Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases.

Joint-on-a-chip (JOC) models are powerful tools that aid in osteoarthritis (OA) research. These microfluidic devices apply emerging organ-on-a-chip technology to recapitulate a multifaceted joint tissue microenvironment. JOCs address the need for advanced, dynamic in vitro models that can mimic the in vivo tissue environment through joint-relevant biomechanical or fluidic integration, an aspect that existing in vitro OA models lack. There are existing review articles on OA models that focus on animal, tissue explant, and two-dimensional and three-dimensional (3D) culture systems, including microbioreactors and 3D printing technology, but there has been limited discussion of JOC models. The aim of this article is to review recent developments in human JOC technology and identify gaps for future advancements. Specifically, mechanical stimulation systems that mimic articular movement, multi-joint tissue cultures that enable crosstalk, and systems that aim to capture aspects of OA inflammation by incorporating immune cells are covered. The development of an advanced JOC model that captures the dynamic joint microenvironment will improve testing and translation of potential OA therapeutics.

Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.

The available data on bone fractures in hemodialysis (HD) patients are limited to results of a few studies of subgroups of patients in the United States. This study describes the prevalence of hip fractures and the incidence and risk factors associated with hip and other fractures in representative groups of HD facilities (n=320) and patients (n=12 782) from the 12 countries in the second phase of the Dialysis Outcomes and Practice Patterns Study (2002-2004). Among prevalent patients, 2.6% had a prior hip fracture. The incidence of fractures was 8.9 per 1000 patient years for new hip fractures and 25.6 per 1000 for any new fracture. Older age (relative risk (RR)(HIP)=1.91, RR(ANY)=1.33, P<0.0001), female sex (RR(HIP)=1.41, P=0.02; RR(ANY)=1.59, P<0.0001), prior kidney transplant (RR(HIP)=2.35, P=0.04; RR(ANY)=1.76, P=0.007), and low serum albumin (RR(HIP)=1.85, RR(ANY)=1.45, per 1 g/dl lower, P<0.0001) were predictive of new fractures. Elevated risk of new hip fracture was observed for selective serotonin reuptake inhibitors and combination narcotic medications (RR=1.63, RR=1.74, respectively, P<0.05). Several medications were associated with risk of any new fracture: narcotic pain medications (RR=1.67, P=0.02), benzodiazepines (RR=1.31, P=0.03), adrenal cortical steroids (RR=1.40, P<0.05), and combination narcotic medications (RR=1.72, P=0.001). Parathyroid hormone (PTH) levels >900 pg/ml were associated with an elevated risk of any new fracture (RR=1.72, P<0.05) versus PTH 150-300. The results suggest that greater selectivity in prescribing several classes of psychoactive drugs and more efficient treatment of secondary hyperparathyroidism may help reduce the burden of fractures in HD patients.

Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.

Longer treatment time (TT) and slower ultrafiltration rate (UFR) are considered advantageous for hemodialysis (HD) patients. The study included 22,000 HD patients from seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Logistic regression was used to study predictors of TT > 240 min and UFR > 10 ml/h/kg bodyweight. Cox regression was used for survival analyses. Statistical adjustments were made for patient demographics, comorbidities, dose of dialysis (Kt/V), and body size. Europe and Japan had significantly longer (P < 0.0001) average TT than the US (232 and 244 min vs 211 in DOPPS I; 235 and 240 min vs 221 in DOPPS II). Kt/V increased concomitantly with TT in all three regions with the largest absolute difference observed in Japan. TT > 240 min was independently associated with significantly lower relative risk (RR) of mortality (RR = 0.81; P = 0.0005). Every 30 min longer on HD was associated with a 7% lower RR of mortality (RR = 0.93; P < 0.0001). The RR reduction with longer TT was greatest in Japan. A synergistic interaction occurred between Kt/V and TT (P = 0.007) toward mortality reduction. UFR > 10 ml/h/kg was associated with higher odds of intradialytic hypotension (odds ratio = 1.30; P = 0.045) and a higher risk of mortality (RR = 1.09; P = 0.02). Longer TT and higher Kt/V were independently as well as synergistically associated with lower mortality. Rapid UFR during HD was also associated with higher mortality risk. These results warrant a randomized clinical trial of longer dialysis sessions in thrice-weekly HD.

Body mass index and mortality in 'healthier' as compared with 'sicker' haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Haemodialysis (HD) patients with lower body mass index (BMI) have a higher relative mortality risk (RR), irrespective of race. However, only Asian Americans treated with HD have been found to have an elevated RR with higher BMI. Asian Americans on HD are 'healthier' than other race groups (i.e. have better overall survival). We hypothesized that an increased mortality risk might be associated with high BMI in a variety of other 'healthier' subgroups of HD patients. METHODS: The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) provided baseline demographic, comorbidity and BMI data on 9714 HD patients in the US and Europe (France, Germany, Italy, Spain, and the UK) from 1996-2000. Using multivariate survival analyses, we evaluated BMI-mortality relationships in HD subpopulations defined by continent, race (black and white), gender, tertiles of severity of illness (based on a score derived from comorbid conditions and serum albumin concentration), age (<45, 45-64, >or=65), smoking, and diabetic status. RESULTS: Relative mortality risk decreased with increasing BMI. This was statistically significant (P<0.007) except for the smallest subgroup of patients who were <45 years old and were also in the healthiest tertile of comorbidity. All else equal, BMI <20 was consistently associated with the highest relative mortality risk. Overall a lower relative mortality risk (RR) as compared with BMI 23-24.9, was found for overweight (BMI 25-29.9; RR 0.84, P=0.008), for mild obesity (BMI 30-34.9; RR 0.73, P=0.0003), and for moderate obesity (BMI 35-39.9; RR 0.76, P=0.02). CONCLUSION: In a wide variety of HD patient subgroups, differing with respect to their baseline health status, increasing body size correlates with a decreased mortality risk. This contrasts with the association between BMI and mortality in the general population, and deserves further study.

Type of vascular access and mortality in U.S. hemodialysis patients.

BACKGROUND: Vascular access (VA) complications account for 16 to 25% of hospital admissions. This study tested the hypothesis that the type of VA in use is correlated with overall mortality and cause-specific mortality. METHODS: Data were analyzed from the U.S. Renal Data System Dialysis Morbidity and Mortality Study Wave 1, a random sample of 5507 patients, prevalent on hemodialysis as of December 31, 1993. The relative mortality risk during a two-year observation was analyzed by Cox-regression methods with adjustments for demographic and comorbid conditions. Using similar methods, cause-specific analyses also were performed for death caused by infection and cardiac causes. RESULTS: In diabetic mellitus (DM) patients with end-stage renal disease, the associated relative mortality risk was higher for those with arteriovenous graft (AVG; RR = 1.41, P < 0.003) and central venous catheter (CVC; RR = 1.54, P < 0.002) as compared with arteriovenous fistula (AVF). In non-DM patients, those with CVC had a higher associated mortality (RR = 1.70, P < 0.001), as did to a lesser degree those with AVG (RR = 1.08, P = 0.35) when compared with AVF. Cause-specific analyses found higher infection-related deaths for CVC (RR = 2.30, P < 0.06) and AVG (RR = 2.47, P < 0.02) compared with AVF in DM; in non-DM, risk was higher also for CVC (RR = 1.83, P < 0.04) and AVG (RR = 1.27, P < 0.33). In contrast to our hypothesis that AV shunting increases cardiac risk, deaths caused by cardiac causes were higher in CVC than AVF for both DM (RR = 1.47, P < 0.05) and non-DM (RR = 1.34, P < 0.05) patients. CONCLUSION: This case-mix adjusted analysis suggests that CVC and AVG are correlated with increased mortality risk when compared with AVF, both overall and by major causes of death.

Incidence trends and mortality in end-stage renal disease attributed to renovascular disease in the United States.

End-stage renal disease (ESRD) attributed to renovascular disease (RVD-ESRD) has been incompletely characterized. We determined incidence trends, clinical features, prior treatment, and survival of patients with RVD-ESRD using the US Renal Data System database. Primary causes of ESRD were assessed in patients starting ESRD therapy during 1991 to 1997. The incidence of RVD-ESRD increased from 2.9/10(6) per year (1.4% of new ESRD cases) to 6.1/10(6) per year (2.1%). The annualized increase was 12.4% per year. This is a greater rate of increase than for ESRD from diabetes mellitis (DM-ESRD; 8.3% per year) and ESRD overall (5.4% per year). The risk for RVD-ESRD versus other-cause ESRD correlated positively with age (odds ratio [OR], 1.7 per 10-year increment; P < 0.0001) and male sex (OR, 1.2; P < 0.0001) and negatively with black (OR, 0.17; P < 0.0001), Asian (OR, 0.29; P < 0.0001), and Native American race (OR, 0.31; P < 0.0001). The unadjusted prevalence of coronary heart disease, cerebrovascular disease, and peripheral vascular disease was greater in patients with RVD-ESRD versus other-cause ESRD (P < 0.001). Of patients with RVD-ESRD, 5% underwent revascularization in the 2 years before ESRD compared with 0.5% of patients with other-cause ESRD, including DM-ESRD. Adjusted for age, race, sex, comorbidity, and laboratory values, the survival of patients with RVD-ESRD was similar to that for patients with other-cause ESRD (risk ratio, 1.01; P = 0.5). These findings suggest that RVD-ESRD is increasing faster than other-cause ESRD and is not independently associated with an increased mortality risk. Strategies may exist to prevent progression to ESRD and merit priority for further study.

[Dialysis Outcomes and Practice Patterns Study: data on the use of central venous catheters in chronic hemodialysis]. / Dialysis Outcomes and Practice Patterns Study: données sur l'utilisation des cathéters veineux centraux en hémodialyse chronique.

Central venous catheters are widely used as vascular accesses for chronic haemodialysis. Different factors may lead to catheter use, whether clinical such as emergency dialysis, or related to practices specific to each dialysis unit or country. The Dialysis Outcomes and Practice Patterns Study is an observational study of more than 10,000 representative patients treated by haemodialysis followed over a two-year period in the United States, Japan, and in five European countries (France, Germany, Italy, Spain, United Kingdom). DOPPS data from the United States and Europe about catheters are reported in this paper. Catheter use is less frequent in Europe than in the US, both in incident and prevalent patients, and in patients who have been seen by a nephrologist in the pre-dialysis period. Tunneled and untunneled catheters are each associated with a significantly higher frequency of access infection compared to native arteriovenous fistulae and grafts. Patients with important comorbidities such as diabetes, cardiovascular diseases, malnutrition or dementia are more likely to be dialysed with tunneled catheters. Furthermore, patients initiating hemodialysis with a tunneled catheter display higher mortality risk compared to patients starting hemodialysis with a permanent access. In summary, DOPPS data indicate that central venous catheters are used for chronic haemodialysis in patients with a high level of morbidity, and that their utilisation is associated to an additional risk, particularly of infection, and to a lower survival for tunneled catheters. Appropriate care should limit the utilisation of central venous catheters to clinically undisputable indications.

Cross-sectional and longitudinal predictors of serum albumin in hemodialysis patients.

BACKGROUND: Lower serum albumin concentrations predict increased mortality in hemodialysis (HD) patients. Many demographic, comorbidity, and modifiable treatment-related factors that predict HD patient outcomes may be associated with serum albumin. METHODS: Cross-sectional predictors of baseline albumin on December 31, 1993 were sought (N = 3981). Additional effects of the same baseline predictors on subsequent trends in albumin over one year were examined in a nested subsample of patients (N = 2245). Wave-1 of the United States Renal Data System Dialysis Morbidity and Mortality special study provided the data. RESULTS: Significant associations (P < 0.05) are summarized as older age, female gender, peripheral vascular disease, chronic obstructive pulmonary disease, and cancer predicted a lower baseline albumin and negatively influenced subsequent albumin trends. Baseline albumin was higher for blacks (vs. whites), lower for smoking and diabetes, and lower during the first year of HD treatment (<3 months and 3 to 12 months, vs.> 1 year). Trend analysis showed more positive albumin slopes for patients in their first year on HD and more negative slopes for Native Americans (vs. whites). Baseline albumin was correlated with the type of vascular access being used [arteriovenous (AV) fistulas > AV grafts > permanent catheters > temporary catheters]. Trend analysis predicted more negative albumin slopes for AV grafts and permanent catheters (vs. AV fistula access). Baseline albumin correlated inversely with bicarbonate and directly with hematocrit. Dialysis with unmodified cellulose membranes, without reuse, predicted lower baseline albumin than the other membrane-reuse categories. CONCLUSIONS: Several exposures, which may be modifiable, were associated with serum albumin.

New phosphate binding agents: ferric compounds.

Several prior studies suggest that ferric compounds bind dietary phosphate and possess clinical potential as phosphate binding agents. Therefore, this study was conducted to measure the effect of several ferric compounds on intestinal phosphate binding and absorption. Balance studies lasting 2 to 4 wk were performed in normal and azotemic (achieved by subtotal nephrectomy) rats maintained on a 1.02% phosphorus diet supplemented with ferric salts (formulated to 0.95% Fe) or no ferric salt (control). In rats with normal renal function (average creatinine clearance, 4.0 ml/min per kg), the average net intestinal absorption of phosphate over all balance periods was 103.3 mg/d for the control group versus 84.7 mg/d for the ferric citrate group (P < 0.005). In the azotemic rats (average creatinine clearance, 3.3 ml/min per kg), the average net intestinal absorption of phosphate over all balance periods was significantly lower for the three ferric groups than the control groups (P < or = 0.02): 95.3 mg/d for the control group versus 75.6 mg/d for the ferric ammonium citrate-treated group (P = 0.058), 77.0 mg/d for the ferric citrate-treated group (P = 0.057), and 62.5 mg/d for the ferric chloride-treated group (P < 0.002). Urinary phosphate excretion fell, sometimes to an even greater extent than did intestinal absorption, yielding no net reduction in phosphate balance in these growing, young animals with relatively preserved renal function. Calcium balance was largely unaffected by the ferric compounds. There were trends toward decreased serum phosphorus and parathyroid hormone concentrations and increased iron and hematocrit in the ferric-treated azotemic groups. All tested ferric compounds were well tolerated, but animal growth was stunted in the ferric chloride animals compared with the control group. Phosphate binding was estimated at 85 to 180 mg per gram of elemental iron, which is comparable to other phosphate binding agents. Ferric salts decrease net intestinal phosphate absorption and hold promise for the treatment of phosphate retention in patients with renal failure.

Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.

BACKGROUND: Renal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients. METHODS: Renal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression. RESULTS: Forty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs). CONCLUSIONS: The strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors.

Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients.

The role of predialysis blood pressure (BP) as a risk factor for the high mortality in chronic hemodialysis (HD) patients has remained controversial. The objective of the current study was to further explore in a national random sample of 4,499 US hemodialysis patients any relationship of systolic or diastolic and predialysis or postdialysis BP with mortality, while considering subgroups of patients and controlling for other patient characteristics and comorbidities. The main finding of this study is the association of a low predialysis systolic BP with an elevated adjusted mortality risk (relative mortality risk [RR] = 1.86 for systolic BP < 110, P < 0.0001). No association with an elevated mortality risk could be observed for predialysis systolic hypertension (RR = 0.98 to 0.99, not significant [NS]), except for an elevated risk of cerebrovascular deaths. Postdialysis systolic BP was associated with an elevated mortality risk both for low and high BP levels as compared with midrange BP. Further evaluation of the elevated mortality risk associated with low predialysis systolic BP indicated similar patterns for both diabetic and nondiabetic subgroups and for patients with and without congestive heart failure (CHF) or coronary artery disease, although it was more pronounced among those with CHF. The level of predialysis fluid excess did not modify these results substantially. The findings from this historical prospective national study do not argue against the treatment of hypertension and suggest greater attention to postdialysis hypertension. The strikingly elevated mortality risk with low predialysis systolic BP suggests that low predialysis BP needs to be viewed with great concern and avoided where possible.

A practical approach to evaluate the potential donor pool and trends in cadaveric kidney donation.

BACKGROUND: The potential supply of transplantable cadaver kidneys is often expressed as donors per million population (pmp), which ignores some essential factors governing organ donation. METHODS: We performed a modeled analysis of kidney donor extraction rates by age, gender, race, cause of death, geographic region, and year in a cohort of evaluable deaths and actual cadaver donors between the ages of 1 and 65 years (1988-1993). Evaluable death was defined as an in-hospital death in patients between the ages of 1 and 65 years whose ICD-9-CM cause of death was not an obvious contraindication to kidney donation. The main outcome measures were the crude donation rate and an adjusted donor extraction rate (DER) per 1000 evaluable deaths. RESULTS: A total of 1.4x10(6) in-hospital deaths produced 300,502 evaluable deaths and 20,575 actual donors. Between 1989 and 1993, DER increased from 61.1 to 75 per 1,000 evaluable deaths. DERs were highest among the youngest age groups, declining significantly with age from 405.0 to 16.7/1,000 evaluable deaths for age groups 1-10 and 56-65 years, respectively. There was a small difference in donors pmp between blacks and whites (15 vs. 18). In contrast, DER was seven times higher in whites compared with blacks (112.5 vs. 16.5/1,000 evaluable deaths; P<0.001). The crude donation rate (per 1,000 evaluable deaths) was high for stroke (604.8) and trauma-related deaths (230.6), resulting in highly efficient donor extraction from these deaths. Region-specific DERs ranged from 49.4 to 83/1,000 evaluable deaths and differed significantly from the corresponding donors pmp. CONCLUSIONS: Estimating kidney donation relative to in-hospital evaluable deaths is a meaningful measure of organ procurement efficiency. Efforts to enhance cadaveric kidney donation should seek to understand and reduce the marked demographic and regional disparity in donor extraction rates.

Intravenous diltiazem and acute renal failure after cardiac operations.

BACKGROUND: Perioperative administration of intravenous diltiazem to patients undergoing cardiac procedures has been shown to decrease the incidence of ischemia and arrhythmias. However, after adopting this practice in our cardiac surgery program, we perceived an increased incidence of postoperative renal dysfunction. METHODS: A directed record review of postoperative renal function was conducted for consecutive patients undergoing cardiac operation for the time periods before and after adoption of prophylactic intravenous diltiazem (0.1 mg.kg-1.h-1 for 24 hours). The two groups were compared using chi 2 and two-sample t tests. The risk of development of postoperative renal failure was modeled with logistic regression. RESULTS: Diltiazem-treated patients (n = 271) were similar to the control patients (n = 143) in terms of age (64 versus 61 years; p = 0.14), ejection fraction (0.46 versus 0.47; p = 0.61), baseline serum creatinine level (1.2 versus 1.1 mg/dL; p = 0.27), prevalence of comorbid conditions, and surgical characteristics. The prevalence of left main coronary artery disease was lower in the diltiazem group than the control group (39% versus 52%; p = 0.01). During the 7-day postoperative period, the average peak serum creatinine level was higher in the diltiazem group (1.7 +/- 0.9 mg/dL; mean +/- 1 standard deviation) than the control group (1.5 +/- 0.5 mg/dL; p = 0.003). The incidence of acute renal failure requiring dialysis was 4.4% in the diltiazem group versus 0.7% in the control group (p = 0.04). There was no difference in length of hospitalization or mortality. The risk of acute renal failure was strongly associated with intravenous diltiazem (adjusted odds ratio [AOR] 6.3; p = 0.08), age (AOR 2.5 per 10 years; p = 0.07), baseline serum creatinine (AOR 4.8 per 1 mg/dL; p = 0.02), the presence of left main coronary disease (AOR 5.3; p = 0.02), and the presence of cerebrovascular disease (AOR 4.5; p = 0.05). CONCLUSIONS: Our retrospective analysis suggests that prophylactic use of intravenous diltiazem in patients undergoing cardiac operations was associated with increased renal dysfunction. Further studies of the risk and benefits of intravenous diltiazem in this setting should be undertaken.

Dialysis dose, membrane type, and anemia control.

Erythropoietin has become an important part of the treatment of patients with end-stage renal disease (ESRD). Erythropoietin treatment and the concomitant increase in red blood cell mass have been associated with improvements in a variety of important clinical outcomes that bear on the morbidity and mortality of dialysis patients. However, many patients do not reach the target hematocrit goals, and there is a large variation among patients in the amount of erythropoietin administered. A number of potentially modifiable factors influence the response to erythropoietin, including higher delivered dose of dialysis. However, the type of dialysis membrane may modify this association. Preliminary data suggest that the hematocrit level among erythropoietin-treated patients is higher in those dialyzed with a synthetic as opposed to a nonsynthetic dialyzer. This article briefly reviews the relationship among erythropoietin response, dialysis dose, dialyzer type, and other modifiable factors.

Coronary subclavian steal syndrome: implications for nursing care.

Coronary artery disease remains the major cause of death and disability in the United States. Surgical procedures such as the internal mammary artery (IMA) bypass grafting of coronary arteries might be associated with complications, such as the coronary subclavian steal syndrome (CSSS). Cardiovascular nurses need to increase their knowledge and skills and be aware of the signs and symptoms of CSSS, which are easily assessed. This will help identify those patients at risk for CSSS. Early detection and identification of this syndrome in postsurgical coronary bypass patients is essential to ensuring appropriate interventions.