Polycystic Kidney Disease

The main feature of ADPKD is a bilateral progressive increase in the number of cysts, which may reduce kidney function to the point where the individual requires kidney replacement therpy (KRT). Hepatic cysts, intracraneal aneurysms, and cardiac valvular abnormalities also may occur.

Although ADPKD is a systemic disease, it shows a focal expression; less than 1% of nephrons become cystic. In ADPKD, each epithelial cell within a renal tubule harbors a germ-line mutation, yet only a tiny fraction of the tubules develop kidney cysts.

It is currently held that the cells are protected by the allele inherited from the parent without ADPKD. When this allele is inactivated by a somatic event (eg, mutation) within a solitary renal tubule cell, the cell divides repeatedly until a cyst develops, with an aberrant growth program causing unchecked expansion.[8] The severity of ADPKD is thought to be a direct consequence of the number of times and the frequency with which this cystogenic process occurs within the kidneys over the life of the patient. 

The hyperplastic cells cause an out-pocketing of the tubule wall, with the formation of a saccular cyst that fills with fluid derived from glomerular filtrate that enters from the afferent tubule segment. Progressive expansion eventually causes most of the emerging cysts to separate from the parent tubule, leaving an isolated sac that fills with fluid by transepithelial secretion. This isolated cyst expands relentlessly as a result of continued proliferation of the mural epithelium together with the transepithelial secretion of sodium chloride and water into the lumen.[8]

The expanding fluid-filled tumor masses elicit secondary and tertiary changes within the renal interstitium evinced by thickening and lamination of the tubule basement membranes, infiltration of macrophages, and neovascularization. Fibrosis within the interstitium begins early in the course of the disease.

Cellular proliferation and fluid secretion may be accelerated by cyclic adenosine monophosphate (cAMP) and growth factors such as epidermal growth factor (EGF). In summary, cysts function as autonomous structures and are responsible for progressive kidney enlargement in ADPKD.[2, 9]

Approximately 85-90% of patients with ADPKD have an abnormality in the PKD1 gene located on the short arm of chromosome 16. Most of the remaining 10-15% of ADPKD cases are caused by pathogenic variants in the PKD2 gene, which is located on the long arm of chromosome 4. A third candidate gene, GANAB (glucosidase II alpha subunit), accounting for a very low number of ADPKD cases, has also been described.[10]  Additional cases caused by mutations in ALG9, DNAJB11, or LRP5 have been reported.[11, 12, 13]

PKD1 and PKD2 are expressed in most organs and tissues of the human body. The proteins that are encoded by PKD1 and PKD2, polycystin 1 (PC1) and polycystin 2 (PC2), seem to function together to regulate the morphologic configuration of epithelial cells. The polycystins are expressed in development as early as the blastocyst stage and are expressed in a broad array of terminally differentiated tissues. PC1 and PC2 belong to a subfamily of transient receptor potential (TRP) channels. The functions of the polycystins have been scrutinized to the greatest extent in epithelial tissues of the kidneys and liver and in vascular smooth muscle.[8, 14] (See Etiology.)

A decrease in urine-concentrating ability is an early manifestation of ADPKD. Plasma vasopressin levels are increased; this may represent the body's attempt to compensate for the reduced concentrating capacity of the kidneys and could contribute to the development of renal cysts, hypertension, and kidney insufficiency.[15]

Bleeding

Renal cysts in ADPKD are associated with excessive angiogenesis evinced by fragile vessels stretched across their distended walls. When traumatized, these vessels may leak blood into the cyst, causing it to expand rapidly, resulting in excruciating pain. If bleeding continues, then the cyst may rupture into the collecting system, causing gross hematuria. Alternatively, the cyst may rupture into the subcapsular compartment and eventually dissect through the renal capsule to fill the retroperitoneal space.

ADPKD is a hereditary disorder with an autosomal dominant pattern of inheritance. The disorder occurs equally in males and females. Each offspring of an affected person has a 50% chance of inheriting the genetic variant responsible for the disease.

ADPKD is a genetically heterogeneous condition that involves at least 2 genes. PKD1 is located on chromosome 16p13.3 and accounts for most ADPKD cases. PKD2 is located on chromosome 4q21-q22 and accounts for up to 15% of ADPKD cases. Other genes identified as rare causes of ADPKD include GANAB, ALG9, DNAJB11, and LRP5.[11, 12]

Polycystin 1 and 2

PKD1 codes for a 4304–amino acid protein, polycystin 1 (PC1). The function of PC1 is not yet fully defined, but this protein interacts with polycystin 2 (PC2) and is involved in cell cycle regulation and intracellular calcium transport. PC1 localizes in the primary cilia of renal epithelial cells, which function as mechanosensors and chemosensors.

PKD2 codes for PC2, a 968–amino acid protein that is structurally similar to PC1 and co-localizes to the primary cilia of renal epithelial cells. It is a member of the family of voltage-activated calcium channels.

PC1 and PC 2 are highly conserved, ubiquitous transmembrane proteins. In the kidney, they are located in the epithelial cells of the renal tubules—in particular, in the primary cilia at the luminal side of the tubules, as well as in other areas of the renal cell epithelium.

PC1 is a large protein with a long extracellular N-terminal region, 11 transmembrane domains, and a short intracellular C-terminal tail. PC2 is structurally related to the transient receptor potential (TRP) channel family, and it is known to function as a nonselective cation channel permeable to Ca2+.

PC1 and PC2 form heteromeric complexes and co-localize in the primary cilium of renal epithelial cells. The primary cilium is a long, nonmotile tubular structure located in the apical surface of the epithelial cells in the renal tubules. Its function was unknown for a long time, but studies now indicate that the primary cilium may be a mechanoreceptor that senses changes in apical fluid flow and transduces them into an intracellular Ca2+ signaling response[9] .

This model involves the participation of PC as a mechanical sensor of ciliary bending induced by luminal fluid flow. Bending of the cilium would cause a conformational change in PC1 that would, in turn, activate the PC2–associated Ca2+ channel, increasing the intracellular Ca2+ concentration and triggering intracellular signaling pathways leading to normal kidney development.[16]

There is a genotype-phenotype correlation for PKD1 mutations. Truncating mutations cause a more severe phenotype than non-truncating ones.[17]

In general, patients with PKD1 pathogenic variants present with more severe disease than patients with PKD2 pathogenic variants. The mean age of requiring kidney replacement therapy is 53 years in patients with PKD1 pathogenic variants, but is 74 years in patients with PKD2 pathogenic variants.[5]

The genetic heterogeneity of ADKPD, and the possible contribution of modifier genes, may explain the wide clinical variability in this disease, both within and among families.[13]

Worldwide, ADPKD affects approximately 4 to 7 million individuals and accounts for 7-15% of patients on kidney replacement therapy (KRT). In North America and Europe, ADPKD is responsible for 6-10% of KRT cases.[18, 2] Approximately one per 800-1000 population carries a pathogenic variant for this condition. Approximately 85-90% of those individuals have PKD1 pathogenic variants; most of the remainder have PKD2 disease-causing variants.

ADPKD is slightly more severe in males than in females.[19]

Symptoms generally increase with age. Children very rarely present with advanced chronic kidney disease from ADPKD.

The prognosis in patients with ADPKD covers a wide spectrum. Typically, however, ADPKD causes progressive kidney dysfunction, resulting in grossly enlarged kidneys and kidney failure by the fourth to sixth decade of life. There is an inverse association between the size of polycystic kidneys and the glomerular filtration rate (GFR).[2]

By the time kidney function begins to decline, the kidneys are usually markedly enlarged and distorted, with little visible parenchyma on imaging studies. At this stage, the average rate of estimated GFR decline is 4.4 to 5.9 mL/min per year. Up to 77% of patients are alive with preserved kidney function at age 50 years, and 52% at age 73 years. Men tend to progress to advanced chronic kidney disease more rapidly and require kidney replacement therapy (KRT) at a younger age than do women. 

The presence of more than one risk factor increases the risk of progression to KRT.[1] Risk factors for progression include the following:

• PKD1 genotype
• Kidney size
• First episode of  hematuria before age 35 years
• Severe and frequent kidney infections
• Hypertension onset before age 35 years
• Multiple pregnancies
• Black racial background
• Male sex

Although PKD1 and PKD2 pathogenic variants result in ADPKD with similar clinical features, they impart strikingly different kidney prognoses.[20]  Patients with PKD2 pathogenic variants show a milder disease: their median age for initiation of KRT is 68 years, compared with 56 years in individuals with PKD1 variants. Nevertheless, even though PKD2 phenotype is milder than PKD1, it has an overall impact on survival and shortens life expectancy.[17] .

Cardiovascular pathology and infections account for approximately 90% of deaths in patients treated with hemodialysis or peritoneal dialysis and after kidney transplantation. A rare cause of mortality is in ADPKD is subarachnoid hemorrhage from intracranial aneurysms.

The Mayo Clinic calculator for ADPKD is a useful tool for predicting disease progression. Recommendations for assessing rapid progression of ADPKD have been provided by European experts.[5, 21, 22] The French PROPKD score predicts risk of progression to KRT in patients with ADPKD. The score is calculated on the basis of the following factors[19] :

• Male sex: 1 point
• Hypertension before 35 years of age: 2 points
• First urologic event before 35 years of age: 2 points
• PKD2 pathogenic variant: 0 points
• Nontruncating PKD1 pathogenic variant: 2 points
• Truncating PKD1 pathogenic variant: 4 points

Risk categories, on the basis of point totals, are as follows:

• 0-3 points: Low risk; median age for KRT onset 70.6 years
• 4-6 points: Intermediate risk; median age for KRT onset 56.9 years
• 7-9 points: High risk; median age for KRT onset 49 years

A PROPKD score of 3 or less eliminates evolution to KRT before 60 years of age, with a negative predictive value of 81.4%. A score higher than 6 forecasts KRT onset before 60 years of age, with a positive predictive value of 90.9%.[19]

Ensure that patients are aware that this disease is hereditary and that their children have a 50% chance of acquiring the disease. Patients should also understand that although several treatments are being tested, this disease currently has no cure. Only interventions that slow the progression of kidney disease (eg, adequate blood pressure control, tolvaptan treatment) are of benefit. Hopefully, effective specific therapy will be available in a few years.

Prenatal diagnosis is available through genetic testing. Suggest that family members who are not screened for ADPKD have annual blood pressure checks and ultrasound screenings for kidney cyst diagnosis.

Patient education information is available at Living With Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder. Patients may present with multiple kidney and extrarenal manifestations.

Kidney pain

Pain—in the abdomen, flank, or back—is the most common initial complaint, and it is almost universally present in patients with ADPKD. The pain can be caused by any of the following[2] :

• Enlargement of one or more cysts
• Bleeding, which may be confined inside the cyst, or lead to gross hematuria with passage of clots or a perinephric hematoma
• Urinary tract infection and cyst infection
• Nephrolithiasis and renal colic
• Rarely, a coincidental hypernephroma

In addition, patients with ADPKD may have abdominal pain related to definitively or presumably associated conditions. Dull aching and an uncomfortable sensation of heaviness may result from significant hepatomegaly due to polycystic liver disease. Rarely, hepatic cysts may become infected.

Individuals with ADPKD may be at a higher risk of developing thoracic aortic aneurysms. However, their risk of abdominal aortic aneurysms is not higher than in the general population.

Pain may also develop for reasons completely unrelated to the underlying disease; thus, abdominal pain in patients with ADPKD may be a diagnostic challenge.

In addition to pain, other physical symptoms that patients with early-stage ADPKD may report include fatigue, breathlessness, weakness, and malaise.[23]

Hematuria

Hematuria frequently is the presenting manifestation and usually is self-limited, lasting 1 week or less. Polycystic kidneys are unusually susceptible to traumatic injury, with hemorrhage occurring in approximately 60% of affected individuals. Mild trauma can lead to intrarenal hemorrhage or bleeding into the retroperitoneal space accompanied by intense pain that often requires narcotics for relief.

Hypertension is one of the most common early manifestations of ADPKD. Even when kidney function is normal, hypertension has been found in 50-75% of patients.

The clinical course of hypertension in ADPKD is very unlike that of hypertension in chronic glomerulonephritis or tubulointerstitial nephropathies. In ADPKD, the hypertension is usually more severe early in the course of the disease and becomes less problematic as the kidney insufficiency progresses.[3, 24] In order to start treatment and delay the progression of chronic kidney disease, early diagnosis of hypertension in young patients is important.[25] A rise in diastolic blood pressure is the rule in ADPKD.

Palpable, bilateral flank masses occur in patients with advanced ADPKD. Nodular hepatomegaly occurs in those with severe polycystic liver disease.

Symptoms related to advanced chronic kidney disease (eg, pallor, uremic fetor, dry skin, edema) are rare on initial presentation.

Kidney failure is the most frequent complication of ADPKD. The prevalence of hypertension increases with age, with a rate of approximately 85% in patients starting kidney replacement therapy (KRT).

Polycystic liver disease

The presence of cysts in the liver, pancreas, and spleen is a well-known feature of polycystic liver disease, which is a frequent extrarenal manifestation of ADPKD. Pain and infection are the only manifestations of hepatic cysts. Most frequently, cysts are asymptomatic.[1]

Polycystic liver disease belongs to a family of liver diseases characterized by an overgrowth of biliary epithelium and supportive connective tissue. It is characterized by multiple cysts that may be microscopic or can occupy most of the abdominal cavity. Liver size may range from normal to massively enlarged.[5]

Women are more likely to have more and larger hepatic cysts than men; this correlates with estrogen exposure and increases with gravidity in women. Liver size in massive polycystic liver disease tends to stabilize after menopause. Hepatic cysts occur in almost 50% of affected patients. The frequency increases with age: cysts are rare in children, occur in approximately 20% of patients during the third decade of life, and occur in 75% during the seventh decade of life. Pancreatic cysts occur at a rate of 9% in patients older than 20 years.

Bilateral nephrectomy in patients with massively enlarged livers may cause portal hypertension. This typically manifests as severe ascites or esophageal varices. The enlarged liver may also cause malnutrition, and in such cases, patients may need a partial resection of the liver or liver transplantation.

Intracranial aneurysms

Cerebral aneurysms are among the most serious complications of ADPKD. They occur in 4-10% of patients with ADPKD.[26, 7]

Rupture of cerebral aneurysms usually occurs in patients younger than 50 years who have uncontrolled hypertension; however, a stroke from hypertension and intracerebral hemorrhage is more common. There is no relationship between the risk of rupture and the severity of kidney disease.[5]

Nephrolithiasis

Nephrolithiasis occurs in 20-30% of patients with ADPKD. Consider this condition in patients with acute pain and hematuria. In contrast to kidney stones in the general population, which most often consist of calcium oxalate, uric acid stones form in as many as 50% of patients with ADPKD. Metabolic abnormalities (eg, decreased urinary citrate) contribute to uric acid kidney stone formation.

Establishing a diagnosis by ultrasonogram is often difficult because of the presence of large cysts. An intravenous pyelogram or a computed tomography scan is the preferred imaging modality.

Ultrasonography is the procedure of choice in the workup of patients with autosomal dominant polycystic kidney disease (ADPKD). It is also ideal for screening patients' family members.[5] Computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) are useful in selected cases.[21]

Blood pressure should be monitored, to detect early onset of hypertension. Ambulatory blood pressure monitoring may be appropriate.

Other studies to perform include those for chronic kidney disease, as follows:

• Serum chemistry profile, including  potassium, calcium and phosphorus
• Complete blood cell count
• Measurement of blood lipid concentrations,
• Urine studies for albuminuria or proteinuria
• Urine culture
• Uric acid determination
• Intact parathyroid hormone and vitamin D assays

An increased hematocrit may result from increased erythropoietin secretion from cysts. A decrease in urine-concentrating ability is an early manifestation of the disease. Microalbuminuria occurs in 35% of patients with ADPKD. However, nephrotic-range proteinuria is uncommon.

Urinary proteomic biomarkers may have the potential for assessing prognosis in patients with ADPKD but are not available in clinical practice. 

Screening for intracranial aneurysm

Intracranial aneurysms are at least twice as common in patients with ADPKD as in the general population. On screening, intracranial aneurysms are found in approximately 10% of asymptomatic patients with ADPKD.[7, 26, 29]

Indications for screening, which is done with head MRI without gadolinium enhancement or CT angiography, include the following[5] :

• Family history of stroke or intracranial aneurysm or hemorrhage; patients with a family history of intracranial aneurysm but a negative screening study should be rescreened at 5–10-year intervals
• Before major elective surgery
• Central nervous system signs or symptoms (eg, nausea and vomiting, lethargy, photophobia, focal signs, seizure, transient ischemic attack, loss of consciousness)
• High-risk occupation, or hobby in which a loss of consciousness may be lethal (eg, airline pilot)
• New-onset severe headache
• Patient anxiety despite adequate information

Cardiac testing

Echocardiography or cardiac MRI, to asses for valvular heart disease, mitral valve prolapse, aortic dilatation, or congenital abnormalities.

Genetic testing 

Genetic testing is not part of regular clinical practice, but may be performed selectively.[5] .Genetic testing can accurately differentiate ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). In ADPKD, the presence of either PKD1 or PKD2 subtypes changes the prognosis and may help guide clinical management.[20, 17]

Genetic counseling

To inform affect individuals and their related family members about diagnosis, prognosis, and treatment.

Ultrasonography is the most widely used imaging technique to help diagnose ADPKD. It can detect cysts from 1-1.5 cm. This study avoids the use of radiation or contrast material, is widely available, and is inexpensive. The sensitivity of ultrasonography for PKD1 phenotype is 99% for at-risk patients older than 20 years; however, false-negative results are more common in younger patients. Sensitivity for PKD2 phenotype is lower and is still not well defined.

Ultrasonography is also useful for exploring abdominal extrarenal features of ADPKD (eg, liver cysts, pancreatic cysts).The presence of hepatic or pancreatic cysts supports the diagnosis of ADPKD.

Ultrasonographic diagnostic criteria for ADPKD in patients with mutations in PKD1 were established by Ravine et al in 1994 and are as follows[6] :

• At least 2 cysts in 1 kidney or 1 cyst in each kidney in an at-risk patient younger than 30 years
• At least 2 cysts in each kidney in an at-risk patient aged 30-59 years
• At least 4 cysts in each kidney for an at-risk patient aged 60 years or older

As the Ravine criteria are less sensitive for individuals with mutations in PKD2, Pei et al proposed the following ultrasonographic diagnostic criteria for ADPKD due to either PKD1 or PKD2 mutations, to screen patients with a family history of ADPKD but unknown genotype[4] :

• Three or more kidney cysts (unilateral or bilateral) in patients aged 15 to 39 years
• Two or more cysts in each kidney in patients aged 40 to 59 years
• Four or more cysts in each kidney in patients aged ≥60 years

The presence of fewer than 2 renal cysts provides a negative predictive value of 100% and can be considered sufficient for ruling out disease in at-risk individuals older than 40 years of age.[4]

CT is more sensitive than ultrasonography and can detect cysts as small as 0.5 cm. However, it exposes the patient to radiation and is more expensive; therefore, it is not used routinely for diagnosis or for follow-up studies of ADPKD. CT may be useful in complicated cases (eg, kidney stone, suspected tumor).

MRI is more sensitive than either ultrasonography or CT scanning. It may be more helpful in distinguishing renal cell carcinoma from simple cysts.

MRI is the best imaging tool for monitoring kidney size before starting tolvaptan treatment, and it is the criterion standard to help determine kidney volume for clinical trials of drugs for ADPKD. However, it is not routinely used because it is expensive and tedious. It should not be used unless the patient is in a protocol or similar situation.

Spithoven et al reported that determining measured total kidney volume (TKV) by MRI and manual tracing took an average of 55 minutes, but a newer proposed MRI method for estimating TKV, eTKV ellipsoid, required an average of only 5 minutes. In their comparison study, eTKV ellipsoid performed relatively well compared with mTKV and could detect change in TKV over time.[30]

Magnetic resonance angiography (MRA) is the preferred imaging technique for diagnosing intracranial aneurysms (ICAs). It is used selectively rather than routinely. Indications for this study are as follows[7] :

• Family history of stroke or intracranial aneurysm or hemorrhage; patients with a family history of ICA and a negative screening study should be rescreened at 5-10–year intervals.
• Before major elective surgery
• Central nervous system signs or symptoms (eg, nausea and vomiting, lethargy, photophobia, focal signs, seizure, transient ischemic attack, loss of consciousness)
• High-risk occupation, or hobby in which a loss of consciousness may be lethal (eg, airline pilot)
• New-onset severe headache
• Patient anxiety despite adequate information

Laboratory studies in patients with ADPK are largely performed to assess for chronic kidney disease, and include the following:

• Complete blood cell count
• Kidney function: Creatinine, estimated glomerular filtration rate
• Serum chemistry profile, including potassium, calcium, and phosphorus
• Measurement of blood lipid concentrations
• Urine studies for albuminuria or proteinuria
• Urine culture
• Uric acid determination
• Intact parathyroid hormone and vitamine D assay

An increased hematocrit may result from increased erythropoietin secretion from cysts. A decrease in urine-concentrating ability is an early manifestation of the disease. Microalbuminuria occurs in 35% of patients with ADPKD, most of them in the context of hypertension. However, nephrotic-range proteinuria is uncommon.

Genetic testing for ADPKD patients is not part of routine clinical practice. Molecular genetic testing approaches can include a multigene panel or genomic testing (exome or genome sequencing), depending on the phenotype. A multigene panel including PKD1, PKD2, ALG5,ALG9, DNAJB11, GANAB, IFT140 and other genes of interest (see differential diagnosis) is most likely to identify the genetic cause of the disease.[31]

Situations in which genetic testing is appropriate include the following[5, 27] :

• When a definitive diagnosis is required in young individuals, such as a potential living-related organ donor in an affected family with no clear imaging information
• In patients with a negative family history of ADPKD in whom alternative causes of cystic kidney disease are considered
• In couples requesting genetic counselling and family planning advice
• In cases of marked clinical discordance, such as very early onset disease or very mild disease, where knowledge of the pathogenic variant may provide an explanation or prognostic information

The aim of current treatment for ADPKD is to slow the decline in kidney function and reduce extrarenal complications. Specific disease features to address include the following[32]  :

• Hypertension; rigorous blood pressure control is recommended in early ADPKD ^{[3, 25]}
• Abnormalities related to kidney failure
• Urinary tract infections
• Cyst hemorrhage and hematuria
• Abdominal pain caused by enlarged kidneys
• Nephrolithiasis
• Polycystic liver disease
• Intracraneal aneurysms

Patients with ADPKD who progress to advanced chronic kidney disease (CKD) may require hemodialysis, peritoneal dialysis, or kidney transplantation. For more information, see Chronic Kidney Disease and Kidney Transplantation.

Metabolic problems associated with advanced CKD that require control include the following[33] :

• Hyperkalemia
• Hyperphosphatemia
• Hypocalcemia
• Hyperparathyroidism
• Metabolic acidosis

Management of intracranial aneurysms is influenced by their size and location; monitoring is usually sufficient for aneurysms that are less than 7 mm in diameter and are located in the anterior circulation, as these are less likely to rupture. When coiling or clipping is used to treat intracranial aneurysms, patients with ADPKD are at greater risk of complications, compared with other patients. Rozenfeld et al reported that patients with ADPKD experienced higher rates of iatrogenic hemorrhage or infarction, embolic infarction, and carotid artery dissection after endovascular coiling, and higher rates of iatrogenic hemorrhage or infarction after surgical clipping.[34, 7, 29]

Tolvaptan

Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved in the United States, Japan, Canada, Europe, and elsewhere for slowing kidney function decline in adults at risk of rapidly progressive ADPKD.[22] Factors used to identify rapidly progressive ADPKD include the following:

• Total kidney volume (TKV)/age and rate of change of TKV
• Estimated glomerular filtration rate (eGFR)/age and rate of decline of eGFR
• Genotype (PRO-PKD score; see Overview/Prognosis)
• Family history

Treatment with tolvaptan led to improvement in eGFR in the 1-year REPRISE (Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD) trial. The change from baseline in the eGFR was -2.34 mL/min/1.73 m2 in the tolvaptan group compared with -3.61 mL/min/1.73 m2 in the placebo group (P < 0.001).[35] In the TEMPO 3:4 and the extension TEMPO 4:4 trial, eGFR differences produced by the third year of the trial were maintained over the next 2 years of tolvaptan treatment.[36]

The primary endpoint in the TEMPO 3:4 and TEMPO 4:4 studies was the intergroup difference for rate of change of total kidney volume (TKV). The TEMPO 3:4 trial met its prespecified primary endpoint of 3-year change in TKV (P< 0.0001). The difference in TKV between treatment groups mostly developed within the first year, the earliest assessment, with little further difference in years 2 and 3. In years 4 and 5 during the TEMPO 3:4 extension trial, both groups received tolvaptan and the difference between the groups in TKV was not maintained.[37, 36]

Tolvaptan causes elevations in liver enzymes in about 5% of recipients. These elevations reverse on discontinuation of the drug.[37]

Investigative Therapies

The two-year phase II TAME-PKD study, conducted in 97 patients with early-stage ADPKD, found that long-term use of metformin is safe and tolerable. However, while metformin reduced the decline in eGFR compared with placebo (-1.71 versus -3.07 mL/min/1.73 m2 per year, respectively), the difference was not statistically significant.[38, 39]

A meta-analysis of 10 randomized controlled trials evaluating somatostatin analogs (eg, octreotide, lanreotide) as therapy for polycystic kidney disease or polycystic liver disease concluded that the use of somatostatin analogs slows increases in total liver volume (TLV) and lower total kidney volume (TKV) but does not affect eGFR.[40]

Salsalate, a prodrug dimer of salicylate, improved kidney survival and reduced cystic kidney disease severity in a mouse model.[41]

Many trials have been completed or are under way to investigate different treatments, including the use of statins, vitamin B3 or niacinamide, antiproliferative drugs, and somatostatin analogues.[1]

The target blood pressure is ≤110/75 mm Hg in patients aged 18-50 years who have an eGFR > 60 mL/min. Otherwise, the target is ≤130/85 mm Hg. Achieving good blood pressure control helps slow the progression of kidney disease, and the importance of early detection and treatment of hypertension in ADPKD has been demonstrated in several studies.

The HALT A and HALT B PKD clinical trials studied hypertensive ADPKD patients.[3, 24] Both studies showed that an angiotensin-converting enzyme inhibitor alone can adequately control hypertension in most patients, justifying its use as first-line treatment for hypertension in this disease. HALT A showed that in young patients with normal kidny functioen, lowering blood pressure to levels below those recommended by hypertension guidelines reduced the rate of increase in kidney volume by 14%, the increase in renal vascular resistance, urine albumin excretion, left ventricular mass index, and the rate of decline in eGFR.[5, 24]

The drugs of choice for this condition are angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril, lisinopril) or angiotensin II receptor blockers (ARBs) such as telmisartan, losartan, irbesartan, and candesartan. Calcium channel blockers are not recommended.

In patients with advanced chronic kidney disease, ACE inhibitors and ARBs can exacerbate kidney failure or increase serum potassium levels. Therefore, these patients require regular monitoring of serum chemistry values.

Urinary tract infections (UTIs) occur in 30-50% of ADPKD patients, most frequently in women. Gram-negative bacteria are the most common pathogens.

Distinguishing between infections of the bladder, renal parenchyma, and cysts is important because the treatment for each condition is different. Treating infected kidney or liver cysts requires antibiotics that penetrate into the cyst. For cyst infections, useful agents are fluorquinolones and trimethoprim-sulfamethoxazole. Recommended durations of treatment vary; these agents are typically given for around 4-6 weeks in complicated cases. Resolution of fever and at least two negative blood and/or urine cultures can be used to determine efficacy of treatment.[5]

Cyst hemorrhage and gross hematuria

Hematuria in patients with ADPKD results from kidney cyst rupture or stone passage. Instruct the patient to drink large amounts of water, to rest, and to take a pain killer if necessary. Hematuria is usually self-limited and responds well to conservative management. Hospitalization is necessary if the bleeding is substantial or persists after several days.

Abdominal pain from enlarged kidneys

The initial approach to pain management is conservative. Nonopioid agents are preferred.[42] Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), because they can worsen kidney function. As in other chronic pain syndromes, tricyclic antidepressants can be helpful and are generally well tolerated. Narcotic analgesics should be reserved for the treatment of acute episodes.

Treatment for severe, refractory cases may also involve surgical cyst decompression, which is effective for pain relief in 60-80% of patients. See Surgical Drainage, below.

Kidney stones

Treatment of nephrolithiasis in patients with ADPKD is the same as in those without ADPKD: high fluid intake and potassium citrate in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. Success can be achieved with extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy[5] .

Polycystic liver disease

Most people with polycystic liver disease (PLD) have no symptoms and do not require treatment. Treatment of symptomatic disease includes avoiding estrogens and using H2 blockers or proton pump inhibitors for symptomatic relief. Infected liver cysts require antibiotics for 4-6 weeks.[5, 1]

Intracranial aneurysms

Asymptomatic patients with aneurysms ≤5.0 mm in diameter diagnosed by screening can be observed and followed initially at yearly intervals. If the size increases, surgery is indicated.The management of aneurysms of 6.0-9.0 mm remains controversial. Surgery is usually indicated for aneurysms > 10.0 mm in diameter, and for those that are causing symptoms or have ruptured.[5] Surgical treatment of a ruptured aneurysm involves clipping it at its neck. For more information, see Neurosurgery for Cerebral Aneurysm.

If infected kidney or hepatic cysts do not respond to conventional antibiotic therapy, surgical drainage may be necessary. This procedure is usually performed with ultrasonographically guided puncture.[43]

Cysts may become large enough to cause abdominal discomfort or pain. Typically, acute pain is from cyst hemorrhage or an obstruction by a clot, stone, or infection.[44] When one or more cysts can be identified as causing the pain, the symptoms can often be abated by open- or fiberoptic–guided surgery to excise the outer walls and to drain them.

Approximately 25% of patients with the most severe pain do not gain relief from surgery or pharmacologic therapy with narcotics. These individuals usually have inaccessible cysts in the medullary portions of the kidneys. Nephrectomy is used as a last resort to control the pain in these patients. Nephrectomy is also often necessary for kidney transplant recipients when there is not enough space for the donor kidney.

Severe polycystic liver disease can result in massive hepatomegaly (see image below). When the liver becomes so large that it prevents the patient from obtaining normal nutrition or causes severe abdominal discomfort, a surgical procedure is necessary. Surgical intervention may range from unroofing several cysts to a partial hepatectomy. Partial hepatectomy is difficult because of the characteristics of the polycystic liver. Only very expert surgeons should proceed with this surgical procedure. When a polycystic liver causes portal hypertension or is very large with nonresectable areas, liver transplantation may be necessary.

Polycystic kidney disease and massive polycystic liver disease.

Special attention should be paid when bilateral nephrectomy has to be carried out in patients with severe liver involvement. Several cases of refractory ascites after bilateral nephrectomy have been reported in these patients.

Consultations may be indicated under the following circumstances[5] :

• Nephrologist, for management of kidney insufficiency, hypertension, albuminuria, or concentrating defect
• Invasive radiologist, for cyst sclerosis or drainage
• General surgeon, for nephrectomy, cyst decompression, unroofing, or surgical hepatic procedures
• Neurosurgeon, for intracranial aneurysms
• Cardiologist, for valvular abnormalities

Ensure that a patient with ADPKD who is nonhypertensive and has normal kidney function undergoes blood testing and ultrasonography of the kidneys every 1-2 years. Schedule more frequent follow-up studies for patients with high blood pressure. Hypertension is common, occurring in as many as 50-70% of patients before the onset of kidney failure. Patients with advanced chronic kidney disease require more frequent monitoring, based on the severity of their condition.

Avoid the use of estrogens and possibly progestogens in individuals with severe polycystic liver disease.

Avoid caffeine in large amounts.[45] There is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD. Avoid a high-salt diet. In a brief pilot study, a low-osmolar diet with adjusted water intake to achieve a urine osmolality of ≤280 mOsm/kg H2O significantly reduced vasopressin in patients with ADPKD.[46]

Patients should avoid contact sports where direct trauma to the back or abdomen is likely. This is particularly important in those with larger, palpable kidneys, to minimize the risk of rupture.

International guidelines and consensus reports related to ADPKD include the following:

• Autosomal Dominant Polycystic Kidney Disease (ADPKD): Report from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, published in 2015. ^[5]
• Consensus document on autosomal dominant polycystic kidney disease from the Spanish Working Group on Inherited Kidney Diseases. Review 2020/Documento de consenso de poliquistosis renal autosómica dominante del grupo de trabajo de enfermedades hereditarias de la Sociedad Española de Nefrología. Revisión 2020, by the Inherited Kidney Disease working group of the Spanish Society of Nephrology ^[47]
• Kidney Health Australia: KHA-CARI Autosomal Dominant Polycystic Kidney Disease Guideline, published in 2015 ^[48]
• Updated Canadian Expert Consensus on Assessing Risk of Disease Progression and Pharmacological Management of Autosomal Dominant Polycystic Kidney Disease, published in 2018 ^[45]  
• The Renal Association (United Kingdom: Clinical Practice Guideline: Monitoring children and young people with, or at risk of developing Autosomal Dominant Polycystic Kidney Disease (ADPKD); published in 2018 ^[49]
• Network for Early Onset Cystic Kidney Disease (NEOCYST): International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people ^[50]

Pharmacologic treatment in patients with autosomal dominant polycystic kidney disease (ADPKD) addresses the complications of the disease and is directed toward the following:

• Relieving abdominal pain: Tricyclic antidepressants can be helpful and are generally well tolerated. Narcotic analgesics should be reserved for the treatment of acute episodes. Do not use nonsteroidal anti-inflammatory drugs (NSAIDs), because of their potential nephrotoxic effect.
• Controlling hypertension: Drugs of choice are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)
• Treating infections: Kidney and liver cyst infections require antibiotics that are gyrase inhibitors (eg, ciprofloxacin, ceftriaxone, meropenem, ertapenem). Trimethoprim-sulfamethoxazole is also an effective antibiotic for reaching the inner cavity of the cyst. ^[5]
• Managing chronic kidney disease (CKD) and slowing the decline in kidney function: Advanced CKD requires drugs to maintain electrolyte levels (eg, calcium carbonate, calcium acetate, sevelamer, lanthanum carbonate, calcitriol, diuretics. ^[33] Approximately 62% of patients with advanced CKD require at least 2 antihypertensive agents for optimal blood pressure control. Tolvaptan, a selective vasopressin V2-receptor antagonist, is indicated for adults at risk of rapidly progressive ADPKD. ^{[37, 35, 36, 32]}

Class Summary

The selective vasopressin V2-receptor antagonist, tolvaptan, causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentration. Liver enzymes should be monitoring during treatment.

Tolvaptan (Jynarque)

Selective vasopressin V2-receptor antagonist that causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentration. Indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

Class Summary

ACE inhibitors suppress the renin-angiotensin-aldosterone system.

Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.

Lisinopril (Prinivil, Zestril)

This agent prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Class Summary

ARBs interfere with the binding of formed angiotensin II to its endogenous receptor. These agents reduce blood pressure and proteinuria, protecting renal function and delaying onset of end-stage renal disease (ESRD).

Valsartan (Diovan)

Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Valsartan may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It is for use in patients unable to tolerate ACE inhibitors.

Losartan (Cozaar)

Losartan is an ARB that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used for patients unable to tolerate ACE inhibitors.

Candesartan (Atacand)

Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used in patients unable to tolerate ACE inhibitors.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to the AT-1 receptor in vascular smooth muscle. Its action is independent of pathways for angiotensin II synthesis.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Ciprofloxacin (Cipro)

Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth. It is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant Staphylococus aureus (MRSA), S epidermidis, and most gram-negative organisms, but no activity against anaerobes. Levofloxacin (Levaquin) overcomes many of these limitations. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared.

Levofloxacin (Levaquin)

Levofloxacin inhibits growth of susceptible organisms by inhibiting DNA gyrase and promoting breakage of DNA strands.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

This agent inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Meropenem (Merrem IV)

Ertapenem (Invanz)

Class Summary

Administer phosphate binders to maintain phosphate levels in renal failure.

Calcium Acetate ( PhosLo, Eliphos)

Calcium acetate reduces the phosphorus load.

Lanthanum carbonate (Fosrenol)

Lanthanum is a noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with ESRD. It directly binds dietary phosphorus in the upper GI tract, thereby inhibiting phosphorus absorption.

Sevelamer hydrochloride (Renagel, Renvela)

This polymeric phosphate binder for oral administration does not contain aluminum. Thus, aluminum intoxication is not a concern.