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 m2 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.

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.

The peritoneal cavity is important in clinical medicine because of its use as a portal of entry for drugs utilized in regional chemotherapy and as a means of dialysis for anephric patients. The barrier between the therapeutic solution in the cavity and the plasma does not correspond to the classic semipermeable membrane but instead is a complex structure of cells, extracellular matrix, and blood microvessels in the surrounding tissue. New research on the nature of the capillary barrier and on the orderly array of extracellular matrix molecules has provided insights into the physiological basis of osmosis and the alterations in transport that result from infusion of large volumes of fluid. The anatomic peritoneum is highly permeable to water, small solutes, and proteins and therefore is not a physical barrier. However, the cells of the mesothelium play an essential role in the immune response in the cavity and produce cytokines and chemokines in response to contact with noncompatible solutions. The process of inflammation, which depends on the interaction of mesothelial, interstitial, and endothelial cells, ultimately leads to angiogenesis and fibrosis and the functional alteration of the barrier. New animal models, such as the transgenic mouse, will accelerate the discovery of methods to preserve the functional peritoneal barrier.

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk)1/2. The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.

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 m2 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.)

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK, and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.

Background In people with early autosomal dominant polycystic kidney disease (ADPKD) average total kidney volume (TKV) is three times normal and increases by an average of 5% per year despite 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 subjects with more advanced disease. Study Design Cross-sectional. Setting & Participants 1043 subjects with ADPKD, hypertension and a baseline estimated glomerular filtration rate (eGFR) >20 mL/min/1.73 m2. Predictors 1) eGFR 2) height-adjusted TKV (htTKV) in subjects with eGFR >60 mL/min/1.73 m2. Outcomes 36-Item Short Form Health Survey (SF-36) and the Wisconsin Brief Pain Survey. Measurements Questionnaires were self- administered. eGFR was estimated from serum creatinine using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. The htTKV was measured by MRI. Results Back pain was reported by 50% of subjects and 20% experienced it ‘often, usually, or always’. In subjects with early disease (eGFR >60 mL/min/1.73 m2) there was no association between pain and htTKV, except in patients with large kidneys (htTKV >1000 mL/m). Comparing across eGFR levels and including patients with eGFR <60 mL/min/ 1.73 m2, patients with eGFR 20–44 mL/min/1.73 m2 were significantly more likely to report that pain impacted on their daily lives and had lower SF-36 scores than patients with eGFR 45–60 and ≥60 mL/min/1.73 m2. Symptoms relating to abdominal fullness were reported by 20% of patients, and were significantly related with lower eGFR in women but not men. Limitations TKV and liver volume were not measured in subjects with eGFR <60 mL/min/1.73 m2. The number of patients with eGFR <30 mL/min/1.73 m2 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 >60 mL/min/1.73 m2), except in individuals with large kidneys (htTKV >1000 mL/m). Symptoms relating to abdominal fullness and pain are greater in patients with more advanced (eGFR 20–45 mL/min/ 1.73 m2) 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 ADPKD patients is warranted.