Warburg's effect on solid tumors.

Lactic acidosis is the result of imbalance between the systemic formation of lactate and its hepatic metabolism. In cancer patients, lactic acidosis is mainly associated with hematologic malignancies (leukemia and lymphomas) and the mechanism is known as Warburg's effect. We report a 76-year-old male known to have hypertension and coronary artery disease, who presented with abdominal distension and lactic acidosis. His initial evaluation showed multiple liver masses that were biopsied and the patient was diagnosed with undifferentiated carcinoma of unknown primary, involving the liver. The patient had progression of lactic acidosis leading to his death on day-15. As the lactic acidosis was not in the setting of hypoxia or hemodynamic instability, we made the diagnosis of malignancy-associated type B lactic acidosis, also known as the Warburg's effect. Warburg's effect can occur in solid cancer if the tumor involves the liver. It has bad prognostic implications. The use of intravenous bicarbonate as a temporary measure is of controversial benefit, as it can potentially worsen the metabolic acidosis and its use should be limited to patients with very low pH. In cancer patients, the use of lactatebased intravenous fluids can be potentially harmful and can increase the risk of tumor metastasis, at least in animal malignancy models.

Belatacept: a new era of immunosuppression?

Full T-cell activation in alloimmunity requires the engagement of several costimulatory molecules. CTLA-4-Ig and its commercially available fusion proteins, belatacept and abatacept, are used to block CD80/86 and promote T-cell tolerance. Belatacept, a higher binding affinity molecule, is currently approved for clinical use in renal transplantation. The results of two Phase III clinical trials showed a similar patient/graft survival, with better renal function at a 3-year follow-up compared with conventional immunosuppression. There was a higher risk of early rejection and post-transplant lymphoproliferative disorder, especially with EBV-negative patients receiving kidneys from EBV-positive donors. Belatacept-treated groups had a better cardiovascular and metabolic profile. The authors review both preclinical and human studies of CTLA-4-Igs.

Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy.

A 70-year-old diabetic male patient with a baseline serum creatinine of 1.4 mg/dL presented with nausea and vomiting. He was diagnosed with metformin-associated lactic acidosis and acute kidney injury. He was managed with continuous veno-venous hemodiafiltration (CVVHDF). By measuring metformin concentration at different time intervals, we calculated the apparent volume of distribution of metformin at 34.7 L. The decline in serum metformin followed single-compartment first-order kinetics with an elimination rate constant of 0.0418/h and a serum half-life of 16.5 h; no metformin rebound was seen after discontinuation of CVVHDF. Using the previously calculated volume of distribution we calculated the expected serum metformin concentration 25 h post CVVHDF to be 3.0-3.7 µg/mL. The measured serum metformin of 3.4 µg/ml fell within the predicted range. During CVVHDF, dialyzer metformin clearance approximates 88.7 % of dialyzer urea clearance and 90.1 % of dialyzer creatinine clearance.

The impact of reporting estimated glomerular filtration rate.

The 'Kidney Disease Outcomes Quality Initiative' guidelines recommend laboratory reporting of a calculated estimated glomerular filtration rate (eGFR). The United Kingdom and several states already mandate reporting eGFR for every laboratory serum creatinine (sCr) measurement. In our study, we evaluated the impact of reporting eGFR on the management of hospitalized patients. We reviewed the medical records for 2000 patients, 1000 pre- and 1000 post-reporting eGFR. We excluded patients with previous diagnosis of chronic kidney disease, acute kidney failure, and end-stage renal disease. We analyzed the subgroup of patients with eGFR <60 and sCr <1.5 mg/dL. We did not notice an increase in the number of renal consult, ordering laboratory or imaging study to evaluate chronic kidney disease. The prescription habits did not change for nephrotoxic medications (nonsteroidal anti-inflammatory drugs and aminoglycosides). We did not find any change in the percentage of patients who received hydration for a radiological contrast study or the use of N-acetylcysteine. In conclusion, reporting eGFR did not improve the renal management of hospitalized patients.

Effects of parathyroid hormone on immune function.

Parathyroid hormone (PTH) function as immunologic mediator has become interesting with the recent usage of PTH analogue (teriparatide) in the management of osteoporosis. Since the early 1980s, PTH receptors were found on most immunologic cells (neutrophils, B and T cells). The in vitro evaluations for a possible role of PTH as immunomodulator have shown inconsistent results mainly due to methodological heterogeneity of these studies: it used different PTH formulations (rat, bovine, and human), at different dosages and different incubating periods. In some of these studies, the lymphocytes were collected from uremic patients or animals, which renders the interpretation of the results problematic due to the effect of uremic toxins. Parathyroidectomy has been found to reverse the immunologic defect in patients with high PTH levels. Nonetheless, the clinical significance of these findings is unclear. Further studies are needed to define if PTH does have immunomodulatory effects.