A new approach to individualize dialysis fluid sodium concentration using a four-stream, bicarbonate-based fluid delivery system.

We propose a new 45X, four-stream, triple-concentrate, bicarbonate-based dialysis fluid delivery system, allowing a wide range of dialysis fluid sodium concentrations\\ (DFNa ) without affecting the concentrations of other crucial solutes. The four streams consist of product water (W), and concentrates with sodium chloride (S), acid (A), and sodium bicarbonate (B). An adjustment in the DFNa in this new system requires changes only in the W and S concentrate streams. The ingredients in A and B concentrates do not change.

A four-stream method for providing variable dialysis fluid bicarbonate concentrations for bicarbonate-based dialysis fluid delivery systems.

BACKGROUND: Hemodialysis corrects metabolic acidosis by transferring bicarbonate or bicarbonate equivalents across the dialysis membrane from the dialysis fluid to the plasma. With the conventional three-stream bicarbonate-based dialysis fluid delivery system, a change in the bicarbonate concentration results in changes in the other electrolytes. In practice, the dialysis machine draws either a little less or more from the bicarbonate concentrate and a little more or less from the acid concentrate, respectively in a three-stream delivery system. The result not only changes the bicarbonate concentration of the final dialysis fluid but also causes a minor change in the other ingredients. METHODS: We propose a four-stream bicarbonate-based dialysis fluid delivery system consisting of an acid concentrate, a base concentrate, a product water, and a new sodium chloride concentrate. RESULTS: By adjusting the flow rate ratio between the sodium chloride and sodium bicarbonate concentrates, one can achieve the desired bicarbonate concentration in the dialysis fluid without changing the concentration of sodium or ingredients in the acid concentrate. The chloride concentration mirrors the change in bicarbonate but in the opposite direction. CONCLUSION: A four-stream, bicarbonate-based dialysis fluid delivery system allows the bicarbonate concentration to be changed without changing the other constituents of the final dialysis fluid.

Osmotic Pressure in Clinical Medicine with an Emphasis on Dialysis.

Since the beginning of life of the first multicellular organisms, the preservation of a physiologic milieu for every cell in the organism has been a critical requirement. A particular range of osmolality of the body fluids is essential for the maintenance of cell volume. In humans the stability of electrolyte concentrations and their resulting osmolality in the body fluids is the consequence of complex interactions between cell membrane functions, hormonal control, thirst, and controlled kidney excretion of fluid and solutes. Knowledge of these mechanisms, of the biochemical principles of osmolality, and of the relevant situations occurring in disease is of importance to every physician. This comprehensive review summarizes the major facts on osmolality, its relation to electrolytes and other solutes, and its relevance in physiology and in disease states with a focus on dialysis-related considerations.

Systematic review of nephrotoxicity of drugs of abuse, 2005-2016.

BACKGROUND: The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes. METHODS: We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies. RESULTS: A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review. CONCLUSION: Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

Favorable outcome of Fournier gangrene in two patients with diabetes mellitus on continuous peritoneal dialysis.

Fournier gangrene (FG), a form of necrotizing fasciitis of the perineum and genitals, with high morbidity and mortality in the general population, carries the additional risk of involvement of the peritoneal catheter tunnel and peritoneal cavity in patients on chronic peritoneal dialysis (PD). We describe two men with diabetes who developed FG in the course of PD. Computed tomography showed no extension of FG to the abdominal wall, and spent peritoneal dialysate was clear in both patients. Broad-spectrum antibiotic therapy with anaerobic coverage and early aggressive debridement followed by negative-pressure wound therapy and repeated debridement led to improvements in clinical status in both cases. Surgical closure and healing of the wound was achieved in one patient; the wound of the second patient is healing, but remains open. Both patients experienced prolonged hospitalization, with a serious decline in nutrition status. In patients on PD, FG can be treated successfully. However, additional measures are required to evaluate for potential involvement of the PD apparatus and the peritoneal cavity in the infectious process; and prolonged hospitalization, worsening nutrition, and multiple surgical interventions can result.

Hypernatremia in Hyperglycemia: Clinical Features and Relationship to Fractional Changes in Body Water and Monovalent Cations during Its Development.

In hyperglycemia, the serum sodium concentration ([Na]S) receives influences from (a) the fluid exit from the intracellular compartment and thirst, which cause [Na]S decreases; (b) osmotic diuresis with sums of the urinary sodium plus potassium concentration lower than the baseline euglycemic [Na]S, which results in a [Na]S increase; and (c), in some cases, gains or losses of fluid, sodium, and potassium through the gastrointestinal tract, the respiratory tract, and the skin. Hyperglycemic patients with hypernatremia have large deficits of body water and usually hypovolemia and develop severe clinical manifestations and significant mortality. To assist with the correction of both the severe dehydration and the hypovolemia, we developed formulas computing the fractional losses of the body water and monovalent cations in hyperglycemia. The formulas estimate varying losses between patients with the same serum glucose concentration ([Glu]S) and [Na]S but with different sums of monovalent cation concentrations in the lost fluids. Among subjects with the same [Glu]S and [Na]S, those with higher monovalent cation concentrations in the fluids lost have higher fractional losses of body water. The sum of the monovalent cation concentrations in the lost fluids should be considered when computing the volume and composition of the fluid replacement for hyperglycemic syndromes.

Pseudohyponatremia: Mechanism, Diagnosis, Clinical Associations and Management.

Pseudohyponatremia remains a problem for clinical laboratories. In this study, we analyzed the mechanisms, diagnosis, clinical consequences, and conditions associated with pseudohyponatremia, and future developments for its elimination. The two methods involved assess the serum sodium concentration ([Na]S) using sodium ion-specific electrodes: (a) a direct ion-specific electrode (ISE), and (b) an indirect ISE. A direct ISE does not require dilution of a sample prior to its measurement, whereas an indirect ISE needs pre-measurement sample dilution. [Na]S measurements using an indirect ISE are influenced by abnormal concentrations of serum proteins or lipids. Pseudohyponatremia occurs when the [Na]S is measured with an indirect ISE and the serum solid content concentrations are elevated, resulting in reciprocal depressions in serum water and [Na]S values. Pseudonormonatremia or pseudohypernatremia are encountered in hypoproteinemic patients who have a decreased plasma solids content. Three mechanisms are responsible for pseudohyponatremia: (a) a reduction in the [Na]S due to lower serum water and sodium concentrations, the electrolyte exclusion effect; (b) an increase in the measured sample's water concentration post-dilution to a greater extent when compared to normal serum, lowering the [Na] in this sample; (c) when serum hyperviscosity reduces serum delivery to the device that apportions serum and diluent. Patients with pseudohyponatremia and a normal [Na]S do not develop water movement across cell membranes and clinical manifestations of hypotonic hyponatremia. Pseudohyponatremia does not require treatment to address the [Na]S, making any inadvertent correction treatment potentially detrimental.

Hypertonic Saline Infusion for Hyponatremia: Limitations of the Adrogué-Madias and Other Formulas.

Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of the volume of infused hypertonic saline ( VInf ) should address prevention of overcorrection or undercorrection. Several formulas computing this VInf have been proposed. The limitations common to these formulas consist of (1) failure to include potential determinants of change in serum sodium concentration ([ Na ]) including exchanges between osmotically active and inactive sodium compartments, changes in hydrogen binding of body water to hydrophilic compounds, and genetic influences and (2) inaccurate estimates of baseline body water entered in any formula and of gains or losses of water, sodium, and potassium during treatment entered in formulas that account for such gains or losses. In addition, computing VInf from the Adrogué-Madias formula by a calculation assuming a linear relation between VInf and increase in [ Na ] is a source of errors because the relation between these two variables was proven to be curvilinear. However, these errors were shown to be negligible by a comparison of estimates of VInf by the Adrogué-Madias formula and by a formula using the same determinants of the change in [ Na ] and the curvilinear relation between this change and VInf . Regardless of the method used to correct hyponatremia, monitoring [ Na ] and changes in external balances of water, sodium, and potassium during treatment remain imperative.

The role of intra- and interdialytic sodium balance and restriction in dialysis therapies.

The relationship between sodium, blood pressure and extracellular volume could not be more pronounced or complex than in a dialysis patient. We review the patients' sources of sodium exposure in the form of dietary salt intake, medication administration, and the dialysis treatment itself. In addition, the roles dialysis modalities, hemodialysis types, and dialysis fluid sodium concentration have on blood pressure, intradialytic symptoms, and interdialytic weight gain affect patient outcomes are discussed. We review whether sodium restriction (reduced salt intake), alteration in dialysis fluid sodium concentration and the different dialysis types have any impact on blood pressure, intradialytic symptoms, and interdialytic weight gain.

Increase in serum creatinine in a patient on continuous peritoneal dialysis: potential mechanisms and management.

A large elevation in serum creatinine (S(Cr)) on an unchanged peritoneal dialysis (PD) schedule is usually caused by a decrease in total creatinine clearance (C(Cr)), but may also reflect an increase in creatinine (Cr) production. A meticulously compliant 43-year-old man with lupus nephritis on automated nocturnal PD plus an additional daytime exchange developed a rise in S(Cr) to 16.73 mg/dL from 8.06 mg/dL after starting fenofibrate, while total C(Cr) decreased only to 61.5 L/1.73 m2 from 77.4 m2 weekly. Creatinine excretion was 16.4 mg/(kg x 24 h) pre-fenofibrate. It increased to a high of 26.2 mg/(kg x 24 h) during the period of fenofibrate intake and returned to 21.9 mg/ (kg x 24 h) 2 months after discontinuation of that drug. The patient's age, weight, height, body mass index, 24-h drain and urine volumes, total Kt/V urea, serum urea nitrogen, urea nitrogen excretion, and (for the pre-fenofibrate period) S(Cr), Cr excretion, estimated Cr production, and measured-to-predicted Cr excretion (using a formula developed in PD patients) were within the 95% confidence intervals (CIs) obtained in a control group of 24 other men on similar PD schedules. The patient's Cr excretion and production were above the 95% CIs of the control group while he was on fenofibrate, and they returned toward or within the 95% CIs after cessation of the drug. The patient's serum creatine phosphokinase was not elevated while he was taking fenofibrate. A thorough investigation of the potential mechanisms of a rise in S(Cr) during the course of PD is warranted to determine if the rise is disproportional to any fall in total C(Cr). In the latter case, Cr excretion and production should be evaluated, and if elevated, conditions potentially causing the rise in Cr production (fenofibrate in this patient) should be sought, and appropriate therapeutic interventions should be implemented.

Using herbs medically without knowing their composition: are we playing Russian roulette?

Herbal medicine, a form of complementary and alternative medicine (CAM), is used throughout the world, in both developing and developed countries. The ingredients in herbal medicines are not standardized by any regulatory agency. Variability exists in the ingredients as well as in their concentrations. Plant products may become contaminated with bacteria and fungi during storage. Therefore, harm can occur to the kidney, liver, and blood components after ingestion. We encourage scientific studies to identify the active ingredients in herbs and to standardize their concentrations in all herbal preparations. Rigorous studies need to be performed in order to understand the effect of herbal ingredients on different organ systems as well as these substances' interaction with other medications.

Development of Lupus Erythematosus Tumidus During the Course of Systemic Sclerosis.

A man with systemic sclerosis (SS), manifested by characteristic skin lesions, gastro-esophageal reflux disease, and pulmonary fibrosis producing progressive respiratory failure, and a positive antinuclear antibody consistent with reactivity to fibrillarin, developed skin lesions with the clinical and histological characteristics of lupus erythematosus tumidus (LET) 10 years after the diagnosis of SS. His respiratory failure progressed and he expired from sepsis after tracheal intubation and mechanical ventilation two years after developing LET. The association of SS and LET, not described until now, raises questions about its pathogenesis and its prognostic significance.

Dysnatremias in Chronic Kidney Disease: Pathophysiology, Manifestations, and Treatment.

The decreased ability of the kidney to regulate water and monovalent cation excretion predisposes patients with chronic kidney disease (CKD) to dysnatremias. In this report, we describe the clinical associations and methods of management of dysnatremias in this patient population by reviewing publications on hyponatremia and hypernatremia in patients with CKD not on dialysis, and those on maintenance hemodialysis or peritoneal dialysis. The prevalence of both hyponatremia and hypernatremia has been reported to be higher in patients with CKD than in the general population. Certain features of the studies analyzed, such as variation in the cut-off values of serum sodium concentration ([Na]) that define hyponatremia or hypernatremia, create comparison difficulties. Dysnatremias in patients with CKD are associated with adverse clinical conditions and mortality. Currently, investigation and treatment of dysnatremias in patients with CKD should follow clinical judgment and the guidelines for the general population. Whether azotemia allows different rates of correction of [Na] in patients with hyponatremic CKD and the methodology and outcomes of treatment of dysnatremias by renal replacement methods require further investigation. In conclusion, dysnatremias occur frequently and are associated with various comorbidities and mortality in patients with CKD. Knowledge gaps in their treatment and prevention call for further studies.

Edelman Revisited: Concepts, Achievements, and Challenges.

The key message from the 1958 Edelman study states that combinations of external gains or losses of sodium, potassium and water leading to an increase of the fraction (total body sodium plus total body potassium) over total body water will raise the serum sodium concentration ([Na]S), while external gains or losses leading to a decrease in this fraction will lower [Na]S. A variety of studies have supported this concept and current quantitative methods for correcting dysnatremias, including formulas calculating the volume of saline needed for a change in [Na]S are based on it. Not accounting for external losses of sodium, potassium and water during treatment and faulty values for body water inserted in the formulas predicting the change in [Na]S affect the accuracy of these formulas. Newly described factors potentially affecting the change in [Na]S during treatment of dysnatremias include the following: (a) exchanges during development or correction of dysnatremias between osmotically inactive sodium stored in tissues and osmotically active sodium in solution in body fluids; (b) chemical binding of part of body water to macromolecules which would decrease the amount of body water available for osmotic exchanges; and (c) genetic influences on the determination of sodium concentration in body fluids. The effects of these newer developments on the methods of treatment of dysnatremias are not well-established and will need extensive studying. Currently, monitoring of serum sodium concentration remains a critical step during treatment of dysnatremias.

Activation of caspase-3 in the skeletal muscle during haemodialysis.

BACKGROUND AND OBJECTIVE: Muscle atrophy in end-stage renal disease (ESRD) may be due to the activation of apoptotic and proteolytic pathways. We hypothesized that activation of caspase-3 in the skeletal muscle mediates apoptosis and proteolysis during haemodialysis (HD). MATERIALS AND METHODS: Eight ESRD patients were studied before (pre-HD) and during HD and the findings were compared with those from six healthy volunteers. Protein kinetics was determined by primed constant infusion of L-(ring (13)C(6) ) Phenylalanine. RESULTS: Caspase-3 activity in the skeletal muscle was higher in ESRD patients pre-HD than in controls (24966·0 ± 4023·9 vs. 15293·3 ± 2120·0 units, P<0·01) and increased further during HD (end-HD) (37666·6 ± 4208·3 units) (P<0·001). Actin fragments (14 kDa) generated by caspase-3 mediated cleavage of actomyosin was higher in the skeletal muscle pre-HD (68%) and during HD (164%) compared with controls. The abundance of ubiquitinized carboxy-terminal actin fragment was also significantly increased during HD. Skeletal muscle biopsies obtained at the end of HD exhibited augmented apoptosis, which was higher than that observed in pre-HD and control samples (P<0·001). IL-6 content in the soluble fraction of the muscle skeletal muscle was increased significantly during HD. Protein kinetic studies showed that catabolism was higher in ESRD patients during HD compared with pre-HD and control subjects. Muscle protein catabolism was positively associated with caspase-3 activity and skeletal muscle IL-6 content. CONCLUSION: Muscle atrophy in ESRD may be due to IL-6 induced activation of caspase-3 resulting in apoptosis as well as muscle proteolysis during HD.

Sources of variation in estimates of lean body mass by creatinine kinetics and by methods based on body water or body mass index in patients on continuous peritoneal dialysis.

OBJECTIVE: We identified factors that account for differences between lean body mass computed from creatinine kinetics (LBM(cr)) and from either body water (LBM(V)) or body mass index (LBM(BMI)) in patients on continuous peritoneal dialysis (CPD). DESIGN: We compared the LBM(cr) and LBM(V) or LBM(BMI) in hypothetical subjects and actual CPD patients. PATIENTS: We studied 439 CPD patients in Albuquerque, Pittsburgh, and Toronto, with 925 clearance studies. INTERVENTION: Creatinine production was estimated using formulas derived in CPD patients. Body water (V) was estimated from anthropometric formulas. We calculated LBM(BMI) from a formula that estimates body composition based on body mass index. In hypothetical subjects, LBM values were calculated by varying the determinants of body composition (gender, diabetic status, age, weight, and height) one at a time, while the other determinants were kept constant. In actual CPD patients, multiple linear regression and logistic regression were used to identify factors associated with differences in the estimates of LBM (LBM(cr)LBM(V). The differences in determinants of body composition between groups with high versus low LBM(cr) were similar in hypothetical and actual CPD patients. Multivariate analysis in actual CPD patients identified serum creatinine, height, age, gender, weight, and body mass index as predictors of the differences LBM(V)-LBM(cr) and LBM(BMI)-LBM(cr). CONCLUSIONS: Overhydration is not the sole factor accounting for the differences between LBM(cr) and either LBM(V) or LBM(BMI) in CPD patients. These differences also stem from the coefficients assigned to major determinants of body composition by the formulas estimating LBM.

Imaging of peritoneal catheter tunnel infection using positron-emission tomography.

Imaging by ultrasonography or scintigraphy may assist in the diagnosis and management of tunnel infections of the peritoneal dialysis (PD) catheter. Here, we report a case of tunnel infection in which imaging with positron-emission tomography (PET) correctly predicted failure of conservative management. A 61-year-old man with diabetic nephropathy commenced PD in January 2008. He developed erythema and drainage at the exit site, with negative cultures in February 2008, and frank exit-site infection (ESI) with purulent drainage growing methicillin-sensitive Staphylococcus aureus [MSSA (treated with 3 weeks of oral dicloxacillin)] in August 2008. Subsequently, MSSA-growing purulent drainage from the exit site persisted. Systemic antibiotics were not administered, but there was gradual improvement with gentamicin ointment alone. In November 2008, the patient developed partial extrusion of the outer cuff of the PD catheter. In January 2009, a new ESI developed. Despite a week of treatment with cefazolin and gentamicin, the patient still developed his first episode of peritonitis with coagulase-negative Staphylococcus. He then received intraperitoneal vancomycin with good response. Although the ESI appeared to have responded to the treatment, PET imaging showed increased fludeoxyglucose (FDG) activity in the whole abdominal wall portion of the PD catheter. The patient resisted removal of the catheter and had no further signs of infection until June 2009. At that time he presented with exuberant inflammatory tissue ("proud flesh") at the exit site. Repeated PET imaging again showed increased FDG activity along the abdominal wall portion of the catheter. The PD catheter was removed and found to be infected. The patient was placed on temporary hemodialysis. This case demonstrates that PET imaging, in addition to other imaging techniques, may be useful for diagnosing and managing PD catheter infections.

Management of extracellular volume in patients with end-stage kidney disease and severe hyperglycemia.

This commentary addresses volume replacement in hyperglycemic crises in patients with end-stage kidney disease (ESKD). The management of volume issues in this group of patients should not be based on guidelines for management of hyperglycemic crises, but should be individualized and based on directed patient medical history, physical examination, and imaging of the heart and lungs. A scheme for combining information from these three sources is provided.

The Corrected Serum Sodium Concentration in Hyperglycemic Crises: Computation and Clinical Applications.

In hyperglycemia, hypertonicity results from solute (glucose) gain and loss of water in excess of sodium plus potassium through osmotic diuresis. Patients with stage 5 chronic kidney disease (CKD) and hyperglycemia have minimal or no osmotic diuresis; patients with preserved renal function and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) have often large osmotic diuresis. Hypertonicity from glucose gain is reversed with normalization of serum glucose ([Glu]); hypertonicity due to osmotic diuresis requires infusion of hypotonic solutions. Prediction of the serum sodium after [Glu] normalization (the corrected [Na]) estimates the part of hypertonicity caused by osmotic diuresis. Theoretical methods calculating the corrected [Na] and clinical reports allowing its calculation were reviewed. Corrected [Na] was computed separately in reports of DKA, HHS and hyperglycemia in CKD stage 5. The theoretical prediction of [Na] increase by 1.6 mmol/L per 5.6 mmol/L decrease in [Glu] in most clinical settings, except in extreme hyperglycemia or profound hypervolemia, was supported by studies of hyperglycemia in CKD stage 5 treated only with insulin. Mean corrected [Na] was 139.0 mmol/L in 772 hyperglycemic episodes in CKD stage 5 patients. In patients with preserved renal function, mean corrected [Na] was within the eunatremic range (141.1 mmol/L) in 7,812 DKA cases, and in the range of severe hypernatremia (160.8 mmol/L) in 755 cases of HHS. However, in DKA corrected [Na] was in the hypernatremic range in several reports and rose during treatment with adverse neurological consequences in other reports. The corrected [Na], computed as [Na] increase by 1.6 mmol/L per 5.6 mmol/L decrease in [Glu], provides a reasonable estimate of the degree of hypertonicity due to losses of hypotonic fluids through osmotic diuresis at presentation of DKH or HHS and should guide the tonicity of replacement solutions. However, the corrected [Na] may change during treatment because of ongoing fluid losses and should be monitored during treatment.

Relationship between dietary sodium and sugar intake: A cross-sectional study of the National Health and Nutrition Examination Survey 2001-2016.

Dietary sodium intake and cardiovascular outcomes have a reported J-shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001-2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24-hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06-2.6 g/d); SQ2(2.6-3.0 g/d); SQ3(3.0-3.4 g/d); SQ4(3.4-4.0 g/d); and SQ5(4.0-29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24-hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.