2358 PART 9 Disorders of the Kidney and Urinary Tract

Continue observation

AKI with features of AIN

Improvement

Withdraw offending agent

Supportive care and close

observation

No improvement in 1 week

OR rapid progression

Classic allergic AIN Atypical features

Corticosteroids Renal biopsy

Classic AIN Fibrosis

Corticosteroids Immunosuppressive drugs Conservative

Granulomatous or other immune IN

FIGURE 316-1 Algorithm for the treatment of allergic and other immune-mediated acute interstitial nephritis (AIN). AKI, acute kidney injury; IN, interstitial nephritis.

See text for immunosuppressive drugs used for refractory or relapsing AIN. (From Treatment of acute interstitial nephritis, S Reddy & DJ Salant: Renal Failure, 07 Jul 2009,

Taylor and Francis. Reprinted by permission of the publisher (Taylor and Francis Ltd, http://www.tandfonline.com).)

TABLE 316-2 Indications for Corticosteroids and Immunosuppressives

in Interstitial Nephritis

Absolute Indications

• Sjögren’s syndrome

• Sarcoidosis

• SLE interstitial nephritis

• Adults with TINU

• Interstitial nephritis from IgG4-related disease

• Idiopathic and other granulomatous interstitial nephritis

Relative Indications

• Drug-induced or idiopathic AIN with:

Rapid progression of renal failure

Diffuse infiltrates on biopsy

Impending need for dialysis

Delayed recovery

• Children with TINU

• Postinfectious AIN with delayed recovery (?)

Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus;

TINU, tubulointerstitial nephritis with uveitis.

Source: From Treatment of acute interstitial nephritis, S Reddy & DJ Salant: Renal

Failure, 07 Jul 2009, Taylor and Francis. Reprinted by permission of the publisher

(Taylor and Francis Ltd, http://www.tandfonline.com).

after 7–10 days of treatment with methicillin or another β-lactam

antibiotic, is the exception rather than the rule. More often, patients

are found incidentally to have a rising serum creatinine or present with

symptoms attributable to acute kidney injury (Chap. 310). Atypical

reactions can occur, most notably with nonsteroidal anti-inflammatory

drug (NSAID)–induced AIN, in which fever, rash, and eosinophilia are

rare, but acute kidney injury with heavy proteinuria is common. A particularly severe and rapid-onset AIN may occur upon reintroduction

of rifampin after a drug-free period. More insidious reactions to the

agents listed in Table 316-1 may lead to progressive tubulointerstitial

damage. Examples include proton pump inhibitors and, rarely, sulfonamide and 5-aminosalicylate (mesalazine and sulfasalazine) derivatives

and antiretrovirals. It is not clear if the recent association of proton

pump inhibitors with incident chronic kidney disease involves an intermediate step of prolonged, subclinical interstitial nephritis.

Diagnosis Finding otherwise unexplained kidney injury with or

without oliguria and exposure to a potentially offending agent usually

points to the diagnosis. Peripheral blood eosinophilia adds supporting

evidence but is present in only a minority of patients. Urinalysis reveals

pyuria with white blood cell casts and hematuria. Urinary eosinophils

are neither sensitive nor specific for AIN; therefore, testing is not

recommended. Kidney biopsy is generally not required for diagnosis

but reveals extensive interstitial and tubular infiltration of leukocytes,

including eosinophils.

TREATMENT

Allergic Interstitial Nephritis

Discontinuation of the offending agent often leads to reversal of the

kidney injury. However, depending on the duration of exposure and

degree of tubular atrophy and interstitial fibrosis that has occurred,

the kidney damage may not be completely reversible. Glucocorticoid therapy may accelerate kidney recovery but does not appear to

impact long-term kidney survival. It is best reserved for those cases

with severe kidney injury in which dialysis is imminent or if kidney

function continues to deteriorate despite stopping the offending

drug (Fig. 316-1 and Table 316-2).

■ SJÖGREN’S SYNDROME

Sjögren’s syndrome is a systemic autoimmune disorder that primarily targets the exocrine glands, especially the lacrimal and salivary

glands, and thus results in symptoms, such as dry eyes and mouth,

that constitute the “sicca syndrome” (Chap. 361). TIN with a predominant lymphocytic infiltrate is the most common renal manifestation

of Sjögren’s syndrome and can be associated with impaired kidney

function, distal RTA, and nephrogenic diabetes insipidus. Diagnosis is

strongly supported by positive serologic testing for anti-Ro (SS-A) and

anti-La (SS-B) antibodies. A large proportion of patients with Sjögren’s

syndrome also have polyclonal hypergammaglobulinemia. Treatment

is initially with glucocorticoids, although patients may require maintenance therapy with azathioprine or mycophenolate mofetil to prevent

relapse (Fig. 316-1 and Table 316-2).

2359Tubulointerstitial Diseases of the Kidney CHAPTER 316

■ TUBULOINTERSTITIAL NEPHRITIS

WITH UVEITIS

Tubulointerstitial nephritis with uveitis (TINU) is a systemic autoimmune disease of unknown etiology. It accounts for <5% of all cases

of AIN, affects females three times more often than males, and has a

median age of onset of 15 years. Its hallmark feature, in addition to a

lymphocyte-predominant interstitial nephritis (Fig. 316-2), is a painful

anterior uveitis, often bilateral and accompanied by blurred vision and

photophobia. Diagnosis is often confounded by the fact that the ocular

symptoms precede or accompany the kidney disease in only one-third

of cases. Additional extrarenal features include fever, anorexia, weight

loss, abdominal pain, and arthralgia. The presence of such symptoms

as well as elevated creatinine, sterile pyuria, mild proteinuria, features

of Fanconi’s syndrome, and elevated erythrocyte sedimentation rate

should raise suspicion for this disorder. Serologies suggestive of the

more common autoimmune diseases are usually negative, and TINU is

often a diagnosis of exclusion after other causes of uveitis and kidney

disease, such as Sjögren’s syndrome, Behçet’s disease, sarcoidosis, and

systemic lupus erythematosus, have been considered. Clinical symptoms are typically self-limited in children but are more apt to follow a

relapsing course in adults. The renal and ocular manifestations generally respond well to oral glucocorticoids, although maintenance therapy with agents such as methotrexate, azathioprine, or mycophenolate

may be necessary to prevent relapses (Fig. 316-1 and Table 316-2).

■ SYSTEMIC LUPUS ERYTHEMATOSUS

An interstitial mononuclear cell inflammatory reaction accompanies

the glomerular lesion in most cases of class III or IV lupus nephritis

(Chap. 314), and deposits of immune complexes can be identified

in tubular basement membranes in ~50% of cases. Occasionally,

however, the tubulointerstitial inflammation predominates and may

manifest with azotemia and type IV RTA rather than features of

glomerulonephritis.

■ GRANULOMATOUS INTERSTITIAL NEPHRITIS

Some patients may present with features of AIN but follow a protracted

and relapsing course. Kidney biopsy in such patients reveals a more

chronic inflammatory infiltrate with granulomas and multinucleated

giant cells. Most often, no associated disease or cause is found; however, some of these cases may have or subsequently develop the pulmonary, cutaneous, or other systemic manifestations of sarcoidosis such as

hypercalcemia. Most patients experience some improvement in kidney

function if treated early with glucocorticoids before the development of

significant interstitial fibrosis and tubular atrophy (Table 316-2). Other

immunosuppressive agents may be required for those who relapse frequently upon steroid withdrawal (Fig. 316-1). Tuberculosis should be

ruled out before starting treatment because this too is a rare cause of

granulomatous interstitial nephritis.

■ IgG4-RELATED SYSTEMIC DISEASE

A form of AIN characterized by a dense inflammatory infiltrate containing IgG4-expressing plasma cells can occur as a part of a syndrome

known as IgG4-related systemic disease (Chap. 368). Autoimmune

pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, and a

chronic sclerosing sialadenitis (mimicking Sjögren’s syndrome) may

variably be present as well. Fibrotic lesions that form pseudotumors in

the affected organs soon replace the initial inflammatory infiltrates and

often lead to biopsy or excision for fear of true malignancy. Although

the involvement of IgG4 in the pathogenesis is not understood, glucocorticoids have been successfully used as first-line treatment in this

group of disorders, once they are correctly diagnosed.

■ AIN ASSOCIATED WITH THE USE OF IMMUNE

CHECKPOINT INHIBITORS

The use of immune checkpoint inhibitors has had a major impact in

cancer care by disrupting mechanisms by which tumor cells elude the

body’s immune surveillance systems. However, such success comes

at the cost of increasing the incidence of autoimmune phenomena.

While dermatologic, gastrointestinal, and endocrine manifestations

prevail, the kidney is impacted in 2% of cases with monotherapy and

up to 5% when dual checkpoint inhibitor therapy is used. An acute rise

in serum creatinine is typically noted within 15 weeks after starting

therapy, although it can occur later during therapy or up to 2 months

following the final dose. Biopsy, when performed, typically shows acute

interstitial inflammation, although glomerular pathologies may also

be found. Patients are often taking medications commonly known to

cause acute drug-associated TIN such as proton pump inhibitors or

NSAIDs. Treatment for severe acute kidney injury includes corticosteroids, discontinuation of potential inciting medications, and avoidance of further checkpoint inhibitor doses until the kidney function

has recovered.

■ IDIOPATHIC AIN

Some patients present with typical clinical and histologic features of

AIN but have no evidence of drug exposure or clinical or serologic

features of an autoimmune disease. The presence in some cases of autoantibodies to a tubular antigen, similar to that identified in rats with

an induced form of interstitial nephritis, suggests that an autoimmune

response may be involved. Like TINU and granulomatous interstitial

nephritis, idiopathic AIN is responsive to glucocorticoid therapy

but may follow a relapsing course requiring maintenance treatment

with another immunosuppressive agent (Fig. 316-1 and Table 316-2).

Recently, cases have been identified in which autoantibodies that may

be important in disease pathogenesis were seen to target antigens

expressed by the collecting duct or proximal tubular brush border.

■ INFECTION-ASSOCIATED AIN

AIN may also occur as a local inflammatory reaction to microbial

infection (Table 316-1) and should be distinguished from acute bacterial pyelonephritis (Chap. 135). Acute bacterial pyelonephritis does

not generally cause acute kidney injury unless it affects both kidneys or

causes septic shock. Presently, infection-associated AIN is most often

seen in immunocompromised patients, particularly kidney transplant

recipients with reactivation of polyomavirus BK (Chaps. 143 and 313).

■ CRYSTAL DEPOSITION DISORDERS AND

OBSTRUCTIVE TUBULOPATHIES

Acute kidney injury may occur when crystals of various types are

deposited in tubular cells and interstitium or when they obstruct

tubules. Impaired kidney function, often accompanied by flank

pain from tubular obstruction, may occur in patients treated with

G

T

*

*

*

FIGURE 316-2 Acute interstitial nephritis (AIN) in a patient who presented with

acute iritis, low-grade fever, erythrocyte sedimentation rate of 103, pyuria and

cellular casts on urinalysis, and a newly elevated serum creatinine of 2.4 mg/dL.

Both the iritis and AIN improved after intravenous methylprednisolone. This PASstained kidney biopsy shows a mononuclear cell interstitial infiltrate (asterisks) and

edema separating the tubules (T) and a normal glomerulus (G). Some of the tubules

contain cellular debris and infiltrating inflammatory cells. The findings in this biopsy

are indistinguishable from those that would be seen in a case of drug-induced AIN.

PAS, Periodic acid–Schiff.

2360 PART 9 Disorders of the Kidney and Urinary Tract

sulfadiazine for toxoplasmosis, indinavir and atazanavir for HIV, and

intravenous acyclovir for severe herpesvirus infections. Urinalysis

reveals “sheaf of wheat” sulfonamide crystals, individual or parallel

clusters of needle-shaped indinavir crystals, or red-green birefringent

needle-shaped crystals of acyclovir. This adverse effect is generally precipitated by hypovolemia and is reversible with saline volume repletion

and drug withdrawal. Distinct from the obstructive disease, a frank

AIN from indinavir crystal deposition has also been reported.

Acute tubular obstruction is also the cause of oliguric kidney injury

in patients with acute urate nephropathy. It typically results from severe

hyperuricemia from tumor lysis syndrome in patients with lymphoor myeloproliferative disorders treated with cytotoxic agents but also

may occur spontaneously before the treatment has been initiated

(Chap. 75). Uric acid crystallization in the tubules and collecting

system leads to partial or complete obstruction of the collecting ducts,

renal pelvis, or ureter. A dense precipitate of birefringent uric acid crystals is found in the urine, usually in association with microscopic or

gross hematuria. Prophylactic allopurinol reduces the risk of uric acid

nephropathy but is of no benefit once tumor lysis has occurred. Once

oliguria has developed, attempts to increase tubular flow and solubility

of uric acid with alkaline diuresis may be of some benefit; however,

emergent treatment with hemodialysis or rasburicase, a recombinant

urate oxidase, is usually required to rapidly lower uric acid levels and

restore kidney function.

Calcium oxalate crystal deposition in tubular cells and interstitium

may lead to permanent kidney dysfunction in patients who survive

ethylene glycol intoxication, in patients with enteric hyperoxaluria

from ileal resection or small-bowel bypass surgery, and in patients

with hereditary hyperoxaluria (Chap. 318). Acute phosphate nephropathy is an uncommon but serious complication of oral Phosphosoda

used as a laxative or for bowel preparation for colonoscopy. It results

from calcium phosphate crystal deposition in tubules and interstitium and occurs especially in subjects with underlying kidney disease

and hypovolemia. Consequently, Phosphosoda should be avoided in

patients with chronic kidney disease.

■ LIGHT CHAIN CAST NEPHROPATHY

Patients with multiple myeloma may develop acute kidney injury

in the setting of hypovolemia, infection, or hypercalcemia or after

exposure to NSAIDs or radiographic contrast media. The diagnosis of

light chain cast nephropathy (LCCN)—commonly known as myeloma

kidney—should be considered in patients who fail to recover when the

precipitating factor is corrected or in any elderly patient with otherwise

unexplained acute kidney injury.

In this disorder, filtered monoclonal immunoglobulin light chains

(Bence-Jones proteins) form intratubular aggregates with secreted

Tamm-Horsfall protein in the distal tubule. Casts, in addition to

obstructing the tubular flow in affected nephrons, incite a giant cell

or foreign-body reaction and can lead to tubular rupture, resulting

in interstitial fibrosis (Fig. 316-3). Although LCCN generally occurs

in patients with known multiple myeloma and a large plasma cell

burden, the disorder should also be considered as a possible diagnosis

in patients who have known monoclonal gammopathy even in the

absence of frank myeloma. Filtered monoclonal light chains may also

cause less pronounced renal manifestations in the absence of obstruction, due to direct toxicity to proximal tubular cells and intracellular

crystal formation. This may result in isolated tubular disorders such as

RTA or full Fanconi’s syndrome.

Diagnosis Clinical clues to the diagnosis include anemia, bone

pain, hypercalcemia, and an abnormally narrow anion gap due to

hypoalbuminemia and hypergammaglobulinemia. Urinary dipsticks

detect albumin but not immunoglobulin light chains; however, laboratory detection of increased amounts of protein in a spot urine specimen and a negative dipstick result are highly suggestive that the urine

contains Bence-Jones protein. Serum and urine should both be sent for

protein electrophoresis and for immunofixation for the detection and

identification of a potential monoclonal band. A sensitive method is

available to detect urine and serum free light chains.

TREATMENT

Light Chain Cast Nephropathy

The goals of treatment are to correct precipitating factors such as

hypovolemia and hypercalcemia, discontinue potential nephrotoxic

agents, and treat the underlying plasma cell dyscrasia (Chap. 111);

plasmapheresis to remove light chains is of questionable value for

LCCN.

■ LYMPHOMATOUS INFILTRATION OF THE KIDNEY

Interstitial infiltration by malignant B lymphocytes is a common

autopsy finding in patients dying of chronic lymphocytic leukemia

and non-Hodgkin’s lymphoma; however, this is usually an incidental

finding. Rarely, such infiltrates may cause massive enlargement of the

kidneys and oliguric acute kidney injury. Although high-dose glucocorticoids and subsequent chemotherapy often result in recovery of

kidney function, the prognosis in such cases is generally poor.

CHRONIC TUBULOINTERSTITIAL

DISEASES

Improved occupational and public health measures, together with the

banning of over-the-counter phenacetin-containing analgesics, has led

to a dramatic decline in the incidence of chronic interstitial nephritis

(CIN) from heavy metal—particularly lead and cadmium—exposure

and analgesic nephropathy in North America. Today, CIN is most

often the result of renal ischemia or secondary to a primary glomerular

disease (Chap. 314). Other important forms of CIN are the result of

developmental anomalies or inherited diseases such as reflux nephropathy or sickle cell nephropathy and may not be recognized until adolescence or adulthood. Although it is impossible to reverse damage that

has already occurred, further deterioration may be prevented or at least

slowed in such cases by treating glomerular hypertension, a common

denominator in the development of secondary FSGS and progressive

loss of functioning nephrons. Therefore, awareness and early detection

of patients at risk may prevent them from developing end-stage renal

disease (ESRD).

■ VESICOURETERAL REFLUX AND

REFLUX NEPHROPATHY

Reflux nephropathy is the consequence of vesicoureteral reflux (VUR)

or other urologic anomalies in early childhood. It was previously called

chronic pyelonephritis because it was believed to result from recurrent urinary tract infections (UTIs) in childhood. VUR stems from

FIGURE 316-3 Histologic appearance of myeloma cast nephropathy. A hematoxylineosin–stained kidney biopsy shows many atrophic tubules filled with eosinophilic

casts (consisting of Bence-Jones protein), which are surrounded by giant cell

reactions. (Courtesy of Dr. Michael N. Koss, University of Southern California Keck

School of Medicine; with permission.)

2361Tubulointerstitial Diseases of the Kidney CHAPTER 316

FIGURE 316-4 Radiographs of vesicoureteral reflux (VUR) and reflux nephropathy. A. Voiding cystourethrogram in a 7-month-old baby with bilateral high-grade VUR

evidenced by clubbed calyces (arrows) and dilated tortuous ureters (U) entering the bladder (B). B. Abdominal computed tomography scan (coronal plane reconstruction)

in a child showing severe scarring of the lower portion of the right kidney (arrow). C. Sonogram of the right kidney showing loss of parenchyma at the lower pole due to

scarring (arrow) and hypertrophy of the mid-region (arrowhead). (Courtesy of Dr. George Gross, University of Maryland Medical Center; with permission.)

A B

C

abnormal retrograde urine flow from the bladder into one or both

ureters and kidneys because of mislocated and incompetent ureterovesical valves (Fig. 316-4). Although high-pressure sterile reflux may

impair normal growth of the kidneys, when coupled with recurrent

UTIs in early childhood, the result is patchy interstitial scarring and

tubular atrophy. Loss of functioning nephrons leads to hypertrophy of

the remnant glomeruli and eventual secondary FSGS. Reflux nephropathy often goes unnoticed until early adulthood when chronic kidney

disease is detected during routine evaluation or during pregnancy.

Affected adults are frequently asymptomatic but may give a history of

prolonged bed-wetting or recurrent UTIs during childhood and may

exhibit variable degrees of kidney injury as well as hypertension, mild

to moderate proteinuria, and an unremarkable urine sediment. When

both kidneys are affected, the disease often progresses inexorably over

several years to ESRD, despite the absence of ongoing urinary infections or reflux. A single affected kidney may go undetected, except for

the presence of hypertension. Kidney ultrasound in adults characteristically shows asymmetric small kidneys with irregular outlines, thinned

cortices, and regions of compensatory hypertrophy (Fig. 316-4).

TREATMENT

Vesicoureteral Reflux and Reflux Nephropathy

Maintenance of sterile urine in childhood has been shown to

limit scarring of the kidneys. Surgical reimplantation of the ureters into the bladder to restore competency is indicated in young

children with persistent high-grade reflux but is ineffective and is

2362 PART 9 Disorders of the Kidney and Urinary Tract

not indicated in adolescents or adults after scarring has occurred.

Aggressive control of blood pressure with an angiotensin-converting

enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)

and other agents is effective in reducing proteinuria and may significantly forestall further deterioration of kidney function.

■ SICKLE CELL NEPHROPATHY

The pathogenesis and clinical manifestations of sickle cell nephropathy are described in Chap. 317. Evidence of tubular injury may be

evident in childhood and early adolescence in the form of polyuria

due to decreased concentrating ability or type IV RTA years before

there is significant nephron loss and proteinuria from secondary FSGS.

Early recognition of these subtle renal abnormalities or development

of microalbuminuria in a child with sickle cell disease may warrant

consultation with a nephrologist and/or therapy with low-dose ACEIs.

Papillary necrosis may result from ischemia due to sickling of red cells

in the relatively hypoxemic and hypertonic medullary vasculature and

present with gross hematuria and ureteric obstruction by sloughed

ischemic papillae (Table 316-3).

■ TUBULOINTERSTITIAL ABNORMALITIES

ASSOCIATED WITH GLOMERULONEPHRITIS

Primary glomerulopathies are often associated with damage to tubules

and interstitium. This may occasionally be due to the same pathologic

process affecting the glomerulus and tubulointerstitium, as is the case

with immune-complex deposition in lupus nephritis. More often, however, chronic tubulointerstitial changes occur as a secondary consequence of prolonged glomerular dysfunction. Potential mechanisms by

which glomerular disease might cause tubulointerstitial injury include

proteinuria-mediated damage to the epithelial cells, activation of tubular cells by cytokines and complement, or reduced peritubular blood

flow leading to downstream tubulointerstitial ischemia, especially in

the case of glomeruli that are globally obsolescent due to severe glomerulonephritis. It is often difficult to discern the initial cause of injury

by kidney biopsy in a patient who presents with advanced kidney

disease in this setting.

■ ANALGESIC NEPHROPATHY

Analgesic nephropathy results from the long-term use of compound

analgesic preparations containing phenacetin (banned in the United

States since 1983), aspirin, and caffeine. In its classic form, analgesic

nephropathy is characterized by impaired kidney function, papillary

necrosis (Table 316-3) attributable to the presumed concentration of

the drug to toxic levels in the inner medulla, and a radiographic constellation of small, scarred kidneys with papillary calcifications best

appreciated by computed tomography (Fig. 316-5). Patients may also

have polyuria due to impaired concentrating ability and non-anion-gap

metabolic acidosis from tubular damage. Shedding of a sloughed

necrotic papilla can cause gross hematuria and ureteric colic due to

ureteral obstruction. Individuals with ESRD as a result of analgesic

nephropathy are at increased risk of a urothelial malignancy compared

to patients with other causes of kidney failure. Recent cohort studies

in individuals with normal baseline kidney function suggest that the

moderate chronic use of current analgesic preparations available in the

United States, including acetaminophen and NSAIDs, does not seem

to cause the constellation of findings known as analgesic nephropathy,

although volume-depleted individuals and those with chronic kidney

disease are at higher risk of NSAID-related renal toxicity. Nonetheless,

it is recommended that heavy users of acetaminophen and NSAIDs be

screened for evidence of kidney disease.

■ ARISTOLOCHIC ACID NEPHROPATHY

Two seemingly unrelated forms of CIN, Chinese herbal nephropathy

and Balkan endemic nephropathy, have recently been linked by the

underlying etiologic agent aristolochic acid and are now collectively

termed aristolochic acid nephropathy (AAN). In Chinese herbal nephropathy, first described in the early 1990s in young women taking traditional Chinese herbal preparations as part of a weight-loss regimen,

one of the offending agents has been identified as aristolochic acid, a

known carcinogen from the plant Aristolochia. Multiple Aristolochia

species have been used in traditional herbal remedies for centuries

and continue to be available despite official bans on their use in many

countries. Molecular evidence has also implicated aristolochic acid in

Balkan endemic nephropathy, a chronic TIN found primarily in towns

along the tributaries of the Danube River and first described in the

1950s. Although the exact route of exposure is not known with certainty, contamination of local grain preparations with the seeds of Aristolochia species seems most likely. Aristolochic acid, after prolonged

exposure, produces renal interstitial fibrosis with a relative paucity of

cellular infiltrates. The urine sediment is bland, with rare leukocytes

and only mild proteinuria. Anemia may be disproportionately severe

relative to the level of kidney dysfunction. Definitive diagnosis of AAN

requires two of the following three features: characteristic histology

on kidney biopsy; confirmation of aristolochic acid ingestion; and

detection of aristolactam-DNA adducts in kidney or urinary tract

tissue. These latter lesions represent a molecular signature of aristolochic acid–derived DNA damage and often consist of characteristic

A:T-to-T:A transversions. Due to this mutagenic activity, AAN is

associated with a very high incidence of upper urinary tract urothelial

cancers, with risk related to cumulative dose. Surveillance with computed tomography, ureteroscopy, and urine cytology is warranted, and

consideration should be given to bilateral nephroureterectomy once a

patient has reached ESRD.

■ KARYOMEGALIC INTERSTITIAL NEPHRITIS

Karyomegalic interstitial nephritis is an unusual form of slowly progressive chronic kidney disease with mild proteinuria, interstitial

fibrosis, tubular atrophy, and oddly enlarged nuclei of proximal tubular

epithelial cells. It has been linked to mutations in FAN1, a nuclease

involved in DNA repair, which may render carriers of the mutation

susceptible to environmental DNA-damaging agents.

■ LITHIUM-ASSOCIATED NEPHROPATHY

The use of lithium salts for the treatment of manic-depressive illness may have several renal sequelae, the most common of which

is nephrogenic diabetes insipidus manifesting as polyuria and polydipsia. Lithium accumulates in principal cells of the collecting duct

by entering through the epithelial sodium channel (ENaC), where it

FIGURE 316-5 Radiologic appearance of analgesic nephropathy. A noncontrast

computed tomography scan shows an atrophic left kidney with papillary

calcifications in a garland pattern. (Reprinted by permission from Macmillan

Publishers, Ltd., MM Elseviers et al: Kidney Int 48:1316, 1995.)

TABLE 316-3 Major Causes of Papillary Necrosis

Analgesic nephropathy

Sickle cell nephropathy

Diabetes with urinary tract infection

Prolonged NSAID use (rare)

Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

2363Tubulointerstitial Diseases of the Kidney CHAPTER 316

inhibits glycogen synthase kinase 3β and downregulates vasopressinregulated aquaporin water channels. Less frequently, chronic TIN

develops after prolonged (>10–20 years) lithium use and is most

likely to occur in patients who have experienced repeated episodes

of toxic lithium levels. Findings on kidney biopsy include interstitial

fibrosis and tubular atrophy that are out of proportion to the degree

of glomerulosclerosis or vascular disease, a sparse lymphocytic infiltrate, and small cysts or dilation of the distal tubule and collecting

duct that are highly characteristic of this disorder. The degree of

interstitial fibrosis correlates with both duration and cumulative

dose of lithium. Individuals with lithium-associated nephropathy

are typically asymptomatic, with minimal proteinuria, few urinary

leukocytes, and normal blood pressure. Some patients develop more

severe proteinuria due to secondary FSGS, which may contribute to

further loss of kidney function.

TREATMENT

Lithium-Associated Nephropathy

Kidney function should be followed regularly in patients taking

lithium, and caution should be exercised in patients with underlying kidney disease. The use of amiloride to inhibit lithium entry

via ENaC has been effective to prevent and treat lithium-induced

nephrogenic diabetes insipidus, but it is not clear if it will prevent lithium-induced CIN. Once lithium-associated nephropathy is

detected, the discontinuation of lithium in attempt to forestall further deterioration of kidney function can be problematic, as lithium

is an effective mood stabilizer that is often incompletely substituted

by other agents. Furthermore, despite discontinuation of lithium,

chronic kidney disease in such patients is often irreversible and can

slowly progress to ESRD. The most prudent approach is to monitor

lithium levels frequently and adjust dosing to avoid toxic levels

(preferably <1 meq/L). This is especially important because lithium

is cleared less effectively as kidney function declines.

■ CALCINEURIN INHIBITOR NEPHROTOXICITY

The calcineurin inhibitor (CNI) immunosuppressive agents cyclosporine and tacrolimus can cause both acute and chronic kidney injury.

Acute forms can result from vascular causes such as vasoconstriction

or the development of thrombotic microangiopathy or can be due to

a toxic tubulopathy. Chronic CNI-induced kidney injury is typically

seen in solid organ (including heart-lung and liver) transplant recipients and manifests with a slow but irreversible reduction of glomerular

filtration rate, with mild proteinuria and arterial hypertension. Hyperkalemia is a relatively common complication and is caused, in part,

by tubular resistance to aldosterone. The histologic changes in kidney

tissue include patchy interstitial fibrosis and tubular atrophy, often in a

“striped” pattern. In addition, the intrarenal vasculature often demonstrates hyalinosis, and focal glomerulosclerosis can be present as well.

Similar changes may occur in patients receiving CNIs for autoimmune

diseases, although the doses are generally lower than those used for

organ transplantation. Dose reduction or CNI avoidance appears to

mitigate the chronic tubulointerstitial changes but may increase the

risk of rejection and graft loss.

■ HEAVY METAL (LEAD) NEPHROPATHY

Heavy metals, such as lead or cadmium, can lead to a chronic tubulointerstitial process after prolonged exposure. The disease entity is no

longer commonly diagnosed, because such heavy metal exposure has

been greatly reduced due to the known health risks from lead and the

consequent removal of lead from most commercial products and fuels.

Nonetheless, occupational exposure is possible in workers involved in

the manufacture or destruction of batteries, removal of lead paint, or

manufacture of alloys and electrical equipment (cadmium) in countries

where industrial regulation is less stringent. In addition, ingestion of

moonshine whiskey distilled in lead-tainted containers has been one

of the more frequent sources of lead exposure.

Early signs of chronic lead intoxication are attributable to proximal

tubule dysfunction, particularly hyperuricemia as a result of diminished urate secretion. The triad of “saturnine gout,” hypertension, and

impaired kidney function should prompt a practitioner to ask specifically about lead exposure. Unfortunately, evaluating lead burden is

not as straightforward as ordering a blood test; the preferred methods

involve measuring urinary lead after infusion of a chelating agent or by

radiographic fluoroscopy of bone. Several recent studies have shown

an association between chronic low-level lead exposure and decreased

kidney function, although either of these two factors may have been

the primary event. In patients who have CIN of unclear origin and an

elevated total body lead burden, repeated treatments of lead chelation

therapy have been shown to slow the decline in kidney function.

METABOLIC DISORDERS

Disorders leading to excessively high or low levels of certain electrolytes and products of metabolism can also lead to chronic kidney

disease if untreated.

■ CHRONIC URIC ACID NEPHROPATHY

The constellation of pathologic findings that represent gouty nephropathy is very uncommon nowadays and is more of historical interest than

clinical importance, as gout is typically well managed with allopurinol

and other agents. However, there is emerging evidence that hyperuricemia is an independent risk factor for the development of chronic

kidney disease, perhaps through endothelial damage. The complex

interactions of hyperuricemia, hypertension, and kidney failure are still

incompletely understood.

Presently, gouty nephropathy is most likely to be encountered in

patients with severe tophaceous gout and prolonged hyperuricemia

from a hereditary disorder of purine metabolism (Chap. 417). This

should be distinguished from juvenile hyperuricemic nephropathy,

a form of medullary cystic kidney disease caused by mutations in

uromodulin (UMOD) (Chap. 315) and now grouped into the larger

category of autosomal dominant tubulointerstitial kidney disease. Histologically, the distinctive feature of gouty nephropathy is the presence

of crystalline deposits of uric acid and monosodium urate salts in the

kidney parenchyma. These deposits not only cause intrarenal obstruction but also incite an inflammatory response, leading to lymphocytic

infiltration, foreign-body giant cell reaction, and eventual fibrosis,

especially in the medullary and papillary regions of the kidney. Since

patients with gout frequently suffer from hypertension and hyperlipidemia, degenerative changes of the renal arterioles may constitute a

striking feature of the histologic abnormality, out of proportion to the

other morphologic defects. Clinically, gouty nephropathy is an insidious cause of chronic kidney disease. Early in its course, glomerular

filtration rate may be near normal, often despite morphologic changes

in medullary and cortical interstitium, proteinuria, and diminished

urinary concentrating ability. Treatment with allopurinol and urine

alkalinization is generally effective in preventing uric acid nephrolithiasis and the consequences of recurrent kidney stones; however, gouty

nephropathy may be intractable to such measures. Furthermore, the

use of allopurinol in asymptomatic hyperuricemia has not been consistently shown to improve kidney function.

■ HYPERCALCEMIC NEPHROPATHY

(See also Chap. 410) Chronic hypercalcemia, as occurs in primary

hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intoxication, or metastatic bone disease, can cause tubulointerstitial disease

and progressive kidney injury. The earliest lesion is a focal degenerative

change in renal epithelia, primarily in collecting ducts, distal tubules,

and loops of Henle. Tubular cell necrosis leads to nephron obstruction

and stasis of intrarenal urine, favoring local precipitation of calcium

salts and infection. Dilation and atrophy of tubules eventually occur, as

do interstitial fibrosis, mononuclear leukocyte infiltration, and interstitial calcium deposition (nephrocalcinosis). Calcium deposition may

also occur in glomeruli and the walls of renal arterioles.

Clinically, the most striking defect is an inability to maximally concentrate the urine, due to reduced collecting duct responsiveness to

2364 PART 9 Disorders of the Kidney and Urinary Tract

arginine vasopressin and defective transport of sodium and chloride

in the loop of Henle. Reductions in both glomerular filtration rate and

renal blood flow can occur, both in acute and in prolonged hypercalcemia. Eventually, uncontrolled hypercalcemia leads to severe tubulointerstitial damage and overt kidney injury. Abdominal x-rays may

demonstrate nephrocalcinosis as well as nephrolithiasis, the latter due

to the hypercalciuria that often accompanies hypercalcemia.

Treatment consists of reducing the serum calcium concentration

toward normal and correcting the primary abnormality of calcium

metabolism (Chap. 410). Acute kidney injury from acute hypercalcemia may be completely reversible. Gradual progressive kidney dysfunction related to chronic hypercalcemia, however, may not improve even

with correction of the calcium disorder.

■ HYPOKALEMIC NEPHROPATHY

Patients with prolonged and severe hypokalemia from chronic laxative

or diuretic abuse, surreptitious vomiting, or primary aldosteronism

may develop a reversible tubular lesion characterized by vacuolar

degeneration of proximal and distal tubular cells. Eventually, tubular

atrophy and cystic dilation accompanied by interstitial fibrosis may

ensue, leading to irreversible chronic kidney disease. Timely correction

of the hypokalemia will prevent further progression, but persistent

hypokalemia can cause ESRD.

GLOBAL PERSPECTIVE

The causes of acute and CIN vary widely across the globe. Analgesic

nephropathy continues to be seen in countries where phenacetincontaining compound analgesic preparations are readily available.

Adulterants in unregulated herbal and traditional medicaments pose

a threat of toxic interstitial nephritis, as exemplified by aristolochic

acid contamination of herbal slimming preparations. Contamination

of food sources with toxins, such as an outbreak of nephrolithiasis

and acute kidney injury from melamine contamination of infant milk

formula, poses a continuing risk. Large-scale exposure to aristolochic

acid remains prevalent in many Asian countries where traditional

herbal medicine use is common. Although industrial exposure to lead

and cadmium has largely disappeared as a cause of CIN in developed

nations, it remains a risk for nephrotoxicity in countries where such

exposure is less well controlled.

New endemic forms of chronic kidney disease continue to be

described. In particular, nephropathies with features of CIN have been

increasing in prevalence among Pacific coastal plantation workers in

Central America (Mesoamerican nephropathy), Sri Lanka (Sri Lankan

nephropathy), and southern India (Uddanam nephropathy). Together,

these disorders have been called chronic interstitial nephritis of agricultural communities (CINAC) and may be related to repetitive episodes of heat exposure, dehydration, and volume depletion in the field

workers. However, toxins, pesticides, and infective agents also remain

as possible etiologic agents. Global warming and regional temperature

variability have been proposed as contributors to these newly described

forms of kidney disease, and tens of thousands of lives have been lost

due to ESRD in these resource-poor areas in which renal replacement

therapy is often not an option.

■ FURTHER READING

Eckardt KU et al: Autosomal dominant tubulointerstitial kidney

disease: Diagnosis, classification, and management: A KDIGO consensus report. Kidney Int 88:676, 2015.

Johnson RJ et al: Chronic kidney disease of unknown cause in agricultural communities. N Engl J Med 380:1843, 2019.

Moledina DG, Perazella MA: Drug-induced acute interstitial

nephritis. Clin J Am Soc Nephrol 12:2046, 2017.

Praga M et al: Changes in the aetiology, clinical presentation and

management of acute interstitial nephritis, an increasingly common

cause of acute kidney injury. Nephrol Dial Transplant 30:1472, 2015.

Seethapathy H et al: The incidence, causes, and risk factors of acute

kidney injury in patients receiving immune checkpoint inhibitors.

Clin J Am Soc Nephrol 14:1692, 2019.

The renal circulation is complex and is characterized by a highly

perfused arteriolar network, reaching cortical glomerular structures

adjacent to lower-flow vasa recta that descend into medullary segments. Disorders of the larger vessels, including renal artery stenosis

and atheroembolic disease, are discussed elsewhere (Chap. 278). This

chapter examines primary disorders of the renal microvessels, many of

which are associated with thrombosis and hemolysis.

THROMBOTIC MICROANGIOPATHY

Thrombotic microangiopathy (TMA) is a pathologic lesion characterized by endothelial cell injury in the terminal arterioles and capillaries.

Platelet and hyaline thrombi causing partial or complete occlusion are

integral to the histopathology of TMA. TMA is usually accompanied by

microangiopathic hemolytic anemia (MAHA) with its typical features

of thrombocytopenia and schistocytes, but not always. In the kidney,

TMA is characterized by swollen endocapillary cells (endotheliosis),

fibrin thrombi, platelet plugs, arterial intimal fibrosis, and a membranoproliferative pattern in the glomerulus. Fibrin thrombi may extend

into the arteriolar vascular pole, producing glomerular collapse and

at times cortical necrosis. In kidneys that recover from acute TMA,

secondary focal segmental glomerulosclerosis may develop. Diseases

associated with this lesion include thrombotic thrombocytopenic

purpura (TTP), hemolytic-uremic syndrome (HUS), malignant

hypertension, scleroderma renal crisis, antiphospholipid syndrome,

preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet

count) syndrome, HIV infection, and radiation nephropathy. TMA can

also be seen in myeloproliferative neoplasm (MPN)–related glomerulopathy and POEMS (polyneuropathy, organomegaly, endocrinopathy,

monoclonal gammopathy, and skin changes) syndrome, which are not

associated with MAHA.

■ HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC

THROMBOCYTOPENIC PURPURA

HUS and TTP are the prototypes for MAHA. Historically, HUS and

TTP were distinguished mainly by their clinical and epidemiologic

differences. TTP develops more commonly in adults and was thought

to have more neurologic complications, while HUS occurs more frequently in children, particularly when associated with hemorrhagic

diarrhea. However, atypical HUS (aHUS) can have its first appearance

in adulthood, and neurologic involvement can be as common in HUS

as in TTP. Currently, HUS and TTP can be differentiated etiologically

and treated according to their specific pathophysiologic features.

Hemolytic-Uremic Syndrome HUS is loosely defined by the

presence of MAHA and renal impairment. At least four variants are

recognized. The most common is Shiga toxin–producing Escherichia

coli (STEC) HUS, which is also known as D+ (diarrhea-associated)

HUS or enterohemorrhagic E. coli (EHEC) HUS. Most cases involve

children <5 years of age, but adults also are susceptible, as evidenced by

a 2011 outbreak in northern Europe. Diarrhea, often bloody, precedes

MAHA within 1 week in >80% of cases. Abdominal pain, cramping,

and vomiting are frequent, whereas fever is typically absent. Neurologic

symptoms, including dysphasia, hyperreflexia, blurred vision, memory

deficits, encephalopathy, perseveration, and agraphia, often develop,

especially in adults. Seizures and cerebral infarction can occur in

severe cases. STEC HUS is caused by the Shiga toxins (Stx1 and Stx2),

which are also referred to as verotoxins. These toxins are produced by

certain strains of E. coli and Shigella dysenteriae. In the United States

and Europe, the most common STEC strain is O157:H7, but HUS has

been reported with other strains (O157/H–

, O111:H–

, O26:H11/H–

,

O145:H28, and O104:H4). After entry into the circulation, Shiga toxin

317 Vascular Injury

to the Kidney

Ronald S. Go, Nelson Leung

2365Vascular Injury to the Kidney CHAPTER 317

endothelial damage (pathologically similar to that of HUS) is the main

cause of the TMA that develops in association with chemotherapeutic agents (e.g., proteasome inhibitors [bortezomib, carfilzomib, and

ixazomib], mitomycin C, and gemcitabine) and immunosuppressive

agents (cyclosporine, interferon, sirolimus, and tacrolimus). This

process is usually dose-dependent. Alternatively, TMA may develop as

a result of drug-induced autoantibodies. This form is less likely to be

dose-dependent and can, in fact, occur after a single dose in patients

with previous exposure (quinine). ADAMTS13 deficiency is found in

fewer than half of patients with clopidogrel-associated TTP. Quinine

appears to induce autoantibodies to granulocytes, lymphocytes, endothelial cells, and platelet glycoprotein Ib/IX or IIb/IIIa complexes, but

not to ADAMTS13. Quinine-associated TTP is more common among

women. TMA has also been reported with drugs that inhibit vascular

endothelial growth factor, such as bevacizumab; the mechanism is not

completely understood.

TREATMENT

Hemolytic-Uremic Syndrome/Thrombotic

Thrombocytopenic Purpura

Treatment should be based on pathophysiology. iTTP and DEAP

HUS respond to the combination of plasma exchange and prednisone. In addition to removing the autoantibodies, plasma exchange

with fresh-frozen plasma replaces ADAMTS13. Twice-daily plasma

exchanges with administration of rituximab may be effective in

refractory cases. The use of caplacizumab, a monoclonal antibody

fragment that binds to the A1 domain of von Willebrand factor, blocking its interaction with platelets, was recently shown to

improve platelet count recovery and reduce the composite risk of

death, disease exacerbation, and thromboembolic events. It is now

approved for use in iTTP in conjunction with plasma exchange and

immunosuppressive therapy. Plasma infusion is usually sufficient

to replace the ADAMTS13 in cTTP. Plasma exchange should be

considered if larger volumes are necessary.

Plasma infusion/exchange is effective in certain types of aHUS

because it replaces complement-regulatory proteins. Eculizumab

and ravulizumab, anti-C5 monoclonal antibodies, are approved for

use in aHUS, and have been shown to abort MAHA and improve

renal function. Antibiotics and washed red cells should be given

in neuraminidase-associated HUS, and plasmapheresis may be

helpful; however, plasma and whole-blood transfusion should be

avoided since these products contain IgM, which may exacerbate

MAHA. Combined factor H and ADAMTS13 deficiency has been

reported. The affected patients are generally less responsive to

plasma infusion, an outcome that illustrates the complexity of the

management of these cases.

Drug-induced TMA secondary to endothelial damage typically

does not respond to plasma exchange and is treated primarily by

discontinuing the use of the agent and, if refractory, a trial of C5

inhibitors. Similarly, STEC HUS should be treated with supportive

measures as plasma exchange has not been found to be effective.

Antimotility agents and antibiotics increase the incidence of HUS

among children, but azithromycin may decrease the duration of

bacterial shedding in adults.

■ HEMATOPOIETIC STEM CELL

TRANSPLANTATION–ASSOCIATED

THROMBOTIC MICROANGIOPATHY

Hematopoietic stem cell transplantation (HSCT)–associated TMA develops after allogeneic HSCT, with an incidence of ~8%. Etiologic factors

include conditioning regimens, immunosuppression, infections, and

graft-versus-host disease. Other risk factors include female sex and

human leukocyte antigen (HLA)–mismatched donor grafts. HSCTTMA usually occurs within the first 100 days of HSCT. Table 317-1

lists definitions of HSCT-TMA currently used for clinical trials.

Diagnosis may be difficult since thrombocytopenia, anemia, and renal

binds to the glycolipid surface receptor globotriaosylceramide (Gb3),

which is richly expressed on cells of the renal microvasculature. Upon

binding, the toxin enters the cells, inducing inflammatory cytokines

(interleukin 8 [IL-8], monocyte chemotactic protein 1 [MCP-1],

and stromal cell–derived factor 1 [SDF-1]) and chemokine receptors

(CXCR4 and CXCR7); this action results in platelet aggregation and

the microangiopathic process. Streptococcus pneumoniae can also

cause HUS. Certain strains produce a neuraminidase that cleaves the

N-acetylneuraminic acid moieties normally covering the ThomsenFriedenreich antigen on platelets and endothelial cells. Exposure of this

cryptic antigen to preformed IgM results in severe MAHA.

aHUS or complement-mediated HUS is the result of complement

dysregulation. The complement dysregulation can be congenital or

acquired. The affected patients often have low C3 and normal C4 levels

characteristic of alternative pathway activation. Factor H deficiency,

the most common defect, has been linked to families with aHUS.

Factor H competes with factor B to prevent the formation of C3bBb

and acts as a cofactor for factor I, which proteolytically degrades C3b.

More than 70 mutations of the factor H gene have been identified. Most

are missense mutations that produce abnormalities in the C-terminus

region, affecting its binding to C3b but not its concentration. Other

mutations result in low levels or the complete absence of the protein.

Deficiencies in other complement-regulatory proteins, such as factor I, factor B, membrane cofactor protein (CD46), C3, complement

factor H (CFH)–related protein 1 (CFHR1), CFHR3, CFHR5, and

thrombomodulin, have also been reported. Finally, an autoimmune

variant of aHUS, DEAP (deficiency of CFHR plasma proteins and

CFH autoantibody positive) HUS, occurs when an autoantibody to

factor H is formed. DEAP HUS is often associated with a deletion of

an 84-kb fragment of the chromosome that encodes for CFHR1 and

CFHR3. The autoantibody blocks the binding of factor H to C3b and

surface-bound C3 convertase. Renal injury is often severe, resulting in

end-stage renal disease. The severity of the renal injury and recurrence

after kidney transplant depend on the complement regulatory protein.

Thrombotic Thrombocytopenic Purpura Traditionally, TTP

is characterized by the pentad of MAHA, thrombocytopenia, neurologic symptoms, fever, and renal failure. The pathophysiology of TTP

involves the accumulation of ultra-large multimers of von Willebrand

factor as a result of the absence or markedly decreased activity of the

plasma protease ADAMTS13, a disintegrin and metalloproteinase with

a thrombospondin type 1 motif, member 13. TTP is now defined as

MAHA associated with ADAMTS13 activity of (<5–10%). These ultralarge multimers form clots and shear erythrocytes, resulting in MAHA;

however, the absence of ADAMTS13 alone may not by itself produce

TTP. Often, an additional inflammatory trigger (such as infection,

surgery, pancreatitis, or pregnancy) is required to initiate clinical TTP.

This may be mediated by human neutrophil peptides that inhibit cleavage of von Willebrand factor by ADAMTS13. TTP can be congenital

from ADAMTS13 mutation (cTTP) or acquired from autoantibody

against ADAMTS13 protein (iTTP).

cTTP, also known as Upshaw-Schülman syndrome, is characterized

by congenital deficiency of ADAMTS13. cTTP can start within the first

weeks of life but, in some instances, may not present until adulthood,

especially during pregnancy. Both environmental and genetic factors are

thought to influence the development of cTTP. Plasma transfusion is an

effective strategy for prevention and treatment. In iTTP, autoantibody

to ADAMTS13 (IgG or IgM) either increases its clearance or inhibits its

activity. Data from the Oklahoma TTP/HUS Registry suggest an iTTP

incidence rate of 2.9 cases/106

 patients in the United States. The median

age of onset is 40 years. The incidence is more than nine times higher

among blacks than nonblacks. Like that of systemic lupus erythematosus, the incidence of iTTP is nearly three times higher among women

than among men. If untreated, iTTP has a mortality rate exceeding

90%. Even with modern therapy, 20% of patients die within the first

month from complications of microvascular thrombosis.

Drug-induced TMA is a recognized complication of treatment

with some chemotherapeutic agents, immunosuppressive agents, and

quinine. Two different mechanisms are now recognized. Toxic or

2366 PART 9 Disorders of the Kidney and Urinary Tract

insufficiency are common after HSCT. HSCT-TMA carries a high

mortality rate (75% within 3 months). The majority of patients have

>10% ADAMTS13 activity, and plasma exchange is beneficial in <25%

of patients. Discontinuation of calcineurin inhibitors and treatment of

infections or sinusoidal obstruction syndrome (if present) are recommended. There are increasing reports of successful use of eculizumab,

but clinical trial data are lacking.

■ HIV-RELATED THROMBOTIC MICROANGIOPATHY

HIV-related TMA is a complication encountered mainly before widespread use of highly active antiretroviral therapy. It is seen in patients

with advanced AIDS and low CD4+ T-cell counts, although it can

be the first manifestation of HIV infection. The presence of MAHA,

thrombocytopenia, and renal failure are suggestive, but renal biopsy

is required for diagnosis since other renal diseases are also associated

with HIV infection. Thrombocytopenia may prohibit renal biopsy

in some patients. The mechanism of injury is unclear, although HIV

can induce apoptosis in endothelial cells. ADAMTS13 activity is not

reduced in these patients. Cytomegalovirus co-infection may also be

a risk factor. Effective antiviral therapy is key, while plasma exchange

should be limited to patients who have evidence of TTP.

■ RADIATION NEPHROPATHY

Either local or total-body irradiation can produce microangiopathic

injury. The kidney is one of the most radiosensitive organs, and injury

can result with as little as 4–5 Gy. Such injury is characterized by renal

insufficiency, proteinuria, and hypertension usually developing ≥6

months after radiation exposure. Renal biopsy reveals classic TMA

with damage to glomerular, tubular, and vascular cells, but systemic

evidence of MAHA is uncommon. Because of its high incidence

after allogeneic HSCT, radiation nephropathy is often referred to as

bone marrow transplant nephropathy. No specific therapy is available,

although observational evidence supports renin-angiotensin system

blockade.

■ SCLERODERMA (PROGRESSIVE SYSTEMIC SCLEROSIS)

Kidney involvement is common (up to 52%) in patients with widespread scleroderma, with 20% of cases resulting directly from scleroderma renal crisis. Other renal manifestations in scleroderma include

transient (prerenal) or medication-related forms of acute kidney injury

(e.g., associated with D-penicillamine, nonsteroidal anti-inflammatory

drugs, or cyclosporine). Scleroderma renal crisis occurs in 12% of

patients with diffuse systemic sclerosis but in only 2% of those with

limited systemic sclerosis. Scleroderma renal crisis is the most severe

manifestation of renal involvement and is characterized by accelerated

hypertension, a rapid decline in renal function, nephrotic-range proteinuria, and hematuria. Retinopathy and encephalopathy may accompany the hypertension. Salt and water retention with microvascular

injury can lead to pulmonary edema. Cardiac manifestations, including

myocarditis, pericarditis, and arrhythmias, denote an especially poor

prognosis. Although MAHA is present in more than half of patients,

coagulopathy is rare.

The renal lesion in scleroderma renal crisis is characterized by arcuate artery intimal and medial proliferation with luminal narrowing.

This lesion is described as “onion-skinning” and can be accompanied

by glomerular collapse due to reduced blood flow. Histologically, scleroderma renal crisis is indistinguishable from malignant hypertension,

with which it can coexist. Fibrinoid necrosis and thrombosis are common. Before the availability of angiotensin-converting enzyme (ACE)

inhibitors, the mortality rate for scleroderma renal crisis was >90% at

1 month. Introduction of renin-angiotensin system blockade has lowered

the mortality rate to 30% at 3 years. Nearly two-thirds of patients with

scleroderma renal crisis may require dialysis support, with recovery of

renal function in 50% (median time, 1 year). Glomerulonephritis and

vasculitis associated with antineutrophil cytoplasmic antibodies and

systemic lupus erythematosus have been described in patients with

scleroderma. An association has been found with a speckled pattern of

antinuclear antibodies and with antibodies to RNA polymerases I and III.

Anti-U3-RNP may identify young patients at risk for scleroderma renal

crisis. Anticentromere antibody, in contrast, is a negative predictor of

this disorder. Because of the overlap between scleroderma renal crisis

and other autoimmune disorders, a renal biopsy is recommended for

patients with atypical renal involvement, especially if hypertension is

absent.

Treatment with ACE inhibition is the first-line therapy unless

contraindicated. The goal of therapy is to reduce systolic and diastolic

blood pressure by 20 mmHg and 10 mmHg, respectively, every 24 h

until blood pressure is normal. Additional antihypertensive therapy

may be given once the dose of drug for ACE inhibition is maximized.

Angiotensin II receptor antagonists are less effective at preventing renal

failure; thus, they are only recommended if the patient is intolerant of

ACE inhibitors. ACE inhibition alone does not prevent scleroderma

renal crisis, but it does reduce the impact of hypertension. In addition,

it has been observed that patients on ACE inhibitors have a higher

renal recovery rate after initiation of dialysis, and thus, ACE inhibitors

are continued even after starting dialysis. Intravenous iloprost has been

used in Europe for blood pressure management and improvement

of renal perfusion. Kidney transplantation is not recommended for

2 years after the start of dialysis since delayed recovery may occur.

Bosentan (endothelin-1 antagonist) and eculizumab have both been

investigated for use in this disease.

■ ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome (Chap. 357) can be either primary or

secondary to systemic lupus erythematosus. It is characterized by a

predisposition to systemic thrombosis (arterial and venous) and fetal

morbidity mediated by antiphospholipid antibodies—mainly anticardiolipin antibodies (IgG, IgM, or IgA), lupus anticoagulant, or anti-β-2

glycoprotein I antibodies (antiβ2GPI). Patients with both anticardiolipin antibodies and antiβ2GPI appear to have the highest risk of

thrombosis. The vascular compartment within the kidney is the main

site of renal involvement. Arteriosclerosis is commonly present in the

arcuate and intralobular arteries. In the intralobular arteries, fibrous

intimal hyperplasia characterized by intimal thickening secondary to

intense myofibroblastic intimal cellular proliferation with extracellular matrix deposition is frequently seen along with onion-skinning.

Arterial and arteriolar fibrous and fibrocellular occlusions are present

in more than two-thirds of biopsy samples. Cortical necrosis and focal

cortical atrophy may result from vascular occlusion. TMA is commonly present in renal biopsies, although signs of MAHA and platelet

consumption are usually absent. TMA is especially common in the catastrophic variant of antiphospholipid syndrome, a condition recently

found to be pathophysiologically linked to uncontrolled complement

activation. In patients with secondary antiphospholipid syndrome,

other glomerulopathies may be present, including membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis,

and pauci-immune crescentic glomerulonephritis.

Large vessels can be involved in antiphospholipid syndrome and

may form the proximal nidus near the ostium for thrombosis of the

TABLE 317-1 Criteria for Establishing Microangiopathic Kidney Injury

Associated with Hematopoietic Stem Cell Transplantation

INTERNATIONAL WORKING GROUP

BLOOD AND MARROW

TRANSPLANT CLINICAL TRIALS

NETWORK TOXICITY COMMITTEE

>4% schistocytes in the blood RBC fragmentation and at least

2 schistocytes per high-power field

De novo, prolonged, or progressive

thrombocytopenia

Concurrent increase in LDH

above baseline

A sudden and persistent increase

in LDH

Negative direct and indirect

Coombs test

Decrease in hemoglobin or increased

RBC transfusion requirement

Concurrent renal and/or neurologic

dysfunction without other explanations

Decrease in haptoglobin concentration

Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.

2367Vascular Injury to the Kidney CHAPTER 317

renal artery. Renal vein thrombosis can occur and should be suspected

in patients with lupus anticoagulant who develop nephrotic-range

proteinuria. Progression to end-stage renal disease can occur, and

thrombosis may form in the vascular access and the renal allografts.

Hypertension is common. Treatment entails lifelong anticoagulation;

however, neither safety nor effectiveness of novel oral anticoagulants

has been established. Glucocorticoids may be beneficial in accelerated

hypertension. Immunosuppression and plasma exchange may be

helpful for catastrophic episodes of antiphospholipid syndrome but

by themselves do not reduce recurrent thrombosis. More recently,

the efficacy of rituximab has been reported in several cases. A pilot

phase 1/2 study has shown rituximab to be safe in these patients. Similarly, eculizumab had been shown to be efficacious in reversing the

acute kidney injury in a number of cases, including in patients with

catastrophic antiphospholipid syndrome. Some of these patients were

refractory to rituximab. Further studies are needed for both of these

medications.

■ HELLP SYNDROME

HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is

a dangerous complication of pregnancy associated with microvascular

injury. Occurring in 0.2–0.9% of all pregnancies and in 10–20% of

women with severe preeclampsia, this syndrome carries a mortality

rate of 7.4–34%. Most commonly developing in the third trimester, 10%

of cases occur before week 27, and 30% occur postpartum. Although a

strong association exists between HELLP syndrome and preeclampsia,

nearly 20% of cases are not preceded by recognized preeclampsia. Risk

factors include abnormal placentation, family history, and elevated

levels of fetal mRNA for FLT1 (vascular endothelial growth factor

receptor 1) and endoglin. Patients with HELLP syndrome have higher

levels of inflammatory markers (C-reactive protein, IL-1Ra, and IL-6)

and soluble HLA-DR than do those with preeclampsia alone.

Renal failure occurs in half of patients with HELLP syndrome,

although the etiology is not well understood. Limited data suggest

that renal failure is the result of both preeclampsia and acute tubular

necrosis. Renal histologic findings are those of TMA with endothelial cell swelling and occlusion of the capillary lumens, but luminal

thrombi are typically absent. However, thrombi become more common

in severe eclampsia and HELLP syndrome. Although renal failure is

common, the organ that defines this syndrome is the liver. Subcapsular

hepatic hematomas sometimes produce spontaneous rupture of the

liver and can be life-threatening. Neurologic complications such as

cerebral infarction, cerebral and brainstem hemorrhage, and cerebral

edema are other potentially life-threatening complications. Nonfatal

complications include placental abruption, permanent vision loss

due to Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy)

retinopathy, pulmonary edema, bleeding, and fetal demise.

Many features are shared by HELLP syndrome and MAHA. Diagnosis of HELLP syndrome is complicated by the fact that aHUS and

TTP also can be triggered by pregnancy; in addition, complement

gene mutations and complement pathway dysfunction are common

(30–40%) among patients with HELLP syndrome. Patients with antiphospholipid syndrome also have an elevated risk of HELLP syndrome.

A history of MAHA before pregnancy is of diagnostic value. Serum

levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP syndrome but not to the levels seen in TTP (<10%). Determination of the

ratio of lactate dehydrogenase to aspartate aminotransferase may be

helpful. This ratio is 13:1 in patients with HELLP syndrome and preeclampsia as opposed to 29:1 in patients without preeclampsia. Other

markers, such as antithrombin III (decreased in HELLP syndrome but

not in TTP) and D-dimer (elevated in HELLP syndrome but not in

TTP), may also be useful. HELLP syndrome usually resolves spontaneously after delivery, although a small percentage of HELLP cases occur

postpartum. Glucocorticoids may decrease inflammatory markers,

although two randomized controlled trials failed to show much benefit. Plasma exchange should be considered if hemolysis is refractory to

glucocorticoids and/or delivery, especially if TTP has not been ruled

out. Eculizumab has been reported to be effective in a small number

of cases, but dosing, efficacy, and indications remain undetermined.

Myeloproliferative Neoplasm–Related Glomerulopathy

While MAHA is often present in TMA, this is not true for all lesions.

Two conditions are now recognized to present with renal TMA but

no evidence of systemic MAHA. The first is MPN-related glomerulopathy. MPN represents a group of clonal disorders that includes

chronic myelogenous leukemia (CML), polycythemia vera (PV),

essential thrombocythemia (ET), primary myelofibrosis (PMF),

chronic eosinophilic leukemia not otherwise specified, chronic

neutrophilic leukemia, and unclassifiable MPN. These patients

present with renal impairment and nephrotic-range proteinuria.

MPN-related glomerulopathy usually occurs late in the course of the

hematologic condition, as median time from diagnosis of MPN to

glomerulopathy is 7.2 years. Renal biopsy shows mesangial expansion, hypercellularity, mesangial and segmental sclerosis, luminal

hyalinosis, loss of overlying podocytes, and adhesions to Bowman’s

capsule and duplication of glomerular basement membranes. Foot

process effacement ranges from 30 to 95%. Arteriosclerosis is common and ranges from mild to severe. Arteriolar hyalinosis can also

be seen. Extramedullary hematopoiesis can sometimes be seen,

especially in patients with myelofibrosis. MPN-related glomerulopathy may develop while patients are on treatment with hydroxyurea

and JAK2 inhibitors. No standard treatment is available. Reninangiotensin system blockade and corticosteroids have been tried

with mixed results.

POEMS Syndrome POEMS syndrome is a systemic disease characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Peripheral neuropathy with

severe motor-sensory deficit is the hallmark of the disease. Patients

also commonly have elevated IL-6 and vascular endothelial growth

factor (VEGF) levels at diagnosis. Another characteristic is that >95%

of monoclonal light chain is of the lambda isotype. IgA also makes up

~50% of the monoclonal proteins involved. Organomegaly can involve

any organ and often presents as lymphadenopathy. In the kidney, the

hypertrophy frequently is unilateral. One study suggests the difference

in kidney size is due to unilateral contraction; however, a volumetric

study showed that enlargement is responsible for the difference in

kidney size in some patients. Glomerulomegaly is not uncommon.

Lobular appearance, endothelial cell swelling, hypercellularity, mesangiolysis, microaneurysm, and glomerular enlargement are reminiscent

of membranoproliferative glomerulonephritis. Most patients present

with mild to moderate renal impairment and low-grade proteinuria.

Progression to end-stage renal disease is rare.

■ SICKLE CELL NEPHROPATHY

Renal complications in sickle cell disease result from occlusion of the

vasa recta in the renal medulla. The low partial pressure of oxygen

and high osmolarity predispose to hemoglobin S polymerization and

erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and

papillary necrosis (which can also occur in sickle trait). The kidney

responds by increasing blood flow and glomerular filtration rate

mediated by prostaglandins. This dependence on prostaglandins may

explain the greater reduction of glomerular filtration rate by nonsteroidal anti-inflammatory drugs in these patients than in others. The

glomeruli are typically enlarged. Intracapillary fragmentation and

phagocytosis of sickled erythrocytes are thought to be responsible

for the membranoproliferative glomerulonephritis–like lesion, and

focal segmental glomerulosclerosis is seen in more advanced cases.

Proteinuria is present in 20–30%, and nephrotic-range proteinuria is

associated with progression to renal failure. ACE inhibitors reduce

proteinuria, although data are lacking on prevention of renal failure.

Patients with sickle cell disease are also more prone to acute renal failure. The cause is thought to reflect microvascular occlusion associated

with nontraumatic rhabdomyolysis, high fever, infection, and generalized sickling. Chronic kidney disease is present in 12–20% of patients.

Despite the frequency of renal disease, hypertension is uncommon in

patients with sickle cell disease. CRISPR gene editing therapy was used

for the first time in a patient with sickle cell anemia in 2019; long-term

results of this novel therapy are pending.

2368 PART 9 Disorders of the Kidney and Urinary Tract

RENAL VEIN THROMBOSIS

Renal vein thrombosis either can present with flank pain, tenderness,

hematuria, rapid decline in renal function, and proteinuria or can

be silent. Occasionally, renal vein thrombosis is identified during a

workup for pulmonary embolism. The left renal vein is more commonly involved, and two-thirds of cases are bilateral. Etiologies can be

divided into three broad categories: endothelial damage, venous stasis,

and hypercoagulability. Homocystinuria, endovascular intervention,

and surgery can produce vascular endothelial damage. Dehydration,

which is more common among male patients, is a common cause of

stasis in the pediatric population. Stasis also can result from compression and kinking of the renal veins from retroperitoneal processes

such as retroperitoneal fibrosis and abdominal neoplasms. Thrombosis

can occur throughout the renal circulation, including the renal veins,

with antiphospholipid syndrome. Renal vein thrombosis can also be

secondary to nephrotic syndrome, particularly membranous nephropathy. Other hypercoagulable states less commonly associated with renal

vein thrombosis include proteins C and S, antithrombin deficiency,

factor V Leiden, disseminated malignancy, and oral contraceptives.

Severe nephrotic syndrome may also predispose patients to renal vein

thrombosis.

Diagnostic screening can be performed with Doppler ultrasonography, which is more sensitive than ultrasonography alone. Computed

tomography angiography is ~100% sensitive. Magnetic resonance

angiography is another option but is more expensive. Treatment for

renal vein thrombosis consists of anticoagulation and therapy for

the underlying cause. Endovascular thrombolysis may be considered

in severe cases. Occasionally, nephrectomy may be undertaken for

life-threatening complications. Vena caval filters are often used to prevent migration of thrombi.

■ FURTHER READING

Al-Nouri ZL et al: Drug-induced thrombotic microangiopathy:

A systematic review of published reports. Blood 125:616, 2015.

Brocklebank V et al: Thrombotic microangiopathy and the kidney.

Clin J Am Soc Nephrol 13:300, 2018.

Fakhouri F et al: Haemolytic uraemic syndrome. Lancet 390:681,

2017.

George JN, Nester CM: Syndromes of thrombotic microangiopathy.

N Engl J Med 371:1847, 2014.

Go RS et al: Thrombotic microangiopathy care pathway: A consensus

statement for the Mayo Clinic Complement Alternative PathwayThrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group.

Mayo Clin Proc 91:1189, 2016.

Zabatta E et al: Therapy of scleroderma renal crisis: State of the art.

Autoimmun Rev 17:882, 2018.

Nephrolithiasis, or kidney stone disease, is a common, painful, and costly

condition. Each year, billions of dollars are spent on nephrolithiasisrelated activity, with the majority of expenditures on surgical treatment of existing stones. While a stone may form due to crystallization

of lithogenic factors in the upper urinary tract, it can subsequently

move into the ureter and cause renal colic. Although nephrolithiasis

is rarely fatal, patients who have had renal colic report that it is the

worst pain they have ever experienced. The evidence on which to base

clinical recommendations is not as strong as desired; nonetheless, most

experts agree that the recurrence of most, if not all, types of stones

can be prevented with careful evaluation and targeted recommendations. Preventive treatment may be lifelong; therefore, an in-depth

understanding of this condition must inform the implementation of

318 Nephrolithiasis

Gary C. Curhan

tailored interventions that are most appropriate for and acceptable to

the patient.

There are several types of kidney stones. It is clinically important

to identify the stone type, which informs prognosis and selection of

the optimal preventive regimen. Calcium oxalate stones are most

common (~75%); next, in order, are calcium phosphate (~15%), uric

acid (~8%), struvite (~1%), and cystine (<1%) stones. Many stones

are a mixture of crystal types (e.g., calcium oxalate and calcium

phosphate) and also contain protein in the stone matrix. Rarely,

stones are composed of medications, such as acyclovir, atazanavir,

and triamterene. Stones that form as a result of an upper tract infection, if not appropriately treated, can have devastating consequences

and lead to end-stage renal disease. Consideration should be given

to teaching practitioners strategies to prevent recurrence of all stone

types and the related morbidity.

■ EPIDEMIOLOGY

Nephrolithiasis is a global disease. Data suggest an increasing prevalence, likely due to Westernization of lifestyle habits (e.g., dietary

changes, increasing body mass index). National Health and Nutrition

Examination Survey data for 2007–2010 indicate that up to 19% of

men and 9% of women will develop at least one stone during their

lifetime. The prevalence is ~50% lower among black individuals than

among whites. The incidence of nephrolithiasis (i.e., the rate at which

previously unaffected individuals develop their first stone) also varies

by age, sex, and race. Among white men, the peak annual incidence

is ~3.5 cases/1000 at age 40 and declines to ~2 cases/1000 by age 70.

Among white women in their thirties, the annual incidence is ~2.5

cases/1000; the figure decreases to ~1.5/1000 at age 50 and beyond.

In addition to the medical costs associated with nephrolithiasis, this

condition also has a substantial economic impact, as those affected are

often of working age. Once an individual has had a stone, the prevention of a recurrence is essential. Published recurrence rates vary by the

definitions and diagnostic methods used. Some reports have relied on

symptomatic events, while others have been based on imaging. Most

experts agree that radiographic evidence of a second stone should

be considered to represent a recurrence, even if the stone has not yet

caused symptoms.

■ ASSOCIATED MEDICAL CONDITIONS

Nephrolithiasis is a systemic disorder. Several conditions predispose

to stone formation, including gastrointestinal malabsorption (e.g.,

Crohn’s disease, gastric bypass surgery), primary hyperparathyroidism,

obesity, type 2 diabetes mellitus, and distal renal tubular acidosis. A

number of other medical conditions are more likely to be present in

individuals with a history of nephrolithiasis, including hypertension,

gout, cardiovascular disease, cholelithiasis, reduced bone mineral density, and chronic kidney disease.

Although nephrolithiasis does not directly cause upper urinary

tract infections (UTIs), a UTI in the setting of an obstructing stone

is a urologic emergency (“pus under pressure”) and requires urgent

intervention to reestablish drainage.

■ PATHOGENESIS

In the consideration of the processes involved in crystal formation, it

is helpful to view urine as a complex solution. A clinically useful concept is supersaturation (the point at which the concentration product

exceeds the solubility product). However, even though the urine in

most individuals is supersaturated with respect to one or more types

of crystals, the presence of inhibitors of crystallization prevents the

majority of the population from continuously forming stones. The

most clinically important inhibitor of calcium-containing stones is

urine citrate. While the calculated supersaturation value does not perfectly predict stone formation, it is a useful guide as it integrates the

multiple factors that are measured in a 24-h urine collection.

Recent studies have changed the paradigm for the site of initiation

of stone formation. Renal biopsies of stone formers have revealed

calcium phosphate in the renal interstitium. It is hypothesized that

this calcium phosphate deposits at the thin limb of the loop of Henle

2369 Nephrolithiasis CHAPTER 318

formation more than doubles. Fluid intake is the main determinant of

urine volume, and the importance of fluid intake in preventing stone formation has been demonstrated in observational studies and in a randomized controlled trial. Observational studies have found that coffee, tea,

beer, wine, and orange juice are associated with a reduced risk of stone

formation. Sugar-sweetened beverage consumption may increase risk.

Nondietary Risk Factors Age, race, body size, and environment

are important risk factors for nephrolithiasis. The incidence of stone

disease is highest in middle-aged white men, but stones can form in

infants as well as in the elderly. There is geographic variability, with

the highest prevalence in the southeastern United States. Weight gain

increases the risk of stone formation, and the increasing prevalence of

nephrolithiasis in the United States may be due in part to the increasing

prevalence of obesity. Environmental and occupational influences that

may lead to lower urine volume, such as working in a hot environment or lack of ready access to water or a bathroom, are important

considerations.

Urinary Risk Factors

URINE VOLUME As mentioned above, lower urine volume results

in higher concentrations of lithogenic factors and is a common and

readily modifiable risk factor. A randomized trial has demonstrated

the effectiveness of higher fluid intake in increasing urine volume and

reducing the risk of stone recurrence.

URINE CALCIUM Higher urine calcium excretion increases the likelihood of formation of calcium oxalate and calcium phosphate stones.

While the term hypercalciuria is often used, there is no widely accepted

cutoff that distinguishes between normal and abnormal urine calcium

excretion. In fact, the relation between urine calcium and stone risk

appears to be continuous; thus, the use of an arbitrary threshold should

be avoided. Levels of urine calcium excretion are higher in individuals

with a history of nephrolithiasis; however, the mechanisms remain

poorly understood. Greater gastrointestinal calcium absorption is one

important contributor, and greater bone turnover (with a resultant

reduction in bone mineral density) may be another. Primary renal

calcium loss, with lower serum calcium concentrations and elevated

serum levels of parathyroid hormone (PTH) (and a normal 25-hydroxy

vitamin D level), is rare.

URINE OXALATE Higher urine oxalate excretion increases the likelihood of calcium oxalate stone formation. As for urine calcium, no

definition for “abnormal” urine oxalate excretion is widely accepted.

Given that the relation between urine oxalate and stone risk is continuous, simple dichotomization of urine oxalate excretion is not helpful in

assessing risk. The two sources of urine oxalate are endogenous generation and dietary intake. Dietary oxalate is the major contributor and

also the source that can be modified. Notably, higher dietary calcium

intake reduces gastrointestinal oxalate absorption and thereby reduces

urine oxalate.

URINE CITRATE Urine citrate is a natural inhibitor of calciumcontaining stones; thus, lower urine citrate excretion increases the risk

of stone formation. Citrate reabsorption is influenced by the intracellular pH of proximal tubular cells. Metabolic acidosis, including that

due to higher animal flesh intake, will lead to a reduction in citrate

excretion by increasing reabsorption of filtered citrate. However, a

notable proportion of patients have lower urine citrate for reasons that

remain unclear.

URINE URIC ACID Higher urine levels of uric acid—a risk factor for

uric acid stone formation—are found in individuals with excess purine

consumption and rare genetic conditions that lead to overproduction

of uric acid. This characteristic does not appear to be associated with

the risk of calcium oxalate stone formation.

URINE pH Urine pH influences the solubility of some crystal types.

Uric acid stones form only when the urine pH is consistently ≤5.5,

whereas calcium phosphate stones are more likely to form when the

urine pH is ≥6.5. Cystine is more soluble at higher urine pH. Calcium

oxalate stones are not influenced by urine pH.

and then extends down to the papilla and erodes through the papillary

epithelium, where it provides a site for deposition of calcium oxalate

and calcium phosphate crystals. The majority of calcium oxalate stones

grow on calcium phosphate at the tip of the renal papilla (Randall’s

plaque). Tubular plugs of calcium phosphate may be the initiating

event in calcium phosphate stone development. Thus, the process of

stone formation may begin years before a clinically detectable stone is

identified. The processes involved in interstitial deposition are under

active investigation.

■ RISK FACTORS

Risk factors for nephrolithiasis can be categorized as dietary, nondietary, or urinary. These risk factors vary by stone type and clinical

characteristics.

Dietary Risk Factors Patients who develop stones often change

their diet; therefore, studies that retrospectively assess diet may be

hampered by recall bias. Some studies have examined the relation

between diet and changes in the lithogenic composition of the urine,

often using calculated supersaturation. However, the composition of

the urine does not perfectly predict risk, and not all components that

modify risk are included in the calculation of supersaturation. Thus,

dietary associations are best investigated by prospective studies that

examine actual stone formation as the outcome. Dietary factors that are

associated with an increased risk of nephrolithiasis include animal protein, oxalate, sodium, sucrose, and fructose. Dietary factors associated

with a lower risk include calcium, potassium, and phytate.

CALCIUM The role of dietary calcium deserves special attention.

Although in the distant past dietary calcium had been suspected of

increasing the risk of stone disease, several prospective observational

studies and a randomized controlled trial have demonstrated that

higher dietary calcium intake is related to a lower risk of stone formation. The reduction in risk associated with higher calcium intake may

be due to a reduction in intestinal absorption of dietary oxalate that

results in lower urine oxalate. Low calcium intake is contraindicated

as it increases the risk of stone formation and may contribute to lower

bone density in stone formers.

Despite similar bioavailability, supplemental calcium may increase

the risk of stone formation. The discrepancy between the risks from

dietary calcium and calcium supplements may be due to the timing of

supplemental calcium intake or to higher total calcium consumption

leading to higher urinary calcium excretion.

OXALATE Urinary oxalate is derived from both endogenous production and absorption of dietary oxalate. Owing to its low and often

variable bioavailability, much of the oxalate in food may not be readily absorbed. However, absorption may be higher in stone formers.

Although observational studies demonstrate that dietary oxalate is only

a weak risk factor for stone formation, urinary oxalate is a strong risk

factor for calcium oxalate stone formation, and efforts to avoid high

oxalate intake should thus be beneficial.

OTHER NUTRIENTS Several other nutrients have been studied and

implicated in stone formation. Higher intake of animal protein may

lead to increased excretion of calcium and uric acid as well as to

decreased urinary excretion of citrate, all of which increase the risk of

stone formation. Higher sodium and sucrose intake increases calcium

excretion independent of calcium intake. Higher potassium intake

decreases calcium excretion, and many potassium-rich foods increase

urinary citrate excretion due to their alkali content. Other dietary

factors that have been inconsistently associated with lower stone risk

include magnesium and phytate.

Vitamin C supplements are associated with an increased risk of calcium oxalate stone formation in men, possibly because of raised levels

of oxalate in urine. Thus, male calcium oxalate stone formers should

be advised to avoid vitamin C supplements. Although high doses of

supplemental vitamin B6

 may be beneficial in selected patients with

type 1 primary hyperoxaluria, the risk is not reduced in other patients.

FLUIDS AND BEVERAGES The risk of stone formation increases as urine

volume decreases. When the urine output is <1 L/d, the risk of stone

2370 PART 9 Disorders of the Kidney and Urinary Tract

Genetic Risk Factors The risk of nephrolithiasis is more

than twofold greater in individuals with a family history of stone

disease. This association is likely due to a combination of genetic

predisposition and similar environmental exposures. While a number

of rare monogenic disorders cause nephrolithiasis, the genetic contributors to common forms of stone disease remain to be determined.

The two most common and well-characterized rare monogenic

disorders that lead to stone formation are primary hyperoxaluria and

cystinuria. Primary hyperoxaluria is an autosomal recessive disorder

that causes excessive endogenous oxalate generation by the liver, with

consequent calcium oxalate stone formation and crystal deposition in

organs. Intraparenchymal calcium oxalate deposition in the kidney can

eventually lead to renal failure. Cystinuria is an autosomal recessive disorder that causes abnormal reabsorption of filtered basic amino acids.

The excessive urinary excretion of cystine, which is poorly soluble,

leads to cystine stone formation. Cystine stones are visible on plain

radiographs and often manifest as staghorn calculi or multiple bilateral

stones. Repeat episodes of obstruction and instrumentation can cause

a reduction in the glomerular filtration rate (GFR).

APPROACH TO THE PATIENT

Nephrolithiasis

Evidence-based guidelines for the evaluation and treatment of

nephrolithiasis have been published. Although there is limited evidence for several aspects, there are standard approaches to patients

with acute and chronic presentations that can reasonably guide the

clinical evaluation.

It typically requires weeks to months (and often much longer)

for a kidney stone to grow to a clinically detectable size. Although

the passage of a stone is a dramatic event, stone formation and

growth are characteristically clinically silent. A stone can remain

asymptomatic in the kidney for years or even decades before signs

(e.g., hematuria) or symptoms (e.g., pain) become apparent. Thus,

it is important to remember that the onset of symptoms, typically

attributable to a stone moving into the ureter, does not provide

insight into when the stone actually formed. The factors that induce

stone movement are unknown.

CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS

There are two common presentations for individuals with an acute

stone event: renal colic and painless gross hematuria. Renal colic

is a misnomer because pain typically does not subside completely;

rather, it varies in intensity. When a stone moves into the ureter, the

discomfort often begins with a sudden onset of unilateral flank pain.

The intensity of the pain can increase rapidly, and there are no

alleviating factors. This pain, which is accompanied often by nausea and occasionally by vomiting, may radiate, depending on the

location of the stone. If the stone lodges in the upper part of the

ureter, pain may radiate anteriorly; if the stone is in the lower part

of the ureter, pain can radiate to the ipsilateral testicle in men or

the ipsilateral labium in women. Occasionally, a patient has gross

hematuria without pain.

Other diagnoses may be confused with acute renal colic. If the

stone is lodged at the right ureteropelvic junction, symptoms may

mimic those of acute cholecystitis. If the stone blocks the ureter as

it crosses over the right pelvic brim, symptoms may mimic acute

appendicitis, whereas blockage at the left pelvic brim may be confused with acute diverticulitis. If the stone lodges in the ureter at the

ureterovesical junction, the patient may experience urinary urgency

and frequency. In female patients, the latter symptoms may lead to

an incorrect diagnosis of bacterial cystitis; the urine will contain

red and white blood cells, but the urine culture will be negative. An

obstructing stone with proximal infection may present as acute pyelonephritis. A UTI in the setting of ureteral obstruction is a medical

emergency that requires immediate restoration of drainage by placement of either a ureteral stent or a percutaneous nephrostomy tube.

Other conditions to consider in the differential diagnosis include

muscular or skeletal pain, herpes zoster, duodenal ulcer, abdominal

aortic aneurysm, gynecologic conditions, ureteral stricture, and

ureteral obstruction by materials other than a stone, such as a blood

clot or sloughed papilla. Extraluminal processes can lead to ureteral

compression and obstruction; however, because of the gradual onset,

these conditions do not typically present with renal colic.

DIAGNOSIS AND INTERVENTION

Serum chemistry findings are typically normal, but the white blood

cell count may be elevated. Examination of the urine sediment will

usually reveal red and white blood cells and occasionally crystals

(Fig. 318-1). The absence of hematuria does not exclude a stone,

particularly when urine flow is completely obstructed by a stone.

The diagnosis is often made on the basis of the history, physical

examination, and urinalysis. Thus, it may not be necessary to wait

for radiographic confirmation before treating the symptoms. The

diagnosis is confirmed by an appropriate imaging study—preferably

helical computed tomography (CT), which is highly sensitive,

allows visualization of uric acid stones (traditionally considered

“radiolucent”), and does not require radiocontrast (Fig. 318-2).

Helical CT detects stones as small as 1 mm that may be missed by

other imaging modalities.

FIGURE 318-1 Urine sediment from a patient with calcium oxalate stones (left) and a patient with cystine stones (right). Calcium oxalate dihydrate crystals are bipyramidally

shaped, and cystine crystals are hexagonal. (Left panel image courtesy of Dr. Mark Perazella, Yale School of Medicine; Right panel image courtesy Dr. John Lieske, Mayo Clinic.)