Acquired Cystic Kidney Disease

Acquired cystic kidney disease (ACKD) was previously thought to be a consequence of hemodialysis. Studies have shown that although the association of dialysis and ACKD is indisputable, it is the uremic state that promotes the development of ACKD. The development of ACKD does not appear to be associated with any particular type of kidney disorder. Dialysis prolongs the patient's survival to allow more time for acquired renal cystic disease to occur.

The exact mechanism and pathogenesis is incompletely understood. The postulates are as follows:

• Tubule block: The development of cysts results from tubular obstruction due to oxalate crystals, fibrosis, or micropolyps; and tubular fluid accumulation due to glomerular filtrate and tubular fluid excretion.
• Compensatory growth: The profound loss of renal tissue in end-stage kidney disease promotes tubular cell hypertrophy and hyperplasia. Hypertrophy and hyperplasia, together with transepithelial secretion of fluid by the tubular epithelium, result in the development of cysts. Many factors may influence the process, but most important among them are growth factors and activation of oncogenes.
• Ischemia ^[3] : Kidney atrophy is a recognized consequence of ischemia that may be caused either by primary renal arterial occlusion or by the secondary arterial occlusions that develop after dialysis is begun. Parenchymal acidosis may result from chronic progressive occlusion and, if sustained just short of causing cell death, might result in renal cyst formation.

Research into the cystic fluid and epithelium suggests that the cysts arise from proliferation of renal tubules. ^{[4, 5]} Cystic fluid derives from the ultrafiltrate, transepithelial solute, and fluid secretion and resembles plasma in its composition. ^[4] Additionally, microdissection studies have shown that most cysts have a low cuboidal or columnar epithelium, while some of the cells that line cysts show an apical brush border configuration, suggesting that they stem from proximal tubules. ^[6]

Progressive destruction of the renal parenchyma triggers several mitogenic signals (eg, azotemic products, altered concentration of sodium and potassium, activation of the renin-angiotensin-system, inflammation, local growth factors), ultimately leading to hypertrophy and hyperplasia of renal tubules. ^{[4, 7]} In addition, restricted tubular fluid flow and net fluid secretion contribute to cyst formation. ^[4] Over a period of time, the activation of proto-oncogenes combined with additional risk factors may result in malignant transformation. ^{[4, 8, 9]}  The image below illustrates the proposed pathophysiology of the progression of acquired cystic kidney disease to renal malignancy.

Proposed pathophysiology for cyst formation and malignant transformation in acquired cystic kidney disease. RAAS: Renin-angiotensin-aldosterone system.

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The severity and the duration of azotemia appear to be the critical factors in determining the extent of cyst development.

The causes of multiple renal cysts include the following:

• Autosomal dominant polycystic kidney disease
• Autosomal recessive polycystic kidney disease
• Multicystic renal dysplasia
• Acquired renal cystic disease
• Simple renal cysts
• Medullary sponge kidney
• Familial juvenile nephronophthisis
• Medullary cystic disease
• Von Hippel-Lindau syndrome
• Tuberous sclerosis complex
• Glomerulocystic kidney disease

Frequency

United States

The rates of occurrence of acquired cystic kidney disease (ACKD) are 7-22% in the predialysis population, 44% within 3 years after beginning dialysis, 79% more than 3 years after beginning dialysis, and 90% longer than 10 years after beginning dialysis. The rate of progression appears to slow after 10-15 years of dialysis.

Kidney transplant recipients

The prevalence of ACKD is lower in kidney transplant recipients than in patients on dialysis. In a cohort of 561 kidney transplant recipients, the prevalence of ACKD was 23%, whereas in patients with end-stage kidney disease, the prevalence may vary from 30-90%. ^[10] However, renal cell carcinoma (RCC) develops more often in transplant recipients with ACKD than in those without (19% vs 0.5%). ^[10]

Race-, Sex-, and Age-related Demographics

ACKD is relatively more common in Blacks. Although Blacks comprise only 25% of patients on dialysis in the United States, they account for 53% of cases of ACKD.

ACKD occurs more frequently in men than in women. ACKD-associated RCC is found predominantly in men; the male-to-female ratio is 7:1, compared with 2:1 in the general population.

ACKD occurs with equal frequency in children and adults. ^[11] RCC occurs approximately 20 years earlier in persons with ACKD than in the general population; However, ACKD-associated RCC is rare in children.

Acquired cystic kidney disease (ACKD) reverses in some patients after successful kidney transplantation. Some native kidneys continue to develop cysts after transplantation, and in these patients, kidney function conceivably remains significantly compromised, thereby maintaining the cystogenic state. Cyclosporine use has been associated with a greater prevalence of post-transplant ACKD than in the pre-cyclosoporine era. ^[12]

Development of cysts in other organs does not occur in ACKD, in contrast to autosomal dominant polycystic kidney disease (ADPKD).

ACKD can be progressive in patients who are on dialysis for an extended period; malignant transformation may also occur. The 5-year survival rates after diagnosis of malignancy are comparable to those observed in renal cell carcinoma in the general population. Renal cell carcinoma in patients with ESKD is associated with more favorable histologic features and prognosis. ^[13]  Death is usually associated with metastasis and accounts for 2% of the deaths in kidney transplant patients.

ACKD gives rise to many significant complications, the most serious of which is the development of renal cell neoplasms, ranging from adenoma to metastatic renal cell carcinoma. Other complications include the following:

• Cystic hemorrhage ^[14]
• Cyst infection, abscess formation, and/or sepsis
• Erythrocytosis
• Calcification in or around cysts

Malignant transformation

The incidence of renal cell carcinoma (RCC) is 0.18% per year in patients with acquired cystic kidney disease, compared with 0.005% in the general population. ^[15]  Most patients are asymptomatic, but about 15% of patients present with hematuria and flank pain; patients with metastasis may present with lumbar pain. Risk factors include the following:

• Male sex (male-to-female ratio is 7:1)
• Long duration of dialysis (8-10 years, although cysts can occur before then)
• Black race
• Severe ACKD with marked organomegaly

Renal cancers in ACKD patients are usually limited to the kidneys and in approximately 25-50% of cases are multiple and bilateral, which is consistent with the diffuse nature of the underlying disease. They are predominantly of the clear cell or papillary subtype. ^[10]  Malignancy generally develops after at least 8-10 years of dialysis, although a shorter interval can also be seen.  The International Society of Urological Pathology Vancouver Classification of Renal Neoplasia recognizes acquired cystic disease–associated RCC as a distinct entity within the classification system. ^[16]

Cystic hemorrhage

Hemorrhage is sometimes associated with hematuria. Bleeding may evolve into cyst rupture, with subsequent retroperitoneal or perinephric hemorrhage (Wunderlich syndrome). Rarely, bleeding can be severe enough to cause hypovolemic shock.