Polycystic Kidney Disease

The main feature of ADPKD is a bilateral progressive increase in the number of cysts, which may lead to end-stage renal disease. Hepatic cysts, cerebral aneurysms, and cardiac valvular abnormalities also may occur.[11, 12]

Although ADPKD is a systemic disease, it shows a focal expression because 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 renal 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 (mutation or otherwise) within a solitary renal tubule cell, the cell divides repeatedly until a cyst develops, with an aberrant growth program causing endless expansion. 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. However, it is hard to understand how this hypothesis would apply in neonatal cases.

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.

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.

Approximately 85-90% of patients with ADPKD have an abnormality on the short arm of chromosome 16 (ie, ADPKD type 1 [ADPKD1]). A second defect, termed ADPKD type 2 (ADPKD2), is responsible for 10-15% of ADPKD cases and is found 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.[13]  Additional cases caused by ALG9, DNAJB11 or LRP5  have been reported.[14, 15, 16]

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 and polycystin 2, 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. 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 (see Etiology).

A decrease in urine-concentrating ability is an early manifestation of ADPKD. The cause is not known. Plasma vasopressin levels are increased; this increase 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.[17]

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. The pattern of inheritance is autosomal dominant. Because the disorder occurs equally in males and females, each offspring has a 50% chance of inheriting the responsible mutation and, hence, the disease.

ADPKD is a genetically heterogeneous condition that involves at least 2 genes. PKD1 is located on 16p13.3 and accounts for most ADPKD cases. PKD2 is located on 4q21-q22 and accounts for 15% of ADPKD cases. Other genes identified in the etiology of ADPKD include GANAB, ALG9, DNAJB11 and LRP5.[3]

Polycystin 1 and 2

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

PKD2 codes for a 968–amino acid protein (polycystin 2) that is structurally similar to polycystin 1 and co-localizes to the primary cilia of renal epithelial cells. It is a member of the family of voltage-activated calcium channels.

Polycystin 1 and polycystin 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.

Polycystin 1 is a large protein with a long extracellular N-terminal region, 11 transmembrane domains, and a short intracellular C-terminal tail. Polycystin 2 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+.

Polycystin 1 and polycystin 2 form heteromeric complexes and colocalize 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. However, studies now indicate that the primary cilium may be a mechanoreceptor that senses changes in apical fluid flow and that transduces them into an intracellular Ca2+ signaling response.

This model involves the participation of polycystin 1 as a mechanical sensor of ciliary bending induced by luminal fluid flow. Bending of the cilium would cause a conformational change in polycystin 1 that would, in turn, activate the polycystin 2–associated Ca2+ channel, increasing the intracellular Ca2+ concentration and triggering intracellular signaling pathways leading to normal kidney development.[18]

There is a genotype-phenotype correlation for PKD1, with truncating mutations causing a more severe phenotype than non-truncating ones.[19]

ADPKD1 is more severe than ADPKD2. The mean age of ESRD for patients with ADPKD1 is 53 years. The mean age of ESRD for patients with ADPKD2 is 74 years.

The genetic heterogeneity of ADKPD, and the possible contribution of modifier genes, may explain the wide clinical variability in this disease, both within and between families.[16]

Worldwide, ADPKD affects approximately 4 to 7 million individuals and accounts for 7-15% of patients on renal replacement therapy.[20] In North America and Europe, ADPKD is responsible for 6-10% of ESRD cases. Approximately one per 800-1000 population carries a mutation for this condition. Approximately 85-90% of patients with ADPKD have ADPKD1; most of the remaining patients have ADPKD2.[21]

ADPKD is slightly more severe in males than in females, but the difference is not statistically significant.

Symptoms generally increase with age. Children very rarely present with kidney failure from ADPKD.

The prognosis in patients with ADPKD covers a wide spectrum. Kidney failure has been reported in children; conversely, individuals with ADPKD may live a normal lifespan without knowing that they have the disease. More 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 level of glomerular filtration.[22, 23]

An early study estimated that approximately 70% of patients with ADPKD would develop kidney insufficiency if they survived to age 65 years. Currently, half of all patients with ADPKD require renal replacement therapy by age 60 years. Risk factors for progression include the following:

• PKD1 genotype
• Large kidneys
• Several episodes of gross hematuria ^[24]
• Severe and frequent kidney infections
• Hypertension
• Multiple pregnancies
• Black racial background ^[21]
• Male sex

The presence of more than one risk factor increases the risk of progression to end-stage renal disease (ESRD).

Although the 2 forms of ADPKD, ADPKD1 and ADPKD2, share similar clinical features, renal prognosis is strikingly different.[25, 26] ADPKD2 is a milder disease, based on the age of onset of ESRD. The median age of renal survival for individuals with ADPKD1 is 56 years, compared with 68 years in those with ADPKD2. Nevertheless, even though ADPKD2 is milder than ADPKD1, it has an overall impact on survival and shortens life expectancy.

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.[27]

In a retrospective, observational study of 88 patients with ADPKD who died between 1981 and 1999, Rahman et al determined that almost half of the patients died of cardiovascular problems.[28] The median age of death was 60.5 years. Causes of death included the following:

• Cardiovascular problems - 46.6% of patients
• Infection - 15.9% of patients, with 42% of these deaths resulting from septicemia
• Central nervous system disorders - 11.36% of patients, with 60% of these deaths caused by cerebrovascular events
• Uremia - 2.2% of patients
• Other, miscellaneous causes - 11.36%

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.[29]

The PROPKD score predicts risk of progression to ESRD in patients with ADPKD. The score is calculated on the basis of the following factors[30] :

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

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

• 0-3 points: low risk; median age for ESRD onset 70.6 years
• 4-6 points: intermediate risk; median age for ESRD onset 56.9 years
• 7-9 points: high risk; median age for ESRD onset 49 years

A PROPKD score of 3 or less eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%. A score higher than 6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%.[30]

A study by Sato et al in 55 Japanese patients with ADPKD determined that high serum phosphate levels were independently associated with poor renal prognosis. Risk rose with every 1-mg/dL increase (hazard ratio, 6.78; 95% confidence index, 1.94–34.02; P = 0.002).[31]

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) are of benefit. Hopefully, effective specific therapy will be available in a few years.

Prenatal diagnosis is available through DNA linkage studies, if enough family members cooperate, or through a mutation search. Suggest that family members who are not screened for ADPKD have annual blood pressure checks and urine screenings for hematuria.

Pain—in the abdomen, flank, or back—is the most common initial complaint, and it is almost universally present in patients with autosomal dominant polycystic kidney disease (ADPKD). The pain can be caused by any of the following:

• 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 (eg, acute pyelonephritis, infected cysts, perinephric abscess)
• 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 a large polycystic liver. Rarely, hepatic cysts may become infected, especially after kidney transplantation.

Abdominal pain can also result from diverticulitis, which has been reported to occur in 80% of patients with ADPKD maintained on dialysis, probably from altered connective tissue. However, this rate has not been demonstrated to be higher than the rate among other patients on dialysis.

Patients with ADPKD may be at a higher risk of developing thoracic aortic aneurysms. Abdominal aortic aneurysms are not increased among these patients.

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.[32]

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 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.[4, 5] 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. 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 kidney failure (eg, pallor, uremic fetor, dry skin, edema) are rare upon presentation.

End-stage renal disease (ESRD) is the most frequent complication of ADPKD. The prevalence of hypertension increases with age, with a rate of approximately 85% in patients entering ESRD.

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.[11] Pain and infection are the only symptoms that occur from the presence of hepatic cysts. Most frequently, cysts are asymptomatic.

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 enlarged.

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. Cysts occur in approximately 20% of patients during the third decade of life and in 75% during the seventh decade of life. They are rare in children, and the frequency increases with age. 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 hepatic transplantation.

Cerebral aneurysms

Cerebral aneurysms are among the most serious complications of ADPKD; they occur in 4-10% of patients with ADPKD. Rahman et al reported a mortality rate of approximately 7% from cerebrovascular events in patients with ADPKD.[28]

Rupture 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.

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 stone formation.

Establishing a diagnosis by ultrasonogram is often difficult because of the presence of large cysts. An intravenous pyelogram or a CT 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. Computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) are useful in selected cases. Other studies to perform include the following:

• Serum chemistry profile, including calcium and phosphorus
• Complete blood cell count
• Urinalysis
• Urine culture
• Uric acid determination
• Intact parathyroid hormone 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. However, nephrotic-range proteinuria is uncommon.

Urinary proteomic biomarkers may have the potential for diagnosis and prognosis of ADPKD. In a large clinical proteomic study, Kistler et al reported that the performance of urinary peptidomic biomarker scores in ADPKD is superior to that of other biochemical markers in young patients with this disease and that proteomic profiling is potentially useful in the diagnosis and risk stratification of ADPKD. In the study, urine samples from 1048 patients were analyzed to characterize the urinary peptidomic pattern of patients with early-stage ADPKD.[33]

Genetic testing

Genetic testing may be performed. Genetic testing can accurately differentiate ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominent polycystic liver disease (ADPLD). In ADPKD, the presence of either PKD1 or PKD2 subtypes changes the prognosis and may help guide clinical management.[3]

Genetic testing by means of DNA linkage analysis has an accuracy rate greater than 95% for ADPKD1 and ADPKD2. Mutation screening is commercially available. 

A major indication for genetic screening is in young adults with negative ultrasonographic findings who are being considered as potential kidney donors.[6]  

Staging by glomerular filtration rate

Staging of kidney failure is as follows:

• Stage 1 – Glomerular filtration rate (GFR) >90 mL/min
• Stage 2 - GFR 60-90 mL/min
• Stage 3 - GFR 30-60 mL/min
• Stage 4 - GFR 15-30 mL/min
• Stage 5 - GFR < 15 mL/min

Other studies

Intravenous urography was once widely used in the diagnosis of ADPKD. Among its disadvantages are that it involves contrast medium and it is diagnostic only in advanced-stage ADPKD when distortion of calyces has developed. It is no longer indicated to establish a diagnosis of the disease.

Barium enema may be used to help diagnose colonic diverticula. Doppler studies and 2-dimensional echocardiography are used to exclude mitral prolapse, which is often associated with ADPKD.

Screening for intracranial aneurysm

Intracranial aneurysms are at least twice as common in patients with ADPKD as in the general population.[34] On screening, intracranial aneurysms are found in approximately 10% of asymptomatic patients with ADPKD.[35] Indications for screening, which is done with time-of-flight MRA, include the following[34] :

• 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)
• Family history of intracranial aneurysm or intracranial hemorrhage
• High-risk occupation (eg, airline pilot)
• New-onset severe headache

Ultrasonography is the most widely used imaging technique to help diagnose ADPKD.[36] 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 ADPKD1 is 99% for at-risk patients older than 20 years; however, false-negative results are more common in younger patients. Sensitivity for ADPKD2 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 ADPKD1 were established by Ravine et al in 1994 and are as follows[7] :

• At least 2 cysts in 1 kidney or 1 cyst in each kidney in an at-risk patient younger than 30 yearsAt 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

Ultrasonographic diagnostic criteria for ADPKD in patients with a family history but unknown genotype were established by Pei et al in 2009 and are as follows[8] :

• Three or more (unilateral or bilateral) renal cysts in patients aged 15-39 years
• Two or more cysts in each kidney in patients aged 30-59 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.

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 doubtful cases in children or 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 after treatment to assess progress, and it is the criterion standard to help determine renal 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 recently proposed MRI method for estimating TKV, eTKVellipsoid, required an average of only 5 minutes. In their comparison study, eTKVellipsoid performed relatively well compared with mTKV and could detect change in TKV over time.[37]

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[9, 10] :

• Family history of stroke or ICA
• Development of symptoms suggesting an ICA
• Job or hobby in which a loss of consciousness may be lethal
• Past history of ICA

In patients with autosomal dominant polycystic kidney disease (ADPKD), pharmacologic therapy is necessary to accomplish the following:

• Control blood pressure; rigorous blood pressure control is recommended in early ADPKD ^[38]
• Control abnormalities related to kidney failure
• Treat urinary tract infections
• Treat hematuria
• Reduce abdominal pain produced by enlarged kidneys
• Slow kidney function decline

Patients with ADPKD who progress to end-stage renal disease may require hemodialysis, peritoneal dialysis, or kidney transplantation. For more information, see Chronic Kidney Disease and Kidney Transplantation.

In patients with heart murmurs, institute routine American Heart Association antibiotic prophylaxis.

Metabolic problems related to kidney failure that need to be controlled include the following:

• 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.[34] Rozenfeld and colleagues reported that patients with ADPKD who undergo treatment for intracranial aneurysms are especially likely to experience complications: compared with controls, 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.[39]

Tolvaptan

Tolvaptan (Jynarque), a selective vasopressin V2-receptor antagonist, is approved in the United States and Europe for slowing kidney function decline in adults at risk of rapidly progressive ADPKD.[40, 41] Approval in the US was based on two phase 3 clinical trials.

Treatment with tolvaptan led to improvement in glomerular filtration rate (GFR) during 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 estimated GFR (eGFR) was -2.34 mL/minute per 1.73 m2 in the tolvaptan group compared with -3.61 mL/min/1.73 m2 in the placebo group (P< 0.001).[42] In the extension trial (TEMPO 3:4) eGFR differences produced by the third year of the trial were maintained over the next 2 years of tolvaptan treatment.

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 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.[43, 44]

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 estimated glomerular filtration rate (eGFR) compared with placebo (-1.71 versus -3.07 mL/min/1.73 m2 per year, respectively), the difference was not statistically significant.[45] A major phase III trial of metformin in ADPKD is scheduled.[46]

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.[47]

Salsalate, a prodrug dimer of salicylate, improved kidney survival and reduced cystic kidney disease severity in a mouse model.[48]

Diet and activity

Although a low-salt diet is recommended when hypertension or kidney failure is present, no other special diet reportedly is of benefit.

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

In patients with kidney disease and moderately increased albuminuria, the goal is a blood pressure of 130/80 mm Hg or less.[49] If more than 1 g/day of urinary protein is present, the target blood pressure is less than 125/75 mm Hg. Achieving good blood pressure control helps slow the progression of kidney disease.[50] A study by Patch et al showed that when intensity and coverage of antihypertensive therapy were increased, mortality decreased for patients with ADPKD.[51]

The drugs of choice for this condition are angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril, lisinopril) or angiotensin II receptor blockers (ARBs) such as telmisartan, losartan, irbesartan, and candesartan. These agents remain the most recommended drugs to treat hypertension in patients with ADPKD, although studies of the renin-angiotensin-aldosterone system have not convincingly demonstrated that it plays an important role in its pathogenesis.[52] Calcium channel blockers are not recommended.

In patients with advanced 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 and 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 cysts requires antibiotics that penetrate into the cyst. Useful agents are ciprofloxacin, trimethoprim-sulfamethoxazole, clindamycin, and chloramphenicol.

Hematuria

Hematuria is frequent in patients with ADPKD. It usually results from 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. Hospitalization is necessary if the patient is still bleeding after several days or if the amount of blood is substantial.

Abdominal pain from enlarged kidneys

Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), because they can worsen renal function and potentiate hyperkalemia. Treatment involves surgical cyst decompression, which is effective for pain relief in 60-80% of patients. See Surgical Drainage, below.

If infected renal or hepatic cysts do not respond to conventional antibiotic therapy, surgical drainage may be necessary. This procedure is usually performed with ultrasonographically guided puncture.[53]

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.[54] 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 often necessary when there is not enough room for a kidney graft.

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.

Polycystic kidney disease and massive polycystic liver disease.

Partial hepatectomy is difficult because of the characteristics of the polycystic liver. Only very expert surgeons should proceed with this surgical procedure.

When the polycystic liver causes portal hypertension or is very large with nonresectable areas, liver transplantation may be necessary.

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:

• Nephrologist upon evidence of renal insufficiency, hypertension, microalbuminuria, 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 renal 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 renal failure. Patients with renal failure require more frequent monitoring, based on the severity of their condition.

Tolvaptan (Jynarque), a selective vasopressin V2-receptor antagonist, is approved by the US Food and Drug Administration (FDA) to slow kidney function decline in adults at risk of rapidly progressive autosomal dominant polycystic kidney disease (ADPKD).[43, 42, 44]

The drugs of choice for hypertension related to ADPKD are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Do not treat ADPKD-related abdominal pain with nonsteroidal anti-inflammatory drugs (NSAIDs) because of their potential nephrotoxic effect.

Cyst infections require antibiotics that are gyrase inhibitors (eg, ciprofloxacin, chloramphenicol, clindamycin). Trimethoprim-sulfamethoxazole is also an effective antibiotic for reaching the inner cavity of the cyst.

Kidney failure requires drugs to maintain electrolyte levels (eg, calcium carbonate, calcium acetate, sevelamer, lanthanum carbonate, calcitriol [possibly], diuretics, blood pressure medications). Approximately 62% of patients with kidney insufficiency require at least 2 antihypertensive agents for optimal blood pressure control.

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.

Tolvaptan (Jynarque)

Indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). This indication is specific for Jynarque (ie, not Samsca) as the dosing and duration differs. Because of the potential for serious liver injury, Jynarque is available only through a restricted distribution program.

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.

Captopril

Captopril 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.

Clindamycin (Cleocin)

Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Chloramphenicol

Chloramphenicol binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.

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.