2349 Glomerular Diseases CHAPTER 314

in HIVAN is FSGS, characteristically revealing a collapsing glomerulopathy (see Fig. A4-3) with visceral epithelial cell swelling, microcystic

dilatation of renal tubules, and tubuloreticular inclusion. Renal epithelial cells express replicating HIV virus, but host immune responses also

play a role in the pathogenesis. HIVAN develops almost exclusively in

patients of black race origin, linked to APOL1 polymorphisms. HIV

immune complex kidney disease (HIVICK) is a group of immune

complex–mediated glomerular lesions seen in HIV patients that, on

biopsy, can look like a constellation of other glomerular lesions, including postinfectious glomerulonephritis, MGN, MPGN, DPGN, MCD,

and IgA nephropathy. The HIVICK effect is a complication of active

HIV viremia.

HIV patients with FSGS typically present with nephrotic-range

proteinuria and hypoalbuminemia, but unlike patients with other

etiologies for nephrotic syndrome, they do not commonly have hypertension, edema, or hyperlipidemia. Renal ultrasound also reveals

large, echogenic kidneys despite the finding that renal function in

some patients declines rapidly. Treatment with inhibitors of the reninangiotensin system decreases the proteinuria. Effective antiretroviral

therapy benefits both the patient and the kidney and improves survival

of HIV-infected patients with HIVAN and, in some cases, HIVICKassociated chronic kidney disease or ESRD. In HIV-infected patients not

yet on therapy, the presence of HIVAN is an indication to initiate therapy. Following the introduction of antiretroviral therapy, survival on

dialysis for the HIV-infected patient has improved dramatically. Renal

transplantations in HIV-infected patients without detectable viral loads

or histories of opportunistic infections provide a better survival benefit

over dialysis. Following transplantation, patient and graft survival are

similar to the general transplant population despite frequent rejections.

Hepatitis B and C Typically, infected patients present with microscopic hematuria, nonnephrotic or nephrotic-range proteinuria, and

hypertension. There is a close association between hepatitis B infection

and polyarteritis nodosa, with vasculitis appearing generally in the first

6 months following infection. Renal manifestations include renal artery

aneurysms, renal infarction, and ischemic scars. Alternatively, the

hepatitis B carrier state can produce an MGN with predominant IgG1

deposition that is more common in children than adults or MPGN that

is more common in adults than in children. Renal histology is indistinguishable from idiopathic MGN or MPGN. Viral antigens, most

commonly HBeAG, are found in the renal deposits. Cryoglobulinemic

glomerulonephritis has also been reported. Treatment is with antiviral

agents. Children have a better prognosis than adults.

Up to 30% of patients with chronic hepatitis C infection have some

renal manifestations. Patients often present with type II mixed cryoglobulinemia, nephrotic syndrome, microscopic hematuria, abnormal

liver function tests, depressed C3

 levels, anti–hepatitis C virus (HCV)

antibodies, and viral RNA in the blood. The renal lesions most commonly seen, in order of decreasing frequency, are cryoglobulinemic

glomerulonephritis, MGN, and MPGN, but polyarteritis nodosa

(PAN), IgA nephropathy, and FSGS have been reported. With the availability of direct-acting antivirals, which can achieve a viral remission in

>95% of patients, the prevalence of glomerular disease in HCV patients

should decline. These drugs are currently the treatment of choice for

patients with HCV-related MPGN or PAN.

Other Viruses Other viral infections are occasionally associated

with glomerular lesions, but cause and effect are not well established. These viral infections and their respective glomerular lesions

include cytomegalovirus producing MPGN or FSGS; influenza and

anti-GBM disease; measles-associated endocapillary proliferative glomerulonephritis, with measles antigen in the capillary loops and

mesangium; parvovirus causing mild proliferative or mesangioproliferative glomerulonephritis or FSGS; mumps and mesangioproliferative

glomerulonephritis; Epstein-Barr virus producing MPGN, diffuse

proliferative nephritis, or IgA nephropathy; dengue hemorrhagic fever

causing endocapillary proliferative glomerulonephritis; Hanta virus

and mesangial proliferative glomerulonephritis; and coxsackievirus

producing focal glomerulonephritis or DPGN.

Syphilis Secondary syphilis, with rash and constitutional symptoms, develops weeks to months after the chancre first appears and

occasionally presents with the nephrotic syndrome from MGN caused

by subepithelial immune deposits containing treponemal antigens.

Other lesions have also rarely been described, including interstitial

syphilitic nephritis. The diagnosis is confirmed with nontreponemal and treponemal tests for Treponema pallidum. The renal lesion

responds to treatment with penicillin or an alternative drug, if allergic.

Additional testing for other sexually transmitted diseases is an important part of disease management.

Leprosy Despite aggressive eradication programs, new cases of

leprosy appear primarily in developing countries. The diagnosis is best

made in patients with multiple skin lesions accompanied by sensory

loss in affected areas, using skin smears showing paucibacillary or

multibacillary infection (WHO criteria). Leprosy is caused by infection

with Mycobacterium leprae and can be classified by Ridley-Jopling criteria

into various types: tuberculoid, borderline tuberculoid, mid-borderline

and borderline lepromatous, and lepromatous. Renal involvement in

leprosy is related to the quantity of bacilli in the body, and the kidney

is one of the target organs during splanchnic localization. In some

series, all cases with borderline lepromatous and lepromatous types

of leprosy have various forms of renal involvement including FSGS,

mesangioproliferative glomerulonephritis, or renal amyloidosis; much

less common are the renal lesions of DPGN and MPGN. Treatment of

the infection with multidrug therapy can reduce the incidence of renal

disease or produce remission of the renal disease.

Malaria There are 300–500 million incident cases of malaria each

year worldwide, and the kidney is commonly involved. Glomerulonephritis is due to immune complexes containing malarial antigens

that are implanted in the glomerulus. In malaria from P. falciparum,

mild proteinuria is associated with subendothelial deposits, mesangial

deposits, and mesangioproliferative glomerulonephritis that usually

resolve with treatment. In quartan malaria from infection with Plasmodium malariae, children are more commonly affected and renal

involvement is more severe. Transient proteinuria and microscopic

hematuria can resolve with treatment of the infection. However, resistant nephrotic syndrome with progression to renal failure over 3–5 years

does happen, as <50% of patients respond to steroid therapy. Affected

patients with nephrotic syndrome have thickening of the glomerular

capillary walls, with subendothelial deposits of IgG, IgM, and C3

 associated with a sparse membranoproliferative lesion. The rare mesangioproliferative glomerulonephritis reported with Plasmodium vivax or

Plasmodium ovale typically has a benign course. Acute kidney injury

can often complicate these glomerulopathies.

Schistosomiasis Schistosomiasis affects >300 million people

worldwide and primarily involves the urinary and gastrointestinal

tracts. Glomerular involvement varies with the specific strain of schistosomiasis; Schistosoma mansoni is most commonly associated with

clinical renal disease, and the glomerular lesions can be classified as

follows: class I is a mesangioproliferative glomerulonephritis; class II is

an extracapillary proliferative glomerulonephritis; class III is a membranoproliferative glomerulonephritis; class IV is a focal segmental glomerulonephritis; and class V is amyloidosis. Classes I–II often remit with

treatment of the infection, but class III and IV lesions are associated

with IgA immune deposits and progress despite antiparasitic and/or

immunosuppressive therapy.

Other Parasites Renal involvement with toxoplasmosis infections

is rare. When it occurs, patients present with nephrotic syndrome

and have a histologic picture of MPGN. Fifty percent of patients with

leishmaniasis will have mild to moderate proteinuria and microscopic

hematuria, but renal insufficiency is rare. Acute DPGN, MGN, and

mesangioproliferative glomerulonephritis have all been observed on

biopsy. Filariasis and trichinosis are caused by nematodes and are

sometimes associated with glomerular injury presenting with proteinuria, hematuria, and a variety of histologic lesions that typically

resolve with eradication of the infection.

2350 PART 9 Disorders of the Kidney and Urinary Tract

■ FURTHER READING

DeVriese AS et al: Differentiating primary, genetic, and secondary

FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol

29:759, 2018.

Kupin WL: Viral-associated GN: Hepatitis C and HIV. Clin J Am Soc

Nephrol 12:1337, 2017.

Papazachariou L et al: Frequent COL4 mutations in familial microheamaturia accompanied by later-onset/alport nephropathy due to

focal segmental glomerulosclerosis. Clin Genet 92:517, 2017.

Pickering MC et al: C3

 glomerulopathy: Consensus report. Kidney

Int 84:1079, 2013.

Ronco P, Debiec H: Membranous nephropathy: A fairy tale for

immunopathologists, nephrologists and patients. Mol Immunol

68:57, 2015.

Sethi S et al: Mayo Clinic/Renal Pathology Society consensus report

on pathologic classification, diagnosis, and reporting of GN. J Am

Soc Nephrol 27:1278, 2016.

The polycystic kidney diseases are a group of genetically heterogeneous

disorders and a leading cause of kidney failure. The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, affecting 12 million people

worldwide. The autosomal recessive form of polycystic kidney disease

(ARPKD) is rarer but affects the pediatric population. Kidney cysts

are often seen in a wide range of syndromic diseases. Recent studies

have shown that defects in the structure or function of the primary

cilia may underlie this group of genetic diseases collectively termed

ciliopathies (Table 315-1).

■ AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY

DISEASE

Etiology and Pathogenesis (Fig. 315-1) ADPKD is characterized by progressive formation of epithelial lined cysts in the kidney.

Although cysts occur in only 5% of the tubules in the kidney, the

enormous growth of these cysts ultimately leads to the loss of normal

surrounding tissues and loss of renal function. The cellular defects

in ADPKD that have been known for a long time are increased cell

proliferation and fluid secretion, decreased cell differentiation, and

abnormal extracellular matrix. ADPKD is caused by mutations in

PKD1 and PKD2, which, respectively, code for polycystin-1 (PC1)

and polycystin-2 (PC2). PC1 is a large 11-transmembrane protein

that functions like a G-protein coupled receptor. PC2 is a calciumpermeable six-transmembrane protein that structurally belongs to the

transient receptor potential (TRP) cation channel family. PC1 and PC2

are widely expressed in almost all tissues and organs. PC1 expression is

high in development and low in the adult, whereas PC2 expression is

relatively constant. PC1/2 are found on the primary cilium, a hairlike

structure present on the apical membrane of a cell, in addition to the cell

membranes and cell–cell junctions of tubular epithelial cells. Defects in

the primary cilia are linked to a wide spectrum of human diseases,

collectively termed ciliopathies. The most common phenotype shared

by many ciliopathies is kidney cysts. PC1 and PC2 bind to each other

via their respective C-terminal tails to form a receptor-channel complex and regulate each other’s function. Recent evidence suggests a 1:3

315 Polycystic Kidney Disease

and Other Inherited

Disorders of Tubule

Growth and Development

Jing Zhou, Martin R. Pollak

stoichiometry for PC1:PC2 in the PC1/2 channel complex. The PC1/2

protein complex serves as a mechanosensor or chemical sensor and

regulates calcium and G-protein signaling. The PC1/2 protein complex

may also directly regulate a number of cellular functions, including the

cell cycle, the actin cytoskeleton, planar cell polarity (PCP), and cell

migration. This protein complex has also been implicated in regulating

a number of signaling pathways, including Wnt, mammalian target of

rapamycin (mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K/

Akt), G protein–coupled receptor (GPCR), and epidermal growth factor receptor (EGFR), as well as in the localization and activity of cystic

fibrosis transmembrane conductance regulator (CFTR). One hypothesis is that loss of ciliary function of PC1 and PC2 leads to aberrant

calcium signaling and a subsequent increase of adenylyl cyclase activity and decrease of phosphodiesterase activity, which, in turn, causes

increased cellular cAMP. Increased cAMP promotes protein kinase A

activity, among other effectors, and, in turn, leads to cyst growth by

promoting proliferation and fluid secretion of cyst-lining cells through

chloride and aquaporin channels in ADPKD kidneys.

ADPKD is inherited as an autosomal dominant trait with complete

penetrance, but variable expressivity. The disease affects all ethnic

groups worldwide with an estimated prevalence of 1:1000 to 1:400.

Only half of the patients with ADPKD are clinically diagnosed during

their lifetimes. ADPKD is genetically heterogeneous. The first disease

gene (PKD1) was localized to the region of the alpha-globin gene on

chromosome 16p13 in 1985, and a second disease gene (PKD2) locus

was mapped to chromosome 4q21-q23 in 1993. Mutations of PKD1

and PKD2 are responsible for ~85% and ~15% of ADPKD cases,

respectively. However, patients with PKD2 mutations may be >15%

because they tend to have milder clinical disease and, as a result, are

underdiagnosed. Embryonic lethality of Pkd1 and Pkd2 knockout

mice suggest human homozygotes may be lethal, thus not clinically

recognized.

PKD1 is comprised of 46 exons occupying ~52 kb of genomic

DNA. It produces a ~14 kb transcript that encodes polycystin-1, a

protein of ~4300 amino acids. A feature of the PKD1 gene is that the 5’

three-quarters of PKD1 have been duplicated at six other sites on chromosome 16p, and many of them produce mRNA transcripts, which

provides a major challenge for genetic analysis of the duplicated region.

PKD2 is a single-copy gene with 15 exons producing a ~5.3 kb mRNA

transcript that encodes polycystin-2, a protein of 968 amino acids. Two

additional genes, GANAB and DNAJB11, have been found in patients

with autosomal dominant form of polycystic kidney disease. The

GANAB gene encodes the glucosidase IIa subunit and the DNAJB11

gene produces a cofactor of BiP, a key chaperone in the endoplasmic

reticulum controlling folding, trafficking, and degradation of secreted

and membrane proteins. Both proteins appear to affect PC1 trafficking. However, these mutations have only been found in a very small

number of families.

In ADPKD patients, every cell carries a germline mutant allele of

either PKD1 or PKD2. However, cysts develop in only a small fraction

of the nephrons. Cysts are thought to originate from clonal growth of

single cells that have received a somatic “second hit” mutation in the

“normal” allele of the PKD1 or PKD2 gene. Accumulating evidence in

mouse models now shows that partial loss of function of the second

allele of Pkd1 in a proliferative environment is sufficient for cystogenesis, suggesting that a critical amount of PKD1 is needed in a cell.

Somatic inactivation of the second allele of Pkd1 in adult mice results

in very slow onset of cyst development in the kidney, but a “third hit”

such as an additional genetic or epigenetic event, the inactivation of a

growth suppressor gene, the activation of a growth promoting gene(s),

or an event such as renal injury that activates the developmental program, may promote rapid cyst formation.

Clinical Manifestations ADPKD is characterized by the progressive bilateral formation of renal cysts. Focal renal cysts are typically

detected in affected subjects aged <30 years. Hundreds to thousands

of cysts are usually present in the kidneys of most patients in the

fifth decade (Fig. 315-2). Enlarged kidneys can each reach a fourfold increase in length and weigh up to 20 times the normal weight.

2351Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development CHAPTER 315

The clinical presentations of ADPKD are highly variable. While many

patients are asymptomatic until the fourth to fifth decade of life and

are diagnosed by incidental discoveries of hypertension or abdominal

masses, back or flank pain is a frequent symptom in ~60% of patients

with ADPKD. The pain may result from renal cyst infection, hemorrhage, or nephrolithiasis. Gross hematuria resulting from cyst rupture

occurs in ~40% of patients during the course of their disease, and

many of them will have recurrent episodes. Flank pain and hematuria

may coexist if the cyst that ruptures is connected with the collecting

system. Proteinuria is usually a minor feature of ADPKD. Infection

is the second most common cause of death for patients with ADPKD.

Up to half of patients with ADPKD will have one or more episodes

of renal infection during their lifetimes. An infected cyst and acute

pyelonephritis are the most common renal infections often due to

gram-negative bacteria, which are associated with fever and flank pain,

with or without bacteremia. These complications and renal insufficiency often correlate with structural abnormality of the renal parenchyma. Mutations in GANAB and DNAJB11 genes result in milder

cystic kidney disease than that in classic ADPKD with small renal cysts

and normal-sized kidneys. Sometimes patients with GANAB mutations

present with ADPLD-like phenotype. Patients with DNAJB11 develop

renal fibrosis, characteristic of autosomal dominant tubulointerstitial

disease (ADTKD) discussed below. Kidney stones occur in ~20% of

patients with ADPKD. Different from the general population, more

than half of the stones in patients with ADPKD are composed of uric

acid, with the remainder due to calcium oxalate. Distal acidification

defects, abnormal ammonium transport, low urine pH, and hypocitraturia may be important in the pathogenesis of renal stones in ADPKD.

Renal cell carcinoma is a rare complication of ADPKD with no apparent increased frequency compared to the general population. However,

in ADPKD these tumors are more often bilateral at presentation,

multicentric, and sarcomatoid in type. Radiologic imaging is often not

helpful in distinguishing cyst infection and cyst hemorrhage because of

their complexity. CT scan and MRI are often useful in distinguishing

a malignancy from a complex cyst. Cardiovascular complications are

the major cause of mortality in patients with ADPKD. Hypertension is

common, and typically occurs before any reduction in glomerular filtration rate (GFR). Hypertension is a risk factor for both cardiovascular

and kidney disease progression in ADPKD. Notably, some normotensive patients with ADPKD may also have left ventricular hypertrophy.

Hypertension in ADPKD may result from the increased activation

of the renin-angiotensin-aldosterone system, increased sympathetic

nerve activity, and impaired endothelial cilium function-dependent

relaxation of small resistant blood vessels.

The progression of ADPKD has striking inter- and intrafamilial

variability. The disease can present as early as in utero, but end-stage

renal disease (ESRD) typically occurs in late middle age. Risk factors

include early diagnosis of ADPKD, hypertension, gross hematuria,

multiple pregnancies, and large kidney size. Liver cysts derived from

the biliary epithelia are the most common extrarenal complication.

Polycystic liver disease associated with ADPKD is different from autosomal dominant polycystic liver disease (ADPLD), which is caused

TABLE 315-1 Inherited Diseases Commonly Associated with a Cystic Phenotype

DISEASE

MODE OF

INHERITANCE RENAL ABNORMALITIES OTHER CLINICAL FEATURES GENES

Autosomal dominant polycystic

kidney disease

AD Bilaterally enlarged kidneys

with cortical and medullary

cysts

Liver, pancreatic cysts, hypertension,

subarachnoid hemorrhage

PKD1, PKD2

Autosomal dominant polycystic

kidney disease-like

AD Normal to smaller sized

kidneys with fewer cortical

and medullary cysts

Liver cysts at variable degree (from absent to

severe)

GANAB, DNAJB11

Autosomal recessive polycystic

kidney disease

AR Distal and collecting duct

cysts

Oligohydramnios if severe, hypertension,

ascending cholangitis, liver fibrosis

PKHD1

Autosomal dominant

tubulointerstitial kidney disease

AD Small fibrotic kidneys;

medullary cysts

In adults, gout UMOD, MUC1, REN, HNF1b,

SEC61A1

Renal cysts and diabetes

syndrome

AD Kidney cysts, aberrant

nephrogenesis, irregular

collecting systems, abnormal

renal calyces, hyperuricemic

nephropathy. Highly variable.

Diabetes HNF1B

Nephronophthisis AR Small fibrotic kidneys;

medullary cysts

Growth retardation, anemia

(In syndromic forms: visual loss, liver fibrosis,

cerebellar ataxia, other)

NPHP1-20, IQCB1, CEP290, GLIS2,

RPGRIP1L, NEK8, SDCCAG8,

TMEM67, TTC21B

Senior-Loken syndrome AR Renal cysts Juvenile nephronophthisis, Leber amaurosis NPHP1-6, SDCCAG8

Leber congenital amaurosis AR Renal cysts Visual impairment in first year of life;

pigmentary retinopathy

GUCY2D, RPE65, LCA3-14

Meckel-Gruber syndrome AR Cortical and medullary cysts CNS anomalies, polydactyly, congenital heart

defects

MKS1, TMEM216, TMEM67,

TMEM231, TMEM107, CEP290,

RPGRIP1L, CC2D2A, TCTN2, B9D1,

B9D2, NPHP3, KIF14

Bardet-Biedl syndrome AR Renal cysts Obesity, polydactyly, retinitis pigmentosa,

anosmia, congenital heart defects, mental

retardation

BBS1, 2, ARL6, BBS4,5, MKKS,

BBS7, TTC8, BBS9, 10, TRIM32,

BBS12, MKS1, CEP290, C2ORF86

Oral-facial-digital syndrome

type I

X-linked

dominant

Renal cysts Oral cavity, face, and digit anomalies; CNS

abnormalities; cystic kidney disease; X-linked

with male lethality, primary ciliary dyskinesia

OFD1

Tuberous sclerosis AD Renal cysts Angiomyolipomas; renal cell carcinoma

Facial angiofibromas; CNS hamartomas

TSC1, TSC2

Von Hippel-Lindau disease AD Renal cysts Renal cell carcinoma, retinal angiomas; CNS

hemangioblastomas; pheochromocytomas

VHL

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system.

2352 PART 9 Disorders of the Kidney and Urinary Tract

by mutations in at least two distinct genes (PRKCSH and SEC63) and

does not progress to renal failure. Massive polycystic liver disease

occurs almost exclusively in women with ADPKD, particularly those

with multiple pregnancies. Heterozygous loss-of-function variants

in PKHD1, ALG8, GANAB, and SEC61B are now found in ADPLD.

ALG8, GANAB, and SEC61B all encode ER proteins that are involved

in the same pathway as GIIβ and SEC63, and each appears to affect

PC1 biogenesis.

Intracranial aneurysm (ICA) occurs four to five times more frequently in APDKD patients than in the general population and

causes high mortality. The disease gene products PC1 and PC2 may

be directly responsible for defects in arterial smooth muscle cells and

myofibroblasts. The focal nature and the natural history of ICA in

ADPKD remain unclear. A family history of ICA is a risk factor of

aneurysm rupture in ADPKD; whether hypertension and cigarette

smoking are independent risk factors is not clear. About 20–50% of

patients may experience “warning headaches” preceding the index

episode of subarachnoid hemorrhage due to ruptured ICA. A CT scan

is generally used as the first diagnostic test. A lumbar puncture may

be used to confirm the diagnosis. The role of radiologic screening for

ICA in asymptomatic patients with ADPKD remains unclear. ADPKD

patients with a positive family history of ICAs may undergo presymptomatic screening of ICAs by MR angiography. Other vascular abnormalities in ADPKD patients include diffuse arterial dolichoectasias of

the anterior and posterior cerebral circulation, which can predispose to

arterial dissection and stroke. Mitral valve prolapse occurs in up to 30%

of patients with ADPKD, and tricuspid valve prolapse is less common.

Other valvular abnormalities occurring with increased frequency in

ADPKD patients include insufficiency of the mitral, aortic, and tricuspid valves. Most patients are asymptomatic but some may progress and

require valve replacement. The prevalence of colonic diverticulae and

abdominal wall hernias is also increased in ADPKD patients.

Diagnosis A diagnosis is typically made from a positive family

history consistent with autosomal dominant inheritance and multiple kidney cysts bilaterally. Renal ultrasonography is often used

for presymptomatic screening of at-risk subjects and for evaluation

of potential living-related kidney donors from ADPKD families. The

presence of at least two renal cysts (unilateral or bilateral) is sufficient

for diagnosis among at-risk subjects between 15 and 29 years of age

with a sensitivity value of 96% and specificity value of 100%. The presence of at least two cysts in each kidney and at least four cysts in each

kidney, respectively, is required for the diagnosis among at-risk subjects

aged 30–59 years and aged ≥60 years with a sensitivity value of 100%

and specificity value of 100%. This is because there is an increased

frequency of developing simple renal cysts with age. Conversely, in

subjects aged between 30 and 59 years the absence of at least two cysts

in each kidney, which is associated with a false negative rate of 0%, can

be used for disease exclusion. These criteria have a lower sensitivity for

patients with a PKD2 mutation because of a late onset of ADPKD2. CT

scan and T2-MRI, with and without contrast enhancement, are more

sensitive than ultrasonography and can detect cysts of smaller size.

However, a CT scan exposes the patient to radiation and radiocontrast, which may cause serious allergic reactions and nephrotoxicity

in patients with renal insufficiency. T2-MRI, with gadolinium as a

contrast agent, has minimal renal toxicity and can detect cysts of only

2–3 mm in diameter. However, a large majority of cysts may still be

below the detection level. Genetic testing by linkage analyses and mutational analyses is available for ambiguous cases. Because of the large

size of PKD1 gene and the presence of multiple highly homologous

pseudogenes, mutational analysis of PKD1 gene is difficult and costly.

Application of new technologies such as paired-end next-generation

sequencing with multiplexing individually bar-coded long-range PCR

libraries may reduce the costs and improve the sensitivity for clinical

genetic testing.

Ciliary Membrane

Transition

Zone

Basal Body

Nucleus DyneinKinesin-2

Motor

Nephronophthisis (NPHP)

Meckel

Bardet-Biedl (BBS)

Joubert

ARPKD (PKHD1)

ADPKD (PKD1/PKD2)

Extracellular signals

Polycystin-1 Polycystin-2

NPHP1 FPC BBSome Kif3A/B

Ca2+

Receptors

Ca2+

Wnt

Hh

Ca2+, Wnt, SHH, cAMP

and other signaling events

Defective

Planar cell polarity

Cell proliferation

During development

morphogenesis

Primary cilia

“9 + 0”

Post development

maintenance

Mild disease

Late slow onset

Severe disease

Early quick onset

FIGURE 315-1 Scheme of the primary cilium and cystic kidney disease proteins. Left: A scheme of the primary cilium. Primary cilia share a “9+0” organization of microtubule

doublets. Proteins are transported into the cilium by motor protein kinesin 2 and transported out of the cilium by dynein. The cilium is connected to the basal body through the

transition zone. Middle: Topology of ADPKD and ARPKD proteins polycystin 1, polycystin 2, and FPC is shown. Localizations of disease proteins in the cilium, the transition

zone, and the basal body are color coded. Right: Potential disease mechanisms due to cilium-mediated signaling events.

2353Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development CHAPTER 315

TREATMENT

Autosomal Dominant Polycystic Kidney Disease

No specific treatment to prevent cyst growth or the decline of renal

function has been approved by the U.S. Food and Drug Administration. Blood pressure control to a target of 140/90 mmHg is

recommended according to the guidelines from the eighth report

of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VIII report)

for reducing cardiovascular complications in ADPKD and renal

disease progression. More rigorous blood pressure control does not

equal greater clinical benefits. Maintaining a target systolic blood

pressure to 110 mmHg in patients with moderate or advanced disease may increase the risk of renal disease progression by reducing

renal blood flow. Lipid-soluble antibiotics against common gramnegative enteric organisms include trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol, and are preferred for cyst

infection because most renal cysts are not connected to glomerular filtration and antibiotics that are capable of penetrating the

cyst walls are likely to be more effective. Treatment often requires

4–6 weeks. The treatment of kidney stones in ADPKD includes

standard measures such as analgesics for pain relief, and hydration to ensure adequate urine flow. Management of chronic flank,

back, or abdominal pain due to renal enlargement may include

both pharmacologic (nonnarcotic and narcotic analgesics) and

nonpharmacologic (transcutaneous electrical nerve stimulation,

acupuncture, and biofeedback). Occasionally surgical decompression of cysts may be necessary. More than half of ADPKD patients

eventually require peritoneal dialysis, hemodialysis, or kidney

FIGURE 315-2 Photograph showing a kidney from a patient with autosomal

dominant polycystic kidney disease. The kidney has been cut open to expose the

parenchyma and internal aspects of cysts.

transplantation. Peritoneal dialysis may not be suitable for some

patients with massively enlarged polycystic kidneys due to the

small intraabdominal space for efficient peritoneal exchange of

fluid and solutes and increased chance of abdominal hernia and

back pain. Patients with very large polycystic kidneys and recurrent renal cyst infection may require pretransplant nephrectomy

or bilateral nephrectomy to accommodate the allograft and reduce

the pain.

Specific treatment strategies for ADPKD have focused on slowing renal disease progression and lowering cardiovascular risk. For

the latter, the main approach is to control blood pressure by inhibiting the renin-angiotensin-aldosterone system. The HALT PKD trial

was set to evaluate the impact of intensive blockade of the reninangiotensin-aldosterone system and levels of blood pressure control

on progressive renal disease. This trial found that rigorous blood

pressure control could slow cyst growth. Most approaches target

the slowing of renal disease progression by inhibiting cell proliferation and fluid secretion. Several clinical trials have been conducted

targeting cell proliferation: sirolimus and everolimus, inhibitors of

the mammalian target of rapamycin (mTOR) pathway; OPC31260

and tolvaptan, which inhibits cyclic adenosine monophosphate

(cAMP) pathways by antagonizing the activation of vasopressin V2

receptor (V2R) in collecting ducts and reduces cell proliferation

by decreasing renal cAMP levels; and somatostatin analogues,

which reduce cAMP levels by binding to several G-protein coupled receptors. The TAMPO and ALADIN trials showed that V2R

antagonists and somatostatin analogues (octreotide-LAR groups)

respectively slowed the decline of renal function. Some side effects,

such as liver function impairment, polydipsia, and diarrhea, have

been observed for tolvaptan and cholecystitis for octreotide-LAR. A

recent report also showed that tolvaptan reduces renal pain. DIPAK,

a small multicenter European study, showed that nerve block may

be used to relieve pain in ADPKD patients suffering with refractory

chronic pain. A combination of different growth inhibitors may

enhance efficacy and reduce side effects. Notably, treatments may

vary depending on the patient population. For example, the FDA

has indicated tolvaptan to be only for patients at risk of rapidly progressing disease. Combining genotypic and imaging information

may predict kidney growth rates and help in selecting this patient

population.

Additional preclinical studies in animal models include the use

of inhibitors to nonreceptor tyrosine kinase Src, B-raf, cyclinedependent kinase (CDK), transcription factors STAT3 and STAT6

(pyrimethamine and leflunomide), purinergic receptors, hepatocyte growth factor receptor, glucosylceramide, agonists to peroxisome proliferator-activated receptor-gamma (PPARγ) receptors

(thiazolidodinediones), and targeting microRNAs. Reprogramming the metabolic pathway through studies of transcription

regulator super enhancer as well as dietary control including

time-restricted feeding, have been shown in murine models

to reduce cyst area, kidney fibrosis, inflammation, and injury.

Branched chain amino acids appear to enhance cyst development

in a mouse model.

■ AUTOSOMAL RECESSIVE POLYCYSTIC

KIDNEY DISEASE

Genetic Considerations ARPKD is a significant hereditary

renal disease in childhood, with an estimated prevalence of 1 in

20,000 live births. A carrier frequency of up to 1:70 has been

reported. Mutations in a single gene, PKHD1, are responsible for all

the clinical presentations of ARPKD. PKHD1, localized on human

chromosome region 6p21.1–6p12.2, is one of the largest genes in the

genome, occupies ~450 kb of DNA, and contains at least 86 exons. It

produces multiple alternatively spliced transcripts. The largest transcript encodes fibrocystin/polyductin (FPC), which is a large receptorlike integral membrane protein of 4074 amino acids. FPC has a

2354 PART 9 Disorders of the Kidney and Urinary Tract

single transmembrane, a large N-terminal extracellular region, and a

short intracellular cytoplasmic domain. FPC is localized on the primary cilia of epithelia cells of cortical and medullary collecting ducts

and cholangiocytes of bile ducts, similar to polycystins and several

other ciliopathy proteins. FPC is also expressed on the basal body and

plasma membrane. The large extracellular domain of FPC is presumed to bind to an as yet unknown ligand(s) and is involved in cellcell and cell-matrix interactions. FPC interacts with ADPKD protein

PC2, and may also participate in regulation of the mechanosensory

function of the primary cilia, calcium signaling, and PCP, suggesting

a common mechanism underlying cystogenesis between ADPKD and

ARPKD. FPC is also found on the centrosomes and mitotic spindle,

and may regulate centrosome duplication and mitotic spindle assembly during cell division. A large number of various mutations have

been found throughout PKHD1, and are unique to individual families.

Most patients are compound heterozygotes for PKHD1 mutations.

Patients with two truncation mutations appear to have an earlier onset

of the disease.

Clinical Features Classic ARPKD is generally diagnosed in utero

or within the neonatal period, and characterized by greatly enlarged

echogenic kidneys in diseased fetuses. Reduced fetal urine production

may contribute to oligohydroaminos and pulmonary hypoplasia. About

30% of affected neonates die shortly after birth due to respiratory insufficiency. Close to 60% of mortality occurs within the first month of life.

In the classic group, most patients are born with renal insufficiency

and ESRD. However, infants often have a transient improvement in

their GFR; death from renal insufficiency at this stage is rare. Some

patients are diagnosed after the neonatal stage, which form the older

group. Morbidity and mortality in this group often involve systemic

hypertension, progressive renal insufficiency, and liver manifestations.

The hallmarks of ARPKD liver disease are biliary dysgenesis due to a

primary ductal plate malformation with associated periportal fibrosis,

namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic

bile ducts (Caroli disease). CHF and Caroli disease can then lead to

portal hypertension exhibiting hepatosplenomegaly, variceal bleeding,

and cholangitis. Some patients with the diagnosis of ARPKD at 1 year

of age with nephromegaly exhibit slowly declining renal function over

20 years with only minimally enlarged kidneys at ESRD, and markedly

atrophic kidneys following renal transplantation. The slow progression of renal disease is likely due to increasing fibrosis rather than the

development of cysts. Systemic hypertension is common in all ARPKD

patients, even those with normal renal function.

Diagnosis Ultrasonography, CT, and MRI all can be used for diagnosis. Ultrasonography reveals large, echogenic kidneys with poor

corticomedullary differentiation. The diagnosis can be made in utero

after 24 weeks of gestation in severe cases. Macrocysts generally are

not common at birth in ARPKD patients. The absence of renal cysts in

either parent, particularly if they are >40 years of age, on ultrasonography helps distinguish ARPKD from ADPKD in older patients. Clinical,

laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathology demonstrating characteristic ductal plate abnormalities, family

history of affected siblings, or parental consanguinity suggestive of

autosomal recessive inheritance is helpful. The lack of mutational hot

spots and the large and complex genomic structure of PKHD1 make

molecular diagnosis difficult; however, presymptomatic screen of other

at-risk members in a family with already identified ARPKD mutations

is straightforward and inexpensive.

TREATMENT

Autosomal Recessive Polycystic Kidney Disease

There is no specific therapy for ARPKD. Appropriate neonatal intensive care, blood pressure control, dialysis, and kidney

transplantation increase survival into adulthood. Complications of

hepatic fibrosis may necessitate liver transplantation. Patients with

severe Caroli disease may need portosystemic shunting. Upcoming

therapies may target abnormal cell signaling mechanisms, as

described above for ADPKD.

OTHER DISEASES CHARACTERIZED BY

LARGE KIDNEY CYSTS

■ TUBEROUS SCLEROSIS

Tuberous sclerosis (TS) is a rare autosomal dominant syndrome caused

by mutations in one of two genes, TSC1, encoding hamartin, or, TSC2,

encoding tuberin. Published estimates of prevalence vary widely, but it

certainly occurs in <1:5000 births. Kidney cysts are a frequent feature

of this condition, as are two other abnormalities of kidney growth,

renal cell carcinoma and renal angiomyolipomas. TS is a syndrome

affecting multiple organ systems. Other features of TS include benign

growths in the nervous system, eyes, heart, lung, liver, and the skin.

Essentially all TS patients have such skin lesions, and a large proportion

of patients have neurologic and cognitive manifestations. The TSC2

gene is adjacent to PKD1 in the human genome. Some patients have

deletions in their genomic DNA that inactivate these two genes. Such

individuals may have manifestations of both ADPKD and TS. The

majority of TS-causing mutations are found in TSC2.

Renal cysts are observed in about 20–30% of people with TS. The

most common kidney finding in TS is the presence of angiomyolipomas. These growths tend to be multiple and bilateral. While they

are usually benign, they may bleed. Surgical removal is often recommended as a prophylactic measure in people with angiomyolipomas

>4 cm in diameter. The cysts in TS are radiographically similar to those

seen in ADPKD. In contrast to ADPKD, there is a clearly increased

risk of renal cell carcinoma in TS patients. Regular periodic imaging is

recommended in TS patients with kidney involvement to screen for the

development of renal cell carcinoma. These cysts may rarely become

large and hemorrhagic, occasionally requiring nephrectomy when

nephron-sparing surgery is not possible.

Although a rare problem, TS may lead to significant chronic kidney

disease (CKD) and progress to end-stage kidney failure. Patients with

TS and CKD typically have an unremarkable urine sediment and only

minimal to mild amounts of proteinuria.

Mechanistically, the TSC1 and TSC2 gene products tuberin and

hamartin interact physically. This protein complex is localized to the

base of the cilia and inhibits intracellular signaling processes mediated

by mTOR (mammalian target of rapamycin), leading to abnormal

growth in a number of tissues. Everolimus, an mTOR inhibitor, has

been approved in the United States for treatment of TSC-associated

kidney tumors as well as nonkidney manifestations of TS. Regular

surveillance is perhaps the most important component of the clinical

management of the kidney manifestations of TS.

■ VON HIPPEL-LINDAU DISEASE

Von Hippel-Lindau disease (VHL) is an inherited cancer syndrome

with renal manifestations. VHL is an autosomal dominant condition

caused by mutations in the VHL tumor-suppressor gene. The VHL

protein plays a critical role in the regulation of hypoxia pathways and

oxygen sensing via the transcription factor hypoxia-inducible factor

(HIF). Like many other autosomal dominant cancer syndromes, VHL

is recessive at the cellular level: a somatic mutation in the second VHL

allele leads to loss of VHL in the cell and abnormal growth. Kidney

manifestations of VHL include multiple bilateral kidney cysts and

renal cell carcinomas. Kidney cysts and carcinoma affect the majority

of VHL patients. Nonrenal features of VHL include pheochromocytomas, cerebellar hemangioblastomas, and retinal hemangiomas. While

much rarer than ADPKD, VHL is an entity that should be considered

in the differential diagnosis of an individual with newly recognized

kidney cysts.

In these patients, annual screening of the kidneys by imaging with

CT or MRI scanning is recommended for early detection of renal cell

carcinomas. Increasingly, nephron-sparing surgical approaches are

being used for removal of cancerous lesions in order to preserve kidney

function.

2355Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development CHAPTER 315

OTHER INHERITED DISEASES OF TUBULE

GROWTH AND DEVELOPMENT

ADPKD is by far the most common adult-onset single-gene form of

adult-onset kidney disease. The large cysts that are sometimes seen in

VHL and TS are similar in appearance to the cysts seen in ADPKD. A

variety of other inherited disorders affecting primarily tubule and renal

interstitial function can lead to CKD and eventual end-stage kidney

disease in the absence of large tubule-derived cysts.

Inherited diseases affecting the tubulointerstitial compartment of

the kidney can lead to secondary glomerular stress and glomerulosclerosis with some degree of concomitant proteinuria. Similarly, disorders

of glomerular function will typically lead to secondary interstitial

fibrosis and tubule atrophy. From a clinical perspective, therefore, distinguishing between a genetic disease of the renal tubules and a disease

of the glomerulus may not be easy, particularly in the absence of a gross

phenotype such as large kidney cysts.

■ AUTOSOMAL DOMINANT TUBULOINTERSTITIAL

KIDNEY DISEASE (MEDULLARY CYSTIC KIDNEY

DISEASE)

The term autosomal dominant tubulointerstitial kidney disease

(ADTKD) has replaced the phrase medullary cystic kidney disease

(MCKD) as the preferred designation for a group of autosomal dominant disorders characterized by progressive kidney failure and a benign

urine sediment. Despite the old nosology, kidney cysts are not invariably present. Older literature often grouped MCKD together with the

childhood-onset disorders known as the nephronophthises, but these

are distinct clinical and genetic entities.

ADTKD-MUC1 Patients with medullary cystic kidney disease

type I (MCKD I) have mutations in the mucin 1 gene MUC1. In contrast to MCKD II patients, individuals with MCKD I do not have elevated uric acid levels. The disease-causing MUC1 mutations that have

been reported all alter a highly repetitive region within the MUC1 gene.

This leads to the production of a large “neoprotein” fragment that has

toxic effects on the kidney tubule.

Clinically, patients with MCKD I exhibit slowly progressive CKD in

adulthood, with only minimal amounts of increased urine protein and

occasional renal cysts seen on ultrasound examination. Kidney histology shows tubulointerstitial fibrosis and tubular atrophy. Disease does

not recur in transplanted kidneys.

ADTKD-UMOD ADTKD-UMOD (also called MCKD II) is

caused by mutations in the UMOD gene, which encodes the protein

uromodulin, also known as Tamm-Horsfall protein. Uromodulin is

also found on the centrosome, the mitotic spindle, and the primary

cilia; it colocalizes with nephrocystin-1 and KIF3A on the cilia. UMOD

mutations also cause the conditions that have been referred to as familial juvenile hyperuricemic nephropathy (HNFJ1) and glomerulocystic

kidney disease (GCKD), although it is not clear that these different

names represent clearly distinct disorders. The term uromodulinassociated kidney disease (or UAKD) has been suggested as a better

name for MCKD II and the various other related UMOD-associated

diseases. Despite the name, kidney cysts are not a common feature of

MCKD II. MCKD II should be suspected clinically in patients with a

family history of late-onset kidney disease, benign urine sediments,

absence of significant proteinuria, and hyperuricemia. Large genomewide association studies have suggested that certain common noncoding sequence variants in UMOD are associated with a moderately

increased risk of CKD in the general population. UMOD-associated

disease is often associated with gout.

Other Forms of Familial Tubulointerstitial Kidney Disease A

small number of families have been identified with autosomal dominant tubulointerstitial kidney disease and hyperuricemia who lack

UMOD mutations. Some of these families carry disease-segregating

mutations in the renin gene REN (disease designation ADTKD-REN).

ADKTKD-REN patients demonstrate hyporeninemia with mild hyperkalemia, and often have hyperuricemia and gout. Mutations in HNF1β

and SEC61A1 are even rarer causes of ADTKD.

Kidney biopsies in patients with any of the various forms of ADTKD

typically show interstitial fibrosis. These histologic features are not

diagnostic of any particular genetic entity, and the specific diagnosis

must be made by other means. Genetic tests for alterations in specific

genes and in large panels of kidney disease genes are available in the

clinical setting. High cost and complexity in interpretation are the

major barriers to the use of such testing.

Those patients with autosomal dominant interstitial kidney disease,

UMOD or REN mutations, with hyperuricemia and gout should be

treated similarly to others with these findings, with uric-acid lowering

agents, such as allopurinol or febuxostat.

NEPHRONOPHTHISIS

A large and growing number of genetically distinct but related sets

of autosomal recessive disorders are referred to as nephronophthises,

or nephronophthisis-related ciliopathies. These entities should not be

confused with the adult-onset autosomal dominant MCKD discussed

above, despite the often confusing nomenclature seen in older medical

literature. Each of the individual forms of nephronophthisis is quite

rare, but together this category constitutes the most common inherited

childhood form of kidney failure requiring kidney replacement therapy.

Like ADPKD and ARPKD, the various genetically heterogeneous

entities that fall under the category of nephronophthisis (NPHP) are

disorders of ciliary function. Mutations in >90 genes have been identified that lead to NPHP under an autosomal recessive pattern of inheritance. Some of these gene defects cause limited kidney disease, while

many cause ciliopathies characterized by multiple organ involvement.

The various forms of NPHP share common features, including tubulointerstitial fibrosis, corticomedullary cysts, and progressive CKD,

leading to renal failure. Proteinuria is absent or mild, and the urine

sediment is not active.

NPHP is often divided into infantile, juvenile, and adolescent forms.

The juvenile form is the most frequent, and usually caused by mutations

in the NPHP2 gene. The infantile form, usually caused by NPHP2 mutations, is associated with end-stage kidney failure in early childhood.

Patients with the adolescent form of NPHP typically develop end-stage

kidney failure in early adulthood. Hypertension, if present, tends to be

a late finding in the course of the NPHPs. The products of the NPHP

genes are referred to as nephrocystins. NPHP1 through NPHP20 have

been reported; some are referred to by other names, as well.

NPHP can present as an isolated finding, or be part of several multiorgan syndromes. Neurologic abnormalities are present in a significant

number of patients. Bone and liver abnormalities are seen in some

NPHP patients. Senior-Loken syndrome is defined by the presence of

NPHP with retinitis pigmentosa. Joubert syndrome is defined by multiple neurologic findings, including hypoplasia of the cerebellar vermis.

Some forms of this genetically heterogeneous syndrome include NPHP

as a component.

The multisystem disease Bardet-Biedl syndrome (BBS) is defined

clinically by a spectrum of features, including truncal obesity, cognitive

impairment, retinal dystrophy, polydactyly, developmental urogenital

abnormalities, and kidney cysts. The kidney phenotype is NPHP-like,

with small cysts deriving from the tubules, tubulointerstitial and often

secondary glomerular disease, and urine concentrating defects. To

date, 21 BBS genes have been identified. BBS follows autosomal recessive inheritance. Like ADPKD, ARPKD, and NPHP, BBS is a disease of

abnormal ciliary function.

The multiple genes and gene products (nephrocystins) that are

responsible for NPHP are expressed in cilia, basal bodies, and the centrosomes of kidney tubules cells. It has been hypothesized that all of

the NPHP gene defects lead to a clinical phenotype by interfering with

the regulation of PCP.

There are no specific clinical tests that define NPHP. Genetic diagnosis is possible, complicated because of the large number of genes that

can be responsible, but now quite feasible due to new DNA sequencing

technologies. There are no specific therapies for NPHP. Rather, therapy

is aimed at treating signs of these diseases as well as those systemic

abnormalities seen with all CKDs. Chronic dialysis or kidney transplantation are eventually required for NPHP-affected individuals.

2356 PART 9 Disorders of the Kidney and Urinary Tract

KARYOMEGALIC TUBULOINTERSTITIAL

NEPHRITIS

Karyomegalic tubulointerstitial nephritis is an exceptionally rare form

of kidney disease with adult-onset progressive kidney failure. Kidney

biopsy shows chronic tubulointerstitial nephritis, as well as interstitial fibrosis. This is a recessive disorder caused by inheritance of two

mutant copies of the FAN1 gene. FAN1 encodes a component of a

DNA repair machinery complex. Individuals with two mutant FAN1

genes are genetically sensitized to the effect of DNA damage. Kidney

histology shows karyomegaly in addition to the nonspecific findings of

interstitial fibrosis and tubular atrophy.

MEDULLARY SPONGE KIDNEY

Medullary sponge kidney (MSK) is often grouped together with inherited disorders of the kidney affecting tubule growth and development,

although it is usually a sporadic finding rather than an inherited

phenotype. MSK is caused by developmental malformation and cystic

dilatation of the renal collecting ducts. The medullary cysts seen in this

entity can be quite variable in size.

MSK is usually a benign entity. The diagnosis of MSK is often made

incidentally. In the past, the diagnosis of MSK was often made by intravenous pyelography (IVP). CT urography, which has replaced IVPs for

much routine kidney imaging, is not as sensitive in detecting MSK.

MSK is associated with an increased frequency of calcium phosphate and calcium oxalate kidney stones. Altered flow characteristics

in the kidney tubules may lead to the development of formation of a

nidus for stone formation. Kidney stones in this group are treated the

same as are kidney stones in the general population. MSK patients also

often exhibit reduced kidney concentrating ability and an increased

frequency of urinary tract infections.

CONGENITAL ABNORMALITIES OF THE

KIDNEY AND URINARY TRACT

The structural abnormalities known as CAKUT (Congenital Abnormalities of the Kidney and Urinary Tract) are a group of etiologically

and phenotypically heterogeneous disorders. Some form of CAKUT is

estimated to occur in up to 1 in 500 live births. Specific abnormalities

classified as part of the CAKUT spectrum include kidney hypoplasia,

kidney agenesis, ureteropelvic junction obstruction, and vesicoureteral

reflux.

CAKUT can be the cause of clinically significant problems in both

adults and children. However, it is a major contributor to kidney failure

in children, accounting for more than one-third of end-stage kidney

disease in this group.

CAKUT is typically a sporadic finding but can also cluster in families. Familial forms can be observed as parts of multisystem developmental syndromes. A growing list of specific genes have been identified

that when mutated lead to both nonsyndromic and syndromic forms

of CAKUT. For example, the branchio-oto-renal syndrome, characterized by developmental abnormalities in the neck, ears, and kidney,

can be caused by mutations in the EYA1 and SIX1 genes. Mutations in

the PAX2 transcription factor gene can cause the autosomal dominant

renal coloboma syndrome, characterized by optic nerve malformations and hypoplastic kidneys. A nontrivial fraction of children with

CKD have an unsuspected genomic imbalance, often disrupting genes

known to be relevant to CAKUT and kidney development. It is not

uncommon for such genetic lesions to affect both kidney and neurocognitive function.

In many instances, CAKUT is caused by environmental influences

rather than genetic alterations. For example, renal tubular dysgenesis,

defined by altered tubule development, can be caused by prenatal

exposure of angiotensin-converting enzyme inhibitors or angiotensin

receptor blockers.

MITOCHONDRIAL DISEASE

Inherited disorders of the mitochondrial genome (discussed elsewhere in this text [see also Chap. 468]) commonly affect kidney

function. Thirteen of the genes involved in encoding components of

the mitochondrial respiratory chain are located on the mitochondrial

genome that is inherited maternally. The remainder of these components are encoded by the nuclear genome. These defects of oxidative

phosphorylation may affect multiple organs and tissues.

Neuromuscular disease is the best recognized part of this complex

phenotype. Kidney disease is now recognized as a common component, as well. Tubulointerstitial disease may be seen on kidney biopsy,

and progression to kidney failure may occur. Glomerular involvement,

manifest as proteinuria and glomerulosclerosis, can also develop.

Changes in proximal tubule activity are the most common renal phenotype. Patients may have several defects in proximal tubule transport,

including the Fanconi syndrome. Some patients may also have acidosis,

hypophosphatemic rickets, hypercalciuria, glycosuria, and tubular proteinuria. Decreased urine concentrating ability is common.

DIAGNOSTIC CONSIDERTIONS

Recent studies using new DNA sequencing technologies suggest that

variants in Mendelian kidney disease genes contribute to a nontrivial

fraction of CKD cases, even when a clear Mendelian disease phenotype

or family history of disease is lacking. Many studies also lead to the

conclusion that various rare genetically mediated kidney diseases are

difficult to categorize by phenotype alone. These diseases may mimic

each other, an argument for using fairly large panels (or the entire

genome) in genetic testing in the setting of kidney disease. The old and

complicated nomenclature used to describe human kidney diseases

is expected to continue to be replaced by newer, genetically defined,

categories.

■ GLOBAL CONSIDERATIONS

The disorders discussed above are all seen worldwide. In addition, a

previously unrecognized epidemic of kidney disease is leading to very

high rates of kidney failure in and near the western coast of Central

America. This mesoamerican nephropathy is particularly common

in Nicaragua and El Salvador. Mesoamerican nephropathy patients

do not have significant proteinuria, suggesting that this is a disease of

the kidney tubules and interstitium. The cause is unknown, but some

have suggested that a combination of toxic environmental factors and

heat stress underlie the development of this kidney disease, which has

a striking male predominance. However, the fact that in many families,

a large fraction of the men have kidney disease has suggested that a

strong genetic component is involved as well.

■ FURTHER READING

Arts HH, Knoers NV: Current insights into renal ciliopathies: What

can genetics teach us? Pediatr Nephrol 28:863, 2013.

Cornec-Le Gall E et al: Autosomal dominant polycystic kidney disease. Lancet 393:919, 2019.

Devuyst O et al: Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers 5:60, 2019.

Grantham JJ et al: Detected renal cysts are tips of the iceberg in adults

with ADPKD. Clin J Am Soc Nephrol 7:1087, 2012.

Hays T et al: Genetic testing for kidney disease of unknown etiology.

Kidney Int 98:590, 2020.

Lam HC et al: Renal disease in tuberous sclerosis complex: Pathogenesis

and therapy. Nat Rev Nephrol 14:704, 2018.

LaRiviere WB et al: Novel therapeutic approaches to autosomal dominant polycystic kidney disease. Transl Res 165:488, 2015.

Ong AC, Harris PC: A polycystin-centric view of cyst formation and

disease: The polycystins revisited. Kidney Int 88:699, 2015.

Porath B et al: Mutations in GANAB, encoding the glucosidase IIalpha

subunit, cause autosomal-dominant polycystic kidney and liver disease.

Am J Hum Genet 98:1193, 2016.

Reddy BV, Chapman AB: The spectrum of autosomal dominant polycystic kidney disease in children and adolescents. Pediatr Nephrol

32:31, 2017.

Vivante A, Hildebrandt F: Exploring the genetic basis of early-onset

chronic kidney disease. Nat Rev Nephrol 12:133, 2016.

Zhou J: Polycystins and primary cilia: primers for cell cycle progression. Ann Rev Physiol 71:83, 2009.

2357Tubulointerstitial Diseases of the Kidney CHAPTER 316

Inflammation or fibrosis of the renal interstitium and atrophy of the

tubular compartment are common consequences of diseases that target

the glomeruli or vasculature. Distinct from these secondary phenomena, however, are a group of disorders that primarily affect the tubules

and interstitium, with relative sparing of the glomeruli and renal vessels. Such disorders are conveniently divided into acute and chronic

tubulointerstitial nephritis (TIN) (Table 316-1).

Acute TIN most often presents with acute kidney injury

(Chap. 310). The acute nature of this group of disorders may be caused

by aggressive inflammatory infiltrates that lead to tissue edema, tubular

cell injury, and compromised tubular flow, or by frank obstruction of

the tubules with casts, cellular debris, or crystals. There is sometimes

flank pain due to distention of the renal capsule. Urinary sediment is

often active with leukocytes and cellular casts but depends on the exact

nature of the disorder in question.

The clinical features of chronic TIN are more indolent and may

manifest with disorders of tubular function, including polyuria from

impaired concentrating ability (nephrogenic diabetes insipidus), defective proximal tubular reabsorption leading to features of Fanconi’s

syndrome (glycosuria, phosphaturia, aminoaciduria, hypokalemia, and

type II renal tubular acidosis [RTA] from bicarbonaturia), or nonanion-gap metabolic acidosis and hyperkalemia (type IV RTA) due

to impaired ammoniagenesis, as well as progressive azotemia (rising

creatinine and blood urea nitrogen [BUN]). There is often modest proteinuria (rarely >2 g/d) attributable to decreased tubular reabsorption of

filtered proteins; however, nephrotic-range albuminuria may occur in

some conditions due to the development of secondary focal segmental

glomerulosclerosis (FSGS). Renal ultrasonography may reveal changes

of “medical renal disease,” such as increased echogenicity of the renal

parenchyma with loss of corticomedullary differentiation, prominence

of the renal pyramids, and cortical scarring in some conditions. The

predominant pathology in chronic TIN is interstitial fibrosis with patchy

mononuclear cell infiltration and widespread tubular atrophy, luminal

dilation, and thickening of tubular basement membranes. Because of the

nonspecific nature of the histopathology, biopsy specimens rarely provide a specific diagnosis. Thus, diagnosis relies on careful analysis of history, drug or toxin exposure, associated symptoms, and imaging studies.

ACUTE INTERSTITIAL NEPHRITIS

In 1897, Councilman reported on eight cases of acute interstitial

nephritis (AIN) in the Medical and Surgical Reports of the Boston City

Hospital—three as a postinfectious complication of scarlet fever and

two from diphtheria. Later, he described the lesion as “an acute inflammation of the kidney characterized by cellular and fluid exudation in

the interstitial tissue, accompanied by, but not dependent on, degeneration of the epithelium; the exudation is not purulent in character, and

the lesions may be both diffuse and focal.” Today AIN is far more often

encountered as an allergic reaction to a drug (Table 316-1). Immunemediated AIN may also occur as part of a known autoimmune syndrome, but in some cases, there is no identifiable cause despite features

suggestive of an immunologic etiology (Table 316-1).

■ ALLERGIC INTERSTITIAL NEPHRITIS

Although biopsy-proven AIN accounts for no more than ~15% of cases

of unexplained acute kidney injury, this is likely a substantial underestimate of the true incidence. This is because potentially offending

medications are more often identified and empirically discontinued in

a patient noted to have a rising serum creatinine, without the benefit of

a kidney biopsy to establish the diagnosis of AIN.

Clinical Features The classic presentation of AIN, namely, fever,

rash, peripheral eosinophilia, and oliguric kidney injury occurring

316 Tubulointerstitial

Diseases of the Kidney

Laurence H. Beck Jr., David J. Salant

TABLE 316-1 Classification of the Causes of Tubulointerstitial

Diseases of the Kidney

Acute Tubulointerstitial Disorders

Acute Interstitial Nephritis

Therapeutic agents

• Antibiotics (β-lactams, sulfonamides, quinolones, vancomycin, erythromycin,

linezolid, minocycline, rifampin, ethambutol, acyclovir)

• Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors

• Diuretics (rarely thiazides, loop diuretics, triamterene)

• Anticonvulsants (phenytoin, valproate, carbamazepine, phenobarbital)

• Miscellaneous (proton pump inhibitors, H2

 blockers, captopril, mesalazine,

indinavir, allopurinol, lenalidomide)

Infection

• Bacteria (Streptococcus, Staphylococcus, Legionella, Salmonella, Brucella,

Yersinia, Corynebacterium diphtheriae)

• Viruses (EBV, CMV, hantavirus, polyomavirus, HIV)

• Miscellaneous (Leptospira, Rickettsia, Mycoplasma, Histoplasma)

Autoimmune

• Tubulointerstitial nephritis with uveitis (TINU)

• Sjögren’s syndrome

• Systemic lupus erythematosus

• Granulomatous interstitial nephritis

• IgG4-related systemic disease

• Tubulointerstitial disease related to checkpoint inhibitors

• Anti-brush border disease (anti-LRP2 nephropathy)

• Idiopathic autoimmune interstitial nephritis

Acute Obstructive Disorders

• Light chain cast nephropathy (“myeloma kidney”)

• Acute phosphate nephropathy

• Acute urate nephropathy

Chronic Tubulointerstitial Disorders

• Vesicoureteral reflux/reflux nephropathy

• Sickle cell disease

• Chronic exposure to toxins or therapeutic agents

• Analgesics, especially those containing phenacetin

• Lithium

• Heavy metals (lead, cadmium)

• Aristolochic acid (Chinese herbal and Balkan endemic nephropathies)

• Calcineurin inhibitors (cyclosporine, tacrolimus)

• Chronic interstitial nephritis in agricultural communities

Metabolic Disturbances

• Hypercalcemia and/or nephrocalcinosis

• Hyperuricemia

• Prolonged hypokalemia

• Hyperoxaluria

• Cystinosis (see Chap. 315)

Cystic and Hereditary Disorders (see Chap. 315)

• Polycystic kidney disease

• Nephronophthisis

• Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney

disease)

• Medullary sponge kidney

Miscellaneous

• Aging

• Chronic glomerulonephritis

• Chronic urinary tract obstruction

• Ischemia and vascular disease

• Radiation nephritis (rare)

Abbreviations: CMV, cytomegalovirus; COX, cyclooxygenase; EBV, Epstein-Barr virus.