Journal of the American Society of Nephrology. 2018;29(10):2593-2600
Estimates of Prevalence of Polycystic Kidney Disease Using Population Sequencing
It is difficult to estimate the prevalence of autosomal dominant polycystic kidney disease (ADPKD). Early studies put the lifetime risk of ADPKD at about one per 1000 in the general population; however, recent epidemiologic studies found a point prevalence of three to five cases per 10,000 in the general population.
Matthew B. Lanktree, MD, PhD, and colleagues recently conducted a study to measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime prevalence of ADPKD. The researchers used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences).
Stringent criteria for defining rare variants in the genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5), and potential cystic disease modifiers were used in the study. The researchers evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tolls to predict pathogenicity.
The study resulted in a lower boundary for lifetime ADPKD prevalence of 9.43 cases per 10,000 sequenced pathogenic mutations. Results were similar from whole-genome and exome data. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively.
“Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD,” the researchers said.
Review of Mechanisms Associated with Progression of Renal Injury Progression Other than Cyst Formation
Nephrology Dialysis Transplantation. 2018;33(11):1887-1895
Common clinical manifestations in autosomal dominant polycystic disease (ADPKD) include hypertension and progressive decline in kidney function. Currently, the main pathogenic mechanism for the onset of those manifestations is considered to be cyst formation in patients with ADPKD. However, according to Vasileios Raptis, MD, and colleagues, the presence of polycystins in the vessels and cilia of the endothelial cells and vascular smooth muscle cells, as well as development of hypertension prior to decline in renal function and the prognostic implications for development of hypertension, may indicate that polycystins have a key role for endothelial damage in several vascular beds.
Pathologic polycystins induce abnormalities in intracellular calcium, which affect various cellular organelles and functions and may lead to several abnormal biochemical reactions within endothelial cells and to an imbalance between oxidant and antioxidant capacity. There are consequences to this process including accumulation of asymmetric-dimethylarginine, which is associated with progression of renal damage and interferes with the normal vascular response due to inhibition of nitric oxide. Long-term reduced nitric oxide bioavailability would result in relative vasoconstriction, impaired renal blood flow, and vascular remodeling.
Existing data from studies supporting the hypothesis that mechanisms other than cyst formation also contribute to the pathogenesis of hypertension and decline in renal function in patients with ADPKD are reported in this review.
CHRONIC KIDNEY DISEASE
Health Outcome Priorities among Older Adults with CKD
Journal of the American Society of Nephrology. 2018;29(12):2870-2878
Significant pain and disability characterize advanced chronic kidney disease in older adults. Patient priorities should be considered as part of clinical decision-making to ensure that patients’ nephrology care is consistent with their values.
Sarah J. Ramer and colleagues conducted a study among patients ≥60 years of age with non–dialysis-dependent CKD stage 4 or 5 receiving care at a CKD clinic. The patients completed a validated health outcome prioritization tool to determine their health outcome priorities. The nephrology provider then completed the same tool for each patient. Patients were also asked to self-rate their health and completed an end-of-life scenarios instrument.
The researchers assessed the associations between priorities and self-reported health status and between priorities and acceptance of common end-of-life scenarios. They also measured agreement between patients’ priorities and the providers’ perceptions of priorities.
Among the 217 patients (median 71 years of age), the top health outcome priority was maintaining independence (49%), followed by staying alive (35%), reducing pain (9%), and reducing other symptoms (6%). Staying alive was ranked the third or fourth priority for nearly half of the patients. There was no association between patients’ self-reported health status and top priority; there was significant difference between groups with different top priorities in acceptance of some end-of-life scenarios.
Provider perceptions of patients’ top health outcome priorities were correct only 35% of the time. Likewise, patient-provider agreement for any individual health outcome was poor.
In conclusion, the researchers said, “Nearly half of older adults with advanced CKD ranked maintaining independence as their top health outcome priority. Almost as many ranked being alive as their last or second-to-last priority. Nephrology providers demonstrated limited knowledge of their patients’ priorities.”
Treatment Differences in Kidney Function with Empagliflozin
Journal of the American Society of Nephrology. 2018;29(11):2755-2769
Results of the EMPA-REG OUTCOME trial demonstrated that the progression of chronic kidney disease (CKD) in patients with type 2 diabetes and cardiovascular disease was slowed with empagliflozin. Using a prespecified statistical approach, Christopher Wanner, MD, and colleagues assessed treatment differences in kidney function. The assessment was conducted by analyzing slopes of change in estimated glomerular filtration rate (eGFR).
A total of 7020 participants were randomized 1:1:1 to empagliflozin 10 mg per day, empagliflozin 25 mg per day, or placebo added to standard of care. The researchers calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline top week 4); chronic maintenance treatment (week 4 to last value on treatment): and post-treatment (last value on treatment to follow-up).
Across all periods, compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes. On initiation of treatment, adjusted mean slope eGFR (change in eGFR per week, mL/min/1.73 m2) decreased with empagliflozin (–0.77; 95% confidence interval [CI], –0.83 to –0.71: placebo, 0.01; 95 % CI, –0.08 to 0.10; P<.001).
During chronic treatment, there was no decline in annual mean slope (mL/min/1.73 m2 per year) with empagliflozin (empagliflozin: 0.23; 95% CI, 0.05 to 0.40; placebo: –1.46; 95% CI, –1.74 to –1.17; P<.001). Following drug cessation, the adjusted mean eGFR slope (mL/min/1.73 m2 per week) increased and mean eGFR retuned toward baseline level only in the empagliflozin group (0.56; 95% CI, 0.49 to 0.62: placebo, –0.02; 95% CI, –0.12 to 0.08; P<.001). Across patient subgroups at higher CKD risk, results were similar.
“The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function,” the researchers said.
Cardiorenal Prognosis by Proteinuria Level in Diabetic Kidney Disease
Nephrology Dialysis Transplantation. 2018;33(11):1942-1949
Roberto Minutolo, MD, PhD, and colleagues conducted a pooled analysis to determine whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by diabetes per se or by the extent of proteinuria. The researchers pooled results of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system to compare the risk of end-stage renal disease (ESRD) between patients with (n=693) and without diabetes (n=1481) stratified by proteinuria level (<0.15, 0.15 to 0.49, 0.5 to 1, and >1 g/day).
The DM-CKD group was older (69 vs 65 years), had higher body mass index (29.6 vs 27.5 kg/m2), and systolic blood pressure (143 vs 136 mmHg), prevalent cardiovascular disease (48% vs 29%), and lower estimated glomerular filtration rate (34.5 vs 36.3 mL/min/1.73 m2). In the 4.07 years of follow-up, 466 patients progressed to ESRD, 334 died, and 401 cardiovascular events occurred.
In a patient subgroup with urine protein <0.15 g per day (n=662), the risks of ESRD, cardiovascular events, and mortality were similar in the diabetic and nondiabetic groups. In the patients with DM-CKD, the risk of mortality was higher in proteinuric patients (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.25-2.95); HR, 1.99 (95% CI, 1.26-3.15) and HR, 1.98 (95% CI, 1.28-3.06) for proteinuria 0.15 to 0.49, 0.5 to 1, and >1 g per day, respectively). In the nondiabetic group, the mortality risk increased only for proteinuria 0.5 to 1 g per day (HR, 1.60; 955 CI, 1.07-2.40) and >1 g per day (HR, 1.69; 95% CI, 1.20-2.55).
Cardiovascular risk in both groups had a similar trend. The risk of ESRD increased progressively across strata >0.5 g per day independent of diabetic status.
In conclusion, the researchers said, “We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and cardiovascular events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.”
Prediction of AVF Maturation from Ultrasound Measurements
Journal of the American Society of Nephrology. 2018;29(11):2735-2744
The utility of early postoperative ultrasound measurements in predicting clinical maturation of arteriovenous fistula (AVF) is uncertain. Michelle L. Robbin, MD, and colleagues conducted a study to examine the relationship of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at day 1 and 2 and 6 weeks. The multicenter, observational cohort study included 602 participants. Ultrasound measurements that independently predicted unassisted and overall AVF maturation were identified using a backward elimination algorithm.
Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. The study assessed the accuracy of the resulting models for clinical prediction.
AVF blood flow, diameter, and depth at each ultrasound measurement time each statistically significantly predicted both unassisted and overall clinical maturation. After accounting for blood flow, diameter, and depth, there was no association between the remaining ultrasound parameters or with the case-mix factors and clinical AVF maturation.
The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation.
“AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction,” the researchers said.
Graft and Patient Long-Term Survival among Transplant Recipients with Fabry Disease
Mutations in the a-galactosidase A gene that obliterate or markedly reduce a-galactosidase A activity are the cause of Fabray disease, a rare X-linked lysosomal storage disorder. Reduction in a-galactosidase A results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabray nephropathy can lead to the development of end-stage renal disease and the need for kidney transplantation. There are few data available on the long-term outcomes and overall Fabry disease patient survival after kidney transplantation.
Sara Ersözlü, MD, and colleagues reported on long-term treatment and follow-up of 17 patients with Fabry disease (15 male and two female) who received kidney transplants. The patients were treated at four specialized Fabry centers.
Post-transplant follow-up ranged from 0.8 to 25 years (median, 11.5 years). Compared with matched controls, graft survival was similar and death-censored graft survival was superior in the Fabry group. Fabry patients died with functioning kidneys, mostly from cardiac causes.
In two of the male subjects (14 and 23 years post-transplant), the grafts had few typical Fabry disease lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells.
“We conclude that kidney transplantation has an excellent long-term outcome in Fabry disease,” the researchers said.
Donor-Specific Antibody Screening in Pediatric Transplant Recipients
De novo donor-specific antibodies (dnDSA) have been associated with rejection and graft loss in kidney transplant recipients and DSA screening is recommended in all recipients. However, according to Rachel M. Engen, MD, and colleagues, the clinical significance of dnDSA detected by screening patients with a stable creatinine is unclear.
Dr. Engen et al. conducted a study among 103 patients <18 years who received a first kidney alone transplant between December 1, 2007, and December 31, 2013. The patients underwent DSA screening every 3 months for 2 years post-transplant, with additional testing as clinically indicated. There was no treatment given for DSAs in the absence of biopsy-proven rejection.
Nineteen percent (n=20) of patients had dnDSA first detected in a screening test, and 13% (n=13) had dnDSA first detected on a for-cause test. Mean post-transplant follow-up time was 4.4 years.
There was an association between screening-detected dnDSA and an increased risk of rejection within 3 years, microvascular inflammation, and C4d staining on a 2-year protocol biopsy. In a Cox proportional hazards regression, there was no association between screening-detected dnDSA with time to 30% decline in estimated glomerular filtration rate or graft loss.
There was an association between dnDSA first detected on for-cause testing and a 2.8 times increased risk of decline in graft function and a 7.34 times increased risk of graft loss, compared with those who did not develop dnDSA.
In conclusion, the researchers said, “The clinical setting in which dnDSA is first detected impacts the association between dnDSA and graft function. Further research is needed to clarify the role of dnDSA screening in pediatric kidney transplantation.”