John Danziger

Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification

Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarins effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

Proton-pump inhibitor use is associated with low serum magnesium concentrations.

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.

Carbamylation of Serum Albumin as a Risk Factor for Mortality in Patients with Kidney Failure

Increased carbamylation of serum albumin is associated with increased mortality in patients with kidney failure. Counteracting Carbamylation: A Possible Route to Treating Complications of Kidney Failure Like a canary in a coal mine, too much glycated hemoglobin in the blood is a warning sign that a diabetic patients’ glucose is out of control. Carbamyl groups on another ubiquitous blood protein, albumin, may sound a similar alarm for blood urea, a consequence of failing kidneys. Carbamylation may be harmful in its own right because it has been linked to atherosclerosis and other diseases. By using mass spectroscopy, the authors devised a highly accurate assay for measuring carbamylation of the lysine at position 549 of human albumin. With this assay, they found that in two groups of patients with end-stage renal disease and elevated blood urea, the amount of carbamylated albumin correlated with urea concentrations. Albumin was more carbamylated in patients with end-stage renal disease who died within a year than in those who lived longer. Although knowing the prognosis of patients with kidney failure would let us prioritize transplants for the most needy, it would be even better if we could prevent the complications of kidney failure altogether. The authors have gathered data from biochemical experiments and from mice that suggest that protein carbamylation and its associated pathology might be prevented by boosting amino acid concentrations (which tend to be low in these patients) in the blood through diet or other means. Amino acids can compete with protein side chains during carbamylation, potentially interfering with the reaction and its harmful consequences. Thus, amino acid replacement might help patients with kidney failure. Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys549. The proportion of serum albumin carbamylated on Lys549 (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.

Importance of Low-Grade Albuminuria

The well-described association between chronic kidney disease and cardiovascular disease is typically thought to originate from loss of renal function, as estimated by the glomerular filtration rate. However, recent data suggest that urinary albumin excretion has an important role in this association. Albuminuria is a marker of underlying vascular dysfunction and has been correlated with structural and functional integrity of the vasculature. Although the traditional upper limit of normal daily albumin excretion has been 30 mg/d, recent epidemiologic data suggest that levels in the general population are actually much lower. Further, within this range of low-grade albuminuria (LGA), increasing excretion rates are associated with increasing risk of cardiovascular disease. This association is independent of renal function, and in the earliest stages of chronic kidney disease, LGA seems to be a more important determinant than the glomerular filtration rate. This emerging association underscores the complexity of albumin excretion, in which subtle changes in albumin excretion reflect widespread vascular processes. Using the key words albuminuria, low-grade albuminuria, and microalbuminuria in a PubMed search of literature from January 1, 1995, to February 29, 2008, this review summarizes the most recent data on LGA and its association with cardiovascular and renal disease.

The bone-renal axis in early chronic kidney disease: an emerging paradigm

The prevailing paradigm of mineral metabolism in chronic kidney disease (CKD) is based on two principles. First, as the tradeoff hypothesis suggests, phosphate retention leads to hyperparathyroidism, a response that maintains normal levels of serum phosphorus until relatively late in the CKD process [1–3]. In addition, it is believed that dietary deficiency of 25 hydroxylated vitamin D (25OHD) is important in early CKD, with the deficiency of the activated version, 1,25-hydroxylated vitamin D (1,25OHD), developing only in the later stages. Since the hydroxylation to 1,25OHD is considered to be a renal-dependent mechanism, the deficiency of this activated form is thought to reflect renal dysfunction. Various mechanisms have been impugned, including loss of renal mass, hyperparathyroidism, hyperphosphatemia and uremic toxins. These two principles have shaped the current KDOQI guidelines for the treatment of mineral metabolism in CKD. However, more recent data suggest that this approach to mineral metabolism in CKD may not be wholly accurate. A recent large trial has illustrated that 1,25OHD levels begin to fall at the earliest stage of renal decline, before the development of hyperparathyroidism, hyperphosphatemia or any changes in renal mass [4]. Furthermore, although loss of 1-alpha hydroxylase has been impugned as the cause of 1,25OHD deficiency, animal data suggest that this enzyme is not decreased in CKD [5]. In addition, 1-alpha hydroxylase is expressed in diverse tissues beyond the kidney, potentially providing an extra-renal source of 1,25OHD [6]. It seems that the 1,25OHD decline in CKD is actually a much more complicated process than originally proposed.

Peripheral Edema, Central Venous Pressure, and Risk of AKI in Critical Illness

BACKGROUND AND OBJECTIVES Although venous congestion has been linked to renal dysfunction in heart failure, its significance in a broader context has not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using an inception cohort of 12,778 critically ill adult patients admitted to an urban tertiary medical center between 2001 and 2008, we examined whether the presence of peripheral edema on admission physical examination was associated with an increased risk of AKI within the first 7 days of critical illness. In addition, in those with admission central venous pressure (CVP) measurements, we examined the association of CVPs with subsequent AKI. AKI was defined using the Kidney Disease Improving Global Outcomes criteria. RESULTS Of the 18% (n=2338) of patients with peripheral edema on admission, 27% (n=631) developed AKI, compared with 16% (n=1713) of those without peripheral edema. In a model that included adjustment for comorbidities, severity of illness, and the presence of pulmonary edema, peripheral edema was associated with a 30% higher risk of AKI (95% confidence interval [95% CI], 1.15 to 1.46; P<0.001), whereas pulmonary edema was not significantly related to risk. Peripheral edema was also associated with a 13% higher adjusted risk of a higher AKI stage (95% CI, 1.07 to 1.20; P<0.001). Furthermore, levels of trace, 1+, 2+, and 3+ edema were associated with 34% (95% CI, 1.10 to 1.65), 17% (95% CI, 0.96 to 1.14), 47% (95% CI, 1.18 to 1.83), and 57% (95% CI, 1.07 to 2.31) higher adjusted risk of AKI, respectively, compared with edema-free patients. In the 4761 patients with admission CVP measurements, each 1 cm H2O higher CVP was associated with a 2% higher adjusted risk of AKI (95% CI, 1.00 to 1.03; P=0.02). CONCLUSIONS Venous congestion, as manifested as either peripheral edema or increased CVP, is directly associated with AKI in critically ill patients. Whether treatment of venous congestion with diuretics can modify this risk will require further study.

Obesity, Acute Kidney Injury, and Mortality in Critical Illness.

Objectives:Although obesity is associated with risk for chronic kidney disease and improved survival, less is known about the associations of obesity with risk of acute kidney injury and post acute kidney injury mortality. Design:In a single-center inception cohort of almost 15,000 critically ill patients, we evaluated the association of obesity with acute kidney injury and acute kidney injury severity, as well as in-hospital and 1-year survival. Acute kidney injury was defined using the Kidney Disease Outcome Quality Initiative criteria. Measurements and Main Results:The acute kidney injury prevalence rates for normal, overweight, class I, II, and III obesity were 18.6%, 20.6%, 22.5%, 24.3%, and 24.0%, respectively, and the adjusted odds ratios of acute kidney injury were 1.18 (95% CI, 1.06–1.31), 1.35 (1.19–1.53), 1.47 (1.25–1.73), and 1.59 (1.31–1.87) when compared with normal weight, respectively. Each 5-kg/m2 increase in body mass index was associated with a 10% risk (95% CI, 1.06–1.24; p < 0.001) of more severe acute kidney injury. Within-hospital and 1-year survival rates associated with the acute kidney injury episodes were similar across body mass index categories. Conclusion:Obesity is a risk factor for acute kidney injury, which is associated with increased short- and long-term mortality.

Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms

Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect.

Magnesium Deficiency and Proton‐Pump Inhibitor Use: A Clinical Review

The association of proton‐pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well‐designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations.

Nocturnal versus conventional haemodialysis: some current issues

The burden of kidney disease continues to grow in the United States, and more patients are faced with the need for dialysis [1]. While haemodialysis is a life-saving form of renal replacement therapy, the long-term outlook for patients on the conventional dialysis regimen of 4 h per session three times per week is grim: mortality four times higher than the general population for dialysis patients under 30 and six times higher than the general population for dialysis patients over 65 [2]. The number of patients on home haemodialysis—both conventional haemodialysis (CHD) and nocturnal haemodialysis (NHD)—represents a small fraction of the end-stage renal disease population (ESRD) in the USA and Canada, ∼1500 in 2003, <0.4% of all dialysis patients in the USA [3]. A survey of dialysis machine manufacturers in 2007 estimated that ∼1% of ESRD patients in the USA were doing home dialysis [4]. Home haemodialysis enjoyed early success in the USA with ∼40% of all dialysis patients treated at home at one point [5]. Scribner and colleagues carried out the first nocturnal dialysis in Seattle in the 1960s, using a pumpless plate dialyser [6]. De Palma and colleagues undertook the earliest daily dialysis with a reusable coil dialyser and blood pump [7]. But their early experiment in daily and nocturnal dialysis failed because ‘economic considerations—not quality machinery and ergonomics—came first’ [4]. Others attributed the decline in home haemodialysis and NHD to the advent of continuous ambulatory peritoneal dialysis in the 1970s, improvements in cadaveric transplant survival with the advent of cyclosporine in the 1980s and increased use of living donor kidneys in the 1990s [3]. The USA initially funded home haemodialysis programmes to counter growing costs of in-centre dialysis, but home dialysis fell further out of popularity with passage of amendments to the Social Security act on dialysis payment in 1972 since in-centre dialysis was able to deliver minimum adequacy with three sessions per week [8]. Home NHD is now a little used modality. According to data from the US Renal Data System, only 0.2% of the incident ESRD patients in 2004 started on home haemodialysis of any sort. Of the 472 099 prevalent patients, only 0.4% were on home haemodialysis [9]. In 2005, 428 of 104 018 incident dialysis patients started on home haemodialysis, and 2105 of 340 057 prevalent dialysis patients were on home haemodialysis. In the USA, home haemodialysis patients are less likely to be African American and Hispanic than in-centre dialysis patients [10]. A survey of all known daily dialysis programmes in the USA found 13 centres in North America performing daily NHD as of January 2001, caring for 115 patients [11]. The International Quotidian Dialysis Registry in Ontario recorded 229 patients in 2007, up from 199 in 2006 [12]. Yet data have accumulated showing advantages to more frequent daily or nocturnal dialysis. Based on his experiences observing patients in the intensive care unit [13], Robert Uldall in Toronto initiated a 2-year pilot study with a grant from the government of Ontario to evaluate what he called simplified nocturnal home haemodialysis [14]. He reasoned that frequent long dialysis sessions produced fewer symptoms than short intermittent treatments; at-home dialysis was less expensive than in-centre dialysis; nocturnal dialysis was less disruptive than daytime dialysis. The programme started enrolling the first of 36 patients in 1994. The 30 patients enrolled at 5 years showed improvements in blood pressure, mineral metabolism and cognitive functioning. There was no difference in haemoglobin levels or erythropoietin use [15]. By 2003, the group had trained 90 patients and was dialysing 48 patients nightly and 5 every other night for a total experience of 230 patient-years [16].