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. 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. 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). 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.)

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5` end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3` end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5` end of the gene. These strong genotype–phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

The relationship between renal volume and hypertension in autosomal dominant polycystic kidney disease (ADPKD) occurs in childhood. Hypertension is associated not only with increased kidney volume but also with significantly increased left ventricular mass index. Moreover, this increase in left ventricular mass index occurs in children who have ADPKD with borderline hypertension (75th to 95th percentile) and is prevented with angiotensin-converting enzyme inhibitor (ACEI) monotherapy. Progression from borderline to overt hypertension (> or =95th percentile) occurs during a 5-yr follow-up in approximately 50% of children with ADPKD and borderline hypertension. Renal cyst enlargement in ADPKD in adults is associated with stimulation of both the circulating and intrarenal renin-angiotensin-aldosterone system. In addition to hypertension, the resultant angiotensin in ADPKD is a pivotal factor in cyst proliferation and expansion, increased sympathetic and endothelin activity, oxidant injury, and fibrosis. There is a close correlation between the level of hypertension, left ventricular hypertrophy, deterioration of GFR, and the progressive enlargement of the cystic kidneys in adult ADPKD. Randomized clinical investigation indicates that ACEI and a BP goal of 120/80 mmHg are associated in a 7-yr study to reverse left ventricular hypertrophy. The effect of renin-angiotensin-aldosterone system inhibition with dual blockade, ACEI and angiotensin receptor antagonists, on renal volume and kidney function is under study in the Halt Progression of Polycystic Kidney Disease (HALT PKD) trial.

Context: Normal pregnancy is associated with sodium and water retention, which results in plasma volume expansion prior to placental implantation. The explanation offered for these events is that pregnancy ‘resets’ both volume and osmoreceptors. Evidence Acquisition: The mechanisms for such an enigmatic ‘resetting’ in pregnancy have not previously been explained. However, recent human pregnancy studies have demonstrated that the earliest hemodynamic change in pregnancy is primary systemic arterial vasodilation. This arterial underfilling is associated with a secondary increase in cardiac output and activation of the neurohumoral axis, including stimulation of the renin-angiotensin-aldosterone, sympathetic, and non-osmotic vasopressin systems. Resistance to the pressor effects of angiotensin and sympathetic stimulation in pregnancy is compatible with an increase in endothelial nitric oxide synthase activity. Results: In contrast to the sodium and water retention which occur secondary to the primary arterial vasodilation in cirrhosis, glomerular filtration and renal blood flow are significantly increased in normal pregnancy. A possible explanation for this difference in arterial vasodilation states is that relaxin, an arterial vasodilator which increases during pregnancy, has a potent effect on both systemic and renal circulation. Endothelial damage in pregnancy is pivotal in the pathogenesis of preeclampsia in pregnancy. Conclusions: Against a background of the primary arterial vasodilation hypothesis, it is obvious that reversal of the systemic vasodilatation in pregnancy, without subsequent activation of the renin-angiotensin-aldosterone system (78), will evoke a reversal of all the links in the chain of events in normal pregnancy adaptation, thus, it may cause preeclampsia. Namely, a decrease of renal vasodilation will decrease glomerular filtration rate. Keywords: Pregnancy; Arterial; Osmolar Concentration; Relaxin; Nitric Oxide; Pre-Eclampsia, Endothelium

Physiologic end points for fluid resuscitation in septic shock patients with acute kidney injury (AKI) have been undertaken in randomized studies using the Early Goal-Directed Therapy (EGDT) approach. These studies have demonstrated a beneficial effect on in-hospital mortality with EGDT. The Saline versus Albumin Fluid Evaluation (SAFE) randomized study in critically ill patients demonstrated no difference in survival when saline versus albumin solutions were used for resuscitation. However, a benefit of albumin has been demonstrated in a randomized study on renal function and survival in cirrhotic patients with spontaneous bacterial periotonitis. On the other hand, recent observational studies have shown a correlation between fluid overload and mortality in AKI patients whether or not they necessitated dialysis. Moreover, the Adult Respiratory Distress Syndrome (ARDS) network performed a randomized study in critically ill patients to compare liberal versus conservative fluid administration. The liberal fluid administration group exhibited worse pulmonary function and no protection of renal function. Constancy of central venous pressure (CVP) measurements in the 12-mmHg range were observed in the liberal fluid group despite a mean increase in positive fluid balance of 7 L, thus suggesting increased interstitial fluid accumulation leading to pulmonary congestion. The review presented here discusses these various aspects of fluid administration in critically ill patients, particularly those with AKI, and indicates the potential deleterious effects of fluid overload on lung, heart, and kidney function that could contribute to increased mortality.