Robert W. Schrier

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

BACKGROUNDnHypertension 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.nnnMETHODSnIn 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnIn 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.).

Endothelial dysfunction and oxidative stress in polycystic kidney disease.

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

Catecholamines and Renal Water Excretion

The in vivo mechanisms whereby systemic alpha- and beta-adrenergic stimulation exert opposing effects on renal water excretion are reviewed. An extrarenal mechanism is suggested since the effect of intravenous infusion of norepinephrine or isoproterenol on water excretion cannot be mimicked by the intrarenal administration of these agents. A ROLE OF VASOPRESSIN IS IMPLICATED SINCE NEITHER MAN NOR DOG WITHOUT A PITUITARY SOURCE OF VASOPRESSIN DEMONSTRATE THE SAME EFFECT OF CATECHOLAMINES ON WATER EXCRETION AS OBSERVED IN INTACT MAN AND DOG. Evidence also is presented that systemic alpha- and beta-adrenergic stimulation affect vasopressin release primarily by altering baroreceptor tone. The potential role of the autonomic nervous system in mediating other nonosmotic stimuli for vasopressin is discussed.

Bioactive lipid mediators in polycystic kidney disease.

Inflammatory activity is evident in patients with chronic kidney disease with limited data available in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inflammation is an upstream event in the pathogenesis of ADPKD and may be a contributing factor in the disease severity and progression. Serum samples from 61 HALT study A group patients were compared with samples from 49 patients from HALT study B group with moderately advanced disease. Targeted MS analysis of bioactive lipid mediators as markers of inflammation was performed and correlated with eGFR and total kidney volume (TKV) normalized to the body surface area (BSAR) to assess if these markers are predictive of ADPKD severity. ADPKD patients with eGFR >60 ml/min/1.73 m2 showed higher levels of 5- and 12/15-lipoxygenase (LOX) and cyclooxygenase, and generated higher levels of hydroxy-octadecadienoic acids 9-HODE and 13-HODE and HETEs 8-HETE, 11-HETE, 12-HETE, and 15-HETE as compared with healthy subjects. Linear regression of 9-HODE and 13-HODE revealed a significant relationship with eGFR and TKV, while 15-HETE significantly correlated with TKV/BSAR. Production of 20-HETE, a P450-produced metabolite of arachidonic acid, was higher in ADPKD patients as compared with healthy subjects and significantly correlated with eGFR and TKV/BSAR. Perturbation in fatty acid metabolism is evident early in ADPKD patients, even in those with preserved kidney function. The identified LOX pathways may be potential therapeutic targets for slowing down ADPKD progression.

Outcome Differences in Community- Versus Hospital-Acquired Hyponatremia in Patients With a Diagnosis of Heart Failure

Background—Hyponatremia at hospital admission is a well-known risk factor of morbidity and mortality in patients with heart failure (HF). However, there are few data about hyponatremia developing during hospitalization in patients with HF. The present study compares hospital-acquired hyponatremia (HAH) with community-acquired hyponatremia (CAH) in HF patients with respect to outcome. Methods and Results—A total of 5347 consecutive hospitalized patients with a diagnosis of HF were analyzed. CAH was defined as a serum sodium value of ⩽135 mEq/L at the time of hospital admission. HAH was defined as development of a serum sodium level of ⩽135 mEq/L during hospitalization in the setting of a serum sodium value >135 mEq/L on admission. In-hospital mortality, length of stay, worsening kidney function, and discharge to short-/long-term care facilities were analyzed. CAH and HAH were identified in 1039 patients (19.4%) and in 1302 patients (24.4%) of the 5347 patients admitted, respectively. Both types of hyponatremia were associated with increased mortality, length of stay, rate of discharge to short-/long-term care facilities, and worsening kidney function. In-hospital mortality did not differ between CAH and HAH, but differences in demographics and comorbidities were present. Conclusions—The present results identified HAH as a risk factor for increased mortality in HF as has been previously described for CAH. HAH was associated with increased length of stay, discharge to short-/long-term care facilities, and development of cardio-renal failure. Thus, hyponatremia in hospitalized patients with a diagnosis of HF, either on admission or during hospitalization, is a prognostic marker for poor outcomes.

Interrelationship Between Renal Haemodynamics, Drug Kinetics and Drug Action

SummaryThe renal haemodynamics of a particular patient may affect the pharmacological and pharmacokinetic properties of various drugs. For example, diminution in renal haemodynamics may lead to fluid retention and an increase in the volume of distribution of the drug. Also, fluid retention causes a decrease in plasma protein concentration which for certain drugs can result in altered protein binding and consequently increased proportion of unbound drug and a more marked pharmacological response.The clearance of many drugs and/or metabolites also in influenced by the stale of renal haemodynamics. In states of poor renal perfusion, drugs which are mainly eliminated through renal mechanisms have a reduced rate of clearance. The resultant prolongation of the elimination half-life of the drug may increase its toxicity. Knowledge of the renal haemodynamic state, therefore, should be considered in determining the dose and frequency of drug administration.Studies in man have shown that both renal blood flow and glomerular filtration rate are reduced below normal in states of congestive heart failure, liver disorders such as cirrhosis, and, of course, acute and chronic renal failure. In these pathological states, severe cortical vasoconstriction may be present and primarily account for the impairment in renal haemodynamics and alterations in drug kinetics and action.Not only can the renal haemodynamic state affect the actions of drugs, but also exogenous administration of certain drugs can alter renal haemodynamics. The kidney’s response to these agents is influenced by pathological and physiological factors, including sodium balance and the ability of the kidney to autoregulate its blood flow. In general, however, renal haemodynamics are diminished by renal vasoconstrictors and improved by renal vasodilators. The altered state of renal haemodynamics in turn may modify the pharmacological and pharmacokinetic properties of other drugs present in the body.

The nephrotic syndrome: pathogenesis and treatment of edema formation and secondary complications

Nephrotic syndrome is an important clinical condition affecting both children and adults. Studies suggest that the pathogenesis of edema in individual patients may occur via widely variable mechanisms, i.e., intravascular volume underfilling versus overfilling. Managing edema should therefore be directed to the underlying pathophysiology. Nephrotic syndrome is also associated with clinically important complications related to urinary loss of proteins other than albumin. This educational review focuses on the pathophysiology and management of edema and secondary complications in patients with nephrotic syndrome.

Lipids and renal cystic disease

Summary of key findings Glucosylceramide (GlcCer) levels were found to be higherin kidney tissue of autosomal dominant PKD/conditionalknockout mice and nephronophthisis mice (jck and pcymice) than in normal kidney tissue. The same was foundin renal tissue of human polycystic kidney disease (PKD)as compared with normal kidney tissue. Similarly, inde-pendent of different genetic mutations and clinical hetero-geneity, common defects of most cystic epithelium includeproliferation, apoptosis and activation of growth-regulatingpathways. On this background, an inhibitor of GlcCer syn-thase (Genz-123346) was shown to inhibit cystogenesis inPKD1,jckandpcymice.Molecularanalysisinvitroandinvivo demonstrated that Genz-123346 inhibits two pathwaysthat are dysregulated in PKD, namely Akt protein kinase–mammalian target of rapamycin (mTOR) signalling [1] andcell cycle machinery [2]. The authors suggest that inhibi-tors of GlcCer synthesis may represent a potential newtreatment for PKD. Review of the field

Effects of Smoking on ADPKD: Frequency of Vascular Events and Concentrations of Soluble CD40 Ligand

Background: Cardiovascular disease is the leading cause of death among patients with autosomal dominant polycystic kidney disease (ADPKD). Smoking increases inflammation and contributes to cardiovascular disease in the general population. The purpose of this study was to determine the effects of smoking on health outcomes in patients with ADPKD. nMethods: The study population included 350 smoking and 371 non-smoking ADPKD patients who participated in studies at the University of Colorado between 1985 and 2001. In addition, outcome data collected between 2011 and 2012 by survey from 159 smoking and 259 non-smoking ADPKD patients was analyzed. The frequency of cardiovascular or cerebrovascular events, age at onset of end stage renal disease, and serum and urine chemistries where available were compared in smoking and non-smoking patients. Serum levels of soluble CD40 ligand measured by ELISA were analyzed in a sub-set of 40 patients matched by age, sex, and renal function. nResults: ADPKD smokers from the University of Colorado study cohort had more cardiovascular events and higher urinary protein excretion than ADPKD non-smokers. The ADPKD survey respondents had a higher rate of cerebrovascular events in patients who smoked. Smoking years were associated with increased odds of having a cerebrovascular event. Serum soluble CD40 ligand level was higher in ADPKD patients who smoked compared to non-smoking patients (5293 ± 3168 vs. 3285 ± 2169 pg/mL, P=0.025) indicative of increased inflammation. nConclusions: ADPKD patients who smoke have a higher hazard for cardiovascular and cerebrovascular events and evidence for increased inflammation.