Jared J. Grantham

Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

BACKGROUND The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

Autosomal Dominant Polycystic Kidney Disease

Shortly after being elbowed in the flank during a pickup basketball game, a 35-year-old healthy man has severe, colicky abdominal pain followed by gross hematuria. He is hospitalized, and a renal ultrasound scan reveals bilateral polycystic kidneys and liver cysts, previously unknown to the patient. The blood pressure is 160/100 mm Hg. The serum creatinine concentration is 0.9 mg per deciliter (80 μmol per liter). The pain subsides in 2 days with analgesics, rest, and fluids; the gross hematuria resolves in 4 days, although microscopic hematuria persists. How should his case be further evaluated and managed? The Clinical Problem Autosomal dominant polycystic kidney disease is an inherited systemic disorder with major renal manifestations and, in some cases, abnormalities in the liver, the pancreas, the brain, the arterial blood vessels, or a combination of these sites. 1 The disease affects approximately 300,000 to 600,000 Americans of either sex, and without racial predilection. Each child of an affected parent has a 50% chance of inheriting the mutated gene, which is completely penetrant. Autosomal dominant polycystic kidney disease arises as a spontaneous mutation in approximately 5% of cases. However, in about one fourth of newly diagnosed cases, patients report no history of the disease, indicating that many familial cases go undetected. Affected patients have numerous fluid-filled cysts in the kidneys; these cysts may collect blood after mild or severe trauma or may be the site of pyogenic infection. In rare cases, a malignant neoplasm develops, although the incidence of renal cancer among affected patients is not increased, as compared with the incidence in the general population. Autosomal dominant polycystic kidney disease begins in utero, but signs of the disease may not be detected for several decades. Autosomal dominant polycystic kidney disease is caused by mutations in either of the two genes encoding plasma membrane–spanning polycystin 1 and polycystin 2 (PKD1 and PKD2, respectively). The polycystins regulate tubular and vascular development in the kidneys and other organs (liver, brain, heart, and pancreas) 2 and interact to increase the flow of calcium through a cation channel formed in plasma membranes by polycystin 2. A mutation of either polycystin can disrupt the function of the other, resulting in similar clinical presentations. However, mutations of PKD1 are more common than mutations of PKD2 (accounting for 85% of cases), are likely to be associated with more renal cysts, 3,4 and lead to renal insufficiency on average 20 years earlier (median ages at the time of death or end-stage failure, 53 and 69 years, respectively). 5

Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

Volume Progression in Autosomal Dominant Polycystic Kidney Disease: The Major Factor Determining Clinical Outcomes

Autosomal dominant polycystic kidney disease (PKD) is a hereditary condition characterized by the progressive enlargement of innumerable renal cysts that contribute to life-altering morbidity early in the course of the disease. Evidence indicates that the rate of increase in kidney volume can be reliably measured by magnetic resonance or computed tomography imaging, thus providing objective means to judge the effectiveness of therapies that are targeted to the aberrant growth of renal tubules. It is now possible, therefore, to monitor the effectiveness of potential therapies on the signature abnormality in autosomal dominant PKD before irreversible damage has been done by the cysts. Evidence accumulated from human cross-sectional and longitudinal studies and longitudinal studies of PKD models in animals provide strong support for the view that reducing the rate of kidney volume enlargement will ameliorate the late-stage development of renal insufficiency.

Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased total kidney volume (TKV) and renal failure. This study aimed to determine if height-adjusted TKV (htTKV) predicts the onset of renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective, observational, longitudinal, multicenter study included 241 adults with ADPKD and preserved renal function. Magnetic resonance imaging and iothalamate clearance were used to measure htTKV and GFR, respectively. The association between baseline htTKV and the attainment of stage 3 CKD (GFR <60 ml/min per 1.73 m(2)) during follow-up was determined. RESULTS After a mean follow-up of 7.9 years, stage 3 CKD was attained in 30.7% of the enrollees. Using baseline htTKV, negative correlations with GFR increased from -0.22 at baseline to -0.65 at year 8. In multivariable analysis, a baseline htTKV increase of 100 cc/m significantly predicted the development of CKD within 8 years with an odds ratio of 1.48 (95% confidence interval: 1.29, 1.70). In receiver operator characteristic curve analysis, baseline htTKV of 600 cc/m most accurately defined the risk of developing stage 3 CKD within 8 years with an area under the curve of 0.84 (95% confidence interval: 0.79, 0.90). htTKV was a better predictor than baseline age, serum creatinine, BUN, urinary albumin, or monocyte chemotactic protein-1 excretion (P<0.05). CONCLUSIONS Baseline htTKV ≥600 cc/m predicted the risk of developing renal insufficiency in ADPKD patients at high risk for renal disease progression within 8 years of follow-up, qualifying htTKV as a prognostic biomarker in ADPKD.

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Physical properties of isolated perfused renal tubules and tubular basement membranes

To study the physical properties of renal tubular basement membranes directly, the epithelial layer of single isolated perfused rabbit proximal convoluted, proximal straight, and cortical collecting tubules was removed with sodium desoxycholate. Tubular segments were perfused using micropipets. The distal end of each segment was occluded in order to simplify the measurement of transmembrane water flow. The relation between outer tubular diameter and applied transmural pressure was identical in intact tubules and their respective isolated tubular basement membranes indicating that the basement membrane determines tubular distensibility. Youngs modulus for basement membranes from all tubular segments corresponded to that of tendon collagen. Membrane hydraulic conductivity was measured in two ways: (a) from the rate of transmural flow in response to an applied difference in hydrostatic pressure and, (b) from the rate of transmural flow in response to a difference in colloid osmotic pressure. The hydraulic conductivity of tubular basement membranes was 300-800 times greater than that of the intact epithelial layer. Basement membrane hydraulic conductance was similar to that of peritubular and glomerular capillaries in vivo. The hydrostatic conductance of tubular basement membranes exceeded the osmotic conductance by 3-10-fold owing largely to the fact that the membranes were moderately permeable to the osmotic solute (albumin). In view of these findings we suggest that oncotic and hydrostatic pressure may play an important role in the movement of tubular absorbate from the epithelial compartment into the renal interstitium.

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

Why kidneys fail in autosomal dominant polycystic kidney disease

The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.

The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52 kb gene with a 14 kb mRNA. The PKD2 protein is also large (110 kd) and is thought to interact with polycystin. ADPKD1 is caused by mutated DNA that encodes an abnormal form of polycystin. Polycystin appears to have a normal role in the differentiation of epithelial cells, and when defective, these cells fail to maturate fully. These incompletely differentiated cells proliferate abnormally and express altered amounts of otherwise normal electrolyte transport proteins that result in excessive secretion of solute and fluid into the cysts. The proliferation of the cells and the associated apoptosis, and the secretion of the fluid into the cysts created by the enlarging tubule segments appear to be regulated by growth factors, hormones, and cytokines that can alter the extent to which the disease is clinically expressed among individuals. The formation of the cysts is associated with complex changes in the extracellular matrix of the kidneys and other organs that may be directly or indirectly tied to mutated polycystin. The summation of these pathogenetic elements leads to renal interstitial infiltration, with monocytes, macrophages, and fibroblasts culminating in fibrosis and progressive loss of renal function. The modem understanding of cyst pathogenesis opens opportunities to develop treatments that may diminish or halt altogether the progression of this disease.