Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.

Mineral bone disease in autosomal dominant polycystic kidney disease.

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 µm3/µm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

Expanded Imaging Classification of Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%-10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m2 for class 2Ae, and from -1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m2 for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease.

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5-24.9 kg/m2; reference; n=192), overweight (25.0-29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2 The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (ß=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted ß =-0.08; 95% CI, -0.15 to -0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials.

BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS: Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS: Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES: Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS: Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS: Relatively short follow-up of a clinical trial population. CONCLUSIONS: Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease.

The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.

Angiotensin blockade in late autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS: There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS: Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

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.).

Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial.

BACKGROUND: Patients with mild autosomal dominant polycystic kidney disease (ADPKD) are less likely to be informative in randomized clinical trials (RCTs). We previously developed an imaging classification of ADPKD (typical diffuse cyst distribution Class 1A-E and atypical cyst distribution Class 2) for prognostic enrichment design in RCTs. We investigated whether using this classification would have increased the power to detect a beneficial treatment effect of rigorous blood pressure (BP) control on HALT-PKD participants with early disease (Study A). METHODS: Post hoc analysis of the early disease HALT-PKD study, an RCT that studied the effect of rigorous versus standard BP control on rates of total kidney volume (TKV) increase and estimated glomerular filtration rate (eGFR) decline in ADPKD patients with eGFR >60 mL/min/1.73 m2. RESULTS: Five hundred and fifty-one patients were classified by two observers (98.2% agreement) into Class 1A (6.2%), 1B (20.3%), 1C (34.1%), 1D (22.1%), 1E (11.8%) and 2 (5.4%). The TKV increase and eGFR decline became steeper from Class 1A through 1E. Rigorous BP control had been shown to be associated with slower TKV increase, without a significant overall effect on the rate of eGFR decline (faster in the first 4 months and marginally slower thereafter). Merging Classes 1A and 2 (lowest severity), 1B and 1C (intermediate severity) and 1D and 1E (highest severity) detected stronger beneficial effects on TKV increase and eGFR decline in Class 1D and E with a smaller number of patients. CONCLUSIONS: Strategies for prognostic enrichment, such as image classification, should be used in the design of RCTs for ADPKD to increase their power and reduce their cost.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

TECHNOLOGY AND THE FUTURE OF KIDNEY CARE.

The coming decades will see enormous changes in how kidney disease is diagnosed and treated. We can only predict a small proportion of the discoveries that will catalyze these changes. It is exhilarating to imagine how such discoveries might soon translate into improved medical care for millions of people.

Liver involvement in early autosomal-dominant polycystic kidney disease.

BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.

iPS cell technology: Future impact on renal care.

iPS cells from patients with kidney disease are a new tool with the potential to impact the future of renal care. They can be used in the laboratory to model the pathophysiology of human kidney disease, and have the potential to establish a new area of immunocompatible, on-demand renal transplantation. Critical challenges remain before the full potential of these cells can be accurately assessed. We need to understand whether the derived cell types are mature and can replace kidney function(s). To what extent can iPS cells model kidney disease in the simplified environment of cell culture? Ultimately, successful integration of these cells as autograft therapies will require demonstration of safety and efficacy equal or superior to the existing gold standards of kidney allograft transplantation and dialysis. Specific educational and infrastructural changes will be necessary if these specialized technologies are to be adopted as an accepted modalities in clinical medicine. Given these barriers, the first fruit of these labors is likely to be improved understanding of pathophysiological pathways in human IPS cell disease models, followed by drug discovery and testing. These experiments will lead naturally to improvements in differentiation and experiments in animal models testing function. The time course to achieve the desired goals remains unknown, but the ultimate hope is that new, more effective and less expensive modalities for renal replacement therapy will occur in the foreseeable future. A new standard of care for patients is anticipated that addresses limitations of currently available treatments.

Health-related quality of life in patients with autosomal dominant polycystic kidney disease and CKD stages 1-4: a cross-sectional study.

BACKGROUND: In people with early autosomal dominant polycystic kidney disease (ADPKD), average total kidney volume (TKV) is 3 times normal and increases by an average of 5% per year despite a seemingly normal glomerular filtration rate (GFR). We hypothesized that increased TKV would be a source of morbidity and diminished quality of life that would be worse in patients with more advanced disease. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,043 patients with ADPKD, hypertension, and a baseline estimated GFR (eGFR)> 20mL/min/1.73m(2). PREDICTORS: (1) eGFR, (2) height-adjusted TKV (htTKV) in patients with eGFR> 60mL/min/1.73m(2). OUTCOMES: 36-Item Short Form Health Survey (SF-36) and the Wisconsin Brief Pain Survey. MEASUREMENTS: Questionnaires were self-administered. GFR was estimated from serum creatinine using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. htTKV was measured by magnetic resonance imaging. RESULTS: Back pain was reported by 50% of patients, and 20% experienced it "often, usually, or always." In patients with early disease (eGFR> 60mL/min/1.73m(2)), there was no association between pain and htTKV, except in patients with large kidneys (htTKV> 1,000mL/m). Comparing across eGFR levels and including patients with eGFRs< 60mL/min/1.73m(2), patients with eGFRs of 20-44mL/min/1.73m(2) were significantly more likely to report that pain impacted on their daily lives and had lower SF-36 scores than patients with eGFRs of 45-60 and ≥60mL/min/1.73m(2). Symptoms relating to abdominal fullness were reported by 20% of patients and were related significantly to lower eGFRs in women, but not men. LIMITATIONS: TKV and liver volume were not measured in patients with eGFR < 60mL/min/1.73m(2). The number of patients with eGFRs< 30mL/min/1.73m(2) is small. Causal inferences are limited by cross-sectional design. CONCLUSIONS: Pain is a common early symptom in the course of ADPKD, although it is not related to kidney size in early disease (eGFR> 60mL/min/1.73m(2)), except in individuals with large kidneys (htTKV> 1,000 mL/m). Symptoms relating to abdominal fullness and pain are greater in patients with more advanced (eGFR, 20-45mL/min/1.73m(2)) disease and may be due to organ enlargement, especially in women. More research about the role of TKV in quality of life and outcomes of patients with ADPKD is warranted.

Therapeutic advances in the treatment of polycystic kidney disease.

The spectrum of polycystic kidney disease (PKD) comprises a family of inherited syndromes defined by renal cyst formation and growth, progressive renal function loss and variable extrarenal manifestations. The most common form, autosomal-dominant PKD is caused by mutations in one of two genes, PKD1 or PKD2. Recent developments in genomic and proteomic medicine have resulted in the discovery of novel genes implicated in the wide variety of less frequent, recessive PKD syndromes. Cysts are the disease, and overall cystic burden, measured by MRI as total kidney volume, is being established as the best available biomarker of disease progression. Current state-of-the-art therapy is aimed at quality treatment for chronic renal insufficiency and cyst-related complications. Recent therapeutic studies have focused on mechanisms reducing intracellular cyclic AMP levels, blocking the renin-angiotensin-aldosterone system and inhibiting the mTOR-signaling pathway. PKD therapies with vasopressin antagonists and somatostatin analogues result in the reduction of intracellular cAMP levels and have shown limited clinical success, but side effects are prominent. Similarly, mTOR pathway inhibition has not shown significant therapeutic benefits. While the HALT-PKD study will answer questions by the end of 2014 about the utility of renin-angiotensin-aldosterone system blockade and aggressive blood pressure control, the next generation of PKD therapy studies targeting proliferative mechanisms of cyst expansion are already under way. Advances in research on the molecular mechanisms of cystogenesis will help design novel targeted PKD therapies in the future.

Analysis of baseline parameters in the HALT polycystic kidney disease trials.

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Polycystic kidney disease: a 2011 update.

PURPOSE OF REVIEW: The review will examine clinically relevant advances in the area of polycystic kidney disease (PKD), mainly focusing on autosomal dominant polycystic kidney disease (ADPKD). Discussion will focus on predicting the course of ADPKD, clinical trials and new research endeavors. RECENT FINDINGS: During the past several years PKD research has been one of the most prolific areas in investigative nephrology. Research endeavors have focused on decreasing cyst proliferation and cyst fluid formation based on an understanding of the pathophysiology of these processes. If cysts can be prevented from growing, kidney function can be better preserved. SUMMARY: Progression of this most common inherited kidney disorder can be altered by understanding that cysts are the disease in ADPKD. Assessing total kidney volume and noting its relationship to glomerular filtration rate is key in predicting the course of the disease and will aid in the evaluation of the new research initiatives that are designed to stop cyst proliferation and fluid secretion into the kidney cysts. The role of biomarkers is an advancement in predicting PKD progression and can potentially be used in evaluation of treatments for this disease. Complications of PKD alter the course and prognosis; hence management approaches will be addressed.