Advances in autosomal dominant polycystic kidney disease—2014 and beyond
ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD), which frequently leads to end-stage renal disease, currently has no specific drug therapies. Better understanding of its pathogenesis and recent clinical trials have led to more accurate diagnosis of the disease and its manifestations, as well as to promising new approaches to treatment.
KEY POINTS
- For at-risk patients in the previously difficult diagnostic group from 30 to 39 years of age, newer ultrasonographic criteria for diagnosing PKD1 and PKD2 now require a minimum total of three renal cysts.
- An intracranial aneurysm occurs in approximately 16% of ADPKD patients who have a family member with ADPKD plus an intracranial aneurysm or subarachnoid hemorrhage. Appropriate screening is warranted.
- Combined positron-emission and computed tomography helps identify infected renal or liver cysts and may uncover other unsuspected abdominal or pelvic infections.
- Cyst expansion and increasing total kidney volume might be slowed by increasing water intake to 2,500 to 3,000 mL per day, although formal documentation of this is not published. However, this must be done under a physician’s supervision because of possible adverse effects.
- Tolvaptan, a promising new drug for treating ADPKD, failed to receive US approval. Rapamycin is another potentially effective agent but has had mixed results in clinical trials.
PROGRESSION OF ADPKD
The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study23 evaluated 241 patients with ADPKD (ages 15 to 46) by measuring the annual rate of change in total kidney volume, total cyst volume, and iothalamate glomerular filtration rate (GFR) over 3 years. The annual increase in total kidney volume averaged 5.3%,23 though the reported range with various imaging techniques is from 4% to 12.8% in adults.24 This study focused on macrocystic disease, ie, cysts that are visible by MRI and measurably increase total kidney volume. Although larger total kidney volume at baseline generally predicted a more rapid decline in GFR, there were wide and overlapping variations in yearly GFR declines within and among different total-kidney-volume groups.23
SPECIAL CLINICAL PROBLEMS IN ADPKD
Case 1: A man with ADPKD develops new and increasing proteinuria
A 55-year-old man with ADPKD and stage 3 chronic kidney disease developed new and increasing proteinuria, rising to 5,500 mg per 24 hours. What is the most likely explanation?
- Rapidly progressive renal failure with increasing proteinuria in ADPKD
- Bilateral renal vein thromboses because of cyst compression
- Malignant hypertension with bilateral renal artery compression
- Superimposed primary glomerulopathy
- Multiple infected renal cysts with pyonephrosis
Answer: Superimposed primary glomerulopathy.
ADPKD (similar to uncomplicated obstructive uropathy, pyelonephritis, main renal artery disease, and often cases of interstitial nephritis without secondary glomerular changes) typically does not result in nephrotic-range proteinuria. A superimposed primary glomerulopathy, focal segmental glomerulosclerosis, was the biopsy-proved diagnosis.
At least 21 cases have been reported of AD-PKD with nephrotic-range proteinuria and a renal biopsy showing a primary glomerulopathy, including focal segmental glomerulosclerosis (5 cases), minimal-change disease (5), membranous nephropathy (3), IgA nephropathy (2), and one each of crescentic glomerulonephropathy, diabetic nephropathy, membranoproliferative glomerulonephritis, postinfectious glomerulonephropathy, amyloid glomerulopathy, and mesangioproliferative glomerulopathy.15 Treatment was directed at the primary glomerulopathy, and the outcomes corresponded to the primary diagnosis (eg, with appropriate treatment, three of the five patients with focal segmental glomerulosclerosis progressed to end-stage renal disease, all of the patients with minimal-change disease went into remission, and one of the two cases with IgA nephropathy improved).15
Case 2: A woman with ADPKD and advanced renal failure develops shortness of breath
A 47-year-old woman with very large polycystic kidneys (total kidney volume 7,500 mL; normal range for a single kidney approximately 136–295 mL, mean 196)25 and estimated GFR of 25 mL/min developed new-onset shortness of breath while climbing steps and later even when making a bed. She had no chest pain, cough, or edema. She was sent directly to the emergency department and was admitted and treated; her condition improved, and she was discharged after 6 days. What did she have?
- Presentation of rare cystic pulmonary disease in ADPKD
- Onset of pneumonia with early bacteremia
- Progressive reduction in ventilatory capacity from massive polycystic kidneys and liver elevating both sides of the diaphragm
- Pulmonary emboli from an iliac vein or inferior vena cava source
- Progressive anemia accompanying rapidly worsening stage 4 chronic kidney disease
Answer: She had pulmonary emboli from an iliac vein (right) or inferior vena cava source.
Pulmonary emboli in ADPKD can be caused by thrombi in the inferior vena cava or the iliac or femoral vein because of compression by a massive right polycystic kidney. Four cases were reported at Mayo Clinic,26 three diagnosed by MRI and one with CT. One additional case occurred at Cleveland Clinic. All patients survived after treatment with anticoagulation therapy; early nephrectomy was required in two cases.
Interestingly, following kidney transplantation, the patients at greatest risk for pulmonary emboli are those with ADPKD as their original disease.27
RENAL CYSTS RESULT FROM COMBINED MUTATIONS, INJURY
The germline ADPKD mutation that occurs in one allele of all renal tubular epithelial cells is necessary but not sufficient for cystogenesis.28 One or more additional somatic mutations of the normal allele—the “second hit”—also develop within individual tubular epithelial cells.28,29 These epithelial cells undergo clonal proliferation, resulting in tubular dilatation and cyst formation. Monoclonality of cells in cysts has been documented.
Ischemia-reperfusion injury can be viewed as a “third hit.”30 In PKD1 knockout mice, which at 5 weeks of age normally develop only mild cystic kidney disease, the superimposition of unilateral ischemia-reperfusion injury at 8 weeks caused widespread and rapid cyst formation. It is believed that acute renal injury reactivates developmental signaling pathways within 48 hours that trigger epithelial cell proliferation and then cyst development detectable by MRI 2 weeks later. Although this phenomenon has not been documented in humans, it is a cautionary tale.
CYSTOGENESIS INVOLVES MULTIPLE PATHWAYS
A comprehensive description of pathways leading to renal cyst formation is beyond the scope of this article, and the reader is referred to much more detailed and extensive reviews.2,31 Disturbances in at least three major interconnected pathways promote cystogenesis in renal tubular epithelial cells:
- Normal calcium transport into the endoplasmic reticulum is disrupted by abnormal polycystins on the surface of the primary cilium
- Vasopressin and other stimuli increase the production of cyclic adenosine monophosphate (cAMP)
- The mammalian target of rapamycin (mTOR) proliferative pathway is up-regulated.
DISRUPTION OF CALCIUM TRANSPORT IN THE PRIMARY CILIUM
Primary cilia are nonmotile cellular organelles of varying size, from about 0.25 μm up to about 1 μm.32 Each primary cilium has nine peripheral pairs of microtubules but lacks a centrally located pair that is present in motile cilia. Primary cilia are ubiquitous and have been highly conserved throughout evolution. A single cilium is present on almost all vertebral cells.33
Cilial defects have been identified in autosomal dominant as well as recessive diseases and are known as ciliopathies.33 Although rare in humans, they can affect a broad spectrum of organs other than the kidney, including the eye, liver, and brain.33
Urine flow in a renal tubule is believed to exert mechanical stimulation on the extracellular flagellum-like N-terminal tail of PC1 that extends from a primary cilium into the urinary space. PC1 in concert with PC2 opens PC2 calcium channels, allowing calcium ions to flow down the microtubules to ryanodine receptors and the basal body.32,33 This leads to local release of calcium ions that regulate cell proliferation.32,34 However, in ADPKD kidneys, PC1 and PC2 molecules are sparse or mutated, resulting in defective calcium transport, increased and unregulated tubular epithelial cell proliferation, and cyst formation.
In a totally different clinical setting, biopsies of human renal transplants that sustained acute tubular necrosis during transplantation reveal that a cilium dramatically elongates in response to injury,35 possibly as a compensatory mechanism to maintain calcium transport in the presence of meager urine flow and to restore the proliferation of tubular epithelial cells in a regulated repair process.
