initiated.

177 Suppression

of S.L.’s active LN should be demonstrated by a reduction in proteinuria and

hematuria and an increase in her eGFR.

The addition of cytotoxic agents is reserved for patients who do not respond to

corticosteroids alone, or those who have unacceptable toxicity to corticosteroids,

worsening kidney function, severe proliferative lesions, or evidence of sclerosis on

kidney biopsy. Induction therapy with six monthly pulse doses of IV CYC (0.5–1

g/m2

) or six doses of CYC given every 2 weeks at a dose of 0.5 g/m2 along with

steroid therapy was shown to have improved kidney outcomes with fewer flares and

relapses.

177 Before and for 24 hours after initiating IV CYC, the patient must be well

hydrated to prevent bladder toxicity. Alternatively, MMF (2,000–3,000 mg/day times

6 months) or TAC (0.06–0.1 mg/kg/day) has been proven to be as effective as CYC

in the induction treatment for LN.

181,182 Given the significant toxicities associated with

CYC (e.g., gonadal toxicity and hemorrhagic cystitis), MMF or tacrolimus are

attractive options given their antiinflammatory properties and the lower side effect

profile. Recently, rituximab, an anti-CD20 monoclonal antibody, has demonstrated

similar efficacy as MMF and CYC.

183

Maintenance Therapy

Once the acute flare resolves (generally in up to 12 weeks), low-dose, maintenance

steroid therapy with 5 to 15 mg/day of prednisone can be initiated in combination

with cytotoxic therapy, if indicated, based on the severity of LN. In a meta-analysis

assessing the efficacy of therapeutic agents used to treat LN, improved outcomes

(total mortality and ESRD) were associated with use of oral prednisone in

combination with IV CYC. As a result, the National Institutes of Health recommends

the use of IV CYC pulse therapy (0.5–1 g/m2

) every 3 months for up to 2 years for

maintenance therapy of LN.

177 An additional benefit of combination therapy with

immunosuppressive agents is their steroid-sparing effect and, potentially, lower risk

of steroid toxicity.

Steroid and CYC free regimens are often desired to avoid steroid and CYC

adverse events. Studies have evaluated other immunosuppressive agents (AZA,

MMF) for maintenance therapy in light of the toxicities associated with CYC or

steroids. The KDIGO Clinical Practice Guideline for Glomerulonephritis

recommends AZA (1.5–2.5 mg/kg/day) or MMF (1–2 g/day) and low-dose

corticosteroids (≤10 mg/day prednisone equivalent) for maintenance therapy.

177

A multi-regimen trial compared maintenance therapy with AZA (1–3 mg/day) and

MMF (500–3,000 mg/day) with CYC along with steroids after induction with CYC

in patients with severe LN. Patients receiving AZA had a lower mortality rate than

those treated with CYC, and the MMF treatment group had fewer relapses than the

CYC treatment group.

184 MMF and AZA may be indicated in patients resistant to

CYC therapy or with a more severe type of LN (class III and IV). The addition of

AZA or MMF, along with corticosteroid therapy, should be considered in S.L. once

the acute lupus flare resolves. Once suppression of S.L.’s LN is documented,

initiation of either AZA or MMF and steroids is indicated because of the severity of

her LN (class III). The duration of therapy is dictated by the individual’s response,

but typically patients will require up to 2 years of maintenance therapy.

Alternative Agents

The KDIGO practice guidelines recommend reserving CNI for those intolerant to

MMF or AZA as maintenance therapy.

177 Rituximab, a monoclonal antibody that

inhibits B-cell production, is being studied because B-cell hyperactivity is one of the

major pathophysiologic mechanisms of LN. Small studies in patients with LN

resistant to therapy have shown rituximab to be of benefit. Cyclosporine, in doses of

5 mg/kg/day, may also provide an alternative therapy to treat lupus in the

maintenance phase in patients unresponsive to treatment.

177

WEGENER GRANULOMATOSIS

CASE 28-5

QUESTION 1: J.M. is a 42-year-old white man who presents to the clinic with a 1-month history of cough,

nasal congestion, facial pain with headache, fever, and lethargy. During the past week, he has noted bright red

blood in his phlegm, which has worsened in the past 3 days. Pertinent laboratory values are as follows:

Serum Na, 143 mEq/L

K, 5.1 mEq/L

Cl, 102 mEq/L

CO2

content, 24 mEq/L

SCr, 2.8 mg/dL

BUN, 41 mg/dL

This compares with last year’s physical checkup visit when his SCr and BUN were within the normal range.

Hematologic studies reveal an Hct of 35%, an Hgb of 11.7 g/dL, a mean corpuscular volume of 69 μL, a mean

corpuscular Hgb concentration of 24%, and a reticulocyte count of 1.8%. RBC indices are normal, and the

platelet count is 175,000/μL. His 24-hour urine contains 3.8 g of

p. 626

p. 627

albumin (normal, <30 mg), and his eGFR is calculated to be 27 mL/minute/1.73 m

2

. His urine also contains

many RBC casts and 16 RBCs/HPF (normal, 0–3 RBCs/HPF). Chest radiograph shows alveolar shadowing

spreading from the hilar region. The result of J.M.’s cytoplasmic-staining, antineutrophil cytoplasmic antibody

(c-ANCA) is positive. On the basis of his subjective and objective data, which of the chronic glomerulopathies

is J.M. likely to have?

Wegener granulomatosis is a primary systemic vasculitis characterized by

granulomatous inflammation of the upper and lower respiratory tract and secondary

GN. Primary systemic vasculitic syndromes, such as Wegener granulomatosis, often

cause GN. Although vasculitis involves inflammation of blood vessels of any size,

the small- and medium-size vessels are most commonly affected.

185 The etiology of

Wegener granulomatosis is unclear; however, an autoimmune response is suspected

for two reasons. First, Wegener granulomatosis is a systemic inflammatory disease

without a known infectious etiology. Second, good treatment response can be

obtained with immunosuppressive therapy.

The clinical features of Wegener granulomatosis include upper airway disease,

such as sinusitis, epistaxis, and nasopharyngitis, as well as otitis media caused by

blockage of the eustachian tube. Constitutional symptoms include fever, night sweats,

arthralgia, anorexia, and malaise. After a few months, weakness may progress,

severely limiting physical activity. Although the lungs are invariably affected, most

patients remain asymptomatic; however, cough and hemoptysis may be present.

J.M.’s presenting symptoms are consistent with the above clinical features. The

laboratory signs also are nonspecific and indicate the presence of a systemic

inflammatory process. They include an elevated erythrocyte sedimentation rate in

virtually all patients, anemia of chronic disease, and thrombocytosis.

185 Hematuria

and proteinuria can be prominent features of Wegener granulomatosis and are present

on initial presentation in 80% of patients. The presence of severely diminished

kidney function, seen in approximately 10% of patients, is an ominous sign, with

nearly one-third of these patients progressing to ESRD. All patients with Wegener

granulomatosis are at risk of developing irreversible, rapidly progressive kidney

failure. Kidney histologic findings are nonspecific, with most patients exhibiting

necrotizing crescentic GN.

185

Wegener granulomatosis is diagnosed primarily by the presenting signs and

symptoms. According to the American College of Rheumatology 1990 classification,

a person is diagnosed with Wegener granulomatosis if any two of the following four

criteria are present: (a) nasal or oral inflammation, (b) abnormal chest radiograph,

(c) microhematuria (>5 RBCs/HPF) or RBC casts in the urine sediment, or (d)

granulomatous inflammation on biopsy.

185 J.M. has satisfied three of the four criteria

for diagnosing Wegener granulomatosis.

Treatment

CASE 28-5, QUESTION 2: How should J.M.’s Wegener granulomatosis be treated?

The discovery of c-ANCA and its strong association with Wegener granulomatosis

has permitted a more certain diagnosis. Because of the substantial rise in titer that

commonly precedes relapse of Wegener granulomatosis, the c-ANCA test is best

used to follow the course of disease activity and guide induction of therapy.

Treatment with CYC and corticosteroids results in improvement in kidney function in

approximately 80% to 85% of patients, versus 75% with pulse steroids alone.

177 The

main predictive factors for treatment success are the extent of kidney damage before

therapy starts and how long therapy is delayed after symptoms develop.

Cyclophosphamide

Because Wegener granulomatosis is considered an autoimmune inflammatory

disease, immunosuppressive therapy is the mainstay of treatment. Table 28-12 list

KDIGO guidelines-recommended treatment regimens. Therapy is generally indicated

for 6 months if remission occurs and up to 12 months in resistant cases.

185 J.M.

should be started on oral CYC 2 mg/kg/day, as a single morning dose, and

corticosteroids to prevent irreversible glomerular scarring. High fluid intake (>3

L/day) and mesna reduce the risk of hemorrhagic cystitis. Regular UA should be

performed (every 3–6 months) to detect hematuria caused by hemorrhagic cystitis.

Table 28-12

Recommended Treatment Regimens for ANCA Vasculitis with GN177

Agent Route Initial dose

Cyclophosphamide

a IV 0.75 g/m

2 q 3–4 weeks.

Decrease initial dose to 0.5 g/m

2

if age >60 years or GFR <20 mL/minute/1.73

m

2

.

Adjust subsequent doses to achieve a 2-week nadir leukocyte count

>3,000/mm

3

.

Cyclophosphamide

b PO 1.5–2 mg/kg/day, reduce if age >60 years or GFR <20 mL/minute/1.73 m

2

.

Adjust the daily dose to keep leucocyte count >3,000/mm

3

Corticosteroids IV Pulse methylprednisolone: 500 mg i.v. daily × 3 days.

Corticosteroids PO Prednisone 1 mg/kg/day for 4 weeks, not exceeding 60 mg daily.

Taper down over 3–4 months.

Rituximab

c IV 375 mg/m

2 weekly × 4.

Plasmapheresis

d 60 mL/kg volume replacement.

Vasculitis: 7 treatments over 14 days. If diffuse pulmonary hemorrhage, daily

until the bleeding stops, then every other day, total 7–10 treatments.

Vasculitis in association with anti-GBM antibodies: Daily for 14 days or until

anti-GBM antibodies are undetectable

aGiven with pulse and oral steroids. An alternative IV cyclophosphamide dosing schema is 15 mg/kg given every 2

weeks for three pulses, followed by 15 mg/kg given every 3 weeks for 3 months beyond remission, with reductions

for age and estimated GFR.

bGiven with pulse and oralsteroids.

cGiven with pulse and oralsteroids.

dNot given with pulse methylprednisolone. Replacement fluid is 5% albumin. Add 150 to 300 mL fresh frozen

plasma at the end of each pheresis session if patients have pulmonary hemorrhage, or have had recent surgery,

including kidney biopsy.

ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; GFR, glomerular filtration

rate; GN, glomerulonephritis; IV, intravenous; PO, orally.

p. 627

p. 628

Corticosteroids

The main role of corticosteroids is to induce remission of the disease. J.M. should

receive prednisone 1 mg/kg/day in addition to CYC. The combined regimen should

be continued for 2 to 4 weeks until the immunosuppressive effect of CYC becomes

evident. Then, during the next 2 months, the prednisone dose can be tapered to 60 mg

every other day to reduce the risk of infection. Then, the dose can be tapered by 5

mg/week to discontinue prednisone over the course of 3 to 6 months. For patients

with a more fulminant form of the disease, pulse methylprednisolone 500 mg/day for

three doses is administered. The dose can be repeated in 1 to 2 weeks if disease

progression is uncontrolled.

Alternative Therapies

Rituximab as an induction agent has been evaluated in two randomized controlled

trials. The RITUXVAS randomized 44 subjects to rituximab (375 mg/m2 weekly × 4)

plus IV CYC or to IV CYC alone. Each group received IV methylprednisolone

followed by oral corticosteroids. Remission rates were 76% for the rituximab group

and 82% for CYC. The RAVE trial rituximab was compared to oral CYC (2

mg/kg/day) for up to 3 months plus AZA (2 mg/kg/day) for 4 to 6 months. IV

methylprednisolone plus oral corticosteroid were given to both groups. Rituximab

proved noninferior to the CYC regimen with similar rates, 64% versus 53%,

respectively. There were no significant differences in adverse events rates in either

trial. Although rituximab has performed well in comparison studies, the high cost

limits it acceptance and applicability in clinical practice.

Azathioprine and Mycophenolate Mofetil

AZA (1–2 mg/kg/day) and MMF (up to 1 gram daily) are effective as maintenance

therapy once remission has been achieved with CYC. However, a comparative study

demonstrated mycophenolate to be less effective at maintaining remissions compared

with AZA, thus AZA is the preferred maintenance therapy.

186 Maintenance therapy

should be continued for a minimum of 18 months for patients in complete remission.

Alternative Agents

Methotrexate (MTX) may be beneficial for patients with milder disease, although one

study demonstrated high relapse rates in patients treated initially with weekly MTX

and daily prednisone; disease was controlled in only select patients.

187 However,

MTX should be reserved for patients intolerant of AZA and MMF and GFR >60

mL/min/1.73 m2

. Use of trimethoprim-sulfamethoxazole for 1 year was evaluated for

patients in remission or after treatment with CYC and prednisolone and is

recommended for those with upper respiratory tract disease. A reduction in relapse

rate was demonstrated compared with placebo; however, trimethoprimsulfamethoxazole use is not supported.

187

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

CASE 28-6

QUESTION 1: A.G. is a 37-year-old morbidly obese (body mass index, 40 kg/m

2

), black woman who presents

to the clinic with complaints of increased swelling in her extremities for the last 2 weeks, decreased urine

output, and pink-colored urine. Her medical history is significant only for hypertension, which is well controlled

with amlodipine 5 mg PO every day. She takes no other prescription or over-the-counter medications. Pertinent

laboratory values are as follows

SCr, 2.1 mg/dL (normal, 0.6–1.2 mg/dL)

Spot ACR, 1,200 mg/g (normal, <30 mg/g)

UA, 18 RBCs/HPF (normal, 0–3)

eGFR, 34 mL/minute/1.73 m

2

The nephrologist schedules a biopsy to obtain a definitive diagnosis for her new-onset kidney disease. Biopsy

results are as follows: light micrograph shows a moderately large segmental area of sclerosis with capillary

collapse on the upper left side of the glomerular tuft; the lower right segment is relatively normal. Electron

micrograph shows diffuse epithelial cell foot process fusion with occasional loss of the epithelial cells. The other

major finding is massive subendothelial hyaline deposits under the glomerular basement membrane. The

pathologist’s impression is FSGS. What is the relevance of FSGS, and what are the management strategies for

FSGS?

FSGS is characterized by sclerotic lesions of the glomerulus, which can be either

focal or segmental in nature. The development of FSGS may be idiopathic (primary)

or secondary to other diseases (i.e., morbid obesity, sickle cell disease, congenital

heart disease, AIDS). Currently, FSGS is the leading cause of idiopathic nephrotic

syndrome and accounts for 15% to 20% of the cases. Black patients are 2 to 4 times

more likely to experience idiopathic FSGS than white patients, and they have a

higher incidence of ESRD caused by FSGS.

188 Genetic variants of the apolipoprotein

L1 (APOL1) gene predominate in patients of African ancestry and have been

identified as a major risk factor.

189

Most patients with FSGS will present with proteinuria, but only about half of them

will initially present with the nephrotic syndrome. Patients with the nephrotic

syndrome will also likely present with hypertension, increased SCr levels, and

hematuria. During the early stages of FSGS, the symptoms may be indistinguishable

from minimal-change nephropathy, a glomerulopathy characterized by similar lesions

within the glomeruli. A kidney biopsy is necessary for diagnosis. Predictors of

increased risk of progression to ESRD include massive proteinuria (>10 g/day),

higher SCr level (>1.3 mg/dL), and black race.

188,190

Treatment

Corticosteroids

A.G. should be placed on steroids, in addition to an ACEI or ARB and a loop

diuretic, because she has FSGS and nephrotic syndrome.

177 A course of

corticosteroids 1 mg/kg/day (maximum 80 mg) or 2 mg/kg every other day (maximum

120 mg) for at least 4 weeks and for up to 4 months with tapering of the dose over the

course of 6 months after complete remission is achieved. Complete remission is

defined as reduction of albuminuria <0.3 g/day, normal urine and SCr, and serum

albumin >3.5 g/dL.

177 The median time to remission is 3 to 4 months. Patients whose

proteinuria does not respond after a 4-month trial of therapy should be considered

resistant to steroids and be rapidly tapered off over the course of 6 weeks.

177

Steroid-Resistant Treatment

Calcineurin Inhibitors

The addition of cytotoxic agents (CYC, TAC) may be considered for A.G. if she is

steroid resistant, intolerant of long-term steroid therapy, severely nephrotic,

frequently relapsing, or steroid dependent. The data supporting the use of these agents

in FSGS are limited. Retrospective studies have shown that use of cytotoxic drugs

can produce complete remission in 50% of cases. Length of therapy of these agents

may predict the remission rates of FSGS. Recent prospective studies support a longer

duration of therapy.

Evidence supporting the efficacy and safety of cyclosporine in FSGS stems from

randomized controlled trials. In addition to being

p. 628

p. 629

options for steroid-resistant patients, CNIs provide a steroid-sparing effect in FSGS

steroid-sensitive patients. Cyclosporine studies are the most prevalent of the CNIs.

Cyclosporine response is highly dependent on the previous steroid response.

Complete remission rates of 73% can be seen with cyclosporine in steroid-sensitive

patients.

190 Conversely, therapy with cyclosporine doses of 5 mg/kg/day for 6 to 12

months has been found to be effective and can result in remission rates of up to 69%

in patients resistant to steroids.

191 The current recommendation is CYC of 3 to 5

mg/kg/day in two divided doses. If remission is achieved, continue treatment for 1

year. However, if no remission is achieved by 6 months, discontinue cyclosporine.

Limitations of cyclosporine therapy include high relapse rate (23%–100%) after

withdrawal, side effect profile (nephrotoxicity, hypertension), and resistance to

therapy. Studies evaluating tacrolimus as a treatment option for FSGS are few and

lack randomized controlled trials. Current TAC therapy should be initiated at 0.1 to

0.2 mg/kg/day in two divided doses. Tacrolimus has a similar side effect profile to

that of cyclosporine.

190 Sirolimus is associated with nephrotoxicity in FSGS and is

not recommended for treatment.

Mycophenolate Mofetil

MMF has the potential for a steroid-sparing effect; however, relapses are common.

MMF and high-dose dexamethasone are recommended for steroid-resistant patients

intolerant to cyclosporine therapy. A small study of patients with FSGS resistant to

steroids, cytotoxic agents, or both and cyclosporine received MMF for 6 months.

177

At the end of 6 months, 44% of patients had improved proteinuria, but no patient

achieved complete remission. Other studies examining MMF therapy at doses of up

to 2,000 mg/day have found no clinically significant effect on remission rates.