Key points in the Diagnosis of Autosomal Dominant Polycystic Kidney Disease

The diagnosis of ADPKD is most often obtained by ultrasonography. Given that detection rates are less than 85% for individuals and that ultrasonography positively identifies >98% at risk individuals by age 30, imaging has remained the primary diagnostic approach. The presence of enlarged kidneys with multiple cysts is required for the diagnosis of ADPKD. Age-specific, ultrasound-based diagnosis guidelines for ADPKD have been developed, primarily for PKD1-related disease. These same guidelines are less reliable sensitive for PKD2-related disease, in which a later age of onset occurs. In young individuals with PKD2 alterations who undergo screening, there is an increased likelihood of false-negative results by ultrasonography. The presence of two cysts in each kidney in an at-risk individual younger than 30 years is 99% specific and sensitive for the presence of ADPKD. For those older than 30 years and younger than 60 years, four cysts bilaterally in an at-risk individual (i.e., someone with a known affected parent) are necessary for the same level of diagnostic precision. For those older than 60 years, more than eight cysts bilaterally are needed for a positive diagnosis. In the 10% to 15% of ADPKD individuals who do not have a family history, stricter criteria are required for a diagnosis, and at least five cysts bilaterally by the age of 30 and a phenotype consistent with ADPKD must be present.
A negative ultrasound result in an at-risk individual at age 20 years reduces the likelihood of disease inheritance to below 10% and at age 30 years to below 5%. When disease status must be determined with greater certainty (i.e., during evaluation of a potential donor for living, related transplantation), computed tomography (CT) or magnetic resonance imaging (MRI) and genetic testing may be required.
Mutation screening using direct sequencing of the PKD1 or PKD2 genes is commercially available. Direct sequencing is the most accurate and reliable screening method, but expense is a limiting factor. After a genetic diagnosis is made, other at-risk family members can be screened at reduced cost by performing exon-specific sequencing of the identified mutation. Current mutation detection rates in known affected individuals for PKD2 and PKD1 are 95% and 75%, respectively.

Essential Diagnostic Criteria for the Diagnosis of Syndrome of Inappropriate Vasopressin release (SIADH)

The following criteria should be met in order to diagnose Syndrome of Inappropriate ADH release

1. Decreased extracellular fluid effective osmolality (<270 mOsm/kg H2O)

2. Inappropriate urinary concentration (>100 mOsm/kg H2O) along with Clinical euvolemia

3. Elevated urinary Sodium concentration (>20 mEq/L) under conditions of a normal salt and water intake

4. Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use

Histologic Classifications of Bone Disease Associated with Chronic Kidney Disease

PTH receptors, vitamin D receptors, and calcium-sensing receptors are all present in osteoblasts. Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption through osteoblastic paracrine pathways. The circulating level of PTH is the primary determinant of bone turnover in CKD and is a major determinant of the type of bone disease present. The specific types of histologic changes also depend on the age of the patient, the duration and cause of kidney failure, the type of dialysis therapy used, the presence of acidosis, vitamin D status, accumulation of metals such as aluminum, and other conditions affecting mineralization of the extracellular matrix.


Bone disease associated with CKD (Fig. 58-2) has traditionally been classified histologically according to the degrees of abnormal bone turnover and impaired mineralization of the extracellular matrix. These histologic changes in bone have been best studied in dialysis patients. The current categories are as follows:

	1.	Secondary hyperparathyroidism or high-turnover bone disease or osteitis fibrosa cystica
	2.	Mixed uremic bone disease (a mixture of high-turnover bone disease and osteomalacia)
	3.	Osteomalacia (defective mineralization)
	4.	Adynamic bone disease (decreased rates of bone formation without a mineralization defect)

Sign and Symptoms related to Extrarenal manifestations of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

The following are Sign and Symptoms related to Extrarenal manifestations of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Polycystic liver disease—Polycystic liver disease (PLD) is the most common extrarenal manifestation of ADPKD. Liver cysts originate from small clusters of intralobular bile ductules surrounded by fi brous tissue termed biliary microhamartomas and from peribiliary glands. The occurrence of PLD in ADPKD increases with age from 0% in ADPKD children to 20% in the third decade and over 75% in the seventh decade of life. Women, especially those with multiple pregnancies and/or on oral contraceptive or on estrogen replacement therapy, tend to have an earlier onset and worse PLD.

The majority of PLD patients are asymptomatic. When occurring, the symptoms usually result from either mass effect or cyst-related complications such as cyst hemorrhage, rupture, or infection. The liver synthetic functions are typically preserved because, despite even a signifi cant degree of cystic liver involvement, the total amount of unaffected hepatic parenchyma is not reduced. Symptoms associated with mass effect are dyspnea, orthopnea, early satiety, gastroesophageal refl ux, mechanical back pain, uterine prolapse, rib fracture, and, in severe cases, failure to thrive. In rare cases, a massively enlarged cystic liver can cause obstructions to the hepatic venous outfl ow tract, portal vein and/or bile duct, or the inferior vena cava. These patients may develop portal hypertension, esophageal and/or gastric varices, ascites, and, rarely, obstructive jaundice.

Hepatic cyst hemorrhage and ruptures can present as acute abdominal pain, extrinsic bile duct compression, and liver enzyme elevation. Rarely, cysts can rupture into the peritoneum and cause acute ascites and life-threatening hemoperitoneum.

Patients with hepatic cyst infection may present with fever, chills, localized upper abdominal pain, leukocytosis, and elevation of alkaline phosphatase. Bacteremia is frequently present. The major pathogens are Enterobacteriaceae.

Intracranial aneurysms and other vascular manifestations—The incidence of intracranial aneurysms (ICAs) and ICA ruptures in ADPKD is increased by 5- to 10-fold compared to that in the general population. Family clustering is evident. Patients with a family history of ICA or subarachnoid hemorrhage (SAH, the consequence of ICA rupture) have an ICA occurrence of 21% versus 6% in those without such history.

The majority of ADPKD-associated ICAs are small (<7 mm in diameter) and are located in the anterior circulation (approximately 90%). Although compared to sporadic ones, ICAs in ADPKD have a younger mean age of aneurysmal rupture (39 versus 51 years).

The risk of ICA rupture (extrapolated from the International Study of Unruptured Intracranial Aneurysms) depends on the size and location of the ICAs and whether the patient has a prior episode(s) of SAH.

The yearly risk of rupture is less then 0.1% for the small sized (<7 mm in diameter) anterior circulation ICAs in patients without a prior SAH. The risk is higher for ICAs >7 mm in diameter or in the posterior circulation or in patients with a prior history of SAH.

Unruptured ICAs are generally asymptomatic. Rarely, patients can present with focal neurologic symptoms such as cranial nerve palsy or seizure due to local compression. Rupturing or ruptured ICAs typically present with prominent symptoms including episodes of sudden onset intense headache or headache with a quality different from that experienced before. The pain can radiate to the occipital and cervical region and may be accompanied by nuchal rigidity. Other associated symptoms are nausea, vomiting, photophobia, cranial nerve palsy, seizure, lethargy, and coma.

Other vascular manifestations more frequently seen (an approximately 10-fold increase) in ADPKD are thoracic aortic and cervicocephalic arterial dissections, intracranial arterial dolichoectasia, and coronary artery aneurysms. The symptoms and signs of these complications are similar to those seen in non-ADPKD patients.

Valvular heart disease—Valvular heart diseases occur more frequently in ADPKD patients than in their nonaffected family members or the general population. Of those, mitral valve prolapse is the most common and can be detected by echocardiography in up to 20% of ADPKD patients.

Other more frequent valvular heart diseases include mitral insufficiency, tricuspid insufficiency, tricuspid prolapse, and aortic insufficiency often associated with aortic root dilation. Symptoms vary from asymptomatic or episodic palpitations to, in rare cases, congestive heart failure. When a cardiac murmur is heard, antibiotic prophylaxis against subacute bacterial endocarditis is indicated.

Renal cell carcinoma—Despite the frequent occurrence of hyperplasia and microscopic adenomas on renal pathology, the overall incidence of renal carcinoma in ADPKD is not increased.

However, when occurring, the renal cancer tends to affect younger patients (mean age of 45 versus 55 years in the general population), be multifocal, and possess high-grade sarcomatoid features.

Kidney Related Signs and Symptoms of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

With age, cystic renal enlargement occurs in all ADPKD patients. The severity of structural abnormality generally correlates with the renal manifestations including pain, hematuria, hypertension, and renal dysfunction. Massively enlarged kidneys can also cause compression of the neighboring organs and the inferior vena cava, leading to early satiety, dyspnea, and lower extremity edema.

Hypertension—Hypertension (HTN) occurs before the onset of renal failure in more than 80% of ADPKD patients. Although the prevalence increases with age, ADPKD is associated with an earlier onset and a signifi cantly increased incidence of HTN compared to those in the general population. The cause of HTN is multifactorial including activation of the intrarenal renin–angiotensin system, defects in nitric oxide endothelium-mediated vasorelaxation, elevated sympathetic activity, and possible defects in vascular smooth muscle cells directly associated with the PKD mutations. Early onset and/or uncontrolled HTN are signifi cant risk factors for faster renal disease progression and for mortality from cardiac complications such as left ventricular hypertrophy and coronary artery disease. Uncontrolled HTN can also worsen valvular heart disease and increase the risk of intracranial aneurysmal rupture and morbidity associated with rupture.

Pain—Episodes of acute flank pain are common. The potential etiologies are cyst hemorrhage, infection, stone, or, rarely, renal tumor. Massively enlarged kidneys can cause mechanical lower back pain. A small group of patients develops chronic flank pain without an identifiable etiology except for the enlarged kidneys. These patients are at risk for narcotic and/or analgesic dependence and medication-related complications.

Hematuria, cyst hemorrhage, and retroperitoneal hemorrhage—Gross hematuria may be the initial presenting symptom. It occurs in up to 42% of ADPKD patients and can result from cyst hemorrhage, stone, infection, or renal tumor. Most cyst hemorrhages are self-limited and resolve within 2–7 days. First episodes occurring in patients older than 50 years or episodes persisting for more than a week should be investigated to rule out neoplasm. Occasionally, hemorrhagic cysts can rupture into the retroperitoneum causing retroperitoneal bleeding. This can be severe and life threatening.

Urinary concentration defect—A urine concentration defect, often associated with mild polyuria, is the most common and earliest manifestation of ADPKD. It usually goes unnoticed and is well compensated by adequate fluid intake.

Nephrolithiasis—Nephrolithiasis occurs in approximately 20% of ADPKD patients and is five times more common than in the general population. The majority of stones are composed of uric acid and/or calcium oxalate. Uric acid stones occur more frequently in ADPKD than in non-ADPKD stone formers. Factors that may contribute to the lithogenicity are urinary stasis due to distorted renal architecture, hypocitraturia, and low urinary pH (promoting uric acid stone formation). The symptoms and signs of nephrolithiasis are similar to those of non-ADPKD stone patients.

Urinary tract or cyst infections—Whether urinary tract infections occur more frequently in ADPKD patients is unclear, but their risk of complicated infections is clearly increased. Infections include cystitis, pyelonephritis, renal cyst infection, and perinephric abscesses. They occur more frequently in females than in males. The main pathogens are Escherichia coli, Klebsiella, Proteus, and other Enterobacteriaceae. Symptoms and signs are urinary frequency and urgency for cystitis; fever, chills, nausea, vomiting, and flank pain for pyelonephritis, renal cyst infection, and perinephric abscesses.

Renal failure—ADPKD1 is associated with a 20-year earlier onset of end-stage renal failure compared to that of ADPKD2. Once the renal clearance starts to decline, it decreases linearly at a rate of approximately 5.0–6.4 mL/ minute/year. Both genetic and environmental factors play a role in renal disease progression. Among patients with ADPKD1, the location of the PKD1 mutation may influence renal outcome. The mutations located in the first half of the PKD1 gene (5' region) were shown to be associated with a slightly earlier onset of renal failure compared to the mutations located in the second half of the gene (3' region).

Additional risk factors that portend a poor renal outcome include male gender, sickle cell trait, diagnosis of ADPKD before age 30 years, first episode of gross hematuria before age 30 years, hypertension before age 35 years, hyperlipidemia, low high-density lipoprotein (HDL), and cigarette smoking.

The symptoms and signs of renal failure in ADPKD, which begin to appear when the glomerular filtration rate is reduced to <30–40 mL/minute/1.73 m2, mirror those of non-ADPKD chronic renal failure.

Extrarenal manifestations of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

In addition to its renal manifestations, ADPKD is a multisystemic disorder with prominent extrarenal cystic and noncystic manifestations including polycystic liver disease and cysts in diverse organ systems (pancreas, arachnoid membrane, pineal gland, and seminal vesicles), intracranial saccular aneurysms, thoracic aortic aneurysms and dissections, coronary artery aneurysms, mitral and/or tricuspid valve prolapse, aortic valve insufficiency, aortic root dilation, and possibly colonic diverticula.

Brief Introduction and Genetics of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the most common life-threatening monogenic disease. It occurs worldwide and in all races, affecting 1 in 400–1000 individuals. In the United States, approximately 500,000 people are affected and about 2000 begin hemodialysis each year.

ADPKD is an autosomal dominantly transmitted disease. It is composed of two types: ADPKD1, caused by mutations in the PKD1 gene and responsible for 85% of the clinical cases of ADPKD, and ADPKD2, caused by mutations in the PKD2 gene and accounting for approximately 15% of cases. A very small percentage of ADPKD patients, with a milder form of disease not linked to mutations in either PKD1 or PKD2, might have mutation(s) in a yet to be identified third PKD gene.

The severity of cystic renal dysfunctions is highly heterogeneous with significant interfamilial and intrafamilial variations. In general, ADPKD1 is more severe and is marked by an early onset of end-stage renal failure (mean age of 54 years) versus that of ADPKD2 (mean age of 74 years). Compared to female patients male ADPKD2 patients tend to develop more extensive cystic renal dysfunction, although they have less cystic liver disease.

How to diagnose Autosomal Dominant Polycystic Kidney Disease (ADPKD)

The Essentials of Diagnosis are:

* Two renal cysts unilaterally or bilaterally before age 30 years by renal ultrasound in patients with a family history of ADPKD.

* Two cysts in each kidney between the ages of 30 and 59 years by renal ultrasound in patients with a family history of ADPKD.

* Four or more cysts in each kidney after age 60 years by renal ultrasound in patients with a family history of ADPKD.

Treatment Options for Renal Cystic Diseases

Today, treatment includes risk modification, management of complications, and renal transplant or dialysis. There is no definitive therapy to eliminate or to retard cyst growth. A better understanding of its pathogenesis offers hope in the near future for correcting the underlying abnormalities in cystic pathways.

Brief Introduction to Renal Cystic Disease

Renal cystic disease comprises a wide range of disease entities. They can be classified as either 

(1) hereditary or acquired
or
(2) systemic or renal confined diseases

that have the common feature of multiple renal cysts. Each disease entity differs in its presentation, prognosis, and management.

Renal cysts are smooth-walled, fluid-filled circular structures formed by focal outpouching of renal tubules. The pathogenesis of cyst formation has not been entirely elucidated. However, tremendous strides have been made in recent years. For autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD), a picture is starting to emerge. Defects in the primary ciliary sensing mechanisms, intracellular calcium regulation, and cellular cyclic AMP (cAMP) accumulation all seem to play a role in the altered cellular phenotype and functions.