When the source of inflammation is hiding in plain sight: Failed kidney transplants, clotted arteriovenous grafts, and central venous catheters.

Cardiovascular mortality accounts for most deaths among hemodialysis patients and far exceeds the cardiovascular mortality rate of the general population. One important aspect of cardiovascular risk among dialysis patients is chronic inflammation. Iatrogenic sources of chronic inflammation in the form of failed renal allografts, old clotted arteriovenous grafts, and hemodialysis catheters play important, sometimes, unrecognized roles in this inflammatory state. There is ample observational evidence that these sources of inflammation are associated with hypoalbuminemia, erythropoetin-resistant anemia, and increased markers of chronic inflammation. In dialysis patients with chronic inflammation from potentially modifiable sources, causes should be sought and correction undertaken if possible. Allograft nephrectomy should be offered to patients with a chronic inflammatory state and a failed renal transplant. Unused, clotted AV grafts should be considered a likely source of chronic inflammation as well as infection and should be removed when evidence of infection is present on indium scanning. Catheter rates ought to be kept to a minimum for the many well-recognized reasons for their undesirability as well as for their potential to produce chronic inflammation with all of its ill effects.

Treatment of Hyponatremic Encephalopathy in the Critically Ill.

OBJECTIVES: Hyponatremic encephalopathy, symptomatic cerebral edema due to a low osmolar state, is a medical emergency and often encountered in the ICU setting. This article provides a critical appraisal and review of the literature on identification of high-risk patients and the treatment of this life-threatening disorder. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Online search of the PubMed database and manual review of articles involving risk factors for hyponatremic encephalopathy and treatment of hyponatremic encephalopathy in critical illness. DATA SYNTHESIS: Hyponatremic encephalopathy is a frequently encountered problem in the ICU. Prompt recognition of hyponatremic encephalopathy and early treatment with hypertonic saline are critical for successful outcomes. Manifestations are varied, depending on the extent of CNS's adaptation to the hypoosmolar state. The absolute change in serum sodium alone is a poor predictor of clinical symptoms. However, certain patient specific risks factors are predictive of a poor outcome and are important to identify. Gender (premenopausal and postmenopausal females), age (prepubertal children), and the presence of hypoxia are the three main clinical risk factors and are more predictive of poor outcomes than the rate of development of hyponatremia or the absolute decrease in the serum sodium. CONCLUSIONS: In patients with hyponatremic encephalopathy exhibiting neurologic manifestations, a bolus of 100 mL of 3% saline, given over 10 minutes, should be promptly administered. The goal of this initial bolus is to quickly treat cerebral edema. If signs persist, the bolus should be repeated in order to achieve clinical remission. However, the total change in serum sodium should not exceed 5 mEq/L in the initial 1-2 hours and 15-20 mEq/L in the first 48 hours of treatment. It has recently been demonstrated in a prospective fashion that 500 mL of 3% saline at an infusion rate of 100 mL per hour can be given safely. It is critical to recognize the early signs of cerebral edema (nausea, vomiting, and headache) and intervene with IV 3% sodium chloride as this is the time to intervene rather than waiting until more severe symptoms develop. Cerebral demyelination is a rare complication of overly rapid correction of hyponatremia. The principal risk factors for cerebral demyelination are correction of the serum sodium more than 25 mEq/L in the first 48 hours of therapy, correction past the point of 140 mEq/L, chronic liver disease, and hypoxic/anoxic episode.

Desmopressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series.

BACKGROUND: Desmopressin (DDAVP) is typically prescribed for central diabetes insipidus, von Willebrands disease and for enuresis. DDAVP-associated hyponatremia is a known complication of DDAVP therapy. The currently recommended treatment for this condition calls for discontinuing DDAVP as part of the initial therapy. This recommendation could lead to a water diuresis and potentially over-correction of the serum sodium. METHODS: The 15 patients in this case series developed symptomatic DDAVP-associated hyponatremia and were admitted to acute care hospitals. Thirty-eight percent presented with symptomatic hyponatremia and 62% developed symptomatic hyponatremia due to concomitant DDAVP and hypotonic intravenous fluid administration during a hospital stay. Group 1 patients (n = 13) were treated by withholding DDAVP and providing intravenous saline. Group 2 patients (n = 2) were treated by continuing DDAVP and providing DDAVP and intravenous hypertonic saline. RESULTS: Among Group 1 patients, in whom DDAVP was withheld as initial management of DDAVP-associated hyponatremia (n = 13), the mean change in serum sodium in the first 2 days of treatment was 37.1 ± 8.1 mEq/L. The ultimate outcome in this group was death in 23%, severe brain damage in 69% and moderate brain damage in 8%. In Group 2 patients, in whom DDAVP was continued (n = 2) as part of the initial management strategy, the mean change in serum sodium was 11.0 ± 0 mEq/L in the first 2 days. The ultimate outcome was survival without neurological sequelae in both cases. CONCLUSIONS: Discontinuing DDAVP in a patient with symptomatic DDAVP-associated hyponatremia can lead to rapid correction of the serum sodium and resultant severe neurological injury. In contrast, continuing the medication while correcting DDAVP-associated hyponatremia may lead to better outcomes by avoiding over-correction of the serum sodium. Thus, an alternative approach that we propose is to continue DDAVP as part of the initial management of this disorder.

Inflammation from dialysis, can it be removed?

Mortality among hemodialysis patients remains unacceptably high in the USA, especially among newly diagnosed end-stage renal disease patients. Chronic inflammation is a risk factor for cardiovascular disease among HD patients. It has been shown that complications of the arteriovenous (AV) access are not just limited to overt infectious complications but they may also pose a threat as a haven for occult infection and can aggravate the chronic inflammatory state. This inflammatory state is characterized by failure to thrive, erythropoietin-resistant anemia, hypoalbuminemia, elevated plasma C-reactive protein levels, which are well-known risk factors for increased morbidity and mortality on dialysis. In this issue, Wasse et al. presents a paper that demonstrates in a large cohort that failed AV grafts are associated with increased chronic inflammatory markers. They have provided a mechanistic insight into the causes of the chronic inflammatory state among dialysis patients. Along this line, it has also been demonstrated that failed renal allografts are also harbors of a chronic inflammatory state and that the removal of a failed renal allograft will lead to resolution of both overt inflammation and subclinical inflammatory states. This suggests that in select dialysis patients the surgical removal of foci of chronic inflammation can have an impact on the overall inflammatory state and perhaps survival.

Long term reduction of cardiovascular risk factors associated with three hour daily dialysis: A prospective, cohort study.

INTRODUCTION: Daily hemodialysis (DHD) compared to conventional hemodialysis (CHD) leads to improvements in left ventricular hypertrophy and mineral metabolism at 1-year follow-up. However, there is no information from prospective studies on the long terms effects of DHD on these key cardiovascular risk factors. METHODS: We conducted a 4 year, prospective cohort study of 26 DHD and 51 matched CHD patients on the effect of DHD (six sessions/week × 3 h) versus CHD (three sessions/week × 4 h), 15 DHD, and 26 CHD patients completed 4-years follow-up. Measures of left ventricular mass index (LVMI), blood pressures, hemoglobin, and mineral metabolism markers were performed. RESULTS: Systolic and diastolic blood pressures were significantly lower in the DHD group than the CHD group at 4-year follow-up, 128 mmHg (95% CI, 111-143) versus 148 mmHg (95% CI, 137-158) (p < 0.05) and 60 mmHg (95% CI, 56-63) versus 71 mmHg (95% CI, 64-76) (p < 0.05). DHD was associated with fewer patients taking any anti-hypertensive drug therapy than CHD, 50% versus 80% (p < 0.05). DHD was associated with improved attainment of mineral metabolism goals for phosphorus (adjusted HR 3.6, p = 0.002) and calcium × phosphorus product (adjusted HR 3.66, p = 0.001) at 4-years follow-up compared to CHD. At 4 years, there was a nonsignificant trend toward lower LVMI in the DHD than in the CHD group: 116 g/m2 (95% CI, 97-136) versus 138 g/m2 (95% CI, 115-172) (p = 0.23). Similarly, improvements in hemoglobin also persisted at 4 years follow-up. CONCLUSION: DHD is associated with long-term (4 year) improvements in key cardiovascular risk factors: blood pressure, mineral metabolism, and anemia with trends toward improved LVMI.

Transplant nephrectomy improves survival following a failed renal allograft.

There is a growing number of patients returning to dialysis after a failed kidney transplant, and there is increasing evidence of higher mortality among this population. Whether removal of the failed renal allograft affects survival while receiving long-term dialysis is not well understood. We identified all adults who received a kidney transplant and returned to long-term dialysis after renal allograft failure between January 1994 and December 2004 from the US Renal Data System. Among 10,951 transplant recipients who returned to long-term dialysis, 3451 (31.5%) received an allograft nephrectomy during follow-up. Overall, 34.6% of these patients died during follow-up. Receiving an allograft nephrectomy associated with a 32% lower adjusted relative risk for all-cause death (adjusted hazard ratio 0.68; 95% confidence interval 0.63 to 0.74) after adjustment for sociodemographic characteristics, comorbidity burden, donor characteristics, interim clinical conditions associated with receiving allograft nephrectomy, and propensity to receive an allograft nephrectomy. In conclusion, within a large, nationally representative sample of high-risk patients returning to long-term dialysis after failed kidney transplant, receipt of allograft nephrectomy independently associated with improved survival.

Chronicity of Uncorrected Hyponatremia and Clinical Outcomes in Older Patients Undergoing Hip Fracture Repair.

Background: Chronic hyponatremia is a risk factor for hip fracture but remains uncorrected in most patients. This study evaluated if preoperative chronicity of uncorrected hyponatremia influences outcomes after hip fracture repair. Materials and Methods: Evaluated were older patients hospitalized for hip fracture repair between 2007 and 2012 with plasma sodium measured at admission and ≥1 preadmission outpatient measurement. Patients were classified as being normonatremic (NN; plasma sodium 135-145 mmol/L), chronic prolonged hyponatremia (CPH; ≥2 consecutive plasma sodium values <135 mmol/L over >90 days), or recent hyponatremia (one plasma sodium <135 mmol/L within 30 days before admission with previously normal plasma sodium). Length of hospital stay, in-hospital death, post-operative complications, 30-day readmission, and long-term mortality were the evaluated outcomes. Multivariable Cox regression was used to evaluate the association of hyponatremia status with outcomes. Results: Among 1,571 eligible patients, 76.7% were NN, 14% had CPH, and 9.1% had RH. Compared with NN patients, CHN patients were older and had more prior heart failure, alcoholism, and anticonvulsant drug use. In multivariable analyses, neither CPH or RH was associated with hospital length of stay, in-hospital or 30-day death, or 30-day readmission, while RH was associated with post-operative sepsis [adjusted odds ratio (aOR) 1.84, 95% CI: 1.01-3.35). Only CPH was independently associated with long-term all-cause death (OR 1.53, 95% CI: 1.12-2.09). Conclusions: Hyponatremia affects nearly 25% of patients undergoing hip fracture repair. Preoperative chronic untreated hyponatremia is associated with increased post-operative mortality following surgical repair of a hip fracture in older patients. Future studies should evaluate if correction of hyponatremia could decrease long-term mortality after hip fracture repair.

Use of Desmopressin in Hyponatremia: Foe and Friend.

Use of desmopressin (1-deamino-8-d-arginine vasopressin; DDAVP), a synthetic vasopressin receptor agonist, has expanded in recent years. Desmopressin leads to renal water retention, and iatrogenic hyponatremia may result if fluid intake is not appropriately restricted. It is common practice to stop a medication that is causing toxicity, and this advice is promulgated in Micromedex, which suggests withholding desmopressin if hyponatremia occurs. If intravenous saline solution is administered and desmopressin is withheld at the same time, rapid changes in serum sodium levels may result, which puts the patient at risk for demyelinating lesions. In the management of desmopressin-associated hyponatremia with neurologic symptoms, the drug should not be withheld despite the presence of hyponatremia. The medication should be continued while administering intravenous hypertonic saline solution. Desmopressin is also used to minimize water excretion during the correction of hyponatremia during water diuresis. When treating hyponatremia, clinicians should monitor closely to avoid free-water diuresis. To prevent ongoing water losses in urine and overly rapid "autocorrection" of serum sodium level, desmopressin can be given to reduce free-water losses. These treatment recommendations are the authors' perspective from previously published work and personal clinical experience.

The role of daily dialysis in the control of hyperphosphatemia.

The role of daily dialysis in the control of hyperphosphatemia. In patients with end-stage renal disease (ESRD), hyperphosphatemia occurs in the vast majority of patients. The numerous clinical sequelae of hyperphosphatemia include secondary hyperparathyroidism and increased risk of cardiovascular death. Chronic hemodialysis as it is currently practiced in the United States does not remove sufficient phosphate to control serum levels within accepted guidelines. The inadequacy of conventional hemodialysis in removing phosphate mandates the use of phosphate binders in virtually all hemodialysis patients. Despite their proven efficacy, these medications fail to control phosphorous in 70% of hemodialysis patients. Additionally, these medications may have untoward side effects that must be considered since they are typically intended for lifetime use. Quotidian hemodialysis has in previous uncontrolled studies shown promise in reducing serum phosphorus while at the same time reducing or eliminating the need for phosphate binders. Recent results from our group demonstrate for the first time in a controlled fashion the efficacy of short daily dialysis in controlling serum phosphorus.

The role of vitamin D in left ventricular hypertrophy and cardiac function.

The role of vitamin D in left ventricular hypertrophy and cardiac function. Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Traditional cardiac risk factors, as well as other factors specific to the ESRD population such as hyperphosphatemia, elevated calcium and phosphate product, abnormal lipid metabolism, hyperhomocysteinemia, and chronic inflammation play a role in the excessive risk of cardiovascular death in this population. Left ventricular disorders are proven risk factors for cardiac mortality in hemodialysis patients. These disorders are present in incident ESRD patients at rates far above the general population. There is an accumulating body of evidence that suggests that vitamin D plays a role in cardiovascular disease. Abnormal vitamin metabolism, through deficiency of the active form of 1,25-dihydroxyvitamin D(3), and acquired vitamin D resistance through the uremic state, have been shown to be important in ESRD. Vitamin D deficiency has long been known to affect cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation. Recent studies using vitamin D receptor deficient mice as a model demonstrate a crucial role of vitamin D in regulation of the renin-angiotensin system. Additionally, there is emerging evidence linking treatment with vitamin D to improved survival on hemodialysis and improvement in cardiac function. The emergence of this data is focusing attention on the previously underappreciated nonmineral homeostatic effects of vitamin D that very likely play an important role in the pathogenesis of cardiac disease in ESRD.

Long-term effects of daily hemodialysis on vascular access outcomes: a prospective controlled study.

Daily hemodialysis has been associated with surrogate markers of improved survival among hemodialysis patients. A potential disadvantage of daily hemodialysis is that frequent vascular access cannulations may affect long-term vascular access patency. The study design was a 4-year, nonrandomized, contemporary control, prospective study of 77 subjects in either 3-h daily hemodialysis (six 3-h dialysis treatments weekly; n = 26) or conventional dialysis (three 4-h dialysis treatments weekly; n = 51). Outcomes of interest were vascular access procedures (fistulagram, thrombectomy and access revision). Total access procedures (fistulagram, thrombectomy and access revision) were 543.2 (95% confidence interval [CI]: 432.9, 673.0) per 1000 person-years in the conventional dialysis group vs. 400.8 (95% CI: 270.2, 572.4) per 1000 person-years in the daily hemodialysis dialysis group (incidence rate ratio = 0.74 with 95% CI: from 0.40 to 1.36, P = 0.33), after adjusting for age, gender, diabetes status, serum phosphorus, hemoglobin level and erythropoietin dose, there was no significant differences in incidence rate of total access procedures (P-value > 0.05). There was no difference in time to first access revision between the daily dialysis and the conventional dialysis groups after adjustment for covariates (hazard ratio = 0.99 95% CI: 0.42, 2.36, P = 0.96). Daily hemodialysis is not associated with increased vascular access complications, or increased vascular access failure rates.

Use of 3-hour daily hemodialysis and paricalcitol in patients with severe secondary hyperparathyroidism: A case series.

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3-hour daily hemodialysis (3 hours x 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321-1983]-472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium x phosphorus product (80.3 +/- 26.8-48.9 +/- 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 +/- 2.34-4.75 +/- 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 +/- 2.04-9.62 +/- 0.93 mg/dL, P<0.01). Three-hour daily hemodialysis with the use of high-dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.

Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia.

Hyponatremia is the most common electrolyte abnormality in hospitalized patients. When symptomatic (hyponatremic encephalopathy), the overall morbidity is 34%. Individuals most susceptible to death or permanent brain damage are prepubescent children and menstruant women. Failure of the brain to adapt to the hyponatremia leads to brain damage. Major factors that can impair brain adaptation include hypoxia and peptide hormones. In children, physical factors--discrepancy between skull size and brain size--are important in the genesis of brain damage. In adults, certain hormones--estrogen and vasopressin (usually elevated in cases of hyponatremia)--have been shown to impair brain adaptation, decreasing both cerebral blood flow and oxygen utilization. Initially, hyponatremia leads to an influx of water into the brain, primarily through glial cells and largely via the water channel aquaporin (AQP)4. Water is thus shunted into astrocytes, which swell, largely preserving neuronal cell volume. The initial brain response to swelling is adaptation, utilizing the Na(+)-K(+)-ATPase system to extrude cellular Na(+). In menstruant women, estrogen + vasopressin inhibits the Na(+)-K(+)-ATPase system and decreases cerebral oxygen utilization, impairing brain adaptation. Cerebral edema compresses the respiratory centers and also forces blood out of the brain, both lowering arterial Po(2) and decreasing oxygen utilization. The hypoxemia further impairs brain adaptation. Hyponatremic encephalopathy leads to brain damage when brain adaptation is impaired and is a consequence of both cerebral hypoxia and peptide hormones.