Challenges of Hemodialysis in Patients with Hyperglycemic Hyperosmolar States (HHS)

Nephrologists are often challenged by patients with hyperosmolar states requiring hemodialysis (HD). A 25-year-old man with hypertension and obesity presented with nausea, vomiting, polyuria and blurred vision. He was found to have a blood sugar of 1700, serum sodium of 141 (179 corrected), hydroxyburyrate 5.2, lipase 1028 and a CT concerning for pancreatitis. Blood glucose levels were slowly corrected to the 1200s with insulin. He then required HD for AKI and hyperkalemia, leading to an acute drop in glucose to the 800s and a corrected sodium of 158, associated with acute mental status changes. Blood sugars were allowed to rise back to the 1000s, with corresponding corrected sodium of 169. A CT head saw no intracranial abnormalities. Renal function improved with resuscitation and no additional sessions of HD were required. Blood glucoses and corrected serum sodium was then carefully improved with a net change of tonicity of up to 12 mmol/L per day, leading to resolution of mental status changes. HHS is associated with high mortality. Metabolic derangements result from insulin deficiency, increased counter regulatory hormones (glucagon, catecholamines, cortisol) leading to increased gluconeogenesis, accelerated conversion of glycogen to glucose, and inadequate use of glucose by peripheral tissues. This leads to osmotic diuresis resulting in volume depletion, hypotensive shock, rhabdomyolysis, increased risk of thrombosis, and severe multi-organ failure. During extracellular hyperosmolar states, the brain is thought to protect itself against changes in volume by production of unidentified solutes. Rapid correction in plasma osmolality can lead to osmolar gradients, volume shifts, and cerebral edema. This case exemplifies difficulties in treating hyperglycemia and its resultant hyperosmolar state in a HD dependent patient. To avoid rapid changes in tonicity and intracranial fluid shifts during HD, careful manipulation of sodium and possibly concomitant use of mannitol may be required for cranial protection

Non-conventional therapy of a triple acid base disorder.

Severe electrolyte derangements are difficult to correct and standard approaches are not always successful. We present a case in which an unconventional treatment approach led to resolution of a severe, mixed acid-base disorder. A 74-year-old female with a history of stroke, seizures, and chronic hyponatremia presented with confusion, gait difficulty, and poor oral intake. Initial vital signs T 36.3 °C, BP 97/52 mm Hg, HR 70 bpm, RR 16 min-1, BMI 19 kg/m2. Admission lab data revealed Na 118, K 3.2, Cl 89, TCO2 23 mmol/L, BUN 11, SCr 0.76, Mg 1.5, Pi 1.7 mg/dL. ABG pH 7.76, pCO2 12.5 mm Hg. Diagnoses of ketolactic acidosis from starvation with metabolic and respiratory alkaloses were established by elevations of serum lactate (3.9 mmol/L) and beta hydroxybutyrate (1.07 mmol/L) levels. To prevent aggravation of hyponatremia by free-water glucose infusions yet treat the ketosis, a concentrated sugar solution comprised of addition of 20 grams of glucose to 20 oz (contains 77 grams of total carbohydrates) of phosphorus-free Mountain Dew was administered. Cerebral perfusion compromise from hyperventilation and life threateningly high pH were offset by intubation with addition of dead space via increased tubing length. Hypokalemia and hypophosphatemia, from dietary deprivation, were addressed with potassium phosphate administered at 0.5 mmol/kg/day. Hyponatremia, attributed to SIADH with superimposed volume depletion, was gradually corrected at 6-8 mmol/L/day. Within 24 hours, ketone production was suppressed and arterial pH lowered to 7.41 with pCO2 of 31.8 mm Hg. This case demonstrates efficacy of a sugar-sweetened beverage to treat starvation ketosis, and mechanical hypoventilation to correct severe respiratory alkalosis. In addition to utilizing traditional protocols, physicians must be creative and consider non-conventional approaches to patients

The Crystal Structure of Choline Kinase Reveals a Eukaryotic Protein Kinase Fold

AbstractCholine kinase catalyzes the ATP-dependent phosphorylation of choline, the first committed step in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. The 2.0 Å crystal structure of a choline kinase from C. elegans (CKA-2) reveals that the enzyme is a homodimeric protein with each monomer organized into a two-domain fold. The structure is remarkably similar to those of protein kinases and aminoglycoside phosphotransferases, despite no significant similarity in amino acid sequence. Comparisons to the structures of other kinases suggest that ATP binds to CKA-2 in a pocket formed by highly conserved and catalytically important residues. In addition, a choline binding site is proposed to be near the ATP binding pocket and formed by several structurally flexible loops

Crystal sructure of photorespiratory alanine: Glyoxylate aminotransferase 1 (AGT1) from \u3ci\u3eArabidopsis thaliana\u3c/i\u3e

Photorespiration is an energetically costly metabolic pathway for the recycling of phosphoglycolate produced by the oxygenase activity of ribulose-1,5-bisphosphate carboxylase/oxygenase (RUBISCO) to phosphoglycerate. Arabidopsis alanine:glyoxylate aminotransferase 1 (AGT1) is a peroxisomal aminotransferase with a central role in photorespiration. This enzyme catalyzes various aminotransferase reactions, including serine:glyoxylate, alanine:glyoxylate, and asparagine:glyoxylate transaminations. To better understand structural features that govern the specificity of this enzyme, its crystal structures in the native form (2.2-Å resolution) and in the presence of l-serine (2.1-Å resolution) were solved. The structures confirm that this enzyme is dimeric, in agreement with studies of the active enzyme in solution. In the crystal, another dimer related by noncrystallographic symmetry makes close interactions to form a tetramer mediated in part by an extra carboxyl-terminal helix conserved in plant homologs of AGT1. Pyridoxal 5′-phosphate (PLP) is bound at the active site but is not held in place by covalent interactions. Residues Tyr35′ and Arg36′, entering the active site from the other subunits in the dimer, mediate interactions between AGT and l-serine when used as a substrate. In comparison, AGT1 from humans and AGT1 from Anabaena lack these two residues and instead position a tyrosine ring into the binding site, which accounts for their preference for l-alanine instead of l-serine. The structure also rationalizes the phenotype of the sat mutant, Pro251 to Leu, which likely affects the dimer interface near the catalytic site. This structural model of AGT1 provides valuable new information about this protein that may enable improvements to the efficiency of photorespiration

Severe metabolic alkalosis in pregnant patient due to citrate load with plasma exchange

Sodium citrate has been widely utilized as an anticoagulant in plasmapheresis (PP). Metabolic alkalosis is a well-known complication of PP in patients with impaired ability to excrete byproducts of citrate metabolism. We report a rare case of iatrogenic citrate toxicity leading to profound metabolic alkalosis in a pregnant patient. A 22-year-old pregnant female, gestational age 16 weeks, was admitted with fever, rash and myalgias. She was intubated due to respiratory failure with diffuse alveolar hemorrhage. Autoimmune studies and skin biopsy were consistent with a new diagnosis of lupus. Steroids and daily PP were initiated. On admission, patient\u27s height was 150 cm and she weighed 71 kg. Lab data showed serum creatinine levels between 0.21 and 0.51 mg/dL. Patient received six daily PP treatments. Three days after initiation of PP, she was noted to have an increase in serum bicarbonate (TCO2) level from 23 to 42 mmol/L. ABG showed pH of 7.55, pCO2 46.2 mm Hg. Peak pH was 7.62, following which she received one dose of acetazolamide. Her TCO2 levels returned to baseline upon completion of apheresis. Volume of distribution of hydrophilic substances is increased in pregnancy. The patient received 10 L of plasma replacement with total citrate load of 294 mmol in the first three days. Under normal conditions citrate is rapidly metabolized to bicarbonate in the liver. One molecule of citrate can be converted to three molecules of bicarbonate, therefore total bicarbonate load was approximately 882 mmol. Iatrogenic bicarbonate load with plasma exchange led to elevation of TCO2 to a critical level. Contributing factors include hypocapnic state of pregnancy and delayed renal compensation. This case also highlights the utility of acetazolamide in such circumstances. Citrate delivery needs to be protocolized and monitored closely to make it safe and effective

The crystal structure of TrxA(CACA): Insights into the formation of a [2Fe-2S] iron–sulfur cluster in an Escherichia coli thioredoxin mutant

Escherichia coli thioredoxin is a small monomeric protein that reduces disulfide bonds in cytoplasmic proteins. Two cysteine residues present in a conserved CGPC motif are essential for this activity. Recently, we identified mutations of this motif that changed thioredoxin into a homodimer bridged by a [2Fe-2S] iron–sulfur cluster. When exported to the periplasm, these thioredoxin mutants could restore disulfide bond formation in strains lacking the entire periplasmic oxidative pathway. Essential for the assembly of the iron–sulfur was an additional cysteine that replaced the proline at position three of the CGPC motif. We solved the crystalline structure at 2.3 Å for one of these variants, TrxA(CACA). The mutant protein crystallized as a dimer in which the iron–sulfur cluster is replaced by two intermolecular disulfide bonds. The catalytic site, which forms the dimer interface, crystallized in two different conformations. In one of them, the replacement of the CGPC motif by CACA has a dramatic effect on the structure and causes the unraveling of an extended α-helix. In both conformations, the second cysteine residue of the CACA motif is surface-exposed, which contrasts with wildtype thioredoxin where the second cysteine of the CXXC motif is buried. This exposure of a pair of vicinal cysteine residues apparently allows thioredoxin to acquire an iron–sulfur cofactor at its active site, and thus a new activity and mechanism of action

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1.

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders