2325Transplantation in the Treatment of Renal Failure CHAPTER 313

Kidney transplantation is the treatment of choice for patients with

end-stage kidney disease (ESKD). Worldwide, tens of thousands of

kidney transplants have been performed, and >220,000 patients are

living with a functioning kidney transplant in the United States today.

The first successful kidney transplant was performed in Boston in 1954

between identical twins without the need of immunosuppression. The

introduction of immunosuppressive therapies such as azathioprine and

prednisone in the 1960s established kidney transplantation across nonidentical individuals (allografts). However, the results with properly

matched familial donors remained significantly superior to those with

organs from deceased donors. During the 1970s and 1980s, the success

rate at the 1-year mark for deceased-donor allografts rose progressively

after the introduction of calcineurin inhibitors. Currently, 1-year survival rates for living-donor and deceased-donor allografts are 98% and

93%, respectively, in the United States. However, long-term survival

has not improved as much over time, and average allograft survival

times are 14 and 10 years for living-donor and deceased-donor grafts,

respectively.

Age-related mortality rates after transplantation are highest in the

first year due to the surgical risks: 2% for ages 18–34 years, 3% for ages

35–49 years, and 6.8% for ages ≥50–60 years. Despite these outcome

statistics, the actual survival benefit of transplantation compared to

chronic dialysis becomes apparent within days to months following

transplantation, even after risk adjustments for age, diabetes, and

cardiovascular status. While the loss of kidney transplant due to acute

rejection is now a rare event, most allografts eventually succumb at

varying rates to a chronic process consisting of interstitial fibrosis,

tubular atrophy, vasculopathy, and glomerulopathy, the pathogenesis

of which in varying degrees is likely a combination of an alloimmune

response, drug toxicity, and the end result of a variety of other insults.

Overall, transplantation results in an improved life expectancy with a

higher quality of life compared to patients whom remain on dialysis.

RECENT ACTIVITY AND RESULTS

In 2019, >16,000 deceased-donor kidney transplants and 6800

living-donor transplants were performed in the United States, with

the ratio of deceased-donor to living-donor transplants remaining

stable over the past few years. As the number of patients with ESKD

increases, the number of patients on the transplant waitlist also

increases, and the donor shortage remains a critical challenge. As of

2019, there were nearly 59,000 active adult candidates on the waiting

list, with <23,000 patients being transplanted yearly. This imbalance is

set to worsen over the coming years with the predicted increased rates

of kidney failure associated with obesity and diabetes worldwide. In an

attempt to increase utilization of marginal kidneys and allocate organs

313 Transplantation in the

Treatment of Renal Failure

Jamil Azzi, Naoka Murakami, Anil Chandraker

equitably, a new allocation system within the United States was implemented in 2014. The guiding principles of the changes were to offer an

opportunity for transplantation to patients who were highly sensitized

and, thus, less likely to find a suitable donor, while at the same time to

allow patients expected to survive the longest to receive the best-quality

deceased donor organs. The Kidney Donor Profile Index (KDPI) score,

which ranges from 0 to 100%, was introduced to estimate the potential

risk of graft failure after kidney transplant based on 10 donor factors.

The lower KDPI values are associated with higher expected posttransplant survival. Hence, the kidneys with a KDPI <20% are allocated to

the 20% of the potential recipients with the highest expected posttransplant survival. Kidneys with a KDPI >85% (previously called expanded

criteria donor [ECD] kidneys) are directed toward patients who are

expected to fare less well on dialysis and would benefit from being

transplanted earlier even if it means accepting a lower-quality organ. A

variety of other means to increase the donor pool and equity in terms

of wait time for a transplant have also become more popular. Kidneys

from donors after cardiac death (DCD) are being increasingly used to

overcome the demand for organs (Table 313-1). Furthermore, with

the advancement of the direct-acting antiviral therapies for hepatitis

C virus (HCV), transplantation from HCV-positive donors to HCVpositive or -negative recipients has been performed since 2017 in order

to increase the donor pool. Now this practice is incorporated in several

centers in the United States. Recently, the HOPE (Human Immunodeficiency Virus [HIV] Organ Policy Equity) Act authorized organ donation from HIV-positive candidates, and >100 transplants have been

performed. Finally, in the new kidney allocation system, B blood type

candidates who have low anti-A titer are eligible for an allograft from

A blood type donors. This helps improve access and reduce disparities

in wait time for minorities, especially for the African-American ESKD

population, in whom blood type B is more common than in other

ethnicities.

The overall results of transplantation are presented in Table 313-2. At

the 1-year mark, allograft survival is higher for living-donor recipients.

This is most likely related to decreased damage of the organ related

to less ischemic injury. The introduction of more effective drugs and

more sensitive matching between recipients and donors has almost

equalized the risk of graft rejection in the majority of patients within

the first year. At 5- and 10-year follow-up, however, there remains a

steeper decline in survival of those with deceased-donor kidneys.

RECIPIENT EVALUATION

Virtually all patients with ESKD benefit from transplantation with a

longer life expectancy and a better quality of life. While the mortality

rate after transplantation is highest in the first year due to perioperative

complications, recipient evaluation is critical in identifying patients at

risk. It involves a multidisciplinary approach that requires thorough

medical, surgical, social, and psychosocial evaluations to identify the

risk factors that prohibit transplantation or mandate treatment before

proceeding, as well as ensuring the appropriate use of limited organs.

There are a few absolute contraindications to kidney transplantation: chronic illness that limits predicted survival for <2 years, active

TABLE 313-1 Definition of a Non-Heart-Beating Donor (Donation

After Cardiac Deatha

 [DCD])

I: Brought in dead

II: Unsuccessful resuscitation

III: Awaiting cardiac arrest

IV: Cardiac arrest after brainstem death

V: Cardiac arrest in a hospital patient

a

Kidneys can be used for transplantation from categories II–V but are commonly

only used from categories III and IV. The survival of these kidneys has not been

shown to be inferior to that of deceased-donor kidneys.

Note: Kidneys can both have a Kidney Donor Profile Index (KDPI) score >85% and

be DCD. High KDPI kidneys have been shown to have a poorer survival, and there

is a separate shorter waiting list for those kidneys. They are generally utilized

for patients for whom the benefits of being transplanted earlier outweigh the

associated risks of using a lower-quality kidney.

National Kidney Foundation: Kidney disease quality initiative

clinical practice guidelines: Hemodialysis and peritoneal dialysis

adequacy, 2006. Available online: http://www.kidney.org/professionals/

kdoqi/guidelines.cfm.

Rocco MV et al: The effects of frequent nocturnal home hemodialysis: The frequent hemodialysis network nocturnal trial. Kidney Int

80:1080, 2011.

U.S. Renal Data System: USRDS 2019 Annual Data Report: Atlas

of End-Stage Renal Disease in the United States. Bethesda, National

Institutes of Health, National Institute of Diabetes and Digestive and

Kidney Disease, 2019.

2326 PART 9 Disorders of the Kidney and Urinary Tract

TABLE 313-2 Mean Rates of Graft and Patient Survival for Kidneys Transplanted in the United States from 1999 to 2015a

1-YEAR FOLLOW-UP 5-YEAR FOLLOW-UP 10-YEAR FOLLOW-UP

GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, %

Deceased donor 93 96 75 85 48 64

Living donor 98 99 85 92 65 79

a

All patients transplanted are included, and the follow-up unadjusted survival data from the 1-, 5-, and 10-year periods are presented to show the attrition rates over time

within the two types of organ donors.

Source: Data from Summary Tables, 2018 Annual Reports, Scientific Registry of Transplant Recipients.

malignancy, active infection, psychosocial issues affecting adherence to

the medical care, and active substance abuse. Another critically important factor to consider is cardiovascular risk during both the perioperative and postoperative periods. Patients with ESKD are at higher

cardiovascular mortality risk, and thorough cardiovascular evaluation

for coronary artery diseases, valvular diseases, and heart failure is critical.

At most centers, there is no official age limit for transplantation, with

>20% of waitlisted candidates currently being older than 65. However,

overall physical and cognitive function of the candidates needs to be fully

assessed. While history of malignancy itself is not a contraindication for

kidney transplantation, potential recipients should be treated and cured

with a waiting time of 2–5 years depending on the type of malignancy to

decrease the risk of recurrence of the disease. Latent or indolent infection (HIV, hepatitis B or C, tuberculosis) should be a routine part of the

candidate workup. While historically transplant centers considered overt

AIDS and active hepatitis absolute contraindications to transplantation

because of the high risk of opportunistic infection, with the introduction

of potent antiviral regimens, many centers are now transplanting individuals with hepatitis and HIV infection under strict protocols.

One of the few “immunologic” contraindications to transplantation

is the presence of antibodies against the donor kidney at the time of

the anticipated transplant that can cause hyperacute rejection. Those

harmful antibodies include natural antibodies against the ABO blood

group antigens and antibodies against human leukocyte antigen (HLA)

class I (A, B, C) or class II (DR, DQ, DP) antigens. These antibodies

are routinely excluded by proper screening of the candidate’s ABO

compatibility and direct cytotoxic cross-matching of candidate serum

with lymphocytes of the donor. Removal of these antibodies directed

at donor tissue through a variety of strategies (desensitization) is now

routinely performed with varying levels of success.

TISSUE TYPING AND CLINICAL

IMMUNOGENETICS

Matching for antigens of the HLA major histocompatibility complex

(Chap. 350) is an important criterion for the selection of donors. Each

mammalian species has a single chromosomal region that encodes

the strong, or major, transplantation antigens, and this region on the

human chromosome 6 codes the HLA genes. HLA is highly polymorphic; therefore, it can be an immunologic target of organ rejection

when mismatched between the donor and the recipient. Historically,

HLA antigens have been defined by serologic techniques by adding

sera of a recipient (potentially containing anti-HLA antibodies) with

a “library” of leukocytes with known serotypes. However, currently,

molecular typing of HLA by genomic sequencing is almost universally

used. Other “minor,” non-HLA antigens may also elicit an alloimmune

response in addition to the ABH(O) antigens and endothelial antigens

that are not expressed on lymphocytes. The number of HLA antigen

mismatches in A, B, and DR loci correlates with allograft survival; the

more mismatches, the higher is the risk of allograft rejection. Nevertheless, some HLA-identical renal allografts are rejected, often within

the first few weeks after transplantation. These failures may represent

states of prior sensitization to non-HLA antigens. Non-HLA minor

antigens are relatively weak when initially encountered and are, therefore, suppressible by conventional immunosuppressive therapy. If prior

exposure to the antigen and priming of the recipient immune system

has occurred, secondary exposure at the time of transplantation may

lead to an immune response refractory to treatment.

DONOR EVALUATION

■ LIVING-DONOR EVALUATION

Living kidney donors experience the immediate risk of surgery and the

long-term potential risk of developing kidney dysfunction prematurely;

thus, the basic principle of “first, do no harm” (Chap. 11) is important.

Therefore, donor evaluation must take every effort to exclude any medical conditions that may cause morbidity and mortality after kidney

donation, such as hypertension, diabetes, and/or proteinuria. Although

studies have shown that the risk of ESKD after kidney donation is not

greater than that of the general population, donation is associated

with a small but significant potential lifetime risk of ESKD (0.3–0.4%;

absolute risk increased by 0.2–0.3% compared to that of healthy nondonors). The mechanism of premature renal failure is thought to be

due to increased blood flow and hyperfiltration injury in the remaining

kidney. There are a few reports of the development of hypertension,

proteinuria, and even lesions of focal segmental sclerosis in donors

over long-term follow-up. In family members of type 1 diabetics, antiinsulin and anti-islet cell antibodies should be measured, and a glucose

tolerance test should be performed. African-American donors have a

higher risk of ESKD after donation (in line with their higher risk of

kidney failure in general), and the genetic screening for APOL1 risk

alleles may be appropriate (Chap. 314). From the surgical perspective,

selective renal arteriography is essential to reveal any anatomic anomaly and to assess the size imbalance and laterality of donor kidneys.

In most cases, donor nephrectomy is performed laparoscopically to

minimize the surgical scar and to enhance a faster postsurgical recovery. Lastly, although financial and nonfinancial conflicts of interest

between kidney donors and recipients are strictly prohibited, removing

financial disincentives is increasingly accepted as a means to reduce

barriers toward living donation (Chap. 11).

■ DECEASED-DONOR EVALUATION

Deceased donors should be free of malignant neoplastic disease,

hepatitis, and HIV owing to possible transmission to the recipient,

although under certain circumstances, HCV- and HIV-positive organs

may be used. Increased risk of graft failure exists when the donor is

elderly or has acute kidney injury or when the kidney experiences a

prolonged period of ischemia.

In the United States, there is a national system of regulations, allocation support, and outcomes analysis for kidney transplantation called

the Organ Procurement Transplant Network. Studies have shown that

it is possible to remove deceased-donor kidneys and maintain them for

up to 48 h on cold pulsatile perfusion or with simple flushing and cooling, but these practices are not part of clinical care as of yet. Generally,

an ischemic time of <24 h is preferred; this approach permits adequate

time for typing, cross-matching, transportation, and selection issues to

be resolved.

■ PRESENSITIZATION

The presence of antibodies against donor antigens, either HLA or

non-HLA, can be a potential cause of allograft injury following transplantation, and hence, it is important to carry out cross-matching prior

to transplantation. For the purposes of cross-matching, donor T lymphocytes, which express class I but not class II HLA, are used as a surrogate target for detection of circulating anti–class I (HLA-A and -B)

antibodies in the recipient. Note that T cells are used as surrogate cells

2327Transplantation in the Treatment of Renal Failure CHAPTER 313

for the detection of class I HLA as a matter of convenience and this is

unrelated to the risk of T cell–mediated rejection. A positive cytotoxic

cross-match of recipient serum with donor T lymphocytes indicates

the presence of preformed donor-specific anti-HLA class I antibodies

and is usually predictive of an acute vasculitic event termed hyperacute

rejection. This finding represents the only widely accepted absolute

immunologic contraindication for kidney transplantation. Recently, an

increasing number of tissue-typing laboratories have shifted to a more

sensitive flow cytometric–based cross-match assay, which detects the

presence of anti-HLA antibodies that are not necessarily detected on

a cytotoxic cross-match assay and may not be an absolute contraindication to transplantation. The known sources of sensitization are

blood transfusion, a prior transplant, pregnancy, and, less commonly,

vaccination/infection.

Preformed anti–class II (HLA-DR and -DQ) antibodies against the

donor also carry a higher risk of graft loss, particularly in recipients

who have suffered early loss of a prior kidney transplant. B lymphocytes (again, used for convenience), which express both class I and

class II HLA, are used as a surrogate target in these assays. Some nonHLA antigens restricted in expression to endothelium and monocytes

have been described, but their clinical relevance is not well established.

A series of minor histocompatibility antigens do not elicit antibodies,

and sensitization to these antigens is detectable only by cytotoxic

T cells, an assay too cumbersome for routine use.

Desensitization prior to transplantation by reducing the level of antidonor antibodies utilizing plasmapheresis and/or the administration of

pooled immunoglobulin (IV immunoglobulin [IVIG]) has been useful

in reducing the risk of hyperacute rejection following transplantation.

IMMUNOLOGY OF REJECTION

Both T cell–mediated and antibody-mediated effector mechanisms can

play roles in kidney transplant rejection.

T cell–mediated rejection is caused by recipient T lymphocytes

that respond to donor HLA antigens expressed on the organ. CD4+

lymphocytes respond to class II (HLA-DR) incompatibility by proliferating and releasing proinflammatory cytokines that augment the

proliferative response of the immune system. CD8+ cytotoxic lymphocytes respond primarily to class I (HLA-A, -B) antigens and mature

into cytotoxic effector cells that cause organ damage through direct

contact and lysis of donor target cells. Full T-cell activation requires

not only T-cell receptor binding to the alloantigens presented by self

or donor HLA molecules (known as indirect and direct presentation,

respectively), but also engagement of costimulatory molecules such as

CD28 on T cells and CD80 and CD86 ligands on antigen-presenting

cells (Fig. 313-1). Signaling through both of these pathways induces

activation of the kinase activity of calcineurin, which, in turn, activates transcription factors leading to upregulation of multiple genes,

including interleukin (IL) 2 and interferon γ. IL-2 signals through the

target of rapamycin (TOR) to induce cell proliferation in an autocrine

fashion. There is evidence that non-HLA antigens can also play a role

in renal transplant rejection episodes. Recipients who receive a kidney

from an HLA-identical sibling can still have rejection episodes and

require maintenance immunosuppression, whereas true identical twin

transplants require no immunosuppression. There are documented

non-HLA antigens, such as an endothelial-specific antigen system with

limited polymorphism and a tubular antigen, which can act as targets

of humoral or cellular rejection responses, respectively.

Antibody-mediated rejection is caused by circulating antibodies

against donor antigens. After transplantation, donor-derived antigens

are delivered to the recipient’s draining lymph nodes and activate an

alloimmune response. A subset of CD4+ T cells called follicular helper

T cells (Tfh) are activated and promote differentiation of B cells into

antibody-secreting plasma cells. Plasma cells produce donor-targeting

antibodies against HLA and non-HLA antigens, which can deposit

in allograft kidney and cause injury via complement-dependent and

independent mechanisms. C4d deposition in peritubular capillaries

and glomerular basement membrane is a footprint of complement activation and is one of the diagnostic criteria of antibody-mediated rejection, together with the presence of circulating donor-specific antibody.

Allogeneic APC

CD8

MHC molecule

Allogeneic peptide

CD4

Tc

Tc

TH TH

Allogeneic APC Self APC

Direct Pathway Indirect Pathway

B cell

CD4

Cytokines

Activated

cytotoxic T cell

Cellular

rejection

Transplant

arteriosclerosis

Antibody mediated

rejection

Delayed-type

hypersensitivity

Alloantibodies

Macrophage

FIGURE 313-1 Recognition pathways for major histocompatibility complex (MHC)

antigens. Graft rejection is initiated by CD4 helper T lymphocytes (TH) having

antigen receptors that bind to specific complexes of peptides and MHC class II

molecules on antigen-presenting cells (APC). In transplantation, in contrast to other

immunologic responses, there are two sets of T-cell clones involved in rejection.

In the direct pathway, the class II MHC of donor allogeneic APCs is recognized by

CD4 TH cells that bind to the intact MHC molecule, and class I MHC allogeneic cells

are recognized by CD8 T cells. The latter generally proliferate into cytotoxic cells

(TC

). In the indirect pathway, the incompatible MHC molecules are processed into

peptides that are presented by the self-APCs of the recipient. The indirect, but not

the direct, pathway is the normal physiologic process in T-cell recognition of foreign

antigens. Once TH cells are activated, they proliferate and, by secretion of cytokines

and direct contact, exert strong helper effects on macrophages, TC, and B cells.

(From MH Sayegh: The role of T-cell costimulatory activation pathways in transplant

rejection. N Engl J Med 338:1813, 1998. Copyright © 1998, Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.)

IMMUNOSUPPRESSIVE TREATMENT

Kidney transplant recipients need to take immunosuppressive drugs

for life, except identical twins and simultaneous bone marrow–kidney

transplant recipients. Immunosuppressive therapy, as currently available, suppresses all immune responses nonspecifically, including those

to bacteria, fungi, and even malignant tumors. In general, all clinically

available drugs are more selective to primary rather than to memory

immune responses. Agents to suppress the immune response are

divided into induction and maintenance agents. Those currently in

clinical use are listed in Table 313-3.

■ INDUCTION THERAPY

Induction therapy is given to most kidney transplant recipients in the

United States at the time of transplant to reduce the risk of early acute

rejection and to minimize or eliminate the use of either steroids or

calcineurin inhibitors and their associated toxicities. Induction therapy consists of antibodies that could be monoclonal or polyclonal and

depleting or nondepleting.

Depleting Agents Antithymocyte globulin (ATG) is a lymphocytedepleting agent. Peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas are injected into horses

or rabbits to produce antilymphocyte serum, from which the immunoglobulin fraction is then separated. Those polyclonal antibodies

induce lymphocyte depletion, and the immune system may take several

months, if not years, to fully recover.

Monoclonal antibodies against defined lymphocyte subsets offer

a more precise and standardized form of therapy. Alemtuzumab is

2328 PART 9 Disorders of the Kidney and Urinary Tract

directed to CD52, widely expressed on immune cells such as B and

T cells, natural killer cells, macrophages, and some granulocytes.

Nondepleting Agents Another more selective approach is to target the 55-kDa alpha chain of the IL-2 receptor, which is expressed only

on activated T cells. This approach is used as prophylaxis for (but not

treatment of) acute rejection in the immediate posttransplant period

and is effective at decreasing the early acute rejection rate with few

adverse side effects.

■ MAINTENANCE THERAPY

The most frequently used combination is a calcineurin inhibitor (CNI),

usually tacrolimus, and an antimetabolite, usually mycophenolic acid,

with or without early steroid withdrawal. More recently, the U.S.

Food and Drug Administration (FDA) approved a new costimulatory

blocking antibody, belatacept, as a new strategy to prevent long-term

CNI toxicity. The mTOR inhibitors sirolimus and everolimus are infrequently used as first-line maintenance immunosuppression.

Antimetabolites Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides. Thiopurine S-methyltransferase

(TPMT) inactivates azathioprine. Patients with two nonfunctional

TPMT alleles experience life-threatening myelosuppression when

treated with azathioprine, and those who carry one nonfunctional

TPMT allele may also have significant side effects; therefore, the FDA

recommends TPMT genotyping or phenotyping before starting treatment with azathioprine. Azathioprine, which inhibits synthesis of DNA

and RNA and thereby inhibits T-cell proliferation, was the keystone of

immunosuppressive therapy in kidney transplant recipients until the

1990s but has been replaced by more effective agents. Concomitant

use of allopurinol should be avoided, owing to inhibition of xanthine

oxidase.

Mycophenolate mofetil and mycophenolate sodium, both of which

are metabolized to mycophenolic acid, are now used in place of azathioprine based on superior efficacy. Mycophenolic acid has a similar

mode of action as azathioprine and is associated with a mild degree of

gastrointestinal toxicity but less bone marrow suppression.

Steroids Glucocorticoids are important adjuncts to immunosuppressive therapy and used as both induction and maintenance therapy.

In general, methylprednisolone 250–500 mg is given immediately

before or at the time of transplantation, and the dose is tapered to 20 mg

within a week. The side effects of the glucocorticoids, particularly

impairment of wound healing and predisposition to infection, make

it desirable to taper the dose as rapidly as possible in the immediate

postoperative period. Early discontinuation or avoidance of steroids

is common to avoid long-term adverse effects on bone, skin, and

glucose metabolism. Most patients whose renal function is stable after

6 months or a year do not require large doses of prednisone; maintenance doses of 5–10 mg per day are the rule. A major effect of steroids

is preventing the release of IL-6 and IL-1 by monocytes-macrophages.

Calcineurin Inhibitors Cyclosporine is a fungal peptide with

potent immunosuppressive activity. It acts on the calcineurin pathway

to inhibit transcription of IL-2 and other proinflammatory cytokines,

thereby inhibiting T-cell proliferation. It works synergistically with

glucocorticoids and mycophenolate. Among its toxic effects (nephrotoxicity, hepatotoxicity, hirsutism, tremor, gingival hyperplasia, and

diabetes), nephrotoxicity presents a serious management problem and

is further discussed below.

Tacrolimus (FK506) is a fungal macrolide that has the same mode

of action as cyclosporine as well as a similar side effect profile; it does

not, however, produce hirsutism or gingival hyperplasia; in contrast, it

can be associated with hair loss. De novo diabetes mellitus following

transplantation more commonly occurs with tacrolimus. An extendedrelease formulation of tacrolimus is now available and is given once

daily. Owing to its nephrotoxicity and narrow therapeutic window, the

drug level of CNIs should be monitored, and drug–drug interactions

should be carefully examined. Antibiotics and antifungals (e.g., erythromycin, ketoconazole, fluconazole) and nondihydropyridine calcium channel blockers (e.g., diltiazem, verapamil) inhibit the activity of

cytochrome P450 C3A enzyme and cause elevated levels of CNIs. On

the other hand, antiepileptics, such as phenytoin and carbamazepine,

increase metabolism, resulting in lower levels.

mTOR Inhibitors Sirolimus (previously called rapamycin) is

another fungal macrolide but has a different mode of action from

tacrolimus; i.e., it inhibits T-cell growth factor signaling pathways, preventing the response to IL-2 and other cytokines. Sirolimus can be used

in conjunction with cyclosporine or tacrolimus, or with mycophenolic

acid, to avoid the use of CNIs.

Everolimus is another mTOR inhibitor with similar mechanism of

action as sirolimus but with better bioavailability. mTOR inhibitors are

modestly tolerated and are associated with gastrointestinal disturbance,

stomatitis, mucositis, and pneumonitis. Poor wound healing associated

with mTOR inhibitors makes them less preferable agents during the

perisurgical period. While the PI3K-mTOR is the most commonly

mutated cellular pathway in malignant cells, mTOR inhibitors have

been used more frequently in transplant patients who develop cancers,

in particular recurrent skin cancers.

Belatacept Belatacept is a fusion protein composed of the Fc fragment of human IgG1 immunoglobulin and the extracellular domain of

cytotoxic T-lymphocyte associated protein 4 (CTLA-4). It binds to its

TABLE 313-3 Maintenance Immunosuppressive Drugs

AGENT PHARMACOLOGY MECHANISMS SIDE EFFECTS

Glucocorticoids Increased bioavailability with

hypoalbuminemia and liver disease;

prednisone/prednisolone generally used

Binds cytosolic receptors and heat shock proteins.

Blocks transcription of IL-1, -2, -3, -6, TNF-α, and IFN-γ

Hypertension, glucose intolerance,

dyslipidemia, osteoporosis

Cyclosporine (CsA) Lipid-soluble polypeptide, variable

absorption, microemulsion more

predictable

Trimolecular complex with cyclophilin and calcineurin

→ block in cytokine (e.g., IL-2) production; however,

stimulates TGF-β production

Nephrotoxicity, hypertension, dyslipidemia,

glucose intolerance, hirsutism/hyperplasia

of gums

Tacrolimus Macrolide, well absorbed Trimolecular complex with FKBP-12 and calcineurin →

block in cytokine (e.g., IL-2) production; may stimulate

TGF-β production

Similar to CsA, but hirsutism/hyperplasia of

gums unusual, and diabetes more likely

Azathioprine Mercaptopurine prodrug Hepatic metabolites inhibit purine synthesis Marrow suppression (WBC > RBC >

platelets)

Mycophenolate

mofetil/sodium

Metabolized to mycophenolic acid Inhibits purine synthesis via inosine monophosphate

dehydrogenase

Diarrhea/cramps; dose-related liver and

marrow suppression is uncommon

Sirolimus/

everolimus

Macrolide, poor oral bioavailability Complexes with FKBP-12 and then blocks p70 S6 kinase

in the IL-2 receptor pathway for proliferation

Hyperlipidemia, thrombocytopenia

Belatacept Fusion protein, intravenous injections Binds CD80 and CD86, prevents CD28 binding and T-cell

activation

Posttransplant lymphoproliferative disease

(PTLD)

Abbreviations: FKBP-12, FK506 binding protein 12; IFN, interferon; IL, interleukin; RBC, red blood cells; TGF, transforming growth factor; TNF, tumor necrosis factor; WBC,

white blood cells.

2329Transplantation in the Treatment of Renal Failure CHAPTER 313

costimulatory ligands (CD80 and CD86) on antigen-presenting cells,

interrupting their binding to CD28 on T cells. This inhibition leads

to T-cell anergy and apoptosis. Belatacept is FDA approved for kidney

transplant recipients and is given monthly as an intravenous infusion.

The 7-year follow-up of the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial (BENEFIT)

showed improved patient and graft survival for the belatacept-treated

group compared to patients treated with cyclosporine, despite shortterm risks of higher rates of acute rejection.

CLINICAL COURSE AND MANAGEMENT OF

THE RECIPIENT

Adequate hemodialysis should be performed within 48 h of surgery

as needed to control serum potassium to prevent cardiac arrhythmias.

During the transplantation surgery, the kidney allograft is usually

placed in recipient’s iliac fossa using a retroperitoneal approach. An

anastomosis is made between donor renal artery and recipient external iliac artery, and donor renal vein to recipient external iliac vein.

The donor ureter is anastomosed to the recipient bladder mucosa.

Native kidney nephrectomy is rarely performed except in the case of

an extremely enlarged polycystic kidney or chronic pyelonephritis. In

many cases, especially after living kidney transplantation, the allograft

starts to produce urine immediately after anastomosis. The allograft

often has some degree of acute tubular injury due to ischemia, which

accounts for postoperative diuresis. Large amounts of sodium, potassium, and water may be lost postoperatively, which requires close

monitoring and replacement. The recipient’s serum creatinine should

start to fall as the allograft starts to function, and recovery usually

occurs within 2 weeks, although periods as long as 6 weeks have been

reported. Slow recovery or oliguria should prompt an allograft biopsy,

because superimposition of rejection on acute tubular injury is common and difficult to distinguish without an allograft biopsy. Induction

immunosuppression therapy and maintenance steroids and antimetabolites start on the day of surgery, and it is usually safe to delay introduction of a CNI for a few days if a lymphocyte-depleting induction

agent is used. Figure 313-2 illustrates a typical algorithm followed by

transplant centers for early posttransplant management of recipients at

high or low risk of early renal dysfunction.

■ MANAGEMENT OF REJECTION

Early diagnosis of rejection allows prompt institution of therapy to

preserve renal function and prevent irreversible damage. Clinical

evidence of rejection is rarely characterized by fever, swelling, and

tenderness over the allograft. Rejection may present only with a rise

in serum creatinine, with or without a reduction in urine volume. The

focus should be on ruling out other causes of functional deterioration,

Recipient high %PRA (sensitized)

Recipient with prior transplant

Recipient with autoimmune GN

Donor cold ischemia time >24 h or

Donor age >60 years or

Donor with high KDPI

Recipient PRA <10% (unsensitized)

Recipient first transplant, or >65 years old

Original disease non-immune related (DM2, HTN)

Living donor

Donor cold ischemia time <12 h or

Donor age 15–35 years old

High risk Low risk

Antithymocyte globulin induction

Steroids, mycophenolic acid

Calcineurin inhibitor (a few days after)

Basiliximab induction

Steroids, mycophenolic acid

Calcineurin inhibitor (day 1–2)

Persistent allograft dysfunction

Delayed graft function/HD support

Adjust CNI dose.

If kidney function remains inadequate or low.

Allograft biopsy

IV steroid (methylprednisolone, 0.5–1 g/d × 3 days), or

antithymocyte globulin

No rejection Acute rejection

Good urine output

Improvement in Cr

Adjust CNI dose.

Supportive care (BP control, fluid)

Outpatient follow-up

Good urine output

Improvement in Cr

--> Outpatient follow-up

FIGURE 313-2 A typical algorithm for early posttransplant care of a kidney recipient. If any of the recipient or donor “high-risk” factors exist, more aggressive management

is called for. Low-risk patients can be treated with a standard immunosuppressive regimen with no or less-potent induction therapy (e.g., basiliximab). Patients at higher

risk of rejection or early ischemic transplant dysfunction are often induced with an antithymocyte globulin to provide more potent early immunosuppression or to spare

calcineurin use in the immediate posttransplant period. *When there is early transplant dysfunction, prerenal, obstructive, and vascular causes must be ruled out by

ultrasonographic examination. The panel reactive antibody (PRA) is a quantitation of how much antibody is present in a candidate against a panel of cells representing the

distribution of antigens in the donor pool. BP, blood pressure; CNI, calcineurin inhibitor; Cr, creatinine; DM2, type 2 diabetes; GN, glomerulonephritis; HD, hemodialysis; HTN,

hypertension; KDPI, Kidney Donor Profile Index.

2330 PART 9 Disorders of the Kidney and Urinary Tract

such as acute tubular injury, calcineurin toxicity, BK nephropathy, and

recurrent glomerular diseases.

Doppler ultrasonography is useful in ascertaining changes in the

renal vasculature and in renal blood flow. Thrombosis of the renal vein

occurs rarely; it may be reversible if it is caused by technical factors

and intervention is prompt. Diagnostic ultrasound is also helpful in

identifying urinary obstruction or the presence of perirenal collections

of urine (urinoma), blood (hematoma), or lymph (lymphocele).

Allograft biopsy is the gold standard for diagnosis of acute T cell–

mediated and antibody-mediated rejection. Acute T cell–mediated

rejection is diagnosed by the presence of immune cell infiltration in the

interstitial, tubular, or vascular compartments, according to the Banff

classification. Treatment of T cell–mediated rejection involves a high-dose

steroid, e.g., IV administration of methylprednisolone, 500–1000 mg daily

for 3 days. Failure to respond is an indication for antibody therapy,

usually with ATG.

Evidence of antibody-mediated rejection is present when endothelial injury and deposition of complement component C4d is detected in

peritubular capillaries. This is usually accompanied by detection of the

circulating donor-specific antibody in the recipient’s blood. Treatment

of antibody-mediated rejection remains a challenge, and aggressive use

of plasmapheresis, IVIG, anti-CD20 monoclonal antibody (rituximab)

to target B lymphocytes, and bortezomib to target antibody-producing

plasma cells is indicated. Recently, noninvasive biomarkers such as

circulating donor-derived cell-free DNA, urine chemokine markers

(e.g., CXCL9), and characterization of the urine exosome have been

used as adjunct diagnostic markers for rejection.

■ MANAGEMENT OF CHRONIC COMPLICATIONS

Cardiovascular events (29%), infection (18%), and malignancy (17%)

are the major causes of death in kidney transplant recipients. Typical

time courses of opportunistic infections after transplantation are

shown in Table 313-4.

The signs and symptoms of infection may be atypical due to immunosuppression, which makes diagnosis challenging. In addition to

commensal infections, opportunistic infections should be considered

based on the clinical presentation. Diagnostic measures such as culture

(blood, urine, drain fluids), viral load in plasma, and imaging (allograft ultrasound and CT) should be obtained. Overall therapy involves

adequate source control, anti-microorganism therapy, and reduction of

immunosuppression.

Pneumocystis jirovecii is a rare but critical opportunistic infection

(Chap. 220). Aggressive diagnostic procedures, including transbronchial and open-lung biopsy, are frequently indicated. Trimethoprimsulfamethoxazole (TMP-SMX) is the treatment of choice; amphotericin

B has been used effectively in systemic fungal infections. Prophylaxis

against P. jirovecii with daily low-dose TMP-SMX for 6 months is effective. Involvement of the oropharynx with Candida (Chap. 216) may be

treated with local nystatin. Tissue-invasive fungal infections require

treatment with systemic agents such as fluconazole or one of the newer

TABLE 313-4 The Most Common Opportunistic Infections in Renal

Transplant Recipients

Peritransplant (<1 month) Late (>6 months)

Wound infections Aspergillus

Herpesvirus Nocardia

Oral candidiasis BK virus (polyoma)

Urinary tract infection Herpes zoster

Early (1–6 months) Hepatitis B

Pneumocystis carinii Hepatitis C

Cytomegalovirus

Legionella

Listeria

Hepatitis B

Hepatitis C

antifungal agents. Aspergillus (Chap. 217), Nocardia (Chap. 174), and

especially cytomegalovirus (CMV) (Chap. 195) infections also occur.

CMV infection is a serious complication after kidney transplantation associated with increased morbidity and mortality. While the

seronegative recipients of seropositive donors are at the highest risk,

presentation varies from asymptomatic CMV viremia to a systemic

syndrome (fever, leukopenia) and tissue-specific manifestation (hepatitis,

gastroenteritis, and retinopathy). Plasma viral load and a rise in IgM

antibodies to CMV are diagnostic. Valganciclovir has proved effective

in both prophylaxis and treatment of CMV disease. Acyclovir is an

effective therapy for herpes simplex virus infections.

BK virus is a latent polyomavirus that lies dormant in the kidney

and urothelial tract and can be activated in the setting of immunosuppression. Reactivation of BK, if left untreated, will lead to progressive

fibrosis and loss of the graft within 1 year in most cases. However, as

risk of reactivation of BK infection is associated with the overall degree

of immunosuppression, in most cases, BK infection can be managed

by regular testing of BK viral load and judicious reduction of maintenance immunosuppression. Renal biopsy can be useful in examining

for the presence of interstitial nephritis, tubular cytopathic changes of

BK nephropathy, and viral antigens in the allograft. In difficult to treat

cases beyond reduction in immunosuppression, a variety of therapies

including leflunomide, cidofovir, and quinolone antibiotics (which are

effective against polyoma helicase) and IVIG have been tried but with

inconsistent results.

■ CHRONIC LESIONS OF THE TRANSPLANTED

KIDNEY

Although current 1-year transplant survival is excellent, most recipients experience a progressive decline in kidney function over time

thereafter. Chronic renal transplant dysfunction can be caused by

chronic active antibody-mediated rejection, recurrent glomerular

disease, hypertension, CNI nephrotoxicity, secondary focal glomerulosclerosis, or a combination of these pathophysiologies. Chronic

vascular changes with intimal proliferation and medial hypertrophy

are commonly found. Control of systemic and intrarenal hypertension

with angiotensin-converting enzyme (ACE) inhibitors is thought to

have a beneficial influence on the rate of progression of chronic renal

transplant dysfunction. Renal biopsy can distinguish subacute cellular

rejection from recurrent disease or secondary focal sclerosis.

MALIGNANCY

The incidence of tumors in patients on immunosuppressive therapy

is 5–6%, or ~100 times greater than that in the general population in

the same age range. The most common lesions are cancer of the skin

and lips. Hence, surveillance for skin cancers and protection from

ultraviolet radiation are necessary. Solid organ transplant recipients

are at higher risk to develop posttransplant lymphoproliferative disease, most frequently seen early (<1 year) or late (7–10 years) after

transplantation. Most cases are associated with EBV infection, and

the prognosis is poor. The overall malignancy risks are increased in

proportion to the total immunosuppressive load administered and the

time elapsed since transplantation. Treatment of cancer after transplant

involves the reduction of immunosuppression, surgery, conventional

cytotoxic chemotherapy, and radiotherapy. Cancer immunotherapy

is associated with a high risk of allograft rejection (30–40%), and the

multidisciplinary risk-benefit discussion should be made before the

initiation of therapy.

■ OTHER COMPLICATIONS

Both chronic dialysis and renal transplant patients have a higher

incidence of death from myocardial infarction and stroke than the

population at large, and this is particularly true of diabetic patients.

Contributing factors are the use of glucocorticoids and sirolimus,

as well as hypertension. Recipients of renal transplants have a high

prevalence of coronary artery and peripheral vascular diseases. The

percentage of deaths from these causes has been slowly rising as the

numbers of transplanted diabetic patients and the average age of recipients increase. More than 30% of kidney transplant recipient mortality

2331 Glomerular Diseases CHAPTER 314

is attributable to cardiovascular disease. Strict control of blood pressure

and blood sugar and lipid levels is essential in this population.

Hypertension may be caused by (1) native kidney disease, (2) rejection

activity in the transplant, (3) renal artery stenosis if an end-to-end

anastomosis was constructed with an iliac artery branch, and (4) renal

CNI toxicity, which may improve with reduction in dose. Whereas ACE

inhibitors may be useful in the longer term, calcium channel blockers

are more frequently used initially. Amelioration of hypertension to the

range of 120–130/70–80 mmHg should be the goal in all patients.

Hypercalcemia after transplantation may indicate failure of hyperplastic parathyroid glands to regress. Aseptic necrosis of the head of

the femur when it occurs is probably due to preexisting hyperparathyroidism, with aggravation by glucocorticoid treatment. With improved

management of calcium and phosphorus metabolism during chronic

dialysis, the incidence of parathyroid-related complications has fallen

dramatically. Persistent hyperparathyroid activity may require subtotal

parathyroidectomy.

Although most transplant patients have robust production of erythropoietin and normalization of hemoglobin, anemia is commonly

seen in the posttransplant period. Often the anemia is attributable

to bone marrow–suppressant immunosuppressive medications such

as azathioprine, mycophenolic acid, and mTOR inhibitors. Gastrointestinal bleeding is a common side effect of high-dose and long-term

steroid administration. Many transplant patients have creatinine

clearances of 30–50 mL/min and can be considered to have chronic

renal insufficiency for anemia management, including supplemental

erythropoietin.

Chronic hepatitis, particularly when due to hepatitis B virus, can be

a progressive, fatal disease over a decade or so. Patients who are persistently hepatitis B surface antigen–positive are at higher risk, according

to some studies, but the presence of HCV is also a concern when one

embarks on a course of immunosuppression in a transplant recipient.

However, the introduction of the new highly effective, direct-acting

HCV antiviral medications reduced this risk significantly.

In conclusion, while kidney transplantation has progressed significantly toward the goals of longer patient survival and better quality

of life, the field still has significant challenges and unmet needs.

Advanced immunologic and genetic studies have led and will continue

to lead us to detailed understanding of alloimmunity at the molecular

level. Noninvasive biomarkers for monitoring and diagnosing rejection

and novel therapeutic targets will continue to evolve. Further effort

is needed to achieve equity and improve personalized care of kidney

transplant recipients.

■ FURTHER READING

Allen PJ et al: Recurrent glomerulonephritis after kidney transplantation: Risk factors and allograft outcomes. Kidney Int 92:461, 2017.

Chadban SJ et al: Summary of the Kidney Disease: Improving Global

Outcomes (KDIGO) clinical practice guideline on the evaluation and

management of candidates for kidney transplantation. Transplantation 104:708, 2020.

Chapman JR et al: Cancer in the transplant recipient. Cold Spring

Harb Perspect Med 3:pii:a015677, 2013.

Euvrard S et al: Sirolimus and secondary skin-cancer prevention in

kidney transplantation. N Engl J Med 367:329, 2012.

Grams ME et al: Kidney-failure risk projection for the living kidneydonor candidate. N Engl J Med 374:411, 2016.

Hart A et al: OPTN/SRTR 2018 annual data report: Kidney. Am J

Transplant 20(suppl 1):20, 2020.

Hirsh HH et al: BK polyomavirus in solid organ transplantation:

Guidelines from the American Society of Transplantation Infectious

Diseases Community of Practice. Clin Transplant 33:e13528, 2019.

Kotton CN et al: The third international consensus guidelines on

the management of cytomegalovirus in solid-organ transplantation.

Transplantation 102:900, 2018.

Loupy A et al: Complement-binding anti-HLA antibodies and kidneyallograft survival. N Engl J Med 369:1215, 2013.

Orandi BJ et al: Survival benefit with kidney transplants from

HLA-incompatible live donors. N Engl J Med 374:940, 2016.

Two human kidneys harbor nearly 1.8 million glomerular capillary

tufts. Each glomerular tuft resides within Bowman’s space. The capsule

circumscribing this space is lined by parietal epithelial cells that transition into tubular epithelia forming the proximal nephron or migrate

into the tuft to replenish podocytes. The glomerular capillary tuft

derives from an afferent arteriole that forms a branching capillary bed

embedded in mesangial matrix (Fig. 314-1). This capillary network

funnels into an efferent arteriole, which passes filtered blood into

cortical peritubular capillaries or medullary vasa recta that supply and

exchange with a folded tubular architecture. Hence, the glomerular

capillary tuft, fed and drained by arterioles, represents an arteriolar

portal system. Fenestrated endothelial cells resting on a glomerular

basement membrane (GBM) line glomerular capillaries. Delicate foot

processes extending from epithelial podocytes shroud the outer surface

of these capillaries, and adjacent podocytes interconnect to each other

by slit-pore membranes forming a selective filtration barrier.

The glomerular capillaries filter 120–180 L/d of plasma water containing various solutes for reclamation or discharge by downstream

tubules. Most large proteins and all cells are excluded from filtration

by a physicochemical barrier governed by pore size and negative electrostatic charge. The mechanics of filtration and reclamation are quite

complicated for many solutes (Chap. 309). For example, in the case of

serum albumin, the glomerulus is an imperfect barrier. Although albumin has a negative charge, which would tend to repel the negatively

charged GBM, it only has a physical radius of 3.6 nm, while pores in the

GBM and slit-pore membranes have a radius of 4 nm. Consequently,

variable amounts of albumin inevitably cross the filtration barrier to

be reclaimed by megalin and cubilin receptors along the proximal

tubule. Remarkably, humans with normal nephrons excrete on average

8–10 mg of albumin in daily voided urine, ~20–60% of total excreted

protein. This amount of albumin, and other proteins, can rise to gram

quantities following glomerular injury.

The breadth of diseases affecting the glomerulus is expansive

because the microenvironment supporting the glomerular capillaries

can be injured in a variety of ways, producing many different lesions.

Some order to this vast subject is brought by grouping all of these diseases into a smaller number of clinical syndromes.

PATHOGENESIS OF GLOMERULAR DISEASE

There are many forms of glomerular disease with pathogenesis variably

linked to the presence of genetic mutations, infection, toxin exposure,

autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or

diabetes mellitus. Even after careful study, however, the cause often

314 Glomerular Diseases

Julia B. Lewis, Eric G. Neilson

Reese P et al: Twelve-month outcomes after transplant of hepatitis

C-infected kidneys into uninfected recipients. Ann Intern Med

169:273, 2018.

Riella LV, Sheridan AM: Testing for high-risk APOL1 alleles in

potential living kidney donors. Am J Kidney Dis 66:396, 2015.

Stegall MD: Clinical management of renal transplant patients with

donor-specific alloantibody: The state of the art. Clin Transpl 307,

2010.

Stewart DE et al: Changes in deceased donor kidney transplantation

one year after KAS implementation. Am J Transplant 16:1834, 2016.

Vincenti F et al: Belatacept and long-term outcomes in kidney transplantation. N Engl J Med 374:333, 2016.

Wang LW et al: Cardiac testing for coronary artery disease in

potential kidney transplant recipients. Cochrane Database Syst Rev

12:CD008691, 2011.

2332 PART 9 Disorders of the Kidney and Urinary Tract

remains unknown, and the lesion is called idiopathic. Specific or

unique features of pathogenesis are mentioned with the description of

each of the glomerular diseases later in this chapter.

Some glomerular diseases result from genetic mutations producing

familial disease or a founder effect: congenital nephrotic syndrome

from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affects

the slit-pore membrane at birth, and TRPC6 cation channel mutations produce focal segmental glomerulosclerosis (FSGS) in adulthood;

polymorphisms in the gene encoding apolipoprotein L1, APOL1, are a

major risk for nearly 70% of African Americans with nondiabetic endstage renal disease (ESRD), particularly FSGS; monogenetic causes of

FSGS are increasingly linked to early age of onset and to genes encoding type IV collagen in older adults, suggesting that much of FSGS

may be hereditary; mutations in control of the complement pathway

increasingly associate with various forms of membranoproliferative

glomerulonephritis (MPGN) and C3

 glomerulopathies including dense

deposit disease, or atypical hemolytic-uremic syndrome (aHUS); type II

partial lipodystrophy from mutations in genes encoding lamin A/C or

PPARγ cause a metabolic syndrome associated with MPGN; Alport’s

syndrome, from mutations in the genes encoding for the α3, α4, or α5

chains of type IV collagen, produces split basement membranes with glomerulosclerosis; and lysosomal storage diseases, such as α-galactosidase

A deficiency causing Fabry’s disease and N-acetylneuraminic acid

hydrolase deficiency causing nephrosialidosis, produce FSGS.

Systemic hypertension and atherosclerosis can produce pressure

stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis.

Malignant hypertension can quickly complicate glomerulosclerosis with

fibrinoid necrosis of arterioles and glomeruli, thrombotic microangiopathy, and acute renal failure. Diabetic nephropathy is an acquired

sclerotic injury associated with thickening of the GBM secondary to

the long-standing effects of hyperglycemia, advanced glycosylation end

products, and reactive oxygen species.

Inflammation of the glomerular capillaries is called glomerulonephritis. Most glomerular or mesangial antigens involved in immunemediated glomerulonephritis are unknown (Fig. 314-2). Glomerular

epithelial or mesangial cells may shed or express epitopes that mimic

other immunogenic proteins made elsewhere in the body. Bacteria,

fungi, and viruses can directly infect the kidney producing their own

antigens. Autoimmune diseases such as idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, whereas

systemic inflammatory diseases such as lupus nephritis or granulomatosis with polyangiitis spread to the kidney, causing secondary glomerular

injury. Antiglomerular basement membrane disease producing Goodpasture’s syndrome primarily injures both the lung and kidney because

of the narrow distribution of the α3 NC1 domain of type IV collagen

that is the target antigen.

Local activation of Toll-like receptors on glomerular cells, deposition of immune complexes, or complement injury to glomerular structures induces mononuclear cell infiltration, which subsequently leads

to an adaptive immune response attracted to the kidney by local release

of chemokines. Neutrophils, macrophages, and T cells are drawn by

chemokines into the glomerular tuft, where they react with antigens

and epitopes on or near somatic cells or their structures, producing

more cytokines and proteases that damage the mesangium, capillaries,

and/or the GBM. While the adaptive immune response is similar to

that of other tissues, early T-cell activation plays an important role in

the mechanism of glomerulonephritis. Antigens presented by class II

major histocompatibility complex (MHC) molecules on macrophages

and dendritic cells in conjunction with associative recognition molecules engage the CD4/8 T-cell repertoire.

Mononuclear cells by themselves can injure the kidney, but autoimmune events that damage glomeruli classically produce a humoral

immune response. Poststreptococcal glomerulonephritis, lupus nephritis,

and idiopathic membranous nephritis typically are associated with

immune deposits along the GBM, while anti-GBM antibodies produce the linear binding of anti-GBM disease. Preformed circulating

immune complexes can precipitate along the subendothelial side of the

GBM, while other immune deposits form in situ on the subepithelial

side. These latter deposits accumulate when circulating autoantibodies

find their antigen trapped along the subepithelial edge of the GBM.

FIGURE 314-1 Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles leading to an afferent arteriole, glomerular

capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning electron micrograph of podocytes that line the outer

surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. D. The

various normal regions of the glomerulus on light microscopy. (A–C: Courtesy of Dr. Vincent Gattone, Indiana University; with permission.)

2333 Glomerular Diseases CHAPTER 314

Immune deposits in the glomerular mesangium may result from the

deposition of preformed circulating complexes or in situ antigenantibody interactions. Immune deposits stimulate the release of local

proteases and activate the complement cascade, producing C5–9 attack

complexes. In addition, local oxidants damage glomerular structures,

producing proteinuria and effacement of the podocytes. Overlapping

etiologies or pathophysiologic mechanisms can produce similar glomerular lesions, suggesting that downstream molecular and cellular

responses often converge toward common patterns of injury.

PROGRESSION OF GLOMERULAR DISEASE

Persistent glomerulonephritis that worsens renal function is always

accompanied by interstitial nephritis, renal fibrosis, and tubular atrophy (see Fig. A4-27). What is not so obvious, however, is that renal

failure in glomerulonephritis best correlates histologically with the

appearance of tubulointerstitial nephritis rather than with the type of

inciting glomerular injury.

Loss of renal function due to interstitial damage is explained hypothetically by several mechanisms. The simplest explanation is that

urine flow is impeded by tubular obstruction as a result of interstitial

inflammation and fibrosis. Thus, obstruction of the tubules with debris

or by extrinsic compression functionally results in aglomerular nephrons. A second mechanism suggests that interstitial changes, including

interstitial edema or fibrosis, alter tubular and vascular architecture

and thereby compromise the normal tubular transport of solutes and

water from tubular lumen to vascular space. This failure increases the

solute and water content of the tubule fluid, resulting in isosthenuria

and polyuria. Adaptive mechanisms related to tubuloglomerular

feedback also fail, resulting in a reduction of renin output from the

juxtaglomerular apparatus trapped by interstitial inflammation. Consequently, the local vasoconstrictive influence of angiotensin II on

the glomerular arterioles decreases, and filtration drops owing to a

generalized decrease in arteriolar tone. A third mechanism involves

changes in vascular resistance due to damage of peritubular capillaries.

Basement

membrane

Endothelia

Podocytes

Subendothelial

deposit

Subepithelial

deposit

Linear IgG staining IgG Lumpy-bumpy staining

A B C

D

Basement membrane

damage Extracapillary

proliferation

Endocapillary

proliferation

Cytokines

Chemokines

TH1/2

Cytokines

Chemokines

Mθ

N

Oxidants Proteases

C3/C5-9MAC

Immune

deposits

FIGURE 314-2 The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation and collect along the glomerular

basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space. B. Immunofluorescent staining of glomeruli with labeled antiIgG demonstrating linear staining from a patient with anti-GBM disease or immune deposits from a patient with membranous glomerulonephritis. C. The mechanisms of

glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus. T

lymphocytes may follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand this inflammation, and

depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either endocapillary or extracapillary

proliferation.

2334 PART 9 Disorders of the Kidney and Urinary Tract

The cross-sectional volume of these capillaries is decreased by interstitial inflammation, edema, or fibrosis. These structural alterations

in vascular resistance affect renal function through two mechanisms.

First, tubular cells are very metabolically active, and as a result,

decreased perfusion leads to tubular ischemic injury. Second, impairment of glomerular arteriolar outflow leads to increased intravascular

hypertension in less-involved glomeruli; this selective intraglomerular

hypertension aggravates and extends mesangial sclerosis and glomerulosclerosis to less-involved glomeruli. Regardless of the exact mechanism,

early acute tubulointerstitial nephritis (see Fig. A4-27) suggests potentially recoverable renal function, whereas the development of chronic

interstitial fibrosis prognosticates permanent loss (see Fig. A4-30).

Persistent damage to glomerular capillaries spreads to the tubulointerstitium in association with proteinuria. There is a hypothesis

that efferent arterioles leading from inflamed glomeruli carry forward inflammatory mediators, which induces downstream interstitial

nephritis, resulting in fibrosis. Glomerular filtrate from injured glomerular capillaries adherent to Bowman’s capsule may also be misdirected to the periglomerular interstitium. Most nephrologists believe,

however, that proteinuric glomerular filtrate forming tubular fluid is

the primary route to downstream tubulointerstitial injury, although

none of these hypotheses are mutually exclusive.

The simplest explanation for the effect of proteinuria on the development of interstitial nephritis is that increasingly severe proteinuria,

carrying activated cytokines and lipoproteins producing reactive

oxygen species, triggers a downstream inflammatory cascade in and

around epithelial cells lining the tubular nephron. These effects induce

T lymphocyte and macrophage infiltrates in the interstitial spaces

along with fibrosis and tubular atrophy.

Tubules disaggregate following direct damage to their basement

membranes, leading to more interstitial fibroblasts and fibrosis at

the site of injury; recent comprehensive evidence suggests that renal

fibroblasts increase through several mechanisms: epithelial or endothelial-mesenchymal transitions (15%), bone marrow–derived fibrocytes

(35%), and the proliferation of resident fibroblasts (50%). Transforming growth factor β (TGF-β), fibroblast growth factor 2 (FGF-2),

hypoxemia-inducible factor 1α (HIF-1α), and platelet-derived growth

factor (PDGF) are particularly active in this transition. With persistent

nephritis, fibroblasts multiply and lay down tenascin and a fibronectin

scaffold for the polymerization of new interstitial collagen types I/III.

These events form scar tissue through a process called fibrogenesis. In

experimental studies, bone morphogenetic protein 7 and hepatocyte

growth factor can reverse early fibrogenesis and preserve tubular architecture. When fibroblasts outdistance their survival factors, apoptosis

occurs, and the permanent renal scar becomes acellular, leading to

irreversible renal failure.

APPROACH TO THE PATIENT

Glomerular Disease

HEMATURIA, PROTEINURIA, AND PYURIA

Patients with glomerular disease usually have some hematuria

with varying degrees of proteinuria. Hematuria is typically asymptomatic. As few as 3–5 red blood cells in the spun sediment from

first-voided morning urine is suspicious. The diagnosis of glomerular injury can be delayed because patients will not realize they

have microscopic hematuria, and only rarely with the exception of

IgA nephropathy and sickle cell disease is gross hematuria present.

When working up microscopic hematuria, perhaps accompanied

by minimal proteinuria (<500 mg/24 h), it is important to exclude

anatomic lesions, such as malignancy of the urinary tract, particularly in older men. Microscopic hematuria may also appear with

the onset of benign prostatic hypertrophy, interstitial nephritis,

papillary necrosis, hypercalciuria, renal stones, cystic kidney diseases, or renal vascular injury. However, when red blood cell casts

(see Fig. A4-34) or dysmorphic red blood cells are found in the

sediment, glomerulonephritis is likely. A mean of 8–10 mg/24 h

of albumin appears in the urine in the absence of kidney disease.

In early nephropathy, such as in diabetic nephropathy, proteinuria

increases to 30–300 mg/24 h and is called microalbuminuria and

represents the presence of renal disease. Greater than 300 mg/24 h

of albuminuria represents frank proteinuria and more advanced

renal disease (Table 314-1).

Sustained proteinuria >1–2 g/24 h is also commonly associated

with glomerular disease. Patients often will not know they have

proteinuria unless they become edematous or notice foaming urine

on voiding. Sustained proteinuria has to be distinguished from

lesser amounts of so-called benign proteinuria in the normal population. (Table 314-1). This latter class of proteinuria is nonsustained,

generally <1 g/24 h, and is sometimes called functional or transient

proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress,

and congestive heart failure can explain transient proteinuria.

Proteinuria only seen with upright posture is called orthostatic

proteinuria and has a benign prognosis. Isolated proteinuria sustained

over multiple clinic visits is found in many glomerular lesions.

Proteinuria in most adults with glomerular disease is nonselective,

containing albumin and a mixture of other serum proteins, whereas

in children with minimal change disease (MCD), the proteinuria is

selective and composed largely of albumin.

Some patients with inflammatory glomerular disease, such as

acute poststreptococcal glomerulonephritis or MPGN, have pyuria

characterized by the presence of considerable numbers of leukocytes. This latter finding has to be distinguished from urine infected

with bacteria.

CLINICAL SYNDROMES

Various forms of glomerular injury can also be parsed into several distinct syndromes on clinical grounds (Table 314-2). These

syndromes, however, are not always mutually exclusive. There is

an acute nephritic syndrome producing 1–2 g/24 h of proteinuria,

hematuria with red blood cell casts, pyuria, hypertension, fluid

retention, and a rise in serum creatinine associated with a reduction in glomerular filtration. If glomerular inflammation develops slowly, the serum creatinine will rise gradually over many

weeks, but if the serum creatinine rises quickly, particularly over

a few days, acute nephritis is sometimes called rapidly progressive glomerulonephritis (RPGN); the histopathologic term crescentic glomerulonephritis is the pathologic equivalent of the clinical

presentation of RPGN. When patients with RPGN present with

lung hemorrhage from Goodpasture’s syndrome, antineutrophil

cytoplasmic antibody (ANCA)–associated small-vessel vasculitis,

lupus erythematosus, or cryoglobulinemia, they are often diagnosed as having a pulmonary-renal syndrome. Nephrotic syndrome

describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca,

TABLE 314-1 Urine Assays for Albuminuria/Proteinuria

24-h ALBUMINa

 (mg/24 h)

ALBUMINa

/CREATININE

RATIO (mg/g) DIPSTICK PROTEINURIA

24-H URINE PROTEINb

(mg/24 h)

Normal 8–10 <30 – <150

Microalbuminuria 30–300 30–300 –/Trace/1+ –/>150

Proteinuria >300 >300 Trace–3+ >150

a

Albumin detected by radioimmunoassay. b

Albumin represents 20–60% of the total protein excreted in the urine.

2335 Glomerular Diseases CHAPTER 314

TABLE 314-2 Patterns of Clinical Glomerulonephritis

GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY

Acute Nephritic Syndromes

Poststreptococcal glomerulonephritisa +/++ ++/+++ –

Subacute bacterial endocarditisa +/++ ++ –

Lupus nephritisa +/++ ++/+++ +

Antiglomerular basement membrane diseasea ++ ++/+++ –

IgA nephropathya +/++ +++c –

ANCA small-vessel vasculitisa

Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++

Microscopic polyangiitis +/++ ++/+++ ++++

Churg-Strauss syndrome +/++ ++/+++ ++++

Henoch-Schönlein purpuraa +/++ ++/+++c ++++

Cryoglobulinemiaa +/++ ++/+++ ++++

Membranoproliferative glomerulonephritisa ++ ++/+++ –

C3

 glomerulopathies ++ ++/+++ -

Mesangioproliferative glomerulonephritis + +/++ –

Pulmonary-Renal Syndromes

Goodpasture’s syndromea ++ ++/+++ –

ANCA small-vessel vasculitisa

Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++

Microscopic polyangiitis +/++ ++/+++ ++++

Churg-Strauss syndrome +/++ ++/+++ ++++

Henoch-Schönlein purpuraa +/++ ++/+++c ++++

Cryoglobulinemiaa +/++ ++/+++ ++++

Nephrotic Syndromes

Minimal change disease ++++ – –

Focal segmental glomerulosclerosis +++/++++ + –

Membranous glomerulonephritis ++++ + –

Diabetic nephropathy ++/++++ –/+ –

AL and AA amyloidosis +++/++++ + +/++

Light chain deposition disease +++ + –

Fibrillary-immunotactoid disease +++/++++ + +

Fabry’s disease + + –

Basement Membrane Syndromes

Anti-GBM diseasea ++ ++/+++ –

Alport’s syndrome ++ ++ –

Thin basement membrane disease + ++ –

Nail-patella syndrome ++/+++ ++ –

Glomerular Vascular Syndromes

Atherosclerotic nephropathy + + +++

Hypertensive nephropathyb +/++ +/++ ++

Cholesterol emboli +/++ ++ +++

Sickle cell disease +/++ +++c +++

Thrombotic microangiopathies ++ ++ +++

Antiphospholipid syndrome ++ ++ +++

ANCA small-vessel vasculitisa

Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++

Microscopic polyangiitis +/++ ++/+++ ++++

Churg-Strauss syndrome +++ ++/+++ ++++

Henoch-Schönlein purpuraa +/++ ++/+++c ++++

Cryoglobulinemiaa +/++ ++/+++ ++++

AL and AA amyloidosis +++/++++ + +/++

Infectious Disease–Associated Syndromes

Poststreptococcal glomerulonephritisa +/++ ++/+++ –

Subacute bacterial endocarditisa +/++ ++ –

HIV +++ +/++ –

(Continued)

2336 PART 9 Disorders of the Kidney and Urinary Tract

TABLE 314-2 Patterns of Clinical Glomerulonephritis

GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY

Hepatitis B and C +++ +/++ –

Syphilis +++ + –

Leprosy +++ + –

Malaria +++ +/++ –

Schistosomiasis +++ +/++ –

a

Can present as rapidly progressive glomerulonephritis (RPGN); sometimes called crescentic glomerulonephritis. b

Can present as a malignant hypertensive crisis producing

an aggressive fibrinoid necrosis in arterioles and small arteries with microangiopathic hemolytic anemia. c

Can present with gross hematuria.

Abbreviations: AA, amyloid A; AL, amyloid L; ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane.

and microscopic hematuria; if only large amounts of proteinuria are

present without clinical manifestations, the condition is sometimes

called nephrotic-range proteinuria. The glomerular filtration rate

(GFR) in these patients may initially be normal or, rarely, higher

than normal, but with persistent hyperfiltration and continued

nephron loss, it typically declines over months to years. Patients

with a basement membrane syndrome either have genetically abnormal basement membranes (Alport’s syndrome) or an autoimmune

response to basement membrane collagen IV (Goodpasture’s syndrome) associated with microscopic hematuria, mild to heavy

proteinuria, and hypertension with variable elevations in serum

creatinine. Glomerular-vascular syndrome describes patients with

vascular injury producing hematuria and moderate proteinuria.

Affected individuals can have vasculitis, thrombotic microangiopathy, antiphospholipid syndrome, or, more commonly, a systemic

disease such as atherosclerosis, cholesterol emboli, hypertension,

sickle cell anemia, and autoimmunity. Infectious disease–associated

syndrome is most important if one has a global perspective. Save for

subacute bacterial endocarditis (SBE) in the Western Hemisphere,

malaria and schistosomiasis may be the most common causes of

glomerulonephritis throughout the world, closely followed by HIV

and chronic hepatitis B and C. These infectious diseases produce a

variety of inflammatory reactions in glomerular capillaries, ranging

from nephrotic syndrome to acute nephritic injury, and urinalyses

that demonstrate a combination of hematuria and proteinuria.

These six general categories of syndromes are usually determined

at the bedside with the help of a history and physical examination,

blood chemistries, renal ultrasound, and urinalysis. These initial

studies help frame further diagnostic workup that typically involves

testing of the serum for the presence of various proteins (HIV and

hepatitis B and C antigens) or antibodies (anti-GBM, antiphospholipid, antistreptolysin O [ASO], PLA2R, THSD7A, anti-DNAse,

antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and

anti-hepatitis B and C antibodies) or depletion of complement components (C3

 and C4

). The bedside history and physical examination

can also help determine whether the glomerulonephritis is isolated

to the kidney (primary glomerulonephritis) or is part of a systemic

disease (secondary glomerulonephritis).

When confronted with an abnormal urinalysis and elevated

serum creatinine, with or without edema or congestive heart failure, one must consider whether the glomerulonephritis is acute or

chronic. This assessment is best made by careful history (last known

urinalysis or serum creatinine during pregnancy or insurance

physical, evidence of infection, or use of medication or recreational

drugs), the size of the kidneys on renal ultrasound examination,

and how the patient feels at presentation. Chronic glomerular disease often presents with decreased kidney size. Patients who quickly

develop renal failure are fatigued and weak and often have uremic

symptoms associated with nausea, vomiting, fluid retention, and

somnolence. Primary glomerulonephritis presenting with renal

failure that has progressed slowly, however, can be remarkably

asymptomatic, as are patients with acute glomerulonephritis without much loss in renal function. Once this initial information is

collected, selected patients who are clinically stable, have adequate

blood clotting parameters, and are willing and able to receive treatment are encouraged to have a renal biopsy.

■ RENAL PATHOLOGY

A renal biopsy in the setting of glomerulonephritis quickly identifies

the type of glomerular injury and often suggests a course of treatment.

The biopsy is processed for light microscopy using stains for hematoxylin

and eosin (H&E) to assess cellularity and architecture, periodic acid–Schiff

(PAS) to stain carbohydrate moieties in the membranes of the glomerular tuft and tubules, Jones-methenamine silver to enhance basement

membrane structure, Congo red for amyloid deposits, and Masson’s

trichrome to identify collagen deposition and assess the degree of

glomerulosclerosis and interstitial fibrosis. Biopsies are also processed

for direct immunofluorescence using conjugated antibodies against

IgG, IgM, and IgA to detect the presence of “lumpy-bumpy” immune

deposits or “linear” IgG or IgA antibodies bound to GBM, antibodies

against trapped complement proteins (C3

 and C4

), or specific antibodies against a relevant antigen (PLA2R, THSD7A, and DNAJB9).

High-resolution electron microscopy can clarify the principal location

of immune deposits and the status of the basement membrane.

Each region of a renal biopsy is assessed separately. By light microscopy, glomeruli (ideally 20) are reviewed individually for discrete

lesions; <50% involvement is considered focal, and >50% is diffuse.

Injury in each glomerular tuft can be segmental, involving a portion of

the tuft, or global, involving most of the glomerulus. Glomeruli having

proliferative characteristics show increased cellularity. When cells in the

capillary tuft proliferate, it is called endocapillary, and when cellular

proliferation extends into Bowman’s space, it is called extracapillary.

Synechiae are formed when epithelial podocytes attach to Bowman’s

capsule in the setting of glomerular injury; crescents, which in some

cases may be the extension of synechiae, develop when fibrocellular/

fibrin collections fill all or part of Bowman’s space; and sclerotic glomeruli show acellular, amorphous accumulations of proteinaceous

material throughout the tuft with loss of functional capillaries and

normal mesangium. Since age-related glomerulosclerosis is common

in adults, one can estimate the background percentage of sclerosis by

dividing the patient’s age in half and subtracting 10. Immunofluorescent and electron microscopy can detect the presence and location of

subepithelial, subendothelial, or mesangial immune deposits, or reduplication or splitting of the basement membrane. In the other regions

of the biopsy, the vasculature surrounding glomeruli and tubules can

show angiopathy, vasculitis, the presence of fibrils, or thrombi. The

tubules can be assessed for adjacency to one another; separation can be

the result of edema, tubular dropout, or collagen deposition resulting

from interstitial fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and progression to renal failure.

ACUTE NEPHRITIC SYNDROMES

Acute nephritic syndromes classically present with hypertension, hematuria, red blood cell casts, pyuria, and mild to moderate proteinuria.

Extensive inflammatory damage to glomeruli causes a fall in GFR and

eventually produces uremic symptoms with salt and water retention,

leading to edema and hypertension.

(Continued)

2337 Glomerular Diseases CHAPTER 314

■ POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

Poststreptococcal glomerulonephritis is prototypical for acute

endocapillary proliferative glomerulonephritis. The incidence of poststreptococcal glomerulonephritis has dramatically decreased in developed countries, and in these locations is typically sporadic. Acute

nephritis in underdeveloped countries is epidemic and usually affects

children between the ages of 2 and 14 years. In developed countries, it

is more typical in the elderly, especially in association with debilitating

conditions. It is more common in males, and the familial or cohabitant

incidence is as high as 40%. Skin and more commonly throat infections

with particular M types of streptococci (nephritogenic strains) antedate

glomerular disease. Antibiotic therapy does not reduce the occurrence

of nephritis. Poststreptococcal glomerulonephritis due to pharyngitis

develops 1–3 weeks after infection and 2–6 weeks after impetigo.

The renal biopsy in poststreptococcal glomerulonephritis demonstrates hypercellularity of mesangial and endothelial cells; glomerular

infiltrates of polymorphonuclear leukocytes; granular subendothelial

immune deposits of IgG, IgM, C3, C4

, and C5–9; and subepithelial

deposits (which appear as “humps”) (see Fig. A4-6). (See Glomerular

Schematic 1.) Poststreptococcal glomerulonephritis is an immunemediated disease involving putative streptococcal antigens, circulating

immune complexes, and activation of complement in association with

cell-mediated injury. Many candidate antigens have been proposed

over the years; candidates from nephritogenic streptococci are a cationic cysteine proteinase known as streptococcal pyrogenic exotoxin

B (SPEB) and NAPlr, the nephritis-associated plasmin receptor. The

nephritogenic antigen SPEB has been demonstrated inside the subepithelial “humps” on biopsy.

The classic presentation is an acute nephritic picture with hematuria, pyuria, red blood cell casts, edema, hypertension, and oliguric

renal failure, which may be severe enough to appear as RPGN. Systemic symptoms of headache, malaise, anorexia, and flank pain (due

to swelling of the renal capsule) are reported in as many as 50% of

cases. Five percent of children and 20% of adults have proteinuria in

the nephrotic range. In the first week of symptoms, 90% of patients will

have a depressed CH50 and decreased levels of C3

 with normal levels

of C4

. Positive rheumatoid factor (30–40%), cryoglobulins, circulating

immune complexes (60–70%), and ANCA against myeloperoxidase

(10%) are also reported. Positive cultures for streptococcal infection

are inconsistently present (10–70%), but increased titers of ASO (30%),

anti-DNAse (70%), or antihyaluronidase antibodies (40%) can help

confirm the diagnosis. Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a renal biopsy. A subclinical

disease is reported in some series to be 4–5 times as common as clinical

nephritis, and these latter cases are characterized by asymptomatic

microscopic hematuria with low serum C3

 complement levels.

Glomerular schematic 1

POSTSTREPTOCOCCAL

GLOMERULONEPHRITIS

Mesangial

deposits

Poly

Subendothelial

deposits

Hump

Treatment is supportive, with control of hypertension, edema, and

dialysis as needed. Antibiotic treatment for active streptococcal infection should be given to patients and their cohabitants. There is no role

for immunosuppressive therapy, even in the setting of crescents. Recurrent poststreptococcal glomerulonephritis is rare despite repeated

streptococcal infections. Early death is rare in children but does occur

in the elderly. Complete resolution of the azotemia, hematuria, and

proteinuria in the majority of children occurs within 3–6 weeks of

the onset of nephritis, but 3–10% of children may have persistent

microscopic hematuria, nonnephrotic proteinuria, or hypertension.

Overall, the prognosis is good, with ESRD being very uncommon in

children and adults. The prognosis in elderly patients is worse, with a

high incidence of azotemia (up to 60%), nephrotic-range proteinuria,

and ESRD.

■ SUBACUTE BACTERIAL ENDOCARDITIS

Endocarditis-associated glomerulonephritis is typically a complication

of SBE, particularly in patients who remain untreated for a long time,

have negative blood cultures, or have right-sided endocarditis. Common comorbidities are valvular heart disease, intravenous drug use,

hepatitis C, and diabetes mellitus. Glomerulonephritis is unusual in

acute bacterial endocarditis because it takes 10–14 days to develop

immune complex–mediated injury, by which time the patient has been

treated, often with emergent surgery. Grossly, the kidneys in SBE have

subcapsular hemorrhages with a “flea-bitten” appearance, and microscopy on renal biopsy reveals focal proliferation around foci of necrosis

associated with abundant mesangial, subendothelial, and subepithelial

immune deposits of IgG, IgM, and C3

. Commonly patients present

with a clinical picture of RPGN and have crescents on biopsy. Embolic

infarcts or septic abscesses may also be present. The pathogenesis

hinges on the renal deposition of circulating immune complexes in

the kidney with complement activation. Patients present with gross

or microscopic hematuria, pyuria, and mild proteinuria, acute kidney

injury, or RPGN with rapid loss of renal function. A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia,

high titers of rheumatoid factor, type III cryoglobulins, circulating

immune complexes, and ANCAs may be present. Levels of serum creatinine may be elevated at diagnosis, but with modern therapy, there is

little progression to chronic renal failure. Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and if accomplished

expeditiously, the prognosis for renal recovery is good. ANCA-associated

vasculitis sometimes accompanies or is confused with SBE and should

be ruled out, as the treatment is different.

As variants of persistent bacterial infection in blood-associated

glomerulonephritis, postinfectious glomerulonephritis can occur in

patients with ventriculoatrial and ventriculoperitoneal shunts; pulmonary, intraabdominal, pelvic, or cutaneous infections; and infected

vascular prostheses. In developed countries, a significant proportion

of cases afflict adults, especially the immunocompromised, and the

predominant organism is Staphylococcus. The clinical presentation

of these conditions is variable and includes proteinuria, microscopic

hematuria, acute renal failure, and hypertension. Serum complement

levels are low, and there may be elevated levels of C-reactive proteins,

rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal

lesions include MPGN, diffuse proliferative and exudative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis,

sometimes leading to RPGN. Treatment focuses on eradicating the

infection, with most patients treated as if they have endocarditis. The

prognosis is guarded.

■ LUPUS NEPHRITIS

Lupus nephritis is a common and serious complication of systemic

lupus erythematosus (SLE). Clinical manifestations of renal disease are

present in 30% of patients at the time of diagnosis, and the majority

will develop renal abnormalities in the course of their disease; it is

more common in blacks, Asians, and Hispanics than it is in whites.

Lupus nephritis results from the deposition of circulating immune

complexes composed of primarily DNA and anti-DNA, which activate

the complement cascade, leading to complement-mediated damage,