Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology.

Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as "renoprotective" therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors' perspectives on extracorporeal treatments in CN.

Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells.

G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.

Evaluation of pre-procedure ultrasound examination as a screening tool for difficult spinal anaesthesia*.

We performed a pre-procedure ultrasound examination of the spine on 60 patients undergoing lower extremity orthopaedic surgery under spinal anaesthesia. We hypothesised that the inability to identify the posterior longitudinal ligament or vertebral body easily with ultrasound would be associated with difficulty placing a spinal anaesthetic. Clinicians blinded to the ultrasound scan performed the injections using the traditional landmark technique. The spinal procedure was videotaped and subsequently reviewed by independent investigators. We defined procedure difficulty by total procedure time (> 400 s) and number of needle passes (≥ 10) required to achieve return of cerebrospinal fluid, or abandonment of the procedure due to unsuccessful dural puncture. When images of the posterior longitudinal ligament were poor (low score group), the mean (SD) number of passes was 21.2 (30.6), compared with 4.8 (7.5) with good ultrasound images (high score group) (p < 0.01). The mean (SD) time for placement was 420 (300) s in the low score group vs 176 (176) s in the high score group (p < 0.01). You can respond to this article at http://www.anaesthesiacorrespondence.com.

Systemic anticancer therapy in gynecological cancer patients with renal dysfunction.

Chronic kidney disease is a common occurrence in patients with gynecological cancer. Systemic anticancer treatment in such patients is a challenge for clinicians because of altered drug pharmacokinetics. For those drugs that are excreted mainly by the kidneys, decreased renal function may lead to increased systemic exposure and increased toxicity. Dose adjustment based on pharmacokinetic changes is required in this situation to avoid life-threatening toxicity. In this review, we summarize the nephrotoxicity and pharmacokinetic data of agents commonly used in systemic anticancer treatment of gynecological cancers and dose adjustment guidelines in the presence of impaired renal function. We review 17 medications that need dose adjustment (cisplatin, carboplatin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide, topotecan, irinotecan, etoposide, capecitabine, bleomycin, methotrexate, actinomycin D, granulocyte-macrophage colony-stimulating factor, metoclopramide, cimetidine, and diphenhydramine) as well as 27 drugs that do not (paclitaxel, docetaxel, pegylated liposomal doxorubicin, gemcitabine, oxaliplatin, fluorouracil, vincristine, letrozole, anastrozole, tamoxifen, leuprorelin, megestrol, gefitinib, erlotinib, trastuzumab, leucovorin, granulocyte colony-stimulating factor, erythropoietin, ondansetron, granisetron, palonosetron, tropisetron, dolasetron, aprepitant, dexamethasone, lorazepam, and diazepam). We also review the formulae commonly used to estimate creatinine clearance, including Cockcroft-Gault, Chatelut, Jelliffe, Wright, and the Modification of Diet in Renal Disease study formulae.

Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation.

BACKGROUND: Citrate anticoagulation is commonly used for continuous venovenous hemodialysis (CVVHD) to minimize the risk of bleeding complications. We have previously reported a liver failure patient undergoing citrate-based CVVHD with elevated serum total to ionized calcium ratio. Diminished liver metabolism of citrate with resultant elevated systemic citrate was thought to be the cause. METHODS: To determine the incidence and clinical significance of an elevated total to ionized calcium ratio during citrate-based CVVHD, 161 patients undergoing citrate-based CVVHD were screened for the presence of an elevated total to ionized calcium ratio (the subset with increased total to ionized calcium ratio comprised the study group). Because all patients in the study group had liver failure, two control groups of patients with normal total to ionized calcium ratios were formed-those without liver failure (control I) and those with liver failure (control II). RESULTS: An elevated total to ionized calcium ratio was detected in 12% of all patients. Thirty-three percent of liver failure patients demonstrated an elevated total to ionized calcium ratio. The study group demonstrated significantly higher mean total calcium levels, significantly lower mean ionized calcium levels, and significantly higher mean total to ionized calcium ratios than controls. As a result, the study group also had significantly increased mean calcium chloride replacement requirements in comparison with controls. The mean calcium to citrate infusion ratio was elevated in the study group in comparison with controls. An elevated total to ionized calcium ratio was associated with increased mortality in comparison with controls. No patients suffered complications from ionized hypocalcemia or elevated serum total calcium. CONCLUSIONS: Systemic citrate accumulation as evidenced by an elevated total to ionized calcium ratio occurs commonly in patients requiring CVVHD using citrate-based regional anticoagulation. Observing changes in the total to ionized calcium ratio can aid in early detection of patients with hepatic failure who are unable to appropriately metabolize citrate and will require calcium chloride infusion rates significantly above normal.

Unexpected severe hypocalcemia during continuous venovenous hemodialysis with regional citrate anticoagulation.

Citrate is known to induce acute hypocalcemia in patients undergoing liver transplantation during the anhepatic phase. We describe the case of a 71-year-old woman with fulminant hepatic failure secondary to hepatitis A, who was started on continuous venovenous hemodialysis (CVVHD) for acute renal failure. Because anticoagulation with heparin was untenable, regional anticoagulation was accomplished by trisodium citrate (46.7%) infusion. Unfortunately, severe hypocalcemia developed when citrate accumulated because of impaired hepatic metabolism. Because of chelation by citrate, the ionized calcium concentration declined to values as low as 2.72 mg/dL (normal, 4.5 to 5.6 mg/dL), whereas the total calcium concentration remained in the normal range. With an unusually high calcium chloride infusion rate via a central line (up to 140 mL/h of 10 mEq/dL CaCl2) and additional boli of CaCl2 (for a total of 190 mEq), the ionized calcium concentration could be maintained at target levels. Nevertheless, the ionized calcium concentration was maintained in the normal range, and the total calcium concentration increased to a value as high as 15 mg/dL. Thus, the total to ionized calcium ratio was 3.5:1. After 24 hours of treatment, trisodium citrate infusion was gradually reduced from 15 mL/h to 7 mL/h, and the calcium chloride infusion was decreased to 50 mL/h. Nevertheless, persistence of the elevated total to ionized calcium ratio (3:1) indicated citrate accumulation likely secondary to decreased hepatic metabolism. Using this approach, the patient was successfully maintained on CVVHD with regional citrate anticoagulation for a total of 11 days without any additional complications. We conclude that CVVHD with regional citrate anticoagulation can be used in patients with acute hepatic failure if increased CaCl2 requirements are anticipated and if citrate is infused at a lower rate compatible with decreased citrate metabolism. Citrate accumulation should be suspected in patients with an elevated total to ionized Ca++ ratio during CVVHD with citrate anticoagulation.

Hyperphosphatemia associated with phosphorus-containing laxatives in a patient with chronic renal insufficiency.

A patient with chronic renal insufficiency had hyperphosphatemia, hypocalcemia, hypomagnesemia, hypokalemia, metabolic acidosis, and QT prolongation on electrocardiogram after taking prescribed laxatives containing phosphorus. Clinical findings included tetany in the form of Chvostek's and Trousseau's signs. Symptoms resolved after careful rehydration and electrolyte replacement. The interactions between these electrolytes are described. Patients with moderate to severe renal dysfunction should avoid use of laxatives containing phosphorus. If these laxatives are used in patients with mild renal dysfunction, careful monitoring is indicated.

Sexual abuse and incest. What can you do?

The problem of child sexual abuse is of increasing relevance to family physicians. Apart from the need to recognize and manage child victims and their families, it is important to be aware of the incidence and nature of the many sequelae of childhood sexual exploitation. Common signals include physical, psychosomatic, and psychiatric disorders. Some physicians must deal with their own childhood victimization if the best interests of their patients are to be served.

Roles of growth hormone and growth factors in the pathogenesis and treatment of kidney disease.

Growth hormone and a number of polypeptide growth factors exert actions on renal development, growth, and metabolism and on repair processes following renal injury. There is increasing evidence that under selected circumstances, these agents play roles in the pathogenesis of kidney disease and that under others, they may be useful in its treatment. Growth hormone, platelet-derived growth factor, or transforming growth factor-beta may be causative of glomerulosclerosis. The reduction in epidermal growth factor expression within the kidney in the setting of acute ischemic injury could delay regeneration, and replacement may be therapeutic. Insulin-like growth factor I may play a role in the regenerative response to acute renal injury. Pharmacologic properties of growth hormone or insulin-like growth factor I to enhance glomerular filtration rate and renal plasma flow and to increase skeletal growth may be harnessable for treating chronic renal failure and its complications. It is likely that strategies designed to employ growth hormone or growth factors as pharmacologic agents or to block their activities will assume increasingly important roles in therapy for renal disease.

Heterotopic gastric mucosa in the gallbladder: a cause of chronic abdominal pain in a child.

A 12-year-old boy presented with a 7-year history of intermittent colicky epigastric pain. Serial abdominal ultrasound studies showed a contracted gallbladder, and single and double dose oral cholecystograms demonstrated nonfunction. All other investigation results were normal. At cholecystectomy, there was a fibrotic stricture at the junction of the gallbladder neck and cystic duct. The small, thin-walled gallbladder contained white bile. Histologically, the gallbladder was lined with normal mucous secreting columnar epithelium. The area of stricture showed diffuse fibrosis with islands of heterotopic gastric mucosa containing all gastric mucosal cell types. One year postoperatively, there have been no further episodes of abdominal pain. This is the seventh reported case of heterotopic gastric mucosa in the gallbladder of a child causing symptoms necessitating cholecystectomy. We recommend that a child with abdominal pain and a nonfunctioning gallbladder be considered for cholecystectomy even in the absence of cholelithiasis.

Sexual abuse of children: an update.

An increasing number of studies in the past decade have shown that sexual abuse of children is disturbingly common. The author reviews some of the more recent knowledge about the problem, with particular reference to medical implications. The incidence and distribution of the problem and the relative importance of the medical examination are reviewed, and the diagnostic significance of clinical presentations such as vulvovaginitis, recurrent urinary tract infection and masturbation is evaluated. The agents responsible for sexually transmitted diseases in abused children are reviewed. Many crucial psychosocial issues are raised in the evaluation and management of sexual abuse. The author discusses some aspects of abuse that are hard to confront, such as the possible pleasure of the child and the nonoffending role of the mother in cases of incest. Information from sources other than the medical literature on the characteristics of abusers, therapy and prevention is reviewed. The medical implications of the Badgley Report are also discussed.