2338 PART 9 Disorders of the Kidney and Urinary Tract

leukocyte infiltration, activation of procoagulant factors, and release of

various cytokines. In situ immune complex formation also plays a role

in renal injury. These immune deposits may occur in the mesangial,

subendothelial, and/or subepithelial spaces.

The clinical manifestations, course of disease, and treatment of

lupus nephritis are closely linked to renal pathology. The most common clinical sign of renal disease is proteinuria, but hematuria, hypertension, varying degrees of renal failure, and active urine sediment

with red blood cell casts can all be present. Anti-dsDNA antibodies

that fix complement correlate best with the presence of renal disease. Hypocomplementemia is common in patients with acute lupus

nephritis (70–90%), and declining complement levels may herald a

flare. A kidney biopsy should be performed in most patients with renal

involvement to establish the histologic subtype, which guides therapy.

The World Health Organization (WHO) workshop in 1974 first outlined several distinct patterns of lupus-related glomerular injury, and

this classification was modified in 2004. This latest version of lesions

seen on biopsy (Table 314-3) forms the basis for modern treatment

recommendations. Class I nephritis describes normal glomerular histology by normal light microscopy with minimal mesangial deposits

on immunofluorescent or electron microscopy. Class II designates

mesangial immune complexes with mesangial proliferation. Both class I

and II lesions are typically associated with minimal renal manifestation

and normal renal function; nephrotic syndrome is rare. Patients with

lesions limited to the renal mesangium have an excellent prognosis and

generally do not need therapy for their lupus nephritis.

The subject of lupus nephritis is presented under acute nephritic

syndromes because of the aggressive and important proliferative

lesions seen in class III–V renal diseases. Class III describes focal

lesions involving <50% of the glomeruli with proliferation or scarring,

often involving only a segment of the glomerulus (see Fig. A4-12).

Class III lesions have the most varied course. Hematuria and proteinuria are present, and some patients also have an active urinary

sediment, nephrotic syndrome, hypertension, and a decreased GFR.

Patients with mild proliferation involving a small percentage of glomeruli respond well to therapy with steroids alone, and <5% progress

to renal failure over 5 years. Patients with more severe proliferation

involving a greater percentage of glomeruli have a far worse prognosis

and lower remission rates. Treatment of those patients is the same as

that for class IV lesions. Class IV describes diffuse lesions with >50%

of the glomeruli involved and proliferative endocapillary lesions with or

without extracapillary lesions that may be segmental (IV-S), involving

<50% of the glomerular tuft, or global (IV-G), involving >50%. Patients

with class IV lesions commonly have high anti-DNA antibody titers,

low serum complement, hematuria, red blood cell casts, proteinuria,

hypertension, and decreased renal function; 50% of patients have

nephrotic-range proteinuria. Patients with crescents on biopsy often

have a rapidly progressive decline in renal function (see Fig. A4-12).

TABLE 314-3 Classification for Lupus Nephritis

Class I Minimal mesangial Normal histology with mesangial deposits

Class II Mesangial

proliferation

Mesangial hypercellularity with expansion of

the mesangial matrix

Class III Focal nephritis Focal endocapillary ± extracapillary

proliferation with focal subendothelial immune

deposits and mild mesangial expansion

Class IV Diffuse nephritis Diffuse endocapillary ± extracapillary

proliferation with diffuse subendothelial

immune deposits and mesangial alterations

Class V Membranous

nephritis

Thickened basement membranes with diffuse

subepithelial immune deposits; may occur

with class III or IV lesions and is sometimes

called mixed membranous and proliferative

nephritis

Class VI Sclerotic nephritis Global sclerosis of nearly all glomerular

capillaries

Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology

Society Study Group.

Without treatment, this aggressive lesion has the worst renal prognosis, with class IV-S worse than class IV-G. However, if a remission—

defined as a return to near-normal renal function and proteinuria

≤330 mg/dL per day—is achieved with treatment, renal outcomes are

excellent. Current evidence suggests that inducing a remission with

administration of high-dose steroids and either cyclophosphamide

or mycophenolate mofetil for 2–6 months, followed by maintenance

therapy with lower doses of steroids and mycophenolate mofetil or

azathioprine, best balances the likelihood of successful remission with

the side effects of therapy. There is no consensus on use of high-dose

intravenous methylprednisolone versus oral prednisone, monthly

intravenous cyclophosphamide versus daily oral cyclophosphamide, or

other immunosuppressants such as cyclosporine, tacrolimus, or rituximab. Nephrologists tend to avoid prolonged use of cyclophosphamide

in patients of childbearing age without first banking eggs or sperm.

The class V lesion describes subepithelial immune deposits producing a membranous pattern; a subcategory of class V lesions is associated

with proliferative lesions and is sometimes called mixed membranous

and proliferative disease (see Fig. A4-11); this category of injury is

treated like class IV glomerulonephritis. Sixty percent of patients present with nephrotic syndrome or lesser amounts of proteinuria. Patients

with lupus nephritis class V, like patients with idiopathic membranous

nephropathy (IMN), are predisposed to renal vein thrombosis and

other thrombotic complications. A minority of patients with class V

will present with hypertension and renal dysfunction. There are conflicting data on the clinical course, prognosis, and appropriate therapy

for patients with class V disease, which may reflect the heterogeneity

of this group of patients. Patients with severe nephrotic syndrome,

elevated serum creatinine, and a progressive course will probably

benefit from therapy with steroids in combination with other immunosuppressive agents. Therapy with inhibitors of the renin-angiotensin

system also may attenuate the proteinuria. Antiphospholipid antibodies present in lupus may result in glomerular microthromboses and

a thrombotic microangiopathy. The renal prognosis is worse despite

anticoagulant therapy.

Patients with any of the above lesions also can transform to another

lesion; hence, patients often require reevaluation, including repeat

renal biopsy. Lupus patients with class VI lesions have >90% sclerotic

glomeruli and ESRD with interstitial fibrosis. Up to 20% of patients

with lupus nephritis will reach end-stage disease, requiring dialysis

or transplantation. Patients with lupus nephritis have a markedly

increased mortality compared with the general population. Renal

transplantation in renal failure from lupus, usually performed after ~6

months of inactive disease, results in allograft survival rates comparable to patients transplanted for other reasons.

■ ANTIGLOMERULAR BASEMENT MEMBRANE

DISEASE

Patients who develop autoantibodies directed against glomerular

basement antigens frequently develop a glomerulonephritis termed

antiglomerular basement membrane (anti-GBM) disease. When they

present with lung hemorrhage and glomerulonephritis, they have a

pulmonary-renal syndrome called Goodpasture’s syndrome. The target

epitopes for this autoimmune disease lie in the quaternary structure

of α3 NC1 domain of collagen IV. Indeed, anti-GBM disease may

be considered an autoimmune “conformeropathy” that involves the

perturbation of quaternary structure of the α 345NC1 hexamer. MHCrestricted T cells initiate the autoantibody response because humans

are not tolerant to the epitopes created by this quaternary structure.

The epitopes are normally sequestered in the collagen IV hexamer and

can be exposed by infection, smoking, oxidants, or solvents. Goodpasture’s syndrome appears in two age groups: in young men in their late

twenties and in men and women in their sixties and seventies. Younger

patients are more likely to present with the full Goodpasture’s syndrome, with hemoptysis, a sudden fall in hemoglobin, fever, dyspnea,

and hematuria, and older patients are more likely to present with isolated glomerulonephritis. Hemoptysis is largely confined to smokers,

and those who present with lung hemorrhage as a group do better than

older populations who have prolonged, asymptomatic renal injury;

2339 Glomerular Diseases CHAPTER 314

presentation with oliguria is often associated with a particularly bad

outcome. The performance of an urgent kidney biopsy is important in

suspected cases of Goodpasture’s syndrome to confirm the diagnosis

and assess prognosis. Renal biopsies typically show focal or segmental

necrosis that later, with aggressive destruction of the capillaries by

cellular proliferation, leads to crescent formation in Bowman’s space

(see Fig. A4-14). As these lesions progress, there is concomitant interstitial nephritis with fibrosis and tubular atrophy.

The presence of anti-GBM antibodies and complement is recognized

on biopsy by linear immunofluorescent staining for IgG (rarely IgA).

In testing serum for anti-GBM antibodies, it is particularly important

that the α3 NC1 domain of collagen IV alone be used as the target.

This is because nonnephritic antibodies against the α1 NC1 domain

are seen in paraneoplastic syndromes and cannot be discerned from

assays that use whole basement membrane fragments as the binding

target. Between 10 and 15% of sera from patients with Goodpasture’s

syndrome also contain ANCA antibodies against myeloperoxidase.

Prognosis at presentation is worse if there are >50% crescents on renal

biopsy with advanced fibrosis, if serum creatinine is >5–6 mg/dL, if

oliguria is present, or if there is a need for acute dialysis. Patients who

present with hemoptysis should be treated for their lung hemorrhage,

as it responds to plasmapheresis. Treated patients with less severe disease typically respond to 8–10 treatments of plasmapheresis accompanied by oral prednisone and cyclophosphamide. Maintenance therapy

with low-dose immunosuppressants should be considered until antibody titers are negative. There are scarce data alternatively using rituximab, azathioprine, or mycophenolate mofetil. Kidney transplantation

should wait for 6 months and until serum antibodies are undetectable.

■ IgA NEPHROPATHY

Berger first described the glomerulonephritis now termed IgA nephropathy. It is classically characterized by episodic hematuria associated

with the deposition of IgA in the mesangium. IgA nephropathy is one

of the most common forms of glomerulonephritis worldwide. There

is a male preponderance, a peak incidence in the second and third

decades of life, and rare familial clustering. There are geographic differences in the prevalence of IgA nephropathy, with 30% prevalence along

the Asian and Pacific Rim and 20% in southern Europe, compared to a

much lower prevalence in northern Europe and North America. This

may reflect variation in detection or a true variation among racial and

ethnic groups.

IgA nephropathy is predominantly a sporadic disease, but susceptibility to it has been shown uncommonly to have a genetic component depending on geography and the existence of “founder effects.”

Familial forms of IgA nephropathy are more common in northern

Italy and eastern Kentucky. No single causal gene has been identified.

Clinical and laboratory evidence suggests close similarities between

Henoch-Schönlein purpura and IgA nephropathy. Henoch-Schönlein

purpura is distinguished clinically from IgA nephropathy by prominent

systemic symptoms, a younger age (<20 years old), preceding infection,

and abdominal complaints. Deposits of IgA are also found in the glomerular mesangium in a variety of systemic diseases, including chronic

liver disease, Crohn’s disease, celiac disease, chronic bronchiectasis,

idiopathic interstitial pneumonia, dermatitis herpetiformis, mycosis

fungoides, ankylosing spondylitis, HIV infection, and Sjögren’s syndrome. IgA deposition in these entities is not usually associated with

clinically significant renal disease. IgG A-dominant Staphylococcusassociated postinfectious glomerulonephritis is associated with clinically significant renal disease.

The pathognomonic finding on kidney biopsy is dominant or

codominant mesangial IgA deposits, either alone or with IgG, IgM, or

C3

. (See Glomerular Schematic 2.) IgA deposits are typically J-chain

containing polymeric IgA. Abnormalities have been described in

IgA production by plasma cells, in IgA clearance by the liver, and in

mesangial IgA clearance and receptors for IgA. Currently, however,

abnormalities in the O-glycosylation of the hinge region of primarily

polymeric IgA1 seem to best account for the pathogenesis of sporadic

IgA nephropathy. Synthesis of poorly galactosylated IgA1 results in

exposure of N-acetyl-galactosamine in truncated IgA1 hinge regions,

which is recognized by IgG or IgA1 antibodies leading to formation

of immune complexes in the circulation or in situ after glomerular

deposition of galactose-deficient IgA1. A second hit, such as a viral or

other antigen exposure, or hereditary defects in alternative complement pathway proteins may affect the manifestation of disease. Despite

the presence of elevated serum IgA levels in 20–50% of patients and

IgA deposition in skin biopsies in 15–55% of patients, a renal biopsy is

necessary to confirm the diagnosis. Although the immunofluorescent

pattern of IgA on renal biopsy defines IgA nephropathy in the proper

clinical context, a variety of histologic lesions may be seen on light

microscopy (see Fig. A4-8), including DPGN; segmental sclerosis; and,

rarely, segmental necrosis with cellular crescent formation, which typically presents as RPGN.

The two most common presentations of IgA nephropathy are

recurrent episodes of macroscopic hematuria during or immediately

following an upper respiratory infection often accompanied by proteinuria and persistent asymptomatic microscopic hematuria. Nephrotic syndrome is uncommon. Proteinuria can also first appear late

in the course of the disease. Rarely, patients present with acute renal

failure and a rapidly progressive clinical picture. IgA nephropathy is

a benign disease for the majority of patients, and 5–30% of patients

may go into a complete remission, with others having hematuria but

well-preserved renal function. In the minority of patients who have

progressive disease, progression is slow, with renal failure seen in only

25–30% of patients with IgA nephropathy over 20–25 years. This risk

varies considerably among populations. Cumulatively, risk factors for

the loss of renal function identified thus far account for <50% of the

variation in observed outcome but include the presence of hypertension or proteinuria, the absence of episodes of macroscopic hematuria,

male sex, and older age of onset. Mesangial hypercellularity (M),

endocapillary hypercellularity (E), segmental glomerulosclerosis (S),

tubular interstitial fibrosis (T), and crescents (C) have predictive value

as established by the Oxford Classification and the MEST-C score.

Several analyses in large populations of patients found persistent proteinuria for 6 months or longer to have the greatest predictive power

for adverse renal outcomes.

There is no agreement on optimal treatment. Both large studies that

include patients with multiple glomerular diseases and small studies

of patients with IgA nephropathy support the use of angiotensinconverting enzyme (ACE) inhibitors in patients with proteinuria or

declining renal function. In patients with persistent proteinuria after

Glomerular schematic 2

IgA

NEPHROPATHY

Mesangial deposits

plus more

mesangial cells

2340 PART 9 Disorders of the Kidney and Urinary Tract

ACE inhibitor therapy, steroid treatment or other immunosuppressives

have demonstrated conflicting results. Tonsillectomy and fish oil have

also been suggested in small studies to benefit select patients. When

presenting as RPGN, patients typically receive steroids, cytotoxic

agents, and plasmapheresis.

■ ANCA SMALL-VESSEL VASCULITIS

A group of patients with small-vessel vasculitis (arterioles, capillaries, and venules; rarely small arteries) and glomerulonephritis have

serum ANCA; the antibodies are of two types, anti-proteinase 3 (PR3)

or anti-myeloperoxidase (MPO) (Chap. 363). ANCA are produced

with the help of T cells and activate leukocytes and monocytes, which

together damage the walls of small vessels. Endothelial injury also

attracts more leukocytes and extends the inflammation. Granulomatosis with polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome, and renal-limited vasculitis belong to this group because they

are ANCA-positive and have a pauci-immune glomerulonephritis with

few immune complexes in small vessels and glomerular capillaries.

Patients with any of these diseases can have any combination of the

above serum antibodies, but anti-PR3 antibodies are more common in

granulomatosis with polyangiitis, and anti-MPO antibodies are more

common in microscopic polyangiitis or Churg-Strauss. Although each

of these diseases has some unique clinical features, most features do not

predict relapse or progression, and as a group, they are generally treated

in the same way. Once diagnosed, ANCA monitoring has limited value,

but targeted determination of ANCA levels may be useful if a relapse

is clinically suspected. Since mortality is high without treatment, virtually all patients receive urgent treatment. Induction therapy usually

includes glucocorticoids and either cyclophosphamide or rituximab.

Plasmapheresis is recommended in rapidly progressive renal failure or

pulmonary hemorrhage. Remission is induced in 85–90% of patients,

but relapse is common. Steroids are tapered soon after acute inflammation subsides. Maintenance therapy includes low-dose steroids and

cyclophosphamide or less toxic agents such as azathioprine, methotrexate, or rituximab for up to a year to minimize the risk of relapse.

Granulomatosis with Polyangiitis Patients with this disease

classically present with fever, purulent rhinorrhea, nasal ulcers, sinus

pain, polyarthralgias/arthritis, cough, hemoptysis, shortness of breath,

hematuria, and subnephrotic proteinuria; occasionally, there may be

cutaneous purpura and mononeuritis multiplex. Patients may present

without renal involvement, although most of these patients develop

renal injury later. Chest x-ray often reveals nodules and persistent

infiltrates, sometimes with cavities. Biopsy of involved tissue will

show a small-vessel vasculitis and adjacent noncaseating granulomas.

Renal biopsies during active disease demonstrate segmental necrotizing

glomerulonephritis without immune deposits and have been classified

as focal, mixed, crescentic, or sclerotic (see Fig. A4-13). The disease

is more common in patients exposed to silica dust and those with

α1

-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after

achieving remission is common and is more common in patients with

granulomatosis with polyangiitis than the other ANCA-associated vasculitis, necessitating diligent follow-up care. Although associated with

an unacceptable high mortality rate without treatment, the greatest

threat to patients, especially elderly patients in the first year of therapy,

is from adverse events, which are often secondary to treatment, rather

than active vasculitis. Patients should also be monitored long term for

malignancy after immunosuppressive therapy.

Microscopic Polyangiitis Clinically, these patients look somewhat similar to those with granulomatosis with polyangiitis, except

they rarely have significant lung disease or destructive sinusitis. The

distinction is made on biopsy, where the vasculitis in microscopic

polyangiitis is without granulomas. Some patients will also have injury

limited to the capillaries and venules.

Churg-Strauss Syndrome When small-vessel vasculitis is associated with peripheral eosinophilia, cutaneous purpura, mononeuritis,

asthma, and allergic rhinitis, a diagnosis of Churg-Strauss syndrome

(eosinophilic granulomatosis with polyangiitis [EGPA]) is considered.

Hypergammaglobulinemia, elevated levels of serum IgE, or the presence of rheumatoid factor sometimes accompanies the allergic state.

Lung inflammation, including fleeting cough and pulmonary infiltrates, often precedes the systemic manifestations of disease by years;

lung manifestations are rarely absent. A third of patients may have

exudative pleural effusions associated with eosinophils. Small-vessel

vasculitis and focal segmental necrotizing glomerulonephritis without

immune deposits can be seen on renal biopsy, usually absent eosinophils or granulomas. The cause of Churg-Strauss syndrome is autoimmune, but the inciting factors are unknown.

■ C3

 GLOMERULOPATHIES

C3

 glomerulopathy is a recent disease classification that is defined by

the glomerular accumulation of C3

 with little or no immunoglobulin

and encompasses dense deposit disease (DDD), formerly MPGN type

II (see below), and C3

 glomerulonephritis (C3

GN) (Table 314-4). DDD

is defined morphologically by dense deposits forming ribbons in the

GBM. In the absence of this specific morphology, the entity is categorized as C3

GN. Both are associated with the presence of a complement

mutation believed to cause the renal pathology, including mutations in

the complement factor H regulatory (CFHR) protein genes. DDD is

primarily a disease of children and young adults, whereas the other C3

glomerulopathies are reported to present in an older age group (mean

age 30). By definition, kidneys with C3

 glomerulopathy show sole or

dominant staining for C3

 but can have variable light microscopy, with

mesangial proliferative or membranoproliferative patterns seen most

commonly. Morphologically, many cases are not distinguishable from

recovering postinfectious glomerulonephritis. Patients with DDD present with proteinuria, which may be nephrotic range, and/or hematuria,

which may be macroscopic or microscopic. Partial lipodystrophy and

Drusen bodies in the retina may also be present. Prognosis is poor,

with 50% of patients progressing to ESRD. C3

GN patients are clinically

less well defined, but approximately two-thirds have hematuria and

one-third have proteinuria. C3

 levels are low with normal C4

, and C3

nephritic factor is present in most patients with DDD and less commonly in C3

GN. Abnormalities in factor H, soluble C5b-9, paraprotein

detection, and specific CFHR genetic mutations should be assessed as

well. Screening family members may be indicated. The optimal therapies remain undefined but include inhibition of the renin-angiotensin

TABLE 314-4 Membranoproliferative Glomerulonephritis:

Immunoglobulin-Mediated

Type I Disease—Most Common

Idiopathic

Infection: Subacute bacterial endocarditis, hepatitis B and C, fungal and

parasitic infections

Autoimmune diseases: Systemic lupus erythematosus, cryoglobulinemia,

Sjögren’s

Monoclonal gammopathies: Monoclonal gammopathy of undetermined

significance, myeloma, monoclonal gammopathy of renal significance

Cancer: Lung, breast, and ovary (germinal)

Type II Disease

Idiopathic

Dense deposit disease (immunoglobulin-mediated)

Type III Disease

Idiopathic

C3

 Glomerulopathy: C3

 Dominant, Non-Immunoglobulin-Mediated

Dense Deposit Disease (C3

 dominant)

Idiopathic

Specific genetic mutations and/or autoantibodies to alternate complement

pathway factors or regulatory factors of alternate complement pathway

C3

 Glomerulonephritis

Specific genetic mutations and/or autoantibodies to alternate complement

pathway factors or regulatory factors of alternate complement pathway

2341 Glomerular Diseases CHAPTER 314

system, lipid lowering, steroids, and other immunosuppressants. Evidence suggests a benefit of therapy with eculizumab, a monoclonal

antibody directed at C5

, which is activated by C3.

■ MEMBRANOPROLIFERATIVE

GLOMERULONEPHRITIS

MPGN is characterized by thickening of the GBM with mesangioproliferative changes often leading to a lobular appearance of the

glomerular tuft; 70% of patients have hypocomplementemia. MPGN

is rare in African Americans, and idiopathic disease usually presents

in childhood or young adulthood. MPGN has been subdivided based

on histology into type I, type II, and type III disease. Type I MPGN is

immune complex–mediated and commonly associated with persistent

hepatitis B and C, fungal and parasitic infections, SBE, autoimmune

diseases such as lupus or cryoglobulinemia, or monoclonal gammopathies, including monoclonal gammopathy of renal significance

(MGRS), where the only clinically apparent manifestations are in

the kidney (Table 314-4). Types II and III MPGN can be idiopathic

and immunoglobulin-mediated disease (driven by the classical complement pathway), but the vast majority of cases formerly defined as

MPGN type II or III are non-immunoglobulin-mediated and driven

by the alternate complement pathway.

Type I MPGN, the most proliferative of the three types, shows

mesangial proliferation with lobular segmentation on renal biopsy and

mesangial interposition between the capillary basement membrane

and endothelial cells, producing a double contour sometimes called

tram-tracking (see Fig. A4-9). (See Glomerular Schematic 3.) Subendothelial deposits with low serum levels of C3

 are typical, although

50% of patients have normal levels of C3

 and occasional intramesangial

deposits. Low serum C3

 and a dense thickening of the GBM containing

ribbons of dense deposits and C3

 characterize type II MPGN, dense

deposit disease (see Fig. A4-10). Classically, the glomerular tuft has

a lobular appearance; intramesangial deposits are rarely present, and

subendothelial deposits are generally absent. Proliferation in type III

MPGN is less common than the other two types and is often focal;

mesangial interposition is rare, and subepithelial deposits as well as

subendothelial deposits can occur along widened segments of the

GBM that appear laminated and disrupted.

Classic type I MPGN is secondary to glomerular deposition of

circulating immune complexes or their in situ formation. Patients

with MPGN present with proteinuria, hematuria, and pyuria (30%);

systemic symptoms of fatigue and malaise that are most common in

children with type I disease; or an acute nephritic picture with RPGN

and a speedy deterioration in renal function in up to 25% of patients.

Low serum C3

 levels are common. Fifty percent of patients with MPGN

develop ESRD 10 years after diagnosis, and 90% have renal insufficiency after 20 years. Nephrotic syndrome, hypertension, and renal

insufficiency all predict poor outcome. In the presence of proteinuria,

treatment with inhibitors of the renin-angiotensin system is prudent.

Evidence supports the efficacy of treatment of primary MPGN with steroids, particularly in children. There are reports of efficacy with other

immunosuppressive drugs. If defects in the complement pathway are

found, treatment with eculizumab is of benefit. In secondary MPGN,

treating the associated infection, autoimmune disease, or neoplasms is

of demonstrated benefit. Patients with primary MPGN are well known

to be at risk for not only a histologic recurrence in the transplanted

kidney but also a clinically significant recurrence with loss of graft

function.

■ MESANGIOPROLIFERATIVE

GLOMERULONEPHRITIS

Mesangioproliferative glomerulonephritis is characterized by expansion of the mesangium, sometimes associated with mesangial hypercellularity; thin, single contoured capillary walls; and mesangial

immune deposits. Mesangioproliferative pathology may be seen in IgA

nephropathy, Plasmodium falciparum malaria, resolving postinfectious

glomerulonephritis, and class II nephritis from lupus, all of which can

have a similar histologic appearance. With these secondary entities

excluded, the diagnosis of primary mesangioproliferative glomerulonephritis is made in <15% of renal biopsies.

NEPHROTIC SYNDROME

Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema,

and hypertension. If left undiagnosed or untreated, some of these

syndromes will progressively damage enough glomeruli to cause a fall

in GFR, producing renal failure. Multiple studies have noted that the

higher the 24-h urine protein excretion, the more rapid is the decline

in GFR.

Therapies for various causes of nephrotic syndrome are noted

under individual disease headings below. In general, all patients with

hypercholesterolemia secondary to nephrotic syndrome should be

treated with lipid-lowering agents because they are at increased risk

for cardiovascular disease. Edema secondary to salt and water retention can be controlled with the use of diuretics, avoiding intravascular

volume depletion. Venous complications secondary to the hypercoagulable state associated with nephrotic syndrome can be treated with

anticoagulants. The losses of various serum binding proteins, such as

thyroid-binding globulin, lead to alterations in functional tests. Lastly,

proteinuria itself is hypothesized to be nephrotoxic, and treatment of

proteinuria with inhibitors of the renin-angiotensin system can lower

urinary protein excretion.

■ MINIMAL CHANGE DISEASE

MCD, sometimes known as nil lesion, causes 70–90% of nephrotic syndrome in childhood but only 10–15% of nephrotic syndrome in adults.

MCD usually presents as a primary renal disease but can be associated

with several conditions, including Hodgkin’s disease, allergies, use

of nonsteroidal anti-inflammatory agents or lithium, infections, and

other glomerular diseases. MCD on renal biopsy shows no glomerular

lesion by light microscopy and is negative for deposits by immunofluorescent microscopy or occasionally shows small amounts of IgM in the

mesangium (see Fig. A4-1). (See Glomerular Schematic 4.) Electron

microscopy, however, consistently demonstrates an effacement of the

foot processes supporting the epithelial podocytes with weakening of

slit-pore membranes. The pathogenesis of this lesion is unclear. Most

agree there is a disturbance related to T-cell responses, or expression of

CD80 or CD40/40L may alter capillary charge and podocyte integrity;

interestingly, the use of checkpoint inhibitors as chemotherapy is associated with MCD. There also is some circumstantial evidence for the

presence of preceding allergies, altered cell-mediated immunity during

viral infections, and a high frequency of remissions with steroids.

MCD presents clinically with the abrupt onset of edema and nephrotic syndrome accompanied by acellular urinary sediment. Average

urine protein excretion reported in 24 h is 10 g with severe hypoalbuminemia. Less common clinical features include hypertension (30%

in children, 50% in adults), microscopic hematuria (20% in children,

MEMBRANOPROLIFERATIVE

GLOMERULONEPHRITIS TYPE I

Subendothelial

Widened deposits mesangial

Macrophage and

mesangial cells

Mesangial

interposition

Glomerular schematic 3

2342 PART 9 Disorders of the Kidney and Urinary Tract

33% in adults), atopy or allergic symptoms (40% in children, 30% in

adults), and decreased renal function (25–40%), which often returns to

normal after remission of the nephrotic syndrome. The appearance of

acute renal failure in adults is often seen more commonly in patients

with low serum albumin and intrarenal edema (nephrosarca) that is

responsive to diuretics. This presentation must be distinguished from

acute renal failure secondary to hypovolemia. Acute tubular necrosis and interstitial inflammation are also reported. In children, the

abnormal urine principally contains albumin with minimal amounts

of higher-molecular-weight proteins and is sometimes called selective

proteinuria. Although up to 30% of children have a spontaneous

remission, most children today are treated with steroids; only children

who are nonresponders are biopsied. Primary responders are patients

who have a complete remission (<0.2 mg/24 h of proteinuria), often

abruptly after a single course of prednisone; steroid-dependent patients

relapse as their steroid dose is tapered. Frequent relapsers have two or

more relapses in the 6 months following taper, and steroid-resistant

patients fail to respond to steroid therapy. Adults are not considered

steroid-resistant until after 4 months of therapy. Ninety to 95% of children will develop a complete remission after 8 weeks of steroid therapy,

and 80–85% of adults will achieve complete remission, but only after a

longer course of 20–24 weeks. Patients with steroid resistance may have

FSGS on repeat biopsy. If the first renal biopsy does not have a sample

of deeper corticomedullary glomeruli, then the correct diagnosis of

FSGS may be missed.

Relapses occur in 70–75% of children after the first remission, and

early relapse predicts multiple subsequent relapses, as do high levels of

basal proteinuria. The frequency of relapses decreases after puberty.

There is an increased risk of relapse following the rapid tapering of

steroids in all groups. Relapses are less common in adults but are more

resistant to subsequent therapy. Prednisone is first-line therapy, either

given daily or on alternate days. Other immunosuppressive drugs, such

as cyclophosphamide, chlorambucil, and mycophenolate mofetil, are

saved for frequent relapsers, steroid-dependent patients, or steroidresistant patients. Cyclosporine can induce remission, but relapse is

also common when cyclosporine is withdrawn. The long-term prognosis in adults is less favorable when acute renal failure or steroid

resistance occurs.

■ FOCAL SEGMENTAL GLOMERULOSCLEROSIS

FSGS refers to a pattern of renal injury characterized by segmental

glomerular scars that involve some but not all glomeruli (focal); the

clinical findings of FSGS largely manifest as proteinuria. When the

secondary and genetic causes of FSGS are eliminated (Table 314-5),

the remaining patients are considered to have primary FSGS. The

incidence of this disease is increasing, and it now represents up to onethird of cases of nephrotic syndrome in adults and one-half of cases of

nephrotic syndrome in African Americans. The pathogenesis of FSGS

has multiple possible mechanisms including a circulating permeability

factor, an adaptive response to glomerular hypertrophy or hyperfiltration, and podocyte abnormalities associated with direct toxic injury or

genetic mutations. Risk polymorphisms at the APOL1 locus expressed

in podocytes substantially explain the increased burden of FSGS

among African Americans.

The pathologic changes of FSGS are most prominent in glomeruli

located at the corticomedullary junction (see Fig. A4-2), so if the renal

biopsy specimen is from superficial tissue, the lesions can be missed,

which sometimes leads to a misdiagnosis of MCD. In addition to focal

and segmental scarring, other variants have been described, including

cellular lesions with endocapillary hypercellularity and heavy proteinuria; collapsing glomerulopathy (see Fig. A4-3) with segmental or

global glomerular collapse and a rapid decline in renal function; a hilar

stalk lesion (see Fig. A4-4); or the glomerular tip lesion (see Fig. A4-5),

which may have a better prognosis. (See Glomerular Schematic 5.)

FSGS can present with hematuria, hypertension, any level of

proteinuria, and renal insufficiency. Nephrotic-range proteinuria,

African-American race, and renal insufficiency are associated with a

poor outcome, with 50% of patients reaching renal failure in 6–8 years.

FSGS rarely remits spontaneously, but treatment-induced remission

of proteinuria significantly improves prognosis. Treatment of patients

with FSGS should include inhibitors of the renin-angiotensin system.

Patients with primary FSGS with nephrotic-range proteinuria can be

treated with steroids but respond far less often and after a longer course

of therapy than patients with MCD. Proteinuria remits in only 20–45%

of patients receiving a course of steroids over 6–12 months. Limited

evidence suggests the use of cyclosporine in steroid-responsive patients

helps ensure remissions. Relapse frequently occurs after cessation of

cyclosporine therapy, and cyclosporine itself can lead to a deterioration

of renal function due to its nephrotoxic effects. A role for other agents

that suppress the immune system such as rituximab or mycophenolate

mofetil has not been established. Immunosuppressive therapy is not

indicated in secondary or genetic FSGS. FSGS recurs in 30% of renal

transplants, more commonly in primary FSGS, less commonly in secondary FSGS, and rarely in genetic FSGS. In recurrent posttransplant

FSGS, many patients will achieve a full or partial remission with plasmapheresis. The treatment of secondary FSGS typically involves treating the underlying cause and controlling proteinuria. There is no role

for steroids or other immunosuppressive agents in secondary FSGS.

MINIMAL

CHANGE DISEASE

Glomerular schematic 4 TABLE 314-5 Focal Segmental Glomerulosclerosis

Primary focal segmental glomerulosclerosis

Secondary focal segmental glomerulosclerosis

Adaptive response to hyperfiltration/reduced renal mass, obesity

Viruses: HIV/hepatitis B/parvovirus

Hypertensive nephropathy

Reflux nephropathy

Cholesterol emboli

Drugs: Heroin/analgesics/bisphosphonates/ecstasy

Oligomeganephronia

Sickle cell disease

Radiation nephritis

Familial podocytopathies

NPHS1 mutation/nephrin

NPHS2 mutation/podocin

PLCE1 mutation/phospholipase Cε1

INF2 mutation/inverted formin 2

WT1 mutation/Wilms tumor

TRPC6 mutation/cation channel

ACTN4 mutation/actinin

α-Galactosidase A deficiency/Fabry’s disease

N-Acetylneuraminic acid hydrolase deficiency/nephrosialidosis

2343 Glomerular Diseases CHAPTER 314

■ MEMBRANOUS GLOMERULONEPHRITIS

MGN, or membranous nephropathy as it is sometimes called, accounts

for ~25% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male-to-female ratio of

2:1. IMN is rare in childhood and the most common cause of nephrotic

syndrome in the elderly. In 20–30% of cases, MGN is secondary and is

associated with a malignancy (solid tumors of the breast, lung, colon),

infection (hepatitis B, syphilis, malaria, schistosomiasis), rheumatologic disorders such as lupus or rheumatoid arthritis, IgG4 diseases, or

drug exposure (Table 314-6).

Uniform thickening of the basement membrane along the peripheral capillary loops is seen by light microscopy on renal biopsy (see

Fig. A4-7); this thickening needs to be distinguished from that seen

in diabetes and amyloidosis. (See Glomerular Schematic 6.) Immunofluorescence demonstrates diffuse granular deposits of IgG and C3

,

Afferent

arteriole

Efferent

arteriole

Collapsed

capillary

and scar

Detachment

of cell from

GBM

FOCAL

SCLEROSING

GLOMERULONEPHRITIS

Proliferation of

subepithelial cells

Glomerular schematic 5

and electron microscopy typically reveals electron-dense subepithelial

deposits. While different stages (I–V) of progressive membranous

lesions have been described, some published analyses indicate the

degree of tubular atrophy or interstitial fibrosis is more predictive

of progression than is the stage of glomerular disease. The presence

of subendothelial deposits or the presence of tubuloreticular inclusions strongly points to a diagnosis of membranous lupus nephritis,

which may precede the extrarenal manifestations of lupus. In 70% of

cases of IMN, autoantibodies against the M-type phospholipase A2

TABLE 314-6 Membranous Glomerulonephritis

Primary/idiopathic membranous glomerulonephritis

Secondary membranous glomerulonephritis

Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy, filariasis

Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma

Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents,

probenecid, antitumor necrosis factor agents

Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis,

primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid,

myasthenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis

Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes,

Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian disease,

angiofollicular lymph node hyperplasia, IgG4 disease

MEMBRANOUS

GLOMERULONEPHRITIS

Foot process

fusion

Subepithelial

deposits

Glomerular schematic 6

2344 PART 9 Disorders of the Kidney and Urinary Tract

receptor circulate and bind to a conformational epitope present in the

PLA2R on human podocytes, producing characteristic in situ deposits. Three to 10% of IMN patients alternatively have autoantibodies

to thrombospondin type-1 domain containing 7A (THSD7A). Both

antigens co-localize within glomerular subepithelial deposits with IgG4

(PLA2R). Other renal diseases do not involve these autoantibodies.

In most cases of secondary membranous nephropathy, these autoantibodies are absent, with rare reports of autoantibodies to PLA2R

in membranous glomerulopathy associated with hepatitis B, cancer,

and sarcoidosis. Circulating deposits and glomerular deposits of these

autoantibodies have correlated with the likelihood of a spontaneous

remission, severity of IMN, and the response to therapy. Eighty percent

of patients with MGN present with nephrotic syndrome and nonselective proteinuria. Microscopic hematuria is seen but less commonly

than in IgA nephropathy or FSGS. Spontaneous remissions occur in

20–33% of patients and often occur late in the course, which makes

treatment decisions difficult. One-third of patients continue to have

relapsing nephrotic syndrome but maintain normal renal function,

and approximately another third of patients develop renal failure or die

from the complications of nephrotic syndrome. Male gender, older age,

hypertension, and the persistence of nephrotic-range proteinuria are

associated with worse prognosis. Although thrombotic complications

are a feature of all nephrotic syndromes, MGN has the highest reported

incidences of renal vein thrombosis, pulmonary embolism, and deepvein thrombosis. Prophylactic anticoagulation is controversial but has

been recommended for patients with hypoalbuminemia.

In addition to the treatment of edema, dyslipidemia, and hypertension, inhibition of the renin-angiotensin system is recommended.

Therapy with immunosuppressive drugs is also recommended for

patients with primary MGN and persistent proteinuria (>3.0 g/24 h).

The choice of immunosuppressive drugs for therapy is controversial,

but current recommendations are to treat with steroids and cyclophosphamide, chlorambucil, mycophenolate mofetil, or cyclosporine or rituximab, an anti-CD20 antibody directed at B cells. Attaining remission

is associated with a good long-term prognosis.

■ DIABETIC NEPHROPATHY

Diabetic nephropathy is the single most common cause of chronic

renal failure in the United States and worldwide. The dramatic increase

in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity and type 2 diabetes mellitus. Approximately

40% of patients with diabetes develop nephropathy, but due to the

higher prevalence of type 2 diabetes (90%) compared to type 1 (10%),

the majority of patients with diabetic nephropathy have type 2 disease.

Renal lesions are more common in African-American, Native-American,

Polynesian, and Maori populations. Risk factors for the development

of diabetic nephropathy include hyperglycemia, hypertension, dyslipidemia, smoking, a family history of diabetic nephropathy, and gene

polymorphisms.

Within 1–2 years after the onset of clinical diabetes, morphologic

changes appear in the kidney. Thickening of the GBM is a sensitive

indicator for the presence of diabetes but correlates poorly with the

presence or absence of nephropathy. The composition of the GBM is

altered notably with a loss of heparan sulfate moieties that form the

negatively charged filtration barrier resulting in increased filtration of

serum proteins into the urine. The expansion of the mesangium due

to the accumulation of extracellular matrix correlates with the clinical

manifestations of diabetic nephropathy (see stages in Fig. A4-20).

This expansion in mesangial matrix is associated with the development

of mesangial sclerosis. Some patients also develop eosinophilic, PAS+

nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules.

Immunofluorescence microscopy often reveals the nonspecific deposition of IgG (at times in a linear pattern) or complement staining

without immune deposits on electron microscopy. Prominent vascular

changes are frequently seen with hyaline and hypertensive arteriosclerosis. This is associated with varying degrees of chronic glomerulosclerosis and tubulointerstitial changes. Renal biopsies from patients

with types 1 and 2 diabetic nephropathies with albuminuria are largely

indistinguishable. Patients with type 2 diabetes without albuminuria

are classified as having diabetic kidney disease as opposed to diabetic

nephropathy and may have myriad pathologic findings.

Multiple lines of evidence support an important role for changes in

glomerular hemodynamics including increases in glomerular capillary

pressure and glomerular hyperfiltration in these pathologic changes.

Hyperglycemia activates the renin-angiotensin-aldosterone system

and also alters insulin-like growth factor, reactive oxygen species, and

endothelin 1. Diabetes upregulates the sodium-glucose cotransporters

(SGLT1 and SGLT2) in the proximal tubule, resulting in decreased

distal delivery of sodium to the macula densa and further glomerular

hyperfiltration. Sustained glomerular hypertension increases matrix

production and alterations in the GBM with disruption in the filtration

barrier. Other factors that alter matrix production include the accumulation of advanced glycosylation end products, circulating factors

including growth hormone, connective tissue growth factor, TGF-β,

and dyslipidemia.

The natural history of diabetic nephropathy has been historically

well characterized in the ~40% of diabetics who develop it as a progression from glomerular hyperfiltration and renal hypertrophy to

increasing albuminuria followed by declining GFR and ESRD. However, since the onset of type 1 diabetes is readily identifiable and the

onset of type 2 diabetes is not, a patient newly diagnosed with type 2

diabetes may present with advanced diabetic nephropathy. Albuminuria

and decreased GFR are potent risk factors for cardiovascular disease,

with some patients dying before they reach ESRD. Furthermore, contemporary studies reveal that up to 24% of patients with type 1 diabetes

and 50% with type 2 diabetes and chronic kidney disease may be normoalbuminuric. It is unknown whether this alteration in the natural

history reflects contemporary effective interventions or perhaps

other kidney diseases that happen to occur in patients with diabetes.

The degree of early glomerular hyperfiltration does correlate with the

development of albuminuria and declining GFR. Albuminuria in the

range of 30–300 mg/24 h is called microalbuminuria (Table 314-1).

Microalbuminuria appears 5–10 years after the onset of diabetes. It is

currently recommended to test patients with type 1 disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter and,

because the time of onset of type 2 diabetes is often unknown, to test

type 2 patients at the time of diagnosis of diabetes and yearly thereafter.

Microalbuminuria classically progresses over 5–10 years to proteinuria

and declining GFR, but in contemporary studies, greater heterogeneity is reported with regression to normoalbuminuria; however,

albuminuria remains the single most important predictor of a faster

decline in GFR. Regression of albuminuria with a treatment intervention is a good prognostic sign. Proteinuria in diabetic nephropathy

can be variable, ranging from 500 mg to 25 g/24 h. More than 90% of

patients with type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopathy in type 1 patients with proteinuria

should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with type 2 diabetes with nephropathy

have diabetic retinopathy. There is a significant correlation between

the presence of retinopathy and the presence of Kimmelstiel-Wilson

nodules (see Fig. A4-20). Even with advanced chronic kidney disease,

patients with diabetic nephropathy will have enlarged kidneys. Using

the above data, and in the absence of other clinical or serologic data

suggesting another disease, diabetic nephropathy is usually diagnosed

without a renal biopsy. The risk of progression to ESRD is influenced

by treatment and other risk factors, and reports vary from a decline of

1.8–14 mL/min per year. Survival on dialysis is worse for patients with

diabetes. Renal transplantation results in better survival than dialysis.

Good evidence supports the benefits of blood sugar and blood pressure control, inhibitors of the renin-angiotensin-aldosterone system

(RAAS), and inhibitors of SGLT2 in retarding the progression of diabetic nephropathy. In patients with type 1 diabetes, intensive control of

blood sugar clearly prevents the development or progression of diabetic

nephropathy. The evidence for benefit of intensive blood glucose control in patients with type 2 diabetes is less certain, with current studies

reporting conflicting results.

Controlling systemic blood pressure decreases renal and cardiovascular adverse events in this high-risk population. The vast majority of

2345 Glomerular Diseases CHAPTER 314

patients with diabetic nephropathy require three or more antihypertensive drugs to achieve this goal. Drugs that inhibit the RAAS (ACE

inhibitors, angiotensin receptor blockers [ARBs]), independent of their

effects on systemic blood pressure, have been shown in large clinical

trials to slow the progression of diabetic nephropathy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration)

stages. Evidence suggests increased risk for cardiovascular adverse

events without increased efficacy in patients with a combination of

two drugs (ACE inhibitors, ARBs, or renin inhibitors) that suppress

several components of the RAAS. In patients with type 2 diabetes and

kidney disease with albuminuria, the risk of kidney failure and cardiovascular events was lower in those receiving SGLT2 in addition to

inhibitors of the RAAS. Ongoing trials are examining the hypotheses

that other agents may be of benefit, including endothelin antagonists

and aldosterone antagonists.

■ GLOMERULAR DEPOSITION DISEASES

Plasma cell dyscrasias producing excess light chain immunoglobulin

sometimes lead to the formation of glomerular and tubular deposits

that cause heavy proteinuria and renal failure; the same is true for the

accumulation of serum amyloid A protein fragments seen in several

inflammatory diseases. This broad group of proteinuric patients has

glomerular deposition disease.

Light Chain Deposition Disease The biochemical characteristics of nephrotoxic light chains produced in patients with light

chain malignancies confer renal injury; that of either cast nephropathy (see Fig. A4-17), which causes renal failure but not heavy proteinuria or amyloidosis, or light chain deposition disease (LCDD)

(see Fig. A4-16), which produces proteinuria with renal failure.

These latter patients produce kappa light chains that do not have the

biochemical features necessary to form amyloid fibrils. Instead, they

self-aggregate and form granular deposits along the glomerular capillary and mesangium or, more prominently, in the tubular basement

membrane and Bowman’s capsule. Light chain deposits are not fibrillar

and do not stain with Congo red, but they are easily detected with anti–

light chain antibody. A combination of the light chain rearrangement,

self-aggregating properties at neutral pH, and abnormal metabolism

probably contributes to the deposition.

Monoclonal Plasma Cell Disorders Multiple myeloma, Waldenström’s macroglobulinemia, or lymphoma may be present, as well

as heart, liver, and pulmonary involvement. The monoclonal protein

may be found with serum electrophoresis or with serum free light

chain analysis. Nephrotic syndrome may develop, and ~70% of patients

progress to dialysis. Treatment for LCDD is treatment of the primary

disease and, if possible, autologous stem cell transplantation. Rarely,

truncated heavy chains similarly cause nonamyloid deposits.

Renal Amyloidosis Most renal amyloidosis is either the result of

primary fibrillar deposits of immunoglobulin light chains known as

amyloid L (AL) or secondary to fibrillar deposits of serum amyloid A

(AA) protein fragments (Chap. 112). Even though both occur for different reasons, their clinicopathophysiology is quite similar. Amyloid

infiltrates the liver, heart, peripheral nerves, carpal tunnel, upper pharynx, and kidney, producing restrictive cardiomyopathy, hepatomegaly,

macroglossia, and heavy proteinuria sometimes associated with renal

vein thrombosis. In contrast to LCDD, amyloid renal deposits are

fibrillar, stain with Congo red, and contain predominantly the variable

region of lambda chains (see Fig. A4-15). In systemic AL amyloidosis,

also called primary amyloidosis, light chains produced in excess by

clonal plasma cell dyscrasias are made into fragments by macrophages

so they can self-aggregate at acid pH. Approximately 10% of patients

have overt myeloma as defined by CRAB (hypercalcemia, renal insufficiency, anemia, or lytic bone lesions). Nephrotic syndrome is common,

and ~20% of patients progress to dialysis. AA amyloidosis is sometimes

called secondary amyloidosis and also presents as nephrotic syndrome.

It is due to deposition of β-pleated sheets of serum amyloid A protein,

an acute phase reactant. Patients with AA amyloid have associated

inflammatory diseases including rheumatoid arthritis, ankylosing

spondylitis, psoriatic arthritis, juvenile inflammatory arthritis, and

familial Mediterranean fever. An increasing proportion of patients

have unidentified chronic inflammation; this may reflect better treatments for the previously associated diseases or a rise in chronic inflammation due to obesity. Fragments of serum amyloid A protein increase

and self-aggregate by attaching to receptors for advanced glycation end

products in the extracellular environment; nephrotic syndrome is common, and ~40–60% of patient’s progress to dialysis. Serum-free light

chain analysis is useful in the early diagnosis and follow-up of disease

progression. Biopsy of involved liver or kidney is diagnostic 90% of the

time when the pretest probability is high; abdominal fat pad aspirates

are positive ~70% of the time, but apparently less so when looking

for AA amyloid. Amyloid deposits are distributed along blood vessels

and in the mesangial regions of the kidney. The treatment for primary

amyloidosis, melphalan, and autologous hematopoietic stem cell transplantation (HCT) can delay the course of disease. Patients who are not

candidates for HCT often receive bortezomib-based regimens. Secondary amyloidosis is also relentless unless the primary disease can be

controlled. Some new drugs in development that disrupt the formation

of fibrils may be available in the future.

Fibrillary and Immunotactoid Glomerulopathies Fibrillary

and immunotactoid glomerulopathies are rare (<1.0% of renal biopsies), morphologically defined diseases characterized by glomerular

accumulation of nonbranching randomly arranged fibrils that are

Congo red negative. Fibrillary glomerulopathy accounts for 85–90%

of cases and is identified by the presence of the protein DnaJ heat

shock protein family B9 (DNAJB9) in the glomeruli, which is absent

in the rarer immunotactoid glomerulopathy. In both, glomerular and

mesangial deposits contain oligoclonal or oligotypic immunoglobulins

and complement, with 12- to 24-nm fibrils in fibrillary glomerulopathy

and >30-nm fibrils organized into microtubules in immunotactoid

glomerulopathy. The cause of this “nonamyloid” glomerulopathy is

mostly idiopathic; reports of fibrillary glomerulonephritis describe

associations with malignancy, autoimmune disease, and monoclonal

gammopathy, and immunotactoid glomerulopathy has been associated with lymphoma or plasma cell disorders. Both disorders appear

in adults aged 40–80 years old, with moderate to heavy proteinuria

(100%), hematuria (70%), renal insufficiency (50%), and a wide variety

of histologic lesions, including DPGN, MPGN, MGN, or mesangioproliferative glomerulonephritis. Most patients have disease limited to the

kidney. Patients should be screened for associated disorders. Half of

patients develop renal failure over a few years. There is no consensus

on treatment of this uncommon disorder, although rituximab has been

reported to remit proteinuria. These diseases can recur in the renal

transplant.

■ FABRY’S DISEASE

Fabry’s disease is an X-linked inborn error of globotriaosylceramide metabolism secondary to deficient lysosomal α-galactosidase A

(alpha-Gal A) activity, resulting in excessive intracellular storage of

globotriaosylceramide. Affected organs include the vascular endothelium, heart, brain, and kidneys. Classically, Fabry’s disease presents in

childhood in males with acroparesthesias, angiokeratoma, cornea verticillate, and hypohidrosis. Over time, male patients develop cardiomyopathy, cerebrovascular disease, and renal injury, with an average age

of death around 50 years of age. Hemizygotes with hypomorphic mutations sometimes present in the fourth to sixth decade with single-organ

involvement. Rarely, dominant-negative alpha-Gal A mutations or

female heterozygotes with unfavorable X inactivation present with

mild single-organ involvement. Rare females develop severe manifestations including renal failure but do so later in life than males. Renal

biopsy reveals enlarged glomerular visceral epithelial cells packed with

small clear vacuoles containing globotriaosylceramide; vacuoles may

also be found in parietal and tubular epithelia (see Fig. A4-18).

These vacuoles of electron-dense materials in parallel arrays (zebra

bodies) are easily seen on electron microscopy. Ultimately, renal

biopsies reveal FSGS. The nephropathy of Fabry’s disease typically

presents in the third decade as mild to moderate proteinuria, sometimes with microscopic hematuria or nephrotic syndrome. Urinalysis

may reveal oval fat bodies and birefringent glycolipid globules under

2346 PART 9 Disorders of the Kidney and Urinary Tract

polarized light (Maltese cross). Measurement of alpha-Gal A activity

and mutational analysis of the gene is diagnostic, with renal biopsies

sometimes helpful. Progression to renal failure occurs by the fourth

or fifth decade. Treatment with inhibitors of the renin-angiotensin

system is recommended. Treatment with recombinant alpha-Gal A or

migalastat, a chaperone that facilitates trafficking of alpha-Gal A, clears

microvascular endothelial deposits of globotriaosylceramide from the

kidneys, heart, and skin. In patients with advanced organ involvement

including chronic kidney disease, progression of disease occurs despite

enzyme replacement therapy. Variable responses to enzyme therapy

may be due to the occurrence of neutralizing antibodies or differences

in uptake of the enzyme. Graft and patient survival following renal

transplantation in patients with Fabry’s disease are similar to those of

other causes of ESRD.

PULMONARY-RENAL SYNDROMES

Several diseases can present with catastrophic hemoptysis and glomerulonephritis associated with varying degrees of renal failure. The

usual causes include Goodpasture’s syndrome, granulomatosis with

polyangiitis, microscopic polyangiitis, Churg-Strauss vasculitis, and,

rarely, Henoch-Schönlein purpura or cryoglobulinemia. Each of these

diseases can also present without hemoptysis and are discussed in detail

earlier in “Acute Nephritic Syndromes.” (See Glomerular Schematic 7.)

Pulmonary bleeding in this setting is life-threatening and often results in

airway intubation, and acute renal failure requires dialysis. Diagnosis is

difficult initially because biopsies and serologic testing take time. Treatment with plasmapheresis and methylprednisolone is often empirical

and temporizing until results of testing are available.

BASEMENT MEMBRANE SYNDROMES

All kidney epithelia, including podocytes, rest on basement membranes assembled into a planar surface through the interweaving of collagen IV with laminins, nidogen, and sulfated proteoglycans. Structural

abnormalities in GBM associated with hematuria are characteristic

of several familial disorders related to the expression of collagen IV

genes. The extended family of collagen IV contains six chains, which

are expressed in different tissues at different stages of embryonic

development. All epithelial basement membranes early in human

development are composed of interconnected triple-helical protomers rich in α1.α1.α2(IV) collagen. Some specialized tissues undergo a

developmental switch replacing α1.α1.α2(IV) protomers with an α3.α4.

α5(IV) collagen network; this switch occurs in the kidney (glomerular

and tubular basement membrane), lung, testis, cochlea, and eye, while

an α5.α5.α6(IV) network appears in skin, smooth muscle, and esophagus and along Bowman’s capsule in the kidney. This switch probably

occurs because the α3.α4.α5(IV) network is more resistant to proteases

and ensures the structural longevity of critical tissues. When basement

membranes are the target of glomerular disease, they produce moderate proteinuria, some hematuria, and progressive renal failure.

■ ANTI-GBM DISEASE

Autoimmune disease where antibodies are directed against the α3 NC1

domain of collagen IV produces an anti-GBM disease often associated

with RPGN and/or a pulmonary-renal syndrome called Goodpasture’s syndrome. Discussion of this disease is covered earlier in “Acute

Nephritic Syndromes.”

■ ALPORT’S SYNDROME

Classically, patients with Alport’s syndrome develop hematuria, thinning and splitting of the GBMs, and mild proteinuria (<1–2 g/24 h),

which appears late in the course, followed by chronic glomerulosclerosis leading to renal failure in association with sensorineural deafness.

Some patients develop lenticonus of the anterior lens capsule, “dot and

fleck” retinopathy, and rarely, leiomyomatosis. Approximately 85% of

patients with Alport’s syndrome have an X-linked inheritance of mutations in the α5(IV) collagen chain on chromosome Xq22–24. Female

RAPIDLY

PROGRESSIVE

GLOMERULONEPHRITIS

Glomerular schematic 7

2347 Glomerular Diseases CHAPTER 314

carriers have variable penetrance depending on the type of mutation

or the degree of mosaicism created by X inactivation. Fifteen percent

of patients have autosomal recessive disease of the α3(IV) or α4(IV)

chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in α3(IV)

or α4(IV) chains.

Pedigrees with the X-linked syndrome are quite variable in their

rate and frequency of tissue damage leading to organ failure. Seventy

percent of patients have the juvenile form with nonsense or missense

mutations, reading frame shifts, or large deletions and generally

develop renal failure and sensorineural deafness by age 30. Patients

with splice variants, exon skipping, or missense mutations of α-helical

glycines generally deteriorate after the age of 30 (adult form) with

mild or late deafness. Early severe deafness, lenticonus, or proteinuria

suggests a poorer prognosis. Usually females from X-linked pedigrees

have only microhematuria, but up to 25% of carrier females have been

reported to have more severe renal manifestations. Pedigrees with the

autosomal recessive form of the disease have severe early disease in

both females and males with asymptomatic parents.

Clinical evaluation should include a careful eye examination and

hearing tests. However, the absence of extrarenal symptoms does not

rule out the diagnosis. Since α5(IV) collagen is expressed in the skin,

some X-linked Alport’s patients can be diagnosed with a skin biopsy

revealing the lack of the α5(IV) collagen chain on immunofluorescent analysis. Patients with mutations in α3(IV) or α4(IV) require a

renal biopsy. Genetic testing can be used for the diagnosis of Alport’s

syndrome and the demonstration of the mode of inheritance. Early

in their disease, Alport’s patients typically have thin basement membranes on renal biopsy (see Fig. A4-19), which thicken over time into

multilamellations surrounding lucent areas that often contain granules

of varying density—the so-called split basement membrane. In any

Alport’s kidney, there are areas of thinning mixed with splitting of the

GBM. Tubules drop out, glomeruli scar, and the kidney eventually

succumbs to interstitial fibrosis. All affected members of a family with

X-linked Alport’s syndrome should be identified and followed, including mothers of affected males. Primary treatment is control of systemic

hypertension and use of ACE inhibitors to slow renal progression.

Although patients who receive renal allografts usually develop antiGBM antibodies directed toward the collagen epitopes absent in their

native kidney, overt Goodpasture’s syndrome is rare and graft survival

is good.

■ THIN BASEMENT MEMBRANE DISEASE

Thin basement membrane disease (TBMD), a relatively common

disorder characterized by persistent or intermittent, asymptomatic,

usually microscopic hematuria and rarely macroscopic hematuria

with flank pain, is not typically associated with proteinuria, hypertension, or loss of renal function or extrarenal disease. TBMD is often

familial, with pedigrees exhibiting an autosomal dominant pattern. It

usually presents in childhood in multiple family members and is also

called benign familial hematuria. Many cases of TBMD have genetic

defects in type IV collagen, but in contrast to Alport’s syndrome, the

disease behaves as an autosomal dominant disorder that in ~40% of

families segregates with the COL(IV) α3/COL(IV) α4 loci. Mutations

in these loci can result in a spectrum of disease, ranging from TBMD

to autosomal dominant or recessive Alport’s. The GBM shows diffuse

thinning compared to normal values for the patient’s age in otherwise

normal biopsies (see Fig. A4-19). The vast majority of patients have a

benign course.

■ NAIL-PATELLA SYNDROME

Patients with nail-patella syndrome develop iliac horns on the pelvis

and dysplasia of the dorsal limbs involving the patella, elbows, and

nails, variably associated with neural-sensory hearing impairment,

glaucoma, and abnormalities of the GBM and podocytes, leading to

hematuria, proteinuria, and FSGS. The syndrome is autosomal dominant, with haploinsufficiency for the LIM homeodomain transcription

factor LMX1B; pedigrees are extremely variable in the penetrance for

all features of the disease. LMX1B regulates the expression of genes

encoding α3 and α4 chains of collagen IV, interstitial type III collagen,

podocin, and CD2AP that help form the slit-pore membranes connecting podocytes. Mutations in the LIM domain region of LMX1B associate with glomerulopathy in 30–40% of patients and rarely progress to

renal failure. Proteinuria or isolated hematuria is discovered throughout life but usually by the third decade. On renal biopsy, pathognomic

rarefications containing clusters of collagen fibrils within the lamina

densa of the GBM are found, and FSGS may be present. Treatment is

nonspecific, but renin-angiotensin system inhibition is recommended.

Patients with renal failure do well with transplantation.

■ GLOMERULAR-VASCULAR SYNDROMES

A variety of diseases result in classic vascular injury to the glomerular

capillaries. Most of these processes also damage blood vessels elsewhere in the body. The group of diseases discussed here lead to vasculitis, renal endothelial injury, thrombosis, ischemia, and/or lipid-based

occlusions.

ATHEROSCLEROTIC NEPHROPATHY

Aging in the developed world is commonly associated with the occlusion of coronary and systemic blood vessels. The reasons for this

include obesity, insulin resistance, smoking, hypertension, and diets

rich in lipids that deposit in the arterial and arteriolar circulation, producing local inflammation and fibrosis of small blood vessels. When

the renal arterial circulation is involved, the glomerular microcirculation is damaged, leading to chronic nephrosclerosis. Patients with GFRs

<60 mL/min have more cardiovascular events and hospitalizations than

those with higher filtration rates. Several aggressive lipid disorders can

accelerate this process, but most of the time, atherosclerotic progression to chronic nephrosclerosis is associated with poorly controlled

hypertension. Approximately 10% of glomeruli are normally sclerotic

by age 40, rising to 20% by age 60 and 30% by age 80. Serum lipid

profiles in humans are greatly affected by apolipoprotein E polymorphisms; the E4 allele is accompanied by increases in serum cholesterol

and is more closely associated with atherogenic profiles in patients with

renal failure. Mutations in E2 alleles, particularly in Japanese patients,

produce a specific renal abnormality called lipoprotein glomerulopathy

associated with glomerular lipoprotein thrombi and capillary dilation.

■ HYPERTENSIVE NEPHROSCLEROSIS

Systemic hypertension causes permanent damage to the kidneys in

~6% of patients with elevated blood pressure. As many as 27% of

patients with end-stage kidney disease have hypertension as a primary cause, and it is the second most common cause of ESRD after

diabetic nephropathy. Hypertensive nephrosclerosis is fivefold more

frequent in African Americans than whites. Risk alleles associated

with APOL1, a functional gene for apolipoprotein L1 expressed in

podocytes, substantially explain the increased burden of ESRD among

African Americans. Associated risk factors for progression to end-stage

kidney disease include increased age, male gender, race, smoking,

hypercholesterolemia, duration of hypertension, low birth weight, and

preexisting renal injury. Kidney biopsies in patients with hypertension,

microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in the absence of

immune deposits (see Fig. A4-21). Based on a careful history, physical

examination, urinalysis, and some serologic testing, the diagnosis of

chronic nephrosclerosis is usually inferred without a biopsy. Recent

studies suggest, in the absence of diabetes, adults with hypertension

and cardiovascular risk factors benefit from achieving a systolic blood

pressure <120 mmHg, compared to <140 mmHg. In the presence of

kidney disease, most patients begin antihypertensive therapy with two

drugs, classically a thiazide diuretic and an ACE inhibitor; most will

require three drugs. There is strong evidence in African Americans

with hypertensive nephrosclerosis that therapy initiated with an ACE

inhibitor can slow the rate of decline in renal function independent of

effects on systemic blood pressure. Malignant acceleration of hypertension complicates the course of chronic nephrosclerosis, particularly in

the setting of scleroderma or cocaine use (see Fig. A4-24). The hemodynamic stress of malignant hypertension leads to fibrinoid necrosis of

2348 PART 9 Disorders of the Kidney and Urinary Tract

small blood vessels, thrombotic microangiography, a nephritic urinalysis, and acute renal failure. In the setting of renal failure, chest pain,

or papilledema, the condition is treated as a hypertensive emergency.

■ CHOLESTEROL EMBOLI

Aging patients with clinical complications from atherosclerosis sometimes shower cholesterol crystals into the circulation, either spontaneously or, more commonly, following an endovascular procedure with

manipulation of the aorta or with use of systemic anticoagulation.

Spontaneous emboli may shower acutely or shower subacutely and

somewhat more silently. Irregular emboli trapped in the microcirculation produce ischemic damage that induces an inflammatory reaction.

Depending on the location of the atherosclerotic plaques releasing

these cholesterol fragments, one may see cerebral transient ischemic

attacks; livedo reticularis in the lower extremities; Hollenhorst plaques

in the retina with visual field cuts; necrosis of the toes; and acute glomerular capillary injury leading to FSGS sometimes associated with

hematuria, mild proteinuria, and loss of renal function, which typically

progresses over a few years. Occasional patients have fever, eosinophilia, or eosinophiluria. A skin biopsy of an involved area may be

diagnostic. Since tissue fixation dissolves the cholesterol, one typically

sees only residual, biconvex clefts in involved vessels (see Fig. A4-22).

There is no therapy to reverse embolic occlusions, and steroids do not

help. Controlling blood pressure and lipids and cessation of smoking

are usually recommended for prevention.

■ SICKLE CELL DISEASE

Although individuals with SA-hemoglobin are usually asymptomatic,

most will gradually develop hyposthenuria due to subclinical infarction

of the renal medulla, thus predisposing them to volume depletion.

There is an unexpectedly high prevalence of sickle trait among dialysis patients who are African American. Patients with homozygous

SS-sickle cell disease and less commonly SC-sickle cell disease develop

chronic vaso-occlusive disease in many organs. Polymers of deoxygenated SS-hemoglobin distort the shape of red blood cells. These

cells attach to endothelia and obstruct small blood vessels, producing

frequent and painful sickle cell crises over time. Early changes in the

kidney include glomerular hyperfiltration, hyposthenuria, micro- or

macroscopic hematuria, and microalbuminuria. Later changes can

include papillary necrosis, renal infarction and proteinuria, and most

commonly, FSGS on renal biopsy and rarely MPGN. Vessel occlusions

in the kidney produce glomerular hypertension, FSGS, interstitial

nephritis, and renal infarction associated with hyposthenuria, microscopic hematuria, and even gross hematuria; some patients also present

with MPGN. Renal function can be overestimated due to the increased

tubular secretion of creatinine seen in many patients with SS-sickle cell.

By the second or third decade of life, persistent vaso-occlusive disease

in the kidney leads to varying degrees of renal failure. Their prognosis

on dialysis is poor, and anemia management with erythropoiesisstimulating agents is complicated. Treatment is directed to reducing

the frequency of painful crises and administering ACE inhibitors and

hydroxyurea in the hope of delaying a progressive decline in renal

function. In sickle cell patients undergoing renal transplantation, renal

graft survival is comparable to African Americans in the general transplant population.

■ THROMBOTIC MICROANGIOPATHIES

Thrombotic thrombocytopenic purpura (TTP), Shiga toxin–mediated

hemolytic-uremic syndrome (HUS), and complement-mediated HUS

represent a spectrum of thrombotic microangiopathies (TMAs). TTP

and HUS share the general features of idiopathic thrombocytopenic

purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances. Clinically, when patients, particularly children, have evidence

of renal injury, HUS is suspected, and in adults with neurologic disease,

TTP is suspected. On examination of kidney tissue, there is evidence

of glomerular capillary endotheliosis associated with platelet thrombi,

damage to the capillary wall, and formation of fibrin material in and

around glomeruli (see Fig. A4-23). These tissue findings are similar

to what is seen in preeclampsia/HELLP (hemolysis, elevated liver

enzymes, and low platelet count syndrome), malignant hypertension,

and the antiphospholipid syndrome. TMA is also seen postpartum

(and may be complement mediated); with the use of oral contraceptives or quinine; in renal transplant patients given OKT3 for rejection; in patients taking the calcineurin inhibitors cyclosporine and

tacrolimus; in patients taking the antiplatelet agents ticlopidine and

clopidogrel; and following HIV infection. The implicated drug should

be discontinued.

Shiga toxin–mediated HUS is caused by a toxin released by Escherichia coli 0157:H7 and occasionally by Shigella dysenteriae. This Shiga

toxin (verotoxin) directly injures endothelia, enterocytes, and renal

cells, causing apoptosis, platelet clumping, and intravascular hemolysis

by binding to the glycolipid receptors (Gb3). These receptors are more

abundant along endothelia in children compared to adults. Shiga toxin

also inhibits the endothelial production of ADAMTS13. In familial

cases of adult TTP, there is a genetic deficiency of the ADAMTS13

metalloprotease that cleaves large multimers of von Willebrand’s

factor. Absent ADAMTS13, these large multimers cause platelet

clumping and intravascular hemolysis. An antibody to ADAMTS13

is found in many sporadic cases of adult TTP. Patients can be tested

for ADAMTS13 activity, and if low, the presence of antibodies to

ADAMTS13 distinguishes the deficiency from the immune-mediated

disease. Complement-mediated TMA/HUS is a rare hereditary deficiency of one of the regulatory proteins that restrict the activation

of the alternate complement pathway and can present in children or

adults often preceded by an infection. The treatment of adult TTP with

ADAMTS13 antibodies is daily plasmapheresis, which can be lifesaving. Plasmapheresis with fresh frozen plasma is given until the platelet

count rises, but in relapsing patients, it normally is continued well after

the platelet count improves. There is an anecdotal role in relapsing

patients for using splenectomy, steroids, immunosuppressive drugs,

bortezomib, or rituximab. Patients without antibodies and a genetic

deficiency of ADAMTS13 production can be treated with fresh frozen

plasma alone. Patients with Shiga toxin–mediated HUS are not given

antibiotics and are treated with supportive care because antibiotics are

thought to accelerate the release of the toxin and the diarrhea is usually self-limited. Patients with complement-mediated TMA/HUS are

treated with eculizumab, an anticomplement therapy.

■ ANTIPHOSPHOLIPID ANTIBODY SYNDROME

(SEE CHAP. 357)

GLOBAL CONSIDERATIONS

■ INFECTIOUS DISEASE–ASSOCIATED SYNDROMES

A number of infectious diseases will injure the glomerular capillaries

as part of a systemic reaction producing an immune response or from

direct infection of renal tissue. Evidence of this immune response is

collected by glomeruli in the form of immune deposits that damage

the kidney, producing moderate proteinuria and hematuria. A high

prevalence of many of these infectious diseases in developing countries

results in infection-associated renal disease being the most common

cause of glomerulonephritis in many parts of the world.

Poststreptococcal Glomerulonephritis This form of glomerulonephritis is one of the classic complications of streptococcal infection. The discussion of this disease can be found earlier, in the section

“Acute Nephritic Syndromes.”

Subacute Bacterial Endocarditis Renal injury from persistent

bacteremia absent the continued presence of a foreign body, regardless

of cause, is treated presumptively as if the patient has endocarditis. The

discussion of this disease can be found earlier, in the section “Acute

Nephritic Syndromes.”

Human Immunodeficiency Virus Renal disease is an important complication of HIV disease. The risk of development of ESRD

is much higher in HIV-infected African Americans than in HIVinfected whites. About 50% of HIV-infected patients with kidney disease have HIV-associated nephropathy (HIVAN) on biopsy. The lesion