Case

A 44-year-old gentleman with a history of autosomal dominant polycystic kidney disease,

hypertension, atrial fibrillation who was being followed by the nephrology service. Patient was
diagnosed with ADPKD at the age of 27 when he had an episode of flank pain prompting
computed tomography scan of the abdomen/ pelvis which revealed multiple bilateral renal cysts.
Family history of ADPKD including 3 brothers and one daughter, CKD Stage 3a-b, creatinine
stable 1.3 - 2.3 mg/dL for nearly 16 years. However, over the course of the next few months the
patient developed progressive shortness of breath, poor appetite, and ruptured cysts. Computed
tomography scan abdomen/pelvis revealed multiple renal cysts, largest 14 × 11 × 10 cm
displacing the abdominal viscera. Serum creatinine increased to 4.3 mg/dL.

On exam, his blood pressure was 141/81 mmHg and abdominal exam revealed
moderately distended and diffusely tender abdomen, while bowel sounds was loud. No organs or
masses could be identified by palpation. Given progression of his symptoms and worsening renal
function, the patient had an open left nephrectomy with the specimen weighing 20 pounds (9 kg).
Patient tolerated surgery well and was discharged home with a serum creatinine 5.3 mg/ dL
without need for dialysis. The patient’s creatinine continued to rise slowly each month for the next
six months thereafter, however the patient was asymptomatic and did not require any further
hospitalizations during this time.

I. Etiology

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of a group of
congenital diseases in which the renal parenchyma contains many cysts. It affects 1:400–1:1000 people in
the United States, 1/2 of whom eventually develop end-stage renal failure. ADPKD is responsible for 5%
of end-stage renal disease (ESRD) requiring dialysis or transplantation. Only diabetes and hypertension
cause more ESRD than does ADPKD.

Mutations in PKD1 and PKD2 has been described, and this allelic heterogeneity has complicated
genetic diagnosis of this disorder. The PKD1 gene is located on chromosome 16p13.3. It encodes a large
(460-kD) integral membrane protein named polycystin-1, which has a large extracellular region, multiple
transmembrane domains, and a short cytoplasmic tail. Polycystin-1 is expressed in tubular epithelial cells,
particularly those of the distal nephron. At present its precise function is not known, but it contains domains
that are usually involved in cell-cell and cell-matrix interactions. Mutations in PKD1 account for about 85%
of cases. In individuals with these mutations, the likelihood of developing renal failure is less than 5% by
40 years of age, rising to more than 35% by 50 years, more than 70% at 60 years of age, and more than
95% by 70 years of age.

The PKD2 gene, located on chromosome 4q21, accounts for most of the remaining cases of
polycystic disease. Its product, polycystin-2, is an integral membrane protein that is expressed in all
segments of the renal tubules and in many extrarenal tissues. Polycystin-2 functions as a Ca2+-permeable
cation channel. Overall, the disease is less severe than that associated with PKD1 mutations. Renal failure
occurs in less than 5% of patients with PKD2 mutations at 50 years of age, but this rises to 15% at 60 years
of age, and 45% at 70 years of age.
II. Pathogenesis

Some 85% of ADPKD is caused by mutations in polycystic kidney disease 1 gene (PKD1) and
15% by mutations in PKD2. The products of these genes, polycystin-1 and polycystin-2, are in the primary
cilia of tubular epithelial cells and in cell–cell adhesion complexes. These structures sense the extracellular
environment including urine flow, resulting in regulation of intracellular calcium and of tubule epithelial
proliferation, cell polarity and apoptosis. Defects in these proteins result in dysfunction of primary cilia
(ciliopathy) that disrupt calcium signaling, cause disturbed cell polarity and induce tubular epithelial cell
proliferation.

Although the precise pathogenesis of ADPKD remains unclear, it is held that cysts arise in
segments of renal tubules from a few cells that proliferate abnormally. The tubule wall becomes covered
by undifferentiated cells with large nuclei and only few microvilli. Concomitantly, a defective basement
membrane just below the abnormal epithelium allows the affected tubule to dilate. Cyst fluid is initially
derived from the glomerular filtrate, but eventually most cysts lose connection with the tubules, in which
case fluid accumulates by transepithelial secretion. The cysts in ADPKD originate in fewer than 2% of
nephrons. Thus, factors other than crowding of normal tissue by expanding cysts likely impair functional
renal tissue. Apoptotic loss of renal tubules and accumulation of inflammatory mediators have been
incriminated in the destruction of normal renal mass.

III. Morphologic Changes

Microscopic examination reveals functioning nephrons dispersed between the cysts. The cysts may
be filled with a clear, serous fluid or with turbid, red to brown, sometimes hemorrhagic fluid. As these cysts
enlarge, they may encroach on the calyces and pelvis to produce pressure defects. The cysts arise from the
tubules throughout the nephron and therefore have variable lining epithelia. On occasion, papillary
epithelial formations and polyps project into the lumen. Bowman capsules are occasionally involved in cyst
formation, and glomerular tufts may be seen within the cystic space.

Distinctive feature in the kidneys is a glomerular cyst in which a glomerulus is involved with the cystic
change
IV. Clinical Manifestations/Functional Derangements

Cyst development and growth. The renal manifestations of ADPKD include renal function
abnormalities, hypertension, renal pain, and renal insufficiency. These manifestations are directly related
to the development and enlargement of renal cysts.

Renal function abnormalities. Reduction in urinary concentrating capacity and excretion of

ammonia occur early in individuals with ADPKD. The reduction of urinary excretion of ammonia in the
presence of metabolic stresses (e.g., dietary indiscretions) may contribute to the development of uric acid
and calcium oxalate stones, which, in association with low urine pH values and hypocitric aciduria, occur
with increased frequency in individuals with ADPKD. A decline in renal function, detected as a rise in
serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before
ESRD. However, once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-
6 mL/min/yr) The severity of the kidney disease may influence the timing and rate of decline. Hypertension
usually develops before any decline in GFR.

Renal pain. Pain is a common manifestation of ADPKD. Potential etiologies include: cyst
hemorrhage, nephrolithiasis, cyst infection, and, rarely, tumor. Discomfort, ranging from a sensation of
fullness to severe pain, can also result from renal enlargement and distortion by cysts. Gross hematuria can
occur in association with complications such as cyst hemorrhage and nephrolithiasis or as an isolated event.
Passage of clots can also be a source of pain. Cyst hemorrhage can be accompanied by fever, possibly
caused by cyst infection. Most often, the pain is self-limited and resolves within two to seven days. Rarely,
pain may be caused by retroperitoneal bleeding that may be severe and require transfusion.

Nephrolithiasis. The prevalence of renal stone disease in individuals with ADPKD is approximately
20%. The majority of stones are composed of uric acid and/or calcium oxalate. Urinary stasis thought to be
secondary to distorted renal anatomy and metabolic factors plays a role in the pathogenesis. Postulated
factors predisposing to the development of renal stone disease in ADPKD include: decreased ammonia
excretion, low urinary pH, and low urinary citrate concentration. However, these factors occur with the
same frequency in individuals with ADPKD with and without a history of nephrolithiasis.

Urinary tract infection and cyst infection. In the past, the incidence of urinary tract infection may
have been overestimated in individuals with ADPKD because of the frequent occurrence of sterile pyuria.
As in the general population, females experience urinary tract infections more frequently than males; the
majority of infections are caused by E coli and other Enterobacteriaceae. Retrograde infection from the
bladder may lead to pyelonephritis or cyst infection. Renal cyst infections account for approximately 9%
of hospitalizations in individuals with ADPKD.

Renal cell carcinoma (RCC) does not occur more frequently in individuals with ADPKD than in
the general population. However, when RCC develops in individuals with ADPKD, it has a different
biologic behavior, including: earlier age of presentation; frequent constitutional symptoms; and a higher
proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. Males and females with ADPKD
are equally likely to develop RCC. A solid mass on ultrasound; speckled calcifications on CT examination;
and contrast enhancement, tumor thrombus, and regional lymphadenopathies on CT or MRI examination
should raise suspicion for a carcinoma.

Most patients with ADPKD do not manifest clinically until the fourth decade of life, which is why
this condition was once called adult polycystic kidney disease. A small minority of patients develop
symptoms during childhood, and rarely are they symptomatic at birth. Symptoms include a sense of
heaviness in the loins, bilateral flank and abdominal pain, and abdominal masses. Hypertension is one of
the earliest and most common manifestations. Eventually, hematuria, low-level proteinuria and progressive
renal insufficiency develop.

The kidneys in ADPKD both are markedly enlarged and weigh up to 4500 g. The external contours
are distorted by numerous cysts, as large as 5 cm, filled with a straw-colored fluid. These cysts are lined by
cuboidal and columnar epithelium. Cysts arise from any point along the nephron, including glomeruli,
proximal tubules, distal tubules and collecting ducts. Areas of normal renal parenchyma between the cysts
undergo progressive atrophy and fibrosis as the disease advances with age.

Of patients with ADPKD, 1/3 also have hepatic cysts, whose lining resembles bile duct epithelium.
Cysts occur in the spleen (10% of patients) and pancreas (5%) as well. Cerebral aneurysms occur in 1/5 of
patients, and intracranial hemorrhage is the cause of death in 15% of patients with ADPKD. Interestingly,
many patients with ADPKD also develop colonic diverticula.

Liver cysts are usually asymptomatic and never cause liver failure. Symptoms, when they occur,
are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass
effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can
also cause extrinsic compression of the inferior vena cava (IVC), hepatic veins, or bile ducts.

About 40% have one to several cysts in the liver (polycystic liver disease) that are usually asymptomatic.
 Cysts in other organs include: 1) Seminal vesicle cysts, present in 40% of males, rarely result in
infertility. Defective sperm motility is another cause of male infertility in ADPKD, 2)Arachnoid membrane
cysts, present in 8% of affected individuals, are usually asymptomatic, but may increase the risk for
subdural hematomas, 3)Spinal meningeal diverticula may occur with increased frequency and individuals
may present with intracranial hypotension secondary to cerebrospinal fluid leak, 4) Ovarian cysts are not
associated with ADPKD.

Vascular and cardiac manifestations. The most important non-cystic manifestations of ADPKD
include: intracranial and other arterial aneurysms and, more rarely, dolichoectasias, dilatation of the aortic
root, dissection of the thoracic aorta and cervicocephalic arteries, abnormalities of the cardiac valves, and,
possibly, coronary artery aneurysms. Evidence of familial clustering of thoracic aortic dissections in
ADPKD also exists.

Berry aneurysms are the most common types of aneurysms, and usually occur at predictable locations
along the cerebral vasculature. They resemble a small berry or sac, and project off of the side of cerebral
vessels, usually at branch points.

Colonic diverticulosis and diverticulitis are more common in individuals with ESRD associated
with ADPKD than in those with other renal diseases

V. References:

Harris PC, Torres VE. Polycystic Kidney Disease, Autosomal Dominant. 2002 Jan 10 [Updated 2018 Jul
19]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews ® [Internet]. Seattle (WA):
University of Washington, Seattle; 1993-2020.

Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L. 1., Jameson, J. L., & Loscalzo, J., Klatt, E.C. (2015).
Robbins and Cotran Atlas of Pathology, 3rd edition. Philadelphia, PA: Elsevier Saunders

Kumar, V., Abbas, A. and Aster, J.C. (2013). Robbins Basic Pathology 9th edition. Philadelphia, PA:
Elsevier Saunders