Posts Tagged ‘CKD’

Risks for Patients’ and Physician’s Health in the Cath Lab

Reporter and Curator: Aviva Lev-Ari, PhD, RN

On Thursday, June 27th, 2013, Bayer HealthCare, Nuance® Healthcare, and The Mount Sinai Hospital held a live webinar outlining how one of America’s leading Radiology Departments is pioneering the next generation of imaging informatics. If you were unable to watch it live, or would like to view it again, it is now available online here.
The Mount Sinai Hospital in New York has taken Contrast Dose Management and IT interoperability to a new level with two industry-leading forces – Bayer’s Certegra® Informatics Platform and Nuance’s PowerScribe® 360 | Reporting.
The FREE 60-minute webinar includes:
New Trends in Imaging Informatics & Dose Management
Emerging Contrast Dose Management Best Practices as a Standard of Care at The Mount Sinai Hospital
Experiences with Informatics including Point of Care Documentation, Injection Protocol Management for Patient-Based Dosing, Interfacing with IT Systems, and Analytics
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Risks for Physician’s Health in the Cath Lab

EuroIntervention. 2012 Jan;7(9):1081-6. doi: 10.4244/EIJV7I9A172.

Brain tumours among interventional cardiologists: a cause for alarm? Report of four new cases from two cities and a review of the literature.


Interventional Cardiology, Rambam Medical Center, Bruce Rappaport Faculty of Medicine, the Technion, Israel Institute of Technology, Haifa, Israel.



Interventional cardiologists who work in cardiac catheterisation laboratories are exposed to low doses of ionising radiation that could pose a health hazard. DNA damage is considered to be the main initiating event by which radiation damage to cells results in development of cancer.


We report on four interventional cardiologists, all with brain malignancies in the left hemisphere. In a literature search, we found five additional cases and thus present data on six interventional cardiologist and three interventional radiologists who were diagnosed with brain tumours. All worked for prolonged periods with exposure to ionising radiation in the catheterisation laboratory.


In interventional cardiologists and radiologists, the left side of the head is known to be more exposed to radiation than the right. A connection to occupational radiation exposure is biologically plausible, but risk assessment is difficult due to the small population of interventional cardiologists and the low incidence of these tumours. This may be a chance occurrence, but the cause may also be radiation exposure. Scientific study further delineating occupational risks is essential. Since interventional cardiologists have the highest radiation exposure among health professionals, major awareness of radiation safety and training in radiological protection are essential and imperative, and should be used in every procedure.

Risks for Patients’ Health in the Cath Lab

Contrast-Induced Nephropathy

  • Author: Renu Bansal, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN


Contrast-induced nephropathy (CIN) is defined as the impairment of renal function and is measured as either a 25% increase in serum creatinine (SCr) from baseline or 0.5 mg/dL (44 µmol/L) increase in absolute value, within 48-72 hours of intravenous contrast administration. (See Etiology.)

For renal insufficiency (RI) to be attributable to contrast administration, it should be acute, usually within 2-3 days, although it has been suggested that RI up to 7 days post–contrast administration be considered CIN; it should also not be attributable to any other identifiable cause of renal failure. A temporal link is thus implied.[1] Following contrast exposure, SCr levels peak between 2 and 5 days and usually return to normal in 14 days. (See Clinical and Workup.)


CIN is one of the leading causes of hospital-acquired acute renal failure. It is associated with a significantly higher risk of in-hospital and 1-year mortality, even in patients who do not need dialysis.

Nonrenal complications include procedural cardiac complications (eg, Q-wave MI, coronary artery bypass graft [CABG], hypotension, shock), vascular complications (eg, femoral bleeding, hematoma, pseudoaneurysm, stroke), and systemic complications (eg, acute respiratory distress syndrome [ARDS], pulmonary embolism).

There is a complicated relationship between CIN, comorbidity, and mortality. Most patients who develop CIN do not die from renal failure. Death, if it does occur, is more commonly from either a preexisting nonrenal complication or a procedural complication.


Many physicians who refer patients for contrast procedures and some who perform the procedure themselves are not fully informed about the risk of CIN. A survey found that less than half of referring physicians were aware of potential risk factors, including diabetes mellitus. (See Differentials.)

CIN suffers from a lack of consensus regarding its definition and treatment. Studies differ in regard to the marker used for renal function (SCr vs eGFR), the day of initial measurement and remeasurement of the marker, and the percentage increase used to define CIN. This makes it difficult to compare studies, especially in terms of the efficacy of various treatment modalities. (See Treatment and Medication.)[2]

The reported incidence of CIN might be an underestimation. SCr levels normally rise by day 3 of contrast administration. Most patients do not remain hospitalized for so long and there is no specific protocol to order outpatient SCr levels 3-5 days after the procedure.

Other renal function markers

The use of SCr as a marker of renal function has its limitations. Indicators such as the estimated glomerular filtration rate (eGFR) and cystatin C are increasingly considered to be more reliable and accurate reflectors of existing renal function.[3, 4]

The eGFR can be calculated using the Modification of Diet in Renal Disease (MDRD) formula or the Cockroft-Gault formula. The Cockroft-Gault formula calculates eGFR using age, sex, and body weight, which are factors that, independent of GFR, influence SCr. The MDRD equation also includes blood urea nitrogen (BUN) and serum albumin.

The eGFR works best at low creatinine values. SCr and GFR share a curvilinear relationship. At lower SCr values, doubling SCr is associated with a corresponding 50% decrease in GFR. However, in elderly patients with chronic kidney disease(CKD) who have high SCr values at baseline, a 25% rise in SCr is actually indicative of a relatively modest reduction in GFR. Nonetheless, even a 25% increase in SCr in this situation has been shown to have great impact, especially in terms of inhospital and 1-year mortality.[5]

Serum cystatin C is a serum protein that is secreted by nucleated cells. It is freely filtered by the glomerulus and has been found to be an accurate marker of GFR. Compared with SCr, cystatin C changes much earlier after contrast administration and is not subject to confounding factors, such age, sex, and muscle mass, that influence SCr values independent of the underlying GFR. Cystatin C is increasingly being used as a marker of renal function in cardiac surgical patients.

Patient education

Patients with risk factors for CIN should be educated about the necessity of follow-up care with their physicians with a postprocedure SCr estimation, especially if the initial procedure was done on an outpatient basis.


Contrast media (CM) act on distinct anatomic sites within the kidney and exert adverse effects via multiple mechanisms. They cause a direct cytotoxic effect on the renal proximal tubular cells, enhance cellular damage by reactive oxygen species, and increase resistance to renal blood flow. They also exacerbate renal vasoconstriction, particularly in the deeper portions of the outer medulla. This is especially important in patients with CKD, because their preexisting abnormal vascular pathobiology is made worse by the effects of CM.[6, 7]

Renal (particularly medullary) microcirculation depends on a complex interplay of neural, hormonal, paracrine and autocrine influences. Of note are the vasodilator nitric oxide (NO) and the vasoconstrictors vasopressin, adenosine (when it acts via the high affinity A1 receptors), angiotensin II, and endothelins. Prostaglandins cause a redistribution of blood flow to the juxtamedullary cortex and, therefore, are protective.

NO, in particular, seems to be very important, with antiplatelet, vasodilatory, insulin sensitizing, anti-inflammatory, and antioxidant properties. It has been suggested that plasma levels of asymmetrical dimethylarginine (ADMA), which is an endogenous inhibitor of all NO synthase isoforms, can be used as a marker of CIN, especially in patients with unfavorable outcomes.

CM-mediated vasoconstriction is the result of a direct action of CM on vascular smooth muscle and from metabolites such as adenosine and endothelin. Additionally, the osmotic property of CM, especially in the tubular lumen, decreases water reabsorption, leading to a buildup of interstitial pressure. This, along with the increased salt and water load to the distal tubules, reduces GFR and causes local compression of the vasa recta. All of this contributes to worsening medullary hypoxemia and renal vasoconstriction in patients who are already volume depleted.

Finally, CM also increase resistance to blood flow by increasing blood viscosity and by decreasing red cell deformability. This intravascular sludging generates local ischemia and causes activation of reactive oxygen species that result in tubular damage at a cellular level.

Comparison of contrast-agent nephropathy potential

The ability of different classes of CM to cause CIN is influenced by their osmolality, ionicity (the ability of the contrast media to dissociate in water), and molecular structure. Each of these characteristics, in turn, influences their behavior in body fluid and their potential to cause adverse effects. (See Table 1, below.)[8]

Agents are classified as high, low, or iso-osmolar, depending on their osmolality in relation to blood. Low-osmolarity contrast media (LOCM) is actually a misnomer, since these agents have osmolalities of 600-900 mOsm/kg and so are 2-3 times more hyperosmolar than blood. High-osmolarity contrast media (HOCM) are 5-7 times more hyperosmolar than blood, with osmolalities greater than 1500 mOsm/kg.

Molecular structure of CM refers to the number of benzene rings. Most CM that were developed in the 1990s are dimers with 2 benzene rings. Dimeric CM, while nonionic and with low osmolarity, have high viscosity, which may influence renal tubular blood flow.

The ratio of iodine to dissolved particles describes an important relationship between opacification and osmotoxicity of the contrast agent. The higher ratios are more desirable. High-osmolar agents have a ratio of 1.5, low-osmolar agents have a ratio of 3, and iso-osmolar agents have the highest ratio, 6.

While the safety of LOCM over HOCM in terms of CIN seems intuitive, clinical evidence of it came from a meta-analysis by Barrett and Carlisle.[9] They showed the benefit of using LOCM over HOCM mostly in high-risk patients. The Iohexol Cooperative Study was a large, prospective, randomized, double-blinded, multicenter trial that compared the risk of developing CIN in patients receiving the low-osmolarity agent iohexol versus the high-osmolarity agent diatrizoate. While the HOCM group was 3.3 times more likely to develop CIN compared with the LOCM group, this was seen only in patients with preexisting CKD (baseline SCr greater than or equal to 1.5 mg/dL). In addition to CKD; diabetes mellitus, male sex, and contrast volume were found to be independent risk factors.

Even within the LOCM category, the risk is not the same for all agents. High-risk patients receiving iohexol have a higher likelihood of developing CIN than do patients receiving another agent (ie, iopamidol) in the same class.

When LOCM were compared with iso-osmolar contrast media (IOCM), the Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media (NEPHRIC study), arguably the most definitive study in this category to date, found that the odds of developing CIN in high-risk patients were almost 9 times greater for the study’s iohexol group than for the investigation’s iodixanol group (iso-osmolar contrast agent). The incidence of CIN was 3% in the iodixanol group versus 26% in the iohexol group.[10] These results, though promising, were not duplicated in some subsequent studies.

When iodixanol was used, the Rapid Protocol for the Prevention of Contrast-Induced Renal Dysfunction (RAPPID) trial found a 21% incidence of CIN,[11] and the Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty (CONTRAST) trial found a 33% incidence of CIN.[12] Finally, the Renal Toxicity Evaluation and Comparison Between Visipaque (Iodixanol) and Hexabrix (Ioxaglate) in Patients With Renal Insufficiency Undergoing Coronary Angiography (RECOVER) trial compared the iso-osmolar contrast medium iodixanol to the low-osmolarity agent ioxaglate and found a significantly lower incidence of CIN with iodixanol than with ioxaglate (7.9% vs 17%, respectively).[13]

Thus, although the data are by no means uniform, they seem to suggest that the iso-osmolar contrast agent iodixanol may be associated with smaller increases in SCr and lower rates of CIN when compared with low-osmolar agents, especially in patients with CKD and in those with CKD and diabetes mellitus.[14]

Risk factors

Risk factors for CIN can be divided into patient-related, procedure-related, and contrast-related factors (although the risk factors for CIN are still being identified and remain poorly understood). Patient-related risk factors are as follows:

  • Age
  • CKD
  • Diabetes mellitus
  • Hypertension
  • Metabolic syndrome
  • Anemia
  • Multiple myeloma
  • Hypoalbuminemia
  • Renal transplant
  • Hypovolemia and decreased effective circulating volumes – As evidenced by congestive heart failure (CHF), an ejection fraction (EF) of less than 40%, hypotension, and intra-aortic balloon counterpulsation (IABP) use

Procedure-related risk factors are as follows:

  • Urgent versus elective
  • Arterial versus venous
  • Diagnostic versus therapeutic

Contrast-related risk factors are as follows:

  • Volume of contrast
  • Contrast characteristics, including osmolarity, ionicity, molecular structure, and viscosity

The single most important patient-related risk factor is preexisting CKD, even more so than diabetes mellitus.[15] Patients with CKD in the setting of diabetes mellitus have a 4-fold increase in the risk of CIN compared with patients without diabetes mellitus or preexisting CKD.

Table: Physiochemical Properties of Contrast Media

Although the data is by no means uniform, they seem to suggest that the iso-osmolar contrast agent iodixanol may be associated with smaller increases in SCr and lower rates of CIN when compared with low-osmolar agents, especially in patients with CKD and in those with CKD and diabetes mellitus.[14] Guidelines from the American Heart Association (AHA)/American College of Cardiology (ACC) for the management of acute coronary syndromes patients with CKD recommend the use of IOCM (Class I, level of Evidence).

Table 1. Physiochemical Properties of Contrast Media[16] (Open Table in a new window)

Class of Contrast Agent Type of Contrast Agent Iodine Dose(mg/mL) Iodine/Particle Ratio Viscosity(cPs at 37°C) Osmolality(mOsm/kg H2 O) Molecular Weight (Da)
High-osmolar monomers(ionic) Diatrizoate (Renografin)Ioxithalamate (Telebrix) 370350 1.51.5 2.32.5 18702130 636643
Low-osmolar dimers(ionic) Ioxaglate (Hexabrix) 320 3 7.5 600 1270
Low-osmolar monomers(nonionic) Iohexol (Omnipaque)Iopamidol (Isovue)Iomeprol (Iomeron)

Ioversol (Optiray)

Iopromide (Ultravist)

Iopentol (Imagopaque)





















Iso-osmolar dimers(nonionic) Iodixanol (Visipaque)Iotrolan (Isovist) 320320 66 11.88.5 290290 15501620


Occurrence in the United States

CIN is the third leading cause of hospital-acquired renal failure. Decreased renal perfusion and surgery (or in some studies, nephrotoxic medications) are the number one and number two causes, respectively.

An analysis of 15 prospective and retrospective studies from 1976-1996 report an incidence of CIN of 3.1-31%. The number varies depending on the definition used for CIN; the contrast agent characteristics, including the type, amount, duration, and route of administration; preexisting risk factors; and length of follow-up (including the day of measurement of postcontrast serum creatinine).

In patients without risk factors, the incidence may be as low as 2%. With the introduction of risk factors, like diabetes, the number rises to 9%, with incidences being as high as 90% in diabetics with CKD. Therefore, the number and the type of preexisting risk factors directly influence the incidence of renal insufficiency. It is also procedure dependant, with 14.5% overall in patients undergoing coronary interventions compared to 1.6-2.3% for diagnostic intervention, as reported in literature.[17]

Race- and age-related demographics

While African Americans with diabetic nephropathy have a faster acceleration of end-stage renal disease (ESRD), independent of other variables, race has not been found to be a risk factor for CIN.

The incidence of CIN in patients older than age 60 years has been variously reported as 8-16%. It has also been shown that in patients with acute MI who have undergone coronary intervention, an age of 75 years or older is an independent risk factor for CIN.


CIN is normally a transient process, with renal functions reverting to normal within 7-14 days of contrast administration. Less than one-third patients develop some degree of residual renal impairment.

Dialysis is required in less than 1% of patients, with a slightly higher incidence in patients with underlying renal impairment (3.1%) and in those undergoing primary PCI for myocardial infarction (MI) (3%). However, in patients with diabetes and severe renal failure, the rate of dialysis can be as high as 12%.

Of the patients who need dialysis, 18% end up on permanent dialysis therapy. However, many of these patients will have had advanced renal insufficiency and concomitant diabetic nephropathy and will have been destined for dialysis regardless of the episode of CIN.

A growing body of knowledge indicates that acute kidney injury after contrast medium can be a harbinger of CKD or ESRD. In one observational study, the population studied appeared representative of the general population undergoing angiography and the rate of acute kidney ingury was consonant with other studies. The finding that persistent kidney damage can occur after contrast-induced acute kidney injury highlights the potential for acceleration of the progression of kidney injury in individuals with pre-existing CKD.[18]


Patients who require dialysis have a considerably worse mortality rate, with reported rates of 35.7% inhospital mortality (compared with 7.1% in the nondialysis group) and a 2-year survival rate of only 19%.

CIN by itself may be an independent mortality risk factor. Following invasive cardiology procedures, patients with normal baseline renal function who develop CIN have reduced survival compared with patients with baseline chronic CKD who do not develop CIN.

Gadolinium-based agents

Gadolinium-based CM (used for magnetic resonance imaging [MRI]), when compared with iodine-based CM, have a similar, if not worse, adverse effect profile in patients with moderate CKD and eGFR of less than 30 mL/min. Their use has been implicated in the development of nephrogenic systemic fibrosis, a chronic debilitating condition with no cure.

A review of 3 series and 4 case reports suggested that the risk of renal insufficiency with gadolinium is similar to that of iodinated radiocontrast dye. The reported incidence varies from 4% in stage 3 CKD to 20% in stage 4 CKD. It may even be worse, as suggested by some investigators. A prospective study of 57 patients found that acute renal failure was seen in 28% of patients in the gadolinium group, compared with 6.5% of patients in the iodine group, despite prophylactic saline and N-acetylcysteine (NAC).

The risk factor profile is similar to that for iodinated CM; increased incidence of acute renal failure is seen in older patients and in those with lower baseline creatinine clearance, diabetic nephropathy, anemia, and hypoalbuminemia.

Risk stratification scoring systems

CIN is the result of a complex interplay of many of the above risk factors. The presence of 2 or more risk factors is additive, and the likelihood of CIN rises sharply as the number of risk factors increases. Researchers have tried to objectively quantify and predict the contribution of each risk factor to the ultimate outcome of CIN.

Risk stratification scoring systems have been devised to calculate an individual patient’s risk of developing CIN. This has mostly been done in patients undergoing percutaneous coronary intervention (PCI), especially those with preexisting risk factors. Mehran et al developed the following scoring system based on points awarded to each of 7 multivariate predictors[19] :

  • Hypotension = 5 points
  • IABP use = 5 points
  • CHF = 5 points
  • SCr of greater than 1.5 mg/dL = 4 points
  • Age greater than 75 years = 4 points
  • Anemia = 3 points
  • Diabetes mellitus = 3 points
  • Contrast volume = 1 point for each 100 cc used

Based on the total calculated score, patients were divided into low-risk (score of less than or equal to 5), moderate-risk (score of 6-10), high-risk (score of 11-15), and very–high-risk (score of greater than or equal to 16) categories. The rate of CIN and the requirement for dialysis were 7.5 and 0.04%, 14 and 0.12%, 26.1 and 1.09%, and 57.3 and 12.6%, respectively, for each of the 4 groups.

Bartholomew et al worked to create another scoring system and took into consideration 8 variables, including creatinine clearance of less than 60 mL/min, IABP use, urgent coronary procedure, diabetes mellitus, CHF, hypertension, peripheral vascular disease (PVD), and volume of contrast used.[20]

History and Physical Examination


Patients usually present with a history of contrast administration 24-48 hours prior to presentation, having undergone a diagnostic or therapeutic procedure (eg, PCI). The renal failure is usually nonoliguric.

Physical examination

A physical examination is useful for ruling out other causes of acute nephropathy, such as cholesterol emboli (eg, blue toe, livedo reticularis) or drug-induced interstitial nephritis (eg, rash). Patients may have evidence of volume depletion or may be in decompensated CHF.

Diagnostic Considerations

Conditions to consider in the differential diagnosis of CIN include the following:

  • Atheroembolic renal failure – More than 1 week after contrast, blue toes, livedo reticularis, transient eosinophilia, prolonged course, and lower recovery
  • Acute renal failure (includes prerenal and postrenal azotemia) – There may also be associated dehydration from aggressive diuresis, exacerbated by preexisting fluid depletion; the acute renal failure is usually oliguric, and recovery is anticipated in 2-3 weeks
  • Acute interstitial nephritis (triad of fever, skin rash, and eosinophilia) – Also eosinophiluria; the nephritis is usually from drugs such as penicillin, cephalosporins, and nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Acute tubular necrosis – Ischemia from prerenal causes; endogenous toxins, such as hemoglobin, myoglobin, and light chains; exogenous toxins, such as antibiotics, chemotherapeutic agents, organic solvents, and heavy metals

Approach Considerations

SCr concentration usually begins to increase within 24 hours after contrast agent administration, peaks between days 3 and 5, and returns to baseline in 7-10 days. Serum cystatin C (which has been suggested as a surrogate marker of renal function in lieu of SCr) is increased in patients with CIN.

Nonspecific formed elements can appear in the urine, including renal tubular epithelial cells, pigmented granular casts, urate crystals, and debris. However, these urine findings do not correlate with severity.

Urine osmolality tends to be less than 350 mOsm/kg. The fractional excretion of sodium (FENa) may vary widely. In the minority of patients with oliguric CIN, the FENa is low in the early stages, despite no clinical evidence of volume depletion.


CM cause direct toxic effects on renal tubular epithelial cells, characterized by cell vacuolization, interstitial inflammation, and cellular necrosis. In a study, these characteristic changes, called osmotic nephrosis, were observed in 22.3% of patients undergoing renal biopsy, within 10 days of contrast exposure.[21]

Approach Considerations

Hydration therapy is the cornerstone of CIN prevention. Renal perfusion is decreased for up to 20 hours following contrast administration. Intravascular volume expansion maintains renal blood flow, preserves nitric oxide production, prevents medullary hypoxemia, and enhances contrast elimination.

However, a number of other CIN therapies have been investigated, including the use of statins, bicarbonate, N-acetylcysteine (NAC), ascorbic acid, the adenosine antagonists theophylline and aminophylline, vasodilators, forced diuresis, and renal replacement therapy. Patients with CIN should be managed in consultation with a nephrologist.

Hydration Therapy

The first study revealing the benefit of hydration in CIN prevention came from Solomon et al.[22] They also found forced diuresis to be inferior to hydration with 0.45% saline. Fluids with different compositions and tonicity have since been studied, including bicarbonate and mannitol.

Normal saline has been found to be superior to half-normal saline in terms of its enhanced ability in intravascular volume expansion. It also causes increased delivery of sodium to the distal nephron, prevents rennin-angiotensin activation, and thus maintains increased renal blood flow. In terms of route of administration, oral fluids, while beneficial, are not as effective as intravenous hydration.[23, 24]

The CIN Consensus Working Panel found that adequate intravenous volume expansion with isotonic crystalloids (1-1.5 mL/kg/h), 3-12 hours before the procedure and continued for 6-24 hours afterward, decreases the incidence of CIN in patients at risk. The panel studied 6 clinical trials with different protocols for volume expansion. The studies differed in the type of fluid used for hydration (isotonic vs half-normal saline), route, duration, timing, and amount of fluid used.[25]

For hospitalized patients, volume expansion should begin 6 hours prior to the procedure and be continued for 6-24 hours postprocedure. For outpatients, administration of fluids can be initiated 3 hours before and continued for 12 hours after the procedure. Postprocedure volume expansion is more important than preprocedure hydration. It has been suggested that a urine output of 150 mL/h should guide the rate of intravenous fluid replacement, although the CIN Consensus Working Panel did not find it useful to recommend a target urine output.

CHF poses a particular challenge. Patients with compensated CHF should still be given volume, albeit at lower rates. Uncompensated CHF patients should undergo hemodynamic monitoring, if possible, and diuretics should be continued. In emergency situations, one’s clinical judgment should be used, and, in the absence of any baseline renal function, adequate postprocedure hydration should be carried out.

What is interesting, however, is that, while hydration remains the cornerstone for CIN prevention, a randomized, controlled trial comparing a strategy of volume expansion with no volume expansion has not been performed to date.


Statins are widely used in coronary artery disease (CAD) for their pleiotropic effects (favorable effects on endothelin and thrombus formation, plaque stabilization, and anti-inflammatory properties), and it was believed that, given the vascular nature of CIN, they might have similar renoprotective effects. The data for statin use, however, are retrospective and anecdotal; they are taken mostly from patients already on statins who underwent PCI.[26]

A significantly lower incidence of CIN was found in patients treated with statins preoperatively (CIN incidence of 4.37% in the statin group vs 5.93% in the nonstatin group). However, prospective trials looking at statin use in patients undergoing noncardiac procedures are needed to better qualify this initial promise.

Bicarbonate Therapy

Bicarbonate therapy alkalinizes the renal tubular fluid and, thus, prevents free radical injury. Hydrogen peroxide and an oxygen ion (from superoxide) react to form a hydroxide ion, all agents of free radical injury. This reaction, called the Harber-Weiss reaction, is activated in an acidic environment. Bicarbonate, by alkalinizing the environment, slows down the reaction. It also scavenges reactive oxygen species (ROS) from NO, such as peroxynitrite.

Bicarbonate protocols most often include infusion of sodium bicarbonate at the rate of 3 mL/kg/hour an hour before the procedure, continued at 1 mL/kg/hour for 6 hours after. Some investigators have used 1 mL/kg/hour for 24 hours, starting 12 hours before the procedure. The exact duration, however, remains a matter of debate. Hydration with sodium bicarbonate has been found by some researchers to be more protective than normal saline alone.

Treatment controversy

A 2008 retrospective cohort study at the Mayo Clinic assessed the risk of CIN associated with the use of sodium bicarbonate, NAC, and the combination of sodium bicarbonate with NAC and found that, compared with no treatment, sodium bicarbonate used alone was associated with an increased risk of CIN. NAC alone or in combination with sodium bicarbonate did not significantly affect the incidence of CIN. The results were obtained after adjusting for confounding factors, including total volume of hydration, medications, baseline creatinine, and contrast iodine load.[27] Given the above new information, it is recommended that the use of sodium bicarbonate to prevent CIN should be further evaluated.


NAC is acetylated L-cysteine, an amino acid. Its sulfhydryl groups make it an excellent antioxidant and scavenger of free oxygen radicals. It also enhances the vasodilatory properties of nitric oxide. Twelve meta-analyses covering 29 randomized, controlled trials have been published on the effect of NAC therapy in CIN. They all suffer from significant heterogeneity. The standard oral NAC regimen consists of 600 mg twice daily for 24 hours before and on the day of the procedure. Higher doses of 1 g, 1200 mg, and 1500 mg twice daily have also been studied, with no significant dose-related or route-related (oral vs intravenous) difference. NAC has very low oral bioavailability; substantial interpatient variability and inconsistency between the available oral products obscure the picture further.[3, 24, 28]

Treatment controversy

The latest controversy relating to NAC therapy questioned the parameter on which its effectiveness was based. It was suggested that the beneficial effect of NAC in CIN is related to its SCr-lowering ability rather than to improved GFR. It was believed that NAC directly reduces SCr by increasing SCr’s excretion (tubular secretion), decreasing its production (augments activity of creatine kinase), or interfering with its laboratory measurement, enzymatic or nonenzymatic (Jaffe method).

This was supported by a study that demonstrated a significant decrease in SCr after 4 doses of 600 mg of oral NAC in healthy volunteers with normal kidney function and no exposure to radiocontrast media.[29] This would bring doubt into the results of at least 13 randomized, controlled trials that showed NAC to be protective in CIN, with SCr used as the endpoint. However, Haase et al compared the effect of NAC on SCr by simultaneously studying its effect on cystatin C and found that NAC did not artifactually lower SCr when measured by the Jaffe method.[30]

The CIN Working Panel concluded that the existing data on NAC therapy in CIN is sufficiently varied to preclude a definite recommendation.[25] In the practice of medicine, though, it remains part of the standard of care and is routinely administered because of its low cost, lack of adverse effects, and potential beneficial effect, as demonstrated by the relative risk reduction of CIN, ranging from 0.37-0.73, as reported in several meta-analyses.

Renal Replacement Therapy

Less than 1% of patients with CIN ultimately go on to require dialysis, the number being slightly higher in patients with underlying renal impairment (3.1%) and in those undergoing primary PCI for MI (3%). However, in patients with diabetes and severe renal failure, the rate of dialysis can be as high as 12%. Patients who get dialyzed do considerably worse, with inhospital mortality rates of 35.7% (compared with 7.1% in the nondialysis group) and a 2-year survival rate of only 19%.

CM have molecular weights that range between 650 and 1600 mOsm/kg. They have low lipophilicity, low plasma protein binding, and minimal biotransformation. They quickly equilibrate across capillary membranes and have volumes of distribution equivalent to that of the extracellular fluid volume. In patients with normal renal function, CM are excreted with the first glomerular passage and the decrease in their plasma concentration follows a 2-part exponential function, a distribution phase and an elimination phase. However, in patients with renal impairment, the renal clearance values are reduced. For example, 50% of the low-osmolarity contrast agent iomeprol is eliminated within 2 hours in healthy subjects, compared with 16-84 hours in patients with severe renal impairment.

In patients already on dialysis, the commonly sited issues with contrast administration include volume load and direct toxicity of contrast to the remaining nonfunctional nephrons and nonrenal tissues. Thus, the perceived need for emergent dialysis and contrast removal.

Rodby attempted to address these concerns, calculating that the administration of 100 mL of hyperosmolar contrast would move 265 mL of water from the intracellular to the extracellular compartment, resulting in an increase in extracellular volume by 365 mL. The increase in intravascular space would therefore be only a third, or 120 mL. Fluid shifts with LOCM are even less. He also found that extrarenal toxicity of CM was cited in mostly single case reports, and no objective evidence could be identified in 3 prospective studies.[31]

The risk of acute damage from contrast is therefore greatest in patients with CKD. This can be explained by the increase in single nephron GFR and, thus, the filtered load of contrast per nephron. This is akin to a double hit to the remaining nephrons; increased contrast load and prolonged tubular exposure. While this may not seem to be a concern in patients with ESRD who are already on dialysis, residual renal function, in fact, plays a big role in their outcome, more so in patients on peritoneal dialysis. Its preservation is therefore important.[31]

CM can be effectively and efficiently removed by hemodialysis (HD). Factors that influence CM removal include blood flow, membrane surface area, molecular size, transmembrane pressure, and dialysis time. High-flux dialysis membranes with blood flows of between 120-200 mL/min can remove almost 50% of iodinated CM within an hour and 80% in 4 hours. Even in patients with CKD, in whom contrast excretion is delayed, it was found that 70-80% of contrast can be removed by a 4-hour HD treatment. In view of the limited benefit of therapies such as hydration, bicarbonate and NAC, dialysis may seem like the definitive answer.

However, an excellent meta-analysis by Cruz et al—8 trials (6 randomized and 2 nonrandomized, controlled studies) were included in the analysis, with a pooled sample size of 412 patients—indicated that periprocedural extracorporeal blood purification (ECBP) does not significantly reduce the incidence of CIN in comparison with standard medical therapy. ECBP in the study consisted of HD (6 trials), continuous venovenous hemofiltration (1 trial), and continuous venovenous hemodiafiltration (1 trial).[32]

Cruz et al found that the incidence of CIN in the standard medical therapy group was 35.2%, compared with 27.8% in the ECBP group. Renal death (combined endpoint of death or dialysis dependence) was 12.5% in the standard medical therapy group, compared with 7.9% in the ECBP group.

An important consideration is the role of ECBP therapy in patients with severe renal impairment (ie, stage 5 CKD) not yet on maintenance dialysis. A study by Lee et al indicated that in patients with chronic renal failure who are undergoing coronary angiography, prophylactic HD can improve renal outcome. The study included 82 patients with stage 5 CKD who were not on dialysis and who were referred for coronary angiography.[33] The patients were randomly assigned to either undergo prophylactic HD (initiated within 81 ± 32 min) or to receive intravenous normal saline (control group).

The baseline creatinine of the dialysis group was 13.2 mL/min/1.73 m2, comparable to that of the control group (12.6 mL/min/1.73 m2). The investigators’ primary endpoint was change in creatinine clearance in the 2 groups on day 4, which was found to be statistically significant (0.4 ± 0.9 mL/min/1.73 m2 in the dialysis group vs 2.2 ± 2.8 mL/min/1.73 m2 in the control group).

Lee et al found that 35% of the control group required temporary renal replacement therapy, compared with 2% of the dialysis group. In addition, long-term, postdischarge dialysis was required in 13% of the control patients but in none of the dialysis patients. Among those patients who did not require chronic dialysis, an increase in SCr at discharge of over 1 mg/dL from baseline was found in 13 patients in the control group and in 2 patients in the dialysis group.

The study, though hopeful, does raise some concerns. While the change in creatinine clearance on day 4 from baseline was statistically significant, the day 4 creatinine clearance itself was not significantly different between the 2 groups. Also, the results were not expressed as CIN incidence. This patient population is very fragile and is already on the verge of dialysis. How much time off dialysis a single HD session was able to buy these patients was not discussed. The duration of follow-up was also not clear.

Marenzi et al found better outcomes in patients who received venovenous hemofiltration both pre- and post-CM administration than in patients who received post-CM hemofiltration or no hemofiltration at all. These outcomes included a lower likelihood of CIN, no need for HD, and no 1-year mortality, in the pre-/post-CM group.[34]

The biggest confounder in studies of continuous renal replacement therapy (CRRT) is that the outcome measure (SCr) is affected by the treatment itself. While the advantage of CRRT is the lack of delay in its institution, contrast clearance rates would be 1 L/h (16.6 mL/min provided a maximal sieving coefficient for contrast across the hemofiltration membrane of 1), substantially less than standard HD.

Furthermore, continuous venovenous hemofiltration is expensive, highly invasive, and requires trained personnel; the procedure itself needs to be performed in the intensive care unit (ICU). In the face of equivocal benefit of a highly invasive and expensive procedure, the role of continuous venovenous hemofiltration has yet to be accepted as a prophylactic treatment for avoiding CIN.

Dialysis immediately after contrast administration has been suggested for patients already on long-term HD and for those at very high risk of CIN. Three studies looked at its necessity and found that LOCM can be given safely to patients with ESRD who are being maintained on HD without the added expense or inconvenience of emergent postprocedural HD.

The only condition in which HD might be argued to have a beneficial role is in patients on peritoneal dialysis who rely on their residual renal function. In this setting, HD performed soon after CM administration may provide enhanced removal and therefore protect residual renal function. It should be noted, however, that these patients on peritoneal dialysis would therefore need an additional HD procedure with concomitant vascular access, as the clearance with peritoneal dialysis would be far too slow to offer any protection.

In a study to determine if renal replacement therapy in concert with contrast administration helps, Frank et al found that although the overall clearance of contrast was significantly increased by dialysis, the peak plasma concentration of iomeprol 15 minutes after contrast administration was not significantly changed by simultaneous dialysis. In their report, the investigators prospectively studied 17 patients with chronic renal insufficiency (SCr >3 mg/dL), dialysis independent, who were then randomized to receive high-flux HD over 6 hours simultaneously with contrast administration, and[35]

In the study, Frank et al also found that to be clinically effective, simultaneous dialysis should reduce the risk of developing ESRD by 50%. If type 1 and type 2 errors are set at 0.01, the result could be accepted only if none of the 48 sequential patients with simultaneous dialysis required dialysis during the 8 weeks after contrast exposure. To reject the hypothesis, 239 sequential patients with simultaneous dialysis would have to be included. Therefore, most CIN studies, are seriously underpowered.

Studies of HD for CIN vary with respect to the definition of CIN used, the patient population, the type and volume of CM, how long after CM administration HD is started, and, finally, the dialysis treatment modality itself. While existing studies do not show HD to be superior to hydration alone for CIN prevention, if HD is used in conjunction with hydration and CIN protective therapy, such as NAC and bicarbonate, it might prove to be efficacious in some high-risk patients. However, most studies have had only an 8-week follow-up period. While the initiation of long-term dialysis was 5-15%, the progression to uremia over a long-term follow-up period is still unanswered.[16]

Other Therapies

Ascorbic acid, which has antioxidant properties, was studied for its ability to counter the effect of free radicals and reactive oxygen species. One study found that oral ascorbic acid administered in a 3-g dose preprocedure and two 2-g doses postprocedure was associated with a 62% risk reduction in CIN incidence.[36]

Theophylline and aminophylline are adenosine antagonists that counteract the intrarenal vasoconstrictor and tubuloglomerular feedback effects of adenosine. They have been found to have a statistically significant effect in preventing CIN in high-risk patients. However, their use is limited by their narrow therapeutic window and adverse effects profile.

Vasodilators, such as calcium channel blockers, dopamine/fenoldopam, atrial natriuretic peptide, and L-arginine, all with different mechanisms of action, have a favorable effect on renal hemodynamics. However, their use for CIN prevention has not been borne out by most controlled trials, and they are not routinely recommended at this point.

Forced diuresis with furosemide and mannitol was studied in the hope that this procedure would dilute CM within the tubular lumen and enhance their excretion. Furosemide and mannitol in fact worsen CIN by causing dehydration in patients who may already have intravascular volume depletion. Their use at this time is discouraged.

Deterrence and Prevention

The best therapy for CIN is prevention. Physicians need to be increasingly aware that CIN is a common and potentially serious complication. Patients at risk should be identified early, especially those with CKD (ie, eGFR < 60 mL/min/1.73 m2). A detailed history inquiring for risk factors, especially diabetes mellitus, should be ascertained.

In patients with risk factors for CIN, the possibility of alternative imaging studies that do not need contrast should be explored. MRI with gadolinium is no longer considered a safe alternative to contrast because of the risk of nephrogenic systemic fibrosis, an irreversible, debilitating condition seen mostly in patients with an eGFR of less than 30 mL/min/1.73 m2.

In patients with a moderate to severe risk of CIN, creatinine clearance rates or eGFR should be estimated by either the MDRD formula or the Cockroft-Gault formula and then measured again 24-48 hours after contrast administration.

In the emergency setting, where the benefit of very early imaging studies outweighs that of waiting, the imaging procedure can be carried out without an initial estimation of SCr or eGFR.

Intra-arterial administration of iodinated CM poses a greater risk for CIN than does the intravenous approach. For patients at an increased risk for CIN receiving intra-arterial contrast, nonionic iso-osmolar agents (iodixanol) are associated with the lowest risk of CIN.

The amount of contrast used during the procedure should be limited to as little as possible and kept under 100 mL. Most investigators have found this to be the cut-off value below which no patient needed dialysis. The risk of CIN increases by 12% for each 100 mL of contrast used beyond the first 100 mL. Most angiographic diagnostic studies usually require 100 mL of contrast, compared with 200-250 mL for angioplasty. The maximum amount of contrast that can be used safely should be individualized, taking into account the preexisting renal function.

Various formulas for calculating the maximal safe CM dose have been suggested. Two most often cited are those suggested by Cigarroa et al and the European Society of Urogenital Radiology (ESUR).[37, 38] Cigarroa et al, in a retrospective study of 115 patients undergoing cardiac catheterization and angiography, using the HOCM diatrizoate, suggested that the dose of CM should not exceed 5 mL/kg of body weight (maximum 300 mL divided by SCr [mg/dL]). The ESUR, in turn, has published maximal LOCM volumes for various SCr cut-off values.

While the formulas from Cigarroa and the ESUR take into account the SCr, it has been suggested that the eGFR (a more accurate predictor of renal function) and the iodine dose of CM should be reflected in any estimates or predictions of safe CM dosages. There exists, however, no unimpeachably safe CM dose algorithm for CIN prevention.

The length of time between 2 contrast procedures should be at least 48-72 hours. Rapid repetition of contrast administration has been found to be a univariate risk factor for CIN.

Potentially nephrotoxic drugs (eg, NSAIDs, aminoglycosides, amphotericin B, cyclosporin, tacrolimus) should be withdrawn at least 24 hours prior, in patients at risk (eGFR < 60 mL/min).

Metformin, though not nephrotoxic, should be used prudently, because if renal failure does occur, there is risk of concomitant lactic acidosis. Therefore, metformin should be stopped at the time of the procedure and resumed 48 hours later if renal function remains normal.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) cause a 10-15% rise in SCr by reducing intraglomerular pressure. While they should not be started at this time, whether they should be discontinued remains a matter of debate. Much of the literature in this area is unclear and controversial.

Minimizing contrast administration

The amount of contrast used during the procedure should be limited to as little as possible and kept under 100 mL. Most investigators have found this to be the cut-off value below which no patient needed dialysis. The risk of CIN increases by 12% for each 100 mL of contrast used beyond the first 100 mL. Most angiographic diagnostic studies usually require 100 mL of contrast, compared with 200-250 mL for angioplasty. The maximum amount of contrast that can be used safely should be individualized, taking into account the preexisting renal function.

Various formulas for calculating the maximal safe CM dose have been suggested. Two most often cited are those suggested by Cigarroa et al and the European Society of Urogenital Radiology (ESUR).[37, 38] Cigarroa et al, in a retrospective study of 115 patients undergoing cardiac catheterization and angiography, using the HOCM diatrizoate, suggested that the dose of CM should not exceed 5 mL/kg of body weight (maximum 300 mL divided by SCr [mg/dL]). The ESUR, in turn, has published maximal LOCM volumes for various SCr cut-off values.

While the formulas from Cigarroa and the ESUR take into account the SCr, it has been suggested that the eGFR (a more accurate predictor of renal function) and the iodine dose of CM should be reflected in any estimates or predictions of safe CM dosages. There exists, however, no unimpeachably safe CM dose algorithm for CIN prevention.

RAAS blockade

A prospective, 50-month Mayo study found renin-angiotensin-aldosterone system (RAAS) blockade, particularly in older patients with CHD, exacerbates CIN (43% incidence of dialysis and 29% progression to ESRD).[39] The marker used for renal function was eGFR, as calculated by the MDRD formula. The study recommended that RAAS blockade be withheld 48 hours prior to contrast exposure.

RAAS blockage, however, can improve renal perfusion and decrease proximal tubular reabsorption, including CM absorption by the tubular cells. This effect can be documented with the increase in the fractional excretion of urea seen with low-dose RAAS therapy in patients with CHF and moderate CKD (the majority of the CIN-susceptible population).[40] In this group, reduction in intraglomerular pressure and filtration fraction from RAAS therapy might decrease tubular CM concentration and therefore lessen its adverse effects.

Medication Summary

NAC is acetylated L-cysteine, an amino acid. As previously mentioned, its sulfhydryl groups make it an excellent antioxidant and scavenger of free oxygen radicals. It also enhances the vasodilatory properties of nitric oxide. Twelve meta-analyses covering 29 randomized, controlled trials have been published on the effect of NAC therapy in CIN. They all suffer from significant heterogeneity. The standard oral NAC regimen consists of 600 mg twice daily for 24 hours before and on the day of the procedure. Higher doses of 1 g, 1200 mg, and 1500 mg twice daily have also been studied, with no significant dose-related or route-related (oral vs intravenous) difference. NAC has very low oral bioavailability; substantial interpatient variability and inconsistency between the available oral products obscure the picture further.[24, 28]

Antidote, Acetaminophen

Class Summary

Used for prevention of contrast toxicity.

N-acetylcysteine (Acetadote)

Used for prevention of contrast toxicity in susceptible individuals such as those with diabetes mellitus. May provide substrate for conjugation with toxic metabolites.

Antilipemic Agents

Class Summary

These agents are used for their favorable effects on endothelin and thrombus formation, plaque stabilization and anti-inflammatory properties by improving lipid profile.

Simvastatin (Zocor)

Indicated for hyperlipoproteinemia (Type III). Inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibit cholesterol synthesis, and increases cholesterol metabolism. Increase HDL cholesterol and decrease LDL-C, total-C, apolipoprotein B, VLDL cholesterol, and plasma triglycerides.

Atorvastatin (Lipitor)

The most efficacious of the statins at high doses. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. Reports have shown as much as a 60% reduction in LDL-C. The Atorvastatin versus Revascularization Treatment study (AVERT) compared 80 mg atorvastatin daily to standard therapy and angioplasty in patients with CHD. While events at 18 mo were the same between both groups, the length of time until the first CHD event occurred was longer with aggressive LDL-C lowering. The half-life of atorvastatin and its active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h).

May modestly elevate HDL-C levels. Clinically, reduced levels of circulating total cholesterol, LDL-C, and serum TGs are observed.

Before initiating therapy, patients should be placed on a cholesterol-lowering diet for 3-6 mo; the diet should be continued indefinitely.

Lovastatin (Mevacor, Altoprev)

Adjunct to dietary therapy in reducing serum cholesterol. Immediate-release (Mevacor) and extended-release (Altocor) are available.

Fluvastatin (Lescol, Lescol XL)

Synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, structurally distinct and has different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration).

Used as an adjunct to dietary therapy in decreasing cholesterol levels.

Pravastatin (Pravachol)

Effective in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis.

Rosuvastatin (Crestor)

HMG-CoA reductase inhibitor that in turn decreases cholesterol synthesis and increases cholesterol metabolism. Reduces total-C, LDL-C, and TG levels and increases HDL-C level. Used adjunctively with diet and exercise to treat hypercholesterolemia.


Managing Your Risks: Patient and Physician Health in the Cath Lab

flouro image

In this post we’ll explore the issue of radiation exposure, occupational risks in the catheterization lab, and how that can impact your care.

I. Patient Risks in the Cath Lab

Fluoroscopy is a type of medical imaging used during percutaneous coronary interventions that displays a continuous x-ray image. Blood flow and artery blockages are not able to be seen using x-ray only imaging. Physicians inject a contrast solution into the arteries so that when an x-ray beam is passed through the tissue, the physician can get a real-time image of the coronary arteries. On average, angioplasty procedures will last about an hour, this means the patient is exposed to ionizing radiation from the fluoroscopy for a significant amount of time. Lengthy procedures lead to greater exposure to the radiation of fluoroscopy.

Radiation has a cumulative effect and leads to increased risk for many conditions, most notably, cancer.  In healthcare where radiation is required for treatment, there is a prevailing philosophy called ALARA, which stands for as low as (is) reasonably achievable.   Wherever possible, physicians should be looking for ways to limit exposure to radiation to limit the cumulative effects of radiation on patients. Along with the risks posed by radiation, patients in the cath lab also face potentially high doses of the contrast medium which can cause a condition known as contrast induced nephropathy. The contrast solution that is so valuable to imaging can be toxic to the kidneys, and when the body is unable to process the contrast, it leads to CIN in which the kidneys shut down.  While most patients who develop CIN typically recover within 1- 2 weeks, it can cause serious renal (kidney) complications in patients with certain risk factors including diabetes, prior kidney transplant, chronic kidney disease, and hypertensive disorders. Therefore, physicians need to keep a constant watch on the contrast volume used during procedures to minimize the risk of CIN.

II. Occupational Hazards in the Cath Lab

It is well documented that Interventional Cardiologists face serious dangers of long-term radiation exposure in the cath lab. Risks to clinicians include: skin damage to hands and exposed tissue, injury to the lens of the eye/ cataracts, and in some cases the development of brain tumors and other cancers. In a 2012 study, researchers found an increased incidence of left hemisphere brain tumors in a study group of interventional cardiologists that may be attributed to the prolonged exposure to ionizing radiation to the left side of the head during interventional procedures.

Via LifeScience PLUS

Physicians in the Cardiac Cath Lab (Via LifeScience PLUS)

Lead aprons are the standard convention used in Cath labs across the US to reduce radiation exposure to physicians and staff; however these protective barriers can weigh between 15-20 pounds and place up to 300 pounds per square inch of pressure on vertebral disks. In one study more than 400 interventionalists were surveyed and 71% of the study population reported some type of orthopedic disease. According to Dr. Tom Ports, Director of Interventional Cardiology at University of San Francisco, the leading cause of early retirement for interventional cardiologists is spinal injury!

Attention to the danger of radiation exposure and other risks in the cath lab for both patients and staff is on the rise. As more focus is being brought upon safety practices in the cath lab, improved procedural measures are being put in place to protect physicians and staff, and improve the quality of care for patients.


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Reporter: Aviral Vatsa PhD, MBBS

Osteocytes are the professional mechanosensors of bone. They modulate bone remodelling in accordance with external mechanical loads by orchestrating the activity of one forming osteoblasts and bone resorbing osteoclasts. Osteocytes are at the heart of bone metabolism. They constitute >95% of bone cells. They are terminally differentiated cells and reside in the hard mineralised matrix of bone, thus making it difficult to study them in situ. However, recent developments in imaging and tissue processing have made it possible to study osteocytes in their natural milieu. Moreover, increasing number of studies have highlighted the fact that a multifaceted approach from various domains of science such as biomechanics, cell biology, bioengineering, biophysics, biomaterials, computational modelling, endocrinology, and orthopaedics is essential to further our understanding of the intricate processes involved in bone remodelling and the central role of osteocytes in maintaining bone mass and architecture.

In this post a variety of reviews from an upcoming special issue on osteocytes in the journal Bone are highlighted that help us add few more pieces of knowledge to the ever growing eclaircissements on the subject.

1. Measurement and estimation of osteocyte mechanical strain

Review Article
Amber Rath Stern, Daniel P. Nicolella


Osteocytes are the most abundant cell type in bone and are responsible for sensing mechanical strain and signaling bone (re)modeling, making them the primary mechanosensors within the bone. Under aging and osteoporotic conditions, bone is known to be less responsive to loading (exercise), but it is unclear why. Perhaps, the levels of mechanical strain required to initiate these biological events are not perceived by the osteocytes embedded within the bone tissue. In this review we examine the methods used to measure and estimate the strains experienced by osteocytes in vivo as well as the results of related published experiments. Although the physiological levels of strain experienced by osteocytes in vivo are still under investigation, through computational modeling and laboratory experiments, it has been shown that there is significant amplification of average bone strain at the level of the osteocyte lacunae. It has also been proposed that the material properties of the perilacunar region surrounding the osteocyte can have significant effects of the strain perceived by the embedded osteocyte. These facts have profound implications for studies involving osteoporotic bone where the material properties are known to become stiffer.

2. Glucocorticoids and Osteocyte Autophagy

Review Article
Wei Yao, Weiwei Dai, Jean X. Jiang, Nancy E. Lane


Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk is high. While previous studies have found GC effects on both osteoclasts and oteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis. This paper will review the data to support the role of GCs in osteocyte autophagy.

3. Osteocytes remove and replace perilacunar mineral during reproductive cycles

Review Article
John J. Wysolmerski


Lactation is associated with an increased demand for calcium and is accompanied by a remarkable cycle of bone loss and recovery that helps to supply calcium and phosphorus for milk production. Bone loss is the result of increased bone resorption that is due, in part, to increased levels of PTHrP and decreased levels of estrogen. However, the regulation of bone turnover during this time is not fully understood. In the 1960s and 1970s many observations were made to suggest that osteocytes could resorb bone and increase the size of their lacunae. This concept became known as osteocytic osteolysis and studies suggested that it occurred in response to parathyroid hormone and/or an increased systemic demand for calcium. However, this concept fell out of favor in the late 1970s when it was established that osteoclasts were the principal bone-resorbing cells. Given that lactation is associated with increased PTHrP levels and negative calcium balance, we recently examined whether osteocytes contribute to bone loss during this time. Our findings suggest that osteocytes can remodel their perilacunar and pericanalicular matrix and that they participate in the liberation of skeletal calcium stores during reproductive cycles. These findings raise new questions about the role of osteocytes in coordinating bone and mineral metabolism during lactation as well as the recovery of bone mass after weaning. It is also interesting to consider whether osteocyte lacunar and canalicular remodeling contribute more broadly to the maintenance of skeletal and mineral homeostasis.

4. Studying osteocytes within their environment

Review Article
Duncan J. Webster, Philipp Schneider, Sarah L. Dallas, Ralph Müller


It is widely hypothesized that osteocytes are the mechano-sensors residing in the bone’s mineralized matrix which control load induced bone adaptation. Owing to their inaccessibility it has proved challenging to generate quantitative in vivo experimental data which supports this hypothesis. Recent advances in in situ imaging, both in non-living and living specimens, have provided new insights into the role of osteocytes in the skeleton. Combined with the retrieval of biochemical information from mechanically stimulated osteocytes using in vivo models, quantitative experimental data is now becoming available which is leading to a more accurate understanding of osteocyte function. With this in mind, here we review i) state of the art ex vivo imaging modalities which are able to precisely capture osteocyte structure in 3D, ii) live cell imaging techniques which are able to track structural morphology and cellular differentiation in both space and time, and iii) in vivo models which when combined with the latest biochemical assays and microfluidic imaging techniques can provide further insight on the biological function of osteocytes.

5. Osteocyte apoptosis

Review Article
Robert L. Jilka, Brendon Noble, Robert S. Weinstein


Apoptotic death of osteocytes was recognized over 15 years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed. This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines. The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength.

6. Emerging role of primary cilia as mechanosensors in osteocytes

Review Article
An M. Nguyen, Christopher R. Jacobs


The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell. This organelle has established mechanosensory roles in several contexts including kidney, liver, and the embryonic node. Mechanical load deflects the cilium, triggering biochemical responses. Defects in cilium function have been associated with numerous human diseases. Recent research has implicated the primary cilium as a mechanosensor in bone. In this review, we discuss the cilium, the growing evidence for its mechanosensory role in bone, and areas of future study.

7. Mechanosensation and transduction in osteocytes

Review Article
Jenneke Klein-Nulend, Astrid D. Bakker, Rommel G. Bacabac, Aviral Vatsa, Sheldon Weinbaum


The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes.

8. The osteocyte in CKD: New concepts regarding the role of FGF23 in mineral metabolism and systemic complications

Review Article
Katherine Wesseling-Perry, Harald Jüppner


The identification of elevated circulating levels of the osteocytic protein fibroblast growth factor 23 (FGF23) in patients with chronic kidney disease (CKD), along with recent data linking these values to the pathogenesis of secondary hyperparathyroidism and to systemic complications, has changed the approach to the pathophysiology and treatment of disordered bone and mineral metabolism in renal failure. It now appears that osteocyte biology is altered very early in the course of CKD and these changes have implications for bone biology, as well as for progressive cardiovascular and renal disease. Since circulating FGF23 values are influenced by therapies used to treat secondary hyperparathyroidism, the effects of different therapeutic paradigms on FGF23 have important implications for mineral metabolism as well as for morbidity and mortality. Further studies are critically needed to identify the initial trigger for abnormalities of skeletal mineralization and turnover as well as the potential effects that current therapeutic options may have on osteocyte biology.

9. Vitamin D signaling in osteocytes: Effects on bone and mineral homeostasis

Review Article
Liesbet Lieben, Geert Carmeliet


The active form of vitamin D [1,25(OH)2D] is an important regulator of calcium and bone homeostasis, as evidenced by the consequences of 1,25(OH)2D inactivity in man and mice, which include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism and bone abnormalities. The recent generation of tissue-specific (intestine, osteoblast/osteocyte, chondrocyte) vitamin D receptor (Vdr) null mice has provided mechanistic insight in the cell-specific actions of 1,25(OH)2D and their contribution to the integrative physiology of VDR signaling that controls bone and mineral metabolism. These studies have demonstrated that even with normal dietary calcium intake, 1,25(OH)2D is crucial to maintain normal calcium and bone homeostasis and accomplishes this through this primarily through stimulation of intestinal calcium transport. When, moreover, insufficient calcium is acquired from the diet (severe dietary calcium restriction, lack of intestinal VDR activity), 1,25(OH)2D levels will increase and will directly act on osteoblasts and osteocytes to enhance bone resorption and to suppress bone matrix mineralization. Although this system is essential to maintain normal calcium levels in blood during a negative calcium balance, the consequences for bone are disastrous and generate an increased fracture risk. These findings evidently demonstrate that preservation of serum calcium levels has priority over skeletal integrity. Since vitamin D supplementation is an essential part of anti-osteoporotic therapy, mechanistic insight in vitamin D actions is required to define the optimal therapeutic regimen, taking into account the amount of dietary calcium supply, in order to maximize the targeted outcome and to avoid side-effects. We will review the current understanding concerning the functions of osteoblastic/osteocytic VDR signaling which not only include the regulation of bone metabolism, but also comprise the control of calcium and phosphate homeostasis via fibroblast growth factor (FGF) 23 secretion and the maintenance of the hematopoeitic stem cell (HSC) niche, with special focus on the experimental data obtained from systemic and osteoblast/osteocyte-specific Vdr null mice.

10. In vitro and in vivo approaches to study osteocyte biology

Review Article
Ivo Kalajzic, Brya G. Matthews, Elena Torreggiani, Marie A. Harris, Paola Divieti Pajevic, Stephen E. Harris


Osteocytes, the most abundant cell population of the bone lineage, have been a major focus in the bone research field in recent years. This population of cells that resides within mineralized matrix is now thought to be the mechanosensory cell in bone and plays major roles in the regulation of bone formation and resorption. Studies of osteocytes had been impaired by their location, resulting in numerous attempts to isolate primary osteocytes and to generate cell lines representative of the osteocytic phenotype. Progress has been achieved in recent years by utilizing in vivo genetic technology and generation of osteocyte directed transgenic and gene deficiency mouse models.

We will provide an overview of the current in vitro and in vivo models utilized to study osteocyte biology. We discuss generation of osteocyte-like cell lines and isolation of primary osteocytes and summarize studies that have utilized these cellular models to understand the functional role of osteocytes. Approaches that attempt to selectively identify and isolate osteocytes using fluorescent protein reporters driven by regulatory elements of genes that are highly expressed in osteocytes will be discussed.

In addition, recent in vivo studies utilizing overexpression or conditional deletion of various genes using dentin matrix protein (Dmp1) directed Cre recombinase are outlined. In conclusion, evaluation of the benefits and deficiencies of currently used cell lines/genetic models in understanding osteocyte biology underlines the current progress in this field. The future efforts will be directed towards developing novel in vitro and in vivo models that would additionally facilitate in understanding the multiple roles of osteocytes.

11. Gap junction and hemichannel functions in osteocytes

Review Article
Alayna E. Loiselle, Jean X. Jiang, Henry J. Donahue


Cell-to-cell and cell-to-matrix communication in bone cells mediated by gap junctions and hemichannels, respectively, maintains bone homeostasis. Gap junctional communication between cells permits the passage of small molecules including calcium and cyclic AMP. This cell-to-cell communication occurs between bone cells including osteoblasts, osteoclasts and osteocytes, and is important in both bone formation and bone resorption. Connexin (Cx) 43 is the predominant gap junction protein in bone cells, and facilitates the communication of cellular signals either through docking of gap junctions between two cells, or through the formation of un-paired hemichannels. Systemic deletion of Cx43 results in perinatal lethality, so conditional deletion models are necessary to study the postnatal role of gap junctions in bone. These models provide the opportunity to determine the role of gap junctions in specific bone cells, notably the osteocyte. In this review, we summarize the key roles that gap junctions and hemichannels in osteocytes play in bone cell response to many stimuli including mechanical loading, intracellular and extracellular stimuli, such as parathyroid hormone, PGE2, plasma calcium levels and pH, as well as in maintaining osteocyte survival.

12. Effects of PTH on osteocyte function

Review Article
Teresita Bellido, Vaibhav Saini, Paola Divieti Pajevic


Osteocytes are ideally positioned to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. However, evidence supporting the involvement of osteocytes in specific aspects of skeletal biology has been limited mainly due to the lack of suitable experimental approaches. Few crucial advances in the field in the past several years have markedly increased our understanding of the function of osteocytes. The development of osteocytic cell lines initiated a plethora of in vitro studies that have provided insights into the unique biology of osteocytes and continue to generate novel hypotheses. Genetic approaches using promoter fragments that direct gene expression to osteocytes allowed the generation of mice with gain or loss of function of particular genes revealing their role in osteocyte function. Furthermore, evidence that Sost/sclerostin is expressed primarily in osteocytes and inhibits bone formation by osteoblasts, fueled research attempting to identify regulators of this gene as well as other osteocyte products that impact the function of osteoblasts and osteoclasts. The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits sclerostin expression generated a cascade of studies that revealed that osteocytes are crucial target cells of the actions of PTH. This review highlights these investigations and discusses their significance for advancing our understanding of the mechanisms by which osteocytes regulate bone homeostasis and for developing therapies for bone diseases targeting osteocytes.

13. For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases

Review Article
Stavros C. Manolagas, A. Michael Parfitt


Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar–canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab.

14. Osteocyte control of osteoclastogenesis

Review Article
Charles A. O’Brien, Tomoki Nakashima, Hiroshi Takayanagi


Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin. However, the role of osteocytes in the control of bone resorption has been less clear. Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone. The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption.


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  2. W. Yao, W. Dai, J. X. Jiang, and N. E. Lane, “Glucocorticoids and Osteocyte Autophagy,” Bone.
  3. J. J. Wysolmerski, “Osteocytes remove and replace perilacunar mineral during reproductive cycles,” Bone.
  4. D. J. Webster, P. Schneider, S. L. Dallas, and R. Müller, “Studying osteocytes within their environment,” Bone.
  5. R. L. Jilka, B. Noble, and R. S. Weinstein, “Osteocyte apoptosis,” Bone.
  6. A. M. Nguyen and C. R. Jacobs, “Emerging role of primary cilia as mechanosensors in osteocytes,” Bone.
  7. J. Klein-Nulend, A. D. Bakker, R. G. Bacabac, A. Vatsa, and S. Weinbaum, “Mechanosensation and transduction in osteocytes,” Bone.
  8. K. Wesseling-Perry and H. Jüppner, “The osteocyte in CKD: New concepts regarding the role of FGF23 in mineral metabolism and systemic complications,” Bone.
  9. L. Lieben and G. Carmeliet, “Vitamin D signaling in osteocytes: Effects on bone and mineral homeostasis,” Bone.
  10. I. Kalajzic, B. G. Matthews, E. Torreggiani, M. A. Harris, P. Divieti Pajevic, and S. E. Harris, “In vitro and in vivo approaches to study osteocyte biology,” Bone.
  11. A. E. Loiselle, J. X. Jiang, and H. J. Donahue, “Gap junction and hemichannel functions in osteocytes,” Bone.
  12. T. Bellido, V. Saini, and P. D. Pajevic, “Effects of PTH on osteocyte function,” Bone.
  13. S. C. Manolagas and A. M. Parfitt, “For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases,” Bone
  14. C. A. O’Brien, T. Nakashima, and H. Takayanagi, “Osteocyte control of osteoclastogenesis,” Bone.
  15. Bone remodelling in a nutshel June 22, 2012 by aviralvatsa
  16. Isolation of primary osteocytes from skeletally mature mice bones: Reoprt on “Isolation and culture of primary osteocytes from the long bones of skeletally mature and aged mice” (BioTechniques 52:361-373 ( June 2012) doi 10.2144/0000113876 )
  17. Nitric Oxide in bone metabolism July 16, 2012 by aviralvatsa

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