Automated Segmentation of Kidneys from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease

Background and objectives

Our study developed a fully automated method for segmentation and volumetric measurements of kidneys from magnetic resonance images in patients with autosomal dominant polycystic kidney disease and assessed the performance of the automated method with the reference manual segmentation method.

Design, setting, participants, & measurements

Study patients were selected from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. At the enrollment of the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Study in 2000, patients with autosomal dominant polycystic kidney disease were between 15 and 46 years of age with relatively preserved GFRs. Our fully automated segmentation method was on the basis of a spatial prior probability map of the location of kidneys in abdominal magnetic resonance images and regional mapping with total variation regularization and propagated shape constraints that were formulated into a level set framework. T2–weighted magnetic resonance image sets of 120 kidneys were selected from 60 patients with autosomal dominant polycystic kidney disease and divided into the training and test datasets. The performance of the automated method in reference to the manual method was assessed by means of two metrics: Dice similarity coefficient and intraclass correlation coefficient of segmented kidney volume. The training and test sets were swapped for crossvalidation and reanalyzed.

Results

Successful segmentation of kidneys was performed with the automated method in all test patients. The segmented kidney volumes ranged from 177.2 to 2634 ml (mean, 885.4±569.7 ml). The mean Dice similarity coefficient ±SD between the automated and manual methods was 0.88±0.08. The mean correlation coefficient between the two segmentation methods for the segmented volume measurements was 0.97 (P<0.001 for each crossvalidation set). The results from the crossvalidation sets were highly comparable.

Conclusions

We have developed a fully automated method for segmentation of kidneys from abdominal magnetic resonance images in patients with autosomal dominant polycystic kidney disease with varying kidney volumes. The performance of the automated method was in good agreement with that of manual method.     

Autosomal Dominant Polycystic Kidney Disease in which the Polycystic Liver Volume Was Reduced by Rigorous Blood Pressure Control

Polycystic liver disease (PLD) is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). However, current treatments for PLD are only supportive. We experienced a case of enlarged kidneys and liver in a 53-year-old Japanese man with ADPKD who was on hemodialysis. He underwent renal transcatheter arterial embolization (TAE) for enlarged kidneys. His blood pressure (BP) decreased after renal TAE, and his liver volume decreased from 5,259 mL to 4,647 mL (11.6% reduction) within 1 year after renal TAE. This case suggests that rigorous blood pressure control may be beneficial for ameliorating enlarged PLD.     

Changing Referral Characteristics of Patients with Autosomal Dominant Polycystic Kidney Disease

Objective

Autosomal dominant polycystic kidney disease is the most frequent life-threatening hereditary disease. The study objective was to assess whether the clinical characteristics of patients with autosomal dominant polycystic kidney disease who are referred to a major autosomal dominant polycystic kidney disease center have changed over time.

Methods

The clinical characteristics of patients with autosomal dominant polycystic kidney disease were compared between period A (1961-1990) and period B (1991-2011). The study took place at the Autosomal Dominant Polycystic Kidney Disease Center at the University of Colorado. A total of 837 patients referred with autosomal dominant polycystic kidney disease were included. Blood pressure control and renin-angiotensin-aldosterone system inhibition were instituted. Renal function, blood pressure, end-stage renal disease, and mortality were analyzed.

Results

The results in period B compared with period A demonstrated an earlier age of autosomal dominant polycystic kidney disease diagnosis (29 vs 35 years, P < .001), lower mean blood pressure (129/82 vs 142/91 mm Hg, P < .001), better estimated glomerular filtration rate (63.6 vs 44.6 mL/min, P < .001), and more therapy with angiotensin-converting enzyme inhibition (42.5% vs 13.6%, P < .001). Time from birth to end-stage renal disease (52.8 ± 0.6 vs 49.1 ± 0.6 years, P < .001) and birth to death (63.5 ± 1.5 years vs 57.2 ± 1.0 years, P < .001) was longer in period B compared with period A when adjusted for age at diagnosis, sex, and estimated glomerular filtration rate. The study was retrospective, which is a limitation.

Conclusions

In period B, there was significantly better blood pressure control, more renin-angiotensin-aldosterone system inhibition, better preservation of renal function, and a longer period from birth to end-stage renal disease and death.     

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Background and objectives

Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.

Design, setting, participants, & measurements

Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-α were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011–2013 and in 27 controls who were selected from a general population–based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.

Results

Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, 1.4 [interquartile range, 1.2–1.9] versus 0.6 [0.4–0.8] µg/24 hours [P<0.001] and 157.9 [83.1–225.9] versus 77.2 [37.2–174.3] pg/ml [P=0.04]). In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-α did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=−0.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid–binding protein, whereas higher EGF excretion and TGF-α excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2–1.9] to 2.4 [2.1–3.1] µg/24 hours; P<0.001).

Conclusion

In patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.     

Cyst Infections in Patients with Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Cyst infection is a complex diagnostic and therapeutic issue in patients with autosomal dominant polycystic kidney disease (ADPKD); however, published data regarding the diagnosis and the management of cyst infections in patients with ADPKD are sparse.Design, setting, participants, & measurements: A retrospective study was conducted in a referral center for patients with ADPKD in Paris, France. We identified using a computerized database all patients who had ADPKD and were admitted in the nephrology department of Hôpital Necker between January 1998 and August 2008 with likely or definite renal and/or hepatic cyst infection. Medical files of all included patients were reviewed.Results: Among 389 identified patients with ADPKD, 33 (8.4%) had 41 episodes of cyst infection, including eight definite and 33 likely cases. The incidence of cyst infections in patients with ADPKD was 0.01 episode per patient per year. Microbiological documentation was available for 31 episodes (75%), Escherichia coli accounting for 74% of all retrieved bacterial strains. Positron emission tomography scan proved superior to ultrasound, Computed tomography scan, and magnetic resonance imaging for the detection of infected cysts. Clinical efficacy of initial antibiotic treatment was noted in 71% of episodes. Antibiotic treatment modification was more frequently required for patients who were receiving initial monotherapy compared with those who were receiving bitherapy. Large (diameter >5 cm) infected cysts frequently required drainage.Conclusions: Positron emission tomography scan will probably make the diagnosis of cyst infections easier and more accurate. Antibiotic association, including a fluoroquinolone, and the drainage of large infected cysts remain the main treatment for cyst infections.Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited disorder affecting one in 500 to one in 1000 live births and accounting for 4 to 10% of dialysis patients. The most striking feature of ADPKD is the occurrence of numerous renal and hepatic cysts, which arise from various renal tubule segments and lead to an increased kidney size. Cysts are also associated with some of the most common complications of ADPKD: Intracystic bleeding, gross hematuria, obstruction mainly caused by liver cysts, and, most important, infections. Kidney and liver cyst infection is a complex diagnostic and therapeutic challenge; however, the literature on the diagnosis and the management of urinary tract infections and particularly cyst infections in patients with ADPKD is relatively sparse. The clinical, microbiological, and radiologic features of cyst infections as well as treatment regimens remain ill-defined (1–3). We conducted a retrospective, single-center study to assess the clinical and radiologic presentation and treatment outcomes of cyst infections in patients with ADPKD.     

Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease: An Open-Label Randomized Controlled Pilot Study

Background and objectives

The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in ¹²⁵I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily.

Design, setting, participants, & measurements

In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2–5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5–8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography.

Results

Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m²; n=9) than in the SC group (−11.2±9.1 ml/min per 1.73 m²; n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6±12.1 ml/min per 1.73 m²; n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range±SD, 2.40±0.64 to 2.90±1.20 ng/ml) compared with those in the STD group (3.93±2.27 to 5.77±1.06 ng/ml) (P<0.01).

Conclusion

Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.     

Improved Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease in Denmark

Background and objectives: The introduction of new therapies, including agents that block the renin-angiotensin system, may have affected progression of autosomal dominant polycystic kidney disease (ADPKD). We investigated whether the age when reaching ESRD and survival during renal replacement therapy in Danish patients with ADPKD changed from January 1, 1990, through December 31, 2007.Design, setting, participants, & measurements: According to the Danish National Registry on Regular Dialysis and Transplantation, 693 patients with ADPKD reached ESRD in the study period. The 18 years were divided into three consecutive 6-year intervals.Results: The incidence of reaching ESRD for patients with ADPKD increased from 6.45 per million people in 1990 through 1995 to 7.59 per million people in 2002 through 2007, and the mean age at onset of ESRD increased by 4.7 years. The age-adjusted male-to-female ratio for onset of ESRD changed from 1.6 to 1.1, indicating a trend toward similar progression in both genders. From onset of ESRD, a Cox regression analysis to compare the first and second 6-year intervals, adjusted for age, gender, and treatment modality, showed that patient survival improved by 38%. Although NS, a similar trend was found during the second and third time intervals.Conclusions: This study demonstrates that in Danish patients with ADPKD, the prognosis had significantly improved during the study period. Furthermore, the results indicate that male gender may be losing its importance as a risk factor for progression in ADPKD.Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that affects an estimated 4 to 6 million people worldwide (1). In Denmark, the prevalence of ADPKD has been estimated to be one per 1000 people, and it accounts for approximately 8% of patients who are on renal replacement therapy (RRT) (2,3). ADPKD is a genetically heterogeneous disease with mutations in two genes, PKD1 and PKD2, which accounts for 85 and 15% of cases, respectively (4,5). Mutations in PKD1 lead to more severe disease as a result of earlier development of cysts, compared with PKD2 mutations (6). Hypertension is an important contributor to progression in ADPKD, and cardiovascular morbidity and mortality are the main causes of death (7–9). Activation of the intrarenal renin-angiotensin system may be associated with progression in ADPKD (10), and treatment with angiotensin-converting enzyme inhibitors (ACEIs) has been shown to reduce proteinuria and reduce the left ventricular mass index (LVMI) in patients with ADPKD (11,12). Statins may also have beneficial effects in ADPKD (13), and several ongoing clinical trials are investigating various strategies to slow disease progression in ADPKD (14).This study describes the epidemiology of Danish patients with ADPKD who reached ESRD between 1990 and 2007. Our objective was to investigate how the increasing knowledge of factors that influence progression in ADPKD has affected the prognosis for events such as ESRD and death in the Danish population of patients with ADPKD. This has not previously been described in a national study, but others have demonstrated a significant slowing of renal demise in patients with ADPKD between 1985 and 2001 (15).     

Peritoneal Dialysis is Limited by Kidney and Liver Volume in Autosomal Dominant Polycystic Kidney Disease

We evaluated the influence of kidney volume (KV) and liver volume (LV) on continuation of peritoneal dialysis (PD) in patients with autosomal dominant polycystic kidney disease (PKD). Twenty‐two PKD patients on PD were retrospectively investigated after being divided into two groups. Group 1 comprised 15 patients who started PD at our hospital and group 2 was composed of seven patients referred from other hospitals for treatment of renomegaly by transcatheter arterial embolization (TAE) at 47.1 ± 21.8 months after commencing PD. In group 1, KV for both kidneys (mean ± SD) was 2787 ± 1945 mL (range: 1043 to 6816 mL), LV was 2198 ± 1139 mL (1005 to 4116 mL), and the total organ volume (TV = KV + LV) was 4985 ± 1815 mL (2320 to 8912 mL). In the patient with the largest TV from group 1 (KV of 6816 mL, TV of 8912 mL, and TV/BMI ratio of 426, PD was stopped due to dialysate leakage. However, dialysate leakage did not occur in the other 14 patients (TV ≦ 7963 mL and TV/BMI ratio of 353 at the start of PD). In group 2, KV was 5822 ± 1597 mL (3832 to 8862 mL), LV was 1776 ± 519 mL (1271 to 2671 mL), and TV was 7597 ± 1431 mL (5505 to 10358) before TAE. Leakage of dialysate did not occur with a mean infusion volume of 1530 ± 370 mL (1000 mL to 2000 mL), even after renomegaly and hepatomegaly progressed to the maximum TV/BMI ratio of 359. Six patients from the two groups developed new abdominal hernias at 36 ± 5 months (6–55 months) after starting PD. These findings suggest that performance of PD may be limited by renomegaly and hepatomegaly in patients with PKD.     

Early Renal Abnormalities in Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Potential therapeutic interventions are being developed for autosomal dominant polycystic kidney disease (ADPKD). A pivotal question will be when to initiate such treatment, and monitoring disease progression will thus become more important. Therefore, the prevalence of renal abnormalities in ADPKD at different ages was evaluated.Design, setting, participants, & measurements: Included were 103 prevalent ADPKD patients (Ravine criteria). Measured were mean arterial pressure (MAP), total renal volume (TRV), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), and filtration fraction (FF). Twenty-four-hour urine was collected. ADPKD patients were compared with age- and gender-matched healthy controls.Results: Patients and controls were subdivided into quartiles of age (median ages 28, 37, 42, and 52 years). Patients in the first quartile of age had almost the same GFR when compared with controls, but already a markedly decreased ERPF and an increased FF (GFR 117 ± 32 versus 129 ± 17 ml/min, ERPF 374 ± 119 versus 527 ± 83 ml/min, FF 32% ± 4% versus 25% ± 2%, and RVR 12 (10 to 16) versus 8 (7 to 8) dynes/cm², respectively). Young adult ADPKD patients also had higher 24-hour urinary volumes, lower 24-hour urinary osmolarity, and higher urinary albumin excretion (UAE) than healthy controls, although TRV in these young adult patients was modestly enlarged (median 1.0 L).Conclusions: Already at young adult age, ADPKD patients have marked renal abnormalities, including a decreased ERPF and increased FF and UAE, despite modestly enlarged TRV and near-normal GFR. ERPF, FF, and UAE may thus be better markers for disease severity than GFR.Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease with an estimated prevalence between 1:400 and 1:1000 (1). The disease is characterized by pain, hematuria, and most importantly by progressive cyst formation in both kidneys, often leading to ESRD. Annually, 7.8 male and 6.0 female individuals per million of the population start renal replacement therapy in Europe because of polycystic kidneys, which is 6% of the new ESRD patients (2).Current treatment cannot prevent renal failure.(3,4) However, a better understanding of the pathophysiology of the disease and the availability of animal models identified promising candidate drugs for renal preservation (5). Clinical trials have been initiated for vasopressin-2 receptor antagonists, long-acting somatostatin analogues, and mammalian target of rapamycin inhibitors (6).When efficacy of these agents has been established, a pivotal question will be when to initiate such treatment. Given that ADPKD is a progressive condition, it seems most appropriate to initiate intervention as early in life as possible to delay or prevent long-term consequences, including renal failure and cardiac complications. On the other hand, ESRD occurs in approximately 50% of affected subjects (7,8), and it is not appropriate to expose those subjects that will not reach ESRD to excessive medical treatment to such an extent as to cause adverse events, especially because all candidate drugs have considerable side effects. Because of these reasons, it will be important to discover markers that identify ADPKD patients who will develop rapid disease progression. In such patients, therapy could be instituted in an early phase.It will therefore become important to define disease severity in ADPKD. Criteria to make this distinction are not crystal clear. GFR is believed to be stable for a long period, despite progression of renal anatomical abnormalities, because of compensatory hyperfiltration. GFR is therefore assumed not to be representative of disease severity (9,10). Total renal volume (TRV) has been proposed as a surrogate marker for disease progression (10). However, despite a significant overall association, there are subjects with a high TRV but normal renal function (11). Another parameter that is decreased early in the disease is urine concentrating capacity (12). Other candidate markers to define disease severity are albuminuria (13,14) and renal blood flow (RBF) (15,16). Despite evidence for the importance of finding early renal abnormalities in ADPKD, systematic evaluation of hemodynamic parameters, especially with respect to RBF, renal vascular resistance (RVR), and filtration fraction (FF), has received little attention. Therefore, we investigated renal parameters in ADPKD at different ages in comparison to healthy subjects.     

Toll‐Like Receptors in the Progression of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of chronic kidney disease. The intriguing role of innate immune system and inflammation become a target for potential therapeutic approach to slow progression. When toll‐like receptors (TLRs) signaling and their receptors activate, they start a cascade of intracellular signaling that induces the production of the inflammatory cytokines and chemokines. Thus, we aim to investigate the association of TLRs between progression of ADPKD. Ninety ADPKD patients and ninety matched controls were enrolled this prospective study and were followed during 3 years. TLR‐2 and TLR‐4 gene polymorphisms and expressions were measured. Hypertension was diagnosed with ambulatory blood pressure monitoring. Rapid progression was defined as sustained decline in estimated glomerular filtration rate (eGFR) of more than 5 mL/min per 1.73 m² per year. TLR‐4Asp299Gly polymorphisms were significantly different between patient and control group (P < 0.05). Also, TLR‐2 and TLR‐4 gene expressions were significantly different between the ADPKD patients and the control subjects (P < 0.05). The expression levels of both TLR‐2 and TLR‐4 were found to be higher in the rapid progression groups comparing the slow progression group (P < 0.05). TLR‐2 gene expression, hypertension and uric acid were found to be independent risk factors in identifying rapid progression in ADPKD patients. TLR‐2 and TLR‐4 gene expressions are associated with rapid progression in ADPKD patients. TLRs may play a role in the progression of ADPKD.     

Renal Squamous Cell Carcinoma-related Polymyositis in a Patient with Autosomal Dominant Polycystic Kidney Disease

A 74-year-old Japanese woman diagnosed with autosomal dominant polycystic kidney disease (ADPKD) was admitted to our institute for the further examination of right-side groin pain developing in the past week. The patient was diagnosed with polymyositis (PM). Diagnostic imaging showed a mass lesion measuring 8 cm and a renal stone in the right kidney. Immediately following surgical resection of the right kidney, the patient''s serum CK decreased to the normal range. A histopathological analysis showed well-differentiated squamous cell carcinoma. In conclusion, this case showed a close relationship between the occurrence of squamous cell carcinoma and the development of PM in an ADPKD patient.     

Effect of Pravastatin on Total Kidney Volume,Left Ventricular Mass Index,and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

Background and objectives

In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD.

Designs, setting, participants, & measurements

There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a ≥20% change in HtTKV, LVMI, or UAE over the study period.

Results

Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23%±3% versus 31%±3%; P=0.02).

Conclusions

Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.     

Pravastatin Therapy and Biomarker Changes in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease

Background and objectives

Disease-specific treatment options for autosomal dominant polycystic kidney disease are limited. Clinical intervention early in life is likely to have the greatest effect. In a 3-year randomized double-blind placebo-controlled phase 3 clinical trial, the authors recently showed that pravastatin decreased height-corrected total kidney volume (HtTKV) progression of structural kidney disease over a 3-year period. However, the underlying mechanisms have not been elucidated.

Design, setting, participants, & measurements

Participants were recruited nationally from July 2007 through October 2009. Plasma and urine samples collected at baseline, 18 months, and 36 months from 91 pediatric patients enrolled in the above-mentioned clinical trial were subjected to mass spectrometry–based biomarker analysis. Changes in biomarkers over 3 years were compared between placebo and pravastatin-treated groups. Linear regression was used to evaluate the changes in biomarkers with the percent change in HtTKV over 3 years.

Results

Changes in plasma concentrations of proinflammatory and oxidative stress markers (9- hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, and 15-hydroxyeicosatetraenoic acid [HETE]) over 3 years were significantly different between the placebo and pravastatin-treated groups, with the pravastatin group showing a lower rate of biomarker increase. Urinary 8-HETE, 9-HETE, and 11-HETE were positively associated with the changes in HtTKV in the pravastatin group.

Conclusions

Pravastatin therapy diminished the increase of cyclooxygenase- and lipoxygenase-derived plasma lipid mediators. The identified biomarkers and related molecular pathways of inflammation and endothelial dysfunction may present potential targets for monitoring of disease severity and therapeutic intervention of autosomal dominant polycystic kidney disease.     

Paraneoplastic Polymyositis Due to Renal Cell Carcinoma in a Patient with Autosomal Dominant Polycystic Kidney Disease

We herein report a 70-year-old man with malaise and muscle weakness that had developed within a month. The patient also had abdominal fullness due to polycystic kidney disease. Severe proximal skeletal muscle weakness and mild elevation of creatinine kinase to 301 IU/L were noted. A muscle biopsy of the right bicep showed polymyositis. Computed tomography showed a right renal mass, and an analysis after right nephrectomy identified clear cell carcinoma. The muscle weakness subsided one month after nephrectomy and intravenous immunoglobulin therapy. Therefore, we suspect that the development of polymyositis in this patient was closely related to renal cell carcinoma.     

Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease: Utility and Limitations

Background and objectives: Gene-based mutation screening is now available and has the potential to provide diagnostic confirmation or exclusion of autosomal dominant polycystic kidney disease. This study illustrates its utility and limitations in the clinical setting.Design, setting, participants, & measurements: Using a molecular diagnostic service, genomic DNA of one affected individual from each study family was screened for pathologic PKD1 and PKD2 mutations. Bidirectional sequencing was performed to identify sequence variants in all exons and splice junctions of both genes and to confirm the specific mutations in other family members. In two multiplex families, microsatellite markers were genotyped at both PDK1 and PKD2 loci, and pair-wise and multipoint linkage analysis was performed.Results: Three of five probands studied were referred for assessment of renal cystic disease without a family history of autosomal dominant polycystic kidney disease, and two others were younger at-risk members of families with autosomal dominant polycystic kidney disease being evaluated as living-related kidney donors. Gene-based mutation screening identified pathogenic mutations that provided confirmation or exclusion of disease in three probands, but in the other two, only unclassified variants were identified. In one proband in which mutation screening was indeterminate, DNA linkage studies provided strong evidence for disease exclusion.Conclusions: Gene-based mutation screening or DNA linkage analysis should be considered in individuals in whom the diagnosis of autosomal dominant polycystic kidney disease is uncertain because of a lack of family history or equivocal imaging results and in younger at-risk individuals who are being evaluated as living-related kidney donors.Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease worldwide affecting one in 500 to 1000 live births (1,2). It is characterized by focal and sporadic development and progressive enlargement of renal cysts, leading to ESRD in late middle age. Typically, only a few renal cysts are detected in most affected individuals before 30 yr of age; however, by the fifth decade of life, hundreds to thousands of renal cysts will be found in the majority of patients. Overall, it accounts for 5 to 8% of ESRD in developed countries (1,2). ADPKD is a systemic disorder associated with multiple extrarenal complications, such as cysts in nonrenal organs, valvular heart disease, colonic diverticula, inguinal hernias, and intracranial arterial aneurysms. It is genetically heterogeneous, with most cases arising from mutations in PKD1 (MIM 601313) and PKD2 (MIM 173910), located on chromosome 16p13.3 and 4q21–23, respectively (1–4). In a linkage-characterized European sample, PKD1 accounts for approximately 85% of the cases, whereas PKD2 accounts for most of the remainder (3,4). Although the clinical manifestations of the two gene types overlap completely, a strong locus effect is evident with more severe renal disease in PKD1 than PKD2 (median age at ESRD 54 versus 74, respectively) (5). In addition, both environmental and genetic modifiers have been implicated to account for the significant intrafamilial renal disease variability observed (6–8), and a mild allelic effect has been suggested for PKD1 but not PKD2 (7,8).PKD1 is a large gene consisting of 46 exons with an open reading frame of approximately 13 kb and is predicted to encode a protein of 4302 amino acids. Its entire 5′ region up to exon 33 has been duplicated six times more proximally on chromosome 16p, and the presence of these highly homologous pseudogenes has made genetic analysis of PKD1 difficult (1,2). Recent availability of protocols for long-range and locus-specific amplification of PKD1 has enabled the complete mutation screening of this complex gene (9–11). By contrast, PKD2 is a single-copy gene that consists of 15 exons with an open reading frame of approximately 3 kb and is predicted to encode a protein of 968 amino acids (1,2). Marked allelic heterogeneity is evident for ADPKD, with more than 200 different PKD1 and more than 50 different PKD2 mutations reported to date (2,9–11). The majority of these mutations are unique and scattered throughout both genes. Most of them are also predicted to be protein truncating (as a result of frame-shift deletion/insertion, nonsense changes, or splice defects), although a significant number of unclassified variants (UCV; e.g., in-frame deletions, missense changes) have been reported (9–11). Despite sequencing of all of the coding regions and exon-intron splice junctions in both genes only 45 to 63% of pathogenic mutations could be identified in three large clinical series (9–11).The diagnosis of ADPKD is generally straightforward when affected individuals present with a positive family history and enlarged kidneys with multiple cysts (12). Renal ultrasound is a sensitive method for this purpose, and age-dependant criteria based on cyst number have been derived for individuals who are born with 50% risk for PKD1 (13); however, because cyst formation is an age-dependent process, the false-negative rate of ultrasound-based diagnosis is higher in younger at-risk individuals or in those who are affected by PKD2, which is associated with later onset disease (14). Equivocal imaging results can be a source of diagnostic uncertainty in the clinic because the underlying gene type for most patients is unknown. In addition, renal cystic disease without a family history of ADPKD and evaluation of younger at-risk individuals as living-related kidney donors are clinical scenarios that often pose diagnostic challenges (12). Using a case series, we illustrate the utility and limitations of molecular diagnostics for ADPKD in the clinical setting.