Affects: Cats
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.
Signs And Symptoms: ADPKD can result in a wide variety of clinical symptoms. Symptoms may be caused directly by a cyst growing or bursting, or indirectly due to problems with other physiological functions. Most symptoms occur around 40 years of age, but some clinical symptoms can occur decades prior to the development of over kidney disease, with some symptoms presenting as early as childhood.
Primary Symptoms Include:
Early-onset hypertension
Blood in urine
Abdominal, flank, or back pain
Pathophysiology: In many patients with ADPKD, kidney dysfunction is not clinically apparent until 30 or 40 years of age. However, an increasing body of evidence suggests the formation of renal cysts starts in utero. Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled cavities of different sizes. Factors suggested to lead to cystogenesis include a germline mutation in one of the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, and a third hit, which can be a renal insult that triggers cell proliferation, and an injury response. Due to numerous similarities between the pathophysiology of ADPKD and the pathophysiology of the renal response to injury, ADPKD has been described as a state of aberrant and persistent activation of renal injury response pathways. In the progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid secretion, and separation from the parental tubule lead to the formation of cysts.
ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as ciliopathies. Epithelial cells of the renal tubules, including all the segments of the nephron and the collecting ducts (with the exception of intercalated cells) show the presence of a single primary apical cilium. Polycystin-1, the protein encoded by the PKD1 gene, is present on these cilia and is thought to sense the flow with its large extracellular domains, activating the calcium channels associated with polycystin-2, the product of gene PKD2, as a result of the genetic setting of ADPKD as explained in the genetics sub-section above.
Epithelial cell proliferation and fluid secretion lead to cystogenesis, which are two hallmark features of ADPKD. During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts. Once these cysts expand to approximately 2 mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentration of cyclic AMP (cAMP).
Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume. Studies led by Mayo Clinic professionals established that the total kidney volume (TKV) in a large cohort of ADPKD patients was 1060 ± [dose — ask your vet] with a mean increase of [dose — ask your vet] over three years, or 5.27% per year in the natural course of the disease, among other important, novel findings that were extensively studied for the first time.
Diagnosis: Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan, or MRI. However, molecular diagnostics can be necessary in the following situations: 1- when a definite diagnosis is required in young individuals, such as a potential living related donor in an affected family with equivocal imaging data; 2- in patients with a negative family history of ADPKD, because of potential phenotypic overlap with several other kidney cystic diseases; 3- in families affected by early-onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can be involved; and 4- in patients requesting genetic counseling, especially in couples wishing a pre-implantation genetic diagnosis.
The findings of large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provides presumptively, but not definitively, evidence for the diagnosis. In some cases, intracranial aneurysms can be an associated sign of ADPKD, and screening can be recommended for patients with a family history of intracranial aneurysms.
Molecular genetic testing by linkage analysis or direct mutation screening is clinically available; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes, a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations who are younger than age 30.
Treatment: Currently, the only pharmacological treatment available for ADPKD consists of reducing the rate of gain of total kidney volume (TKV) with vasopressin receptor 2 (V2) antagonists (i.e., tolvaptan). Tolvaptan treatment does not halt or reverse disease progression, and patients still progress towards renal failure. Palliative treatment modalities involve symptomatic medications (nonopioid and opioid analgesics) for abdominal/retroperitoneal pain. Options for analgesic-resistant pain include simple or complex surgical procedures (i.e., renal cyst aspiration, cyst decortication, renal denervation, and nephrectomy), which can result in complications inherent to surgery. Recent research suggests that ketogenic dietary interventions beneficially affect the progression and symptoms in individuals with ADPKD. Mild weight loss favorably affects pain indicating the benefit of dietary and lifestyle changes.
Prognosis: In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the disease, glomerular filtration rate remains normal for decades before kidney function starts to progressively deteriorate, making early prediction of renal outcome difficult. The CRISP study, mentioned in the treatment section above, contributed to build a strong rationale supporting the prognostic value of total kidney volume (TKV) in ADPKD; TKV (evaluated by MRI) increases steadily and a higher rate of kidney enlargement correlated with accelerated decline of GFR, while patient height-adjusted TKV (HtTKV) ≥[dose — ask your vet]/m predicts the development of stage 3 chronic kidney disease within 8 years.
Besides TKV and HtTKV, the estimated glomerular filtration rate (eGFR) has also been tentatively used to predict the progression of ADPKD. After the analysis of CT or MRI scans of 590 patients with ADPKD treated at the Mayo Translational Polycystic Kidney Disease Center, Irazabal and colleagues developed an imaging-based classification system to predict the rate of eGFR decline in patients with ADPKD. In this prognostic method, patients are divided into five subclasses of estimated kidney growth rates according to age-specific HtTKV ranges (1A, <1.5%; 1B, 1.5–3.0%; 1C, 3.0–4.5%; 1D, 4.5–6.0%; and 1E, >6.0%) as delineated in the CRISP study. The decline in eGFR over the years following initial TKV measurement is significantly different between all five patient subclasses, with those in subclass 1E having the most rapid decline. Some of the most common causes of death in patients with ADPKD are various infections (25%), a ruptured berry aneurysm (15%), or coronary/hypertensive heart disease (40%).