The ATRIA Risk Prediction Score - A New Tool to Predict Bleeding Risk from Warfarin in Kidney Patients and Others.

A new 5-variable score, developed by Margaret Fang, MD, MPH, of the University of California San Francisco, and colleagues, outperformed six other published and validated risk scores in predicting the risk of warfarin-associated hemorrhage in patients with atrial fibrillation.

Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age 75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%).

Ref: Fang M, et al "A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study" J Am Coll Cardiol 2011; 58: 395-401.

FDA approves a novel anti-rejection medication for kidney transplant recipients.

The US Food and Drug Administration (FDA) approved Belatacept (Nulojix, Bristol-Myers Squibb Company) on June 15th, 2011, for the prevention of acute rejection in adult patients who have had a kidney transplant.

This novel biologic agent is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4. It is an antagonist of the B7 ligands, B7-1 (CD80) and B7-2 (CD86), present on antigen-presenting cells. The CD80 and CD86 are essential precursors to the initiation of "signal 2" in the three-signal transplant model of T-cell activation, This antagonistic effect results in the inability to produce effector cytokines, such as interleukin (IL)-2, and results in inhibition of T-cell activation.It is given in 30-minute intravenous infusions.

Belatacept is approved for use with corticosteroids and the immunosuppressant agents basiliximab and mycophenolate mofetil.

For more information visit: http://www.nulojix.com/hcp/index.aspx

A Rare Case of Kidney Failure Due to Diazoxide Toxicity – Discussion

A Rare Case of Kidney Failure Due to Diazoxide Toxicity – Discussion.

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Separate the public and private persona: Physicans should employ a “dual-citizenship” approach while using social media.

I had the pleasure of listening to a talk on utilizing online resources and social media such as blogs, wikis, Facebook and Twitter for educating medical students and residents yesterday by Dr. Kenar Jhaveri, the founder of Nephron Power.

Online resources are indeed playing an increasing role in educating future doctors in the US and abroad. However, it is imperative that physicans take appropriate precautions while utlizing these resources to maintain confidentiality, honesty, and trust in the medical profession. Drs. Arash Mostaghimi, MD, MPA and Bradley H. Crotty, MD, recently published an excellent article in Annals of Internal Medicine which puts forth guideline for maintaining professionalism in the digital age. among other things they recommend a "dual citizenship" approach of separating the personal and professional persona and taking a pro-active approach to managing one's online presence. I highly recommend reading this article.

Ref: Arash Mostaghimi, MD, MPA, and Bradley H. Crotty, MD.Professionalism in the Digital Age. Ann Intern Med. 2011;154:560-562.

Diuretic Strategies in Patients with Acute Decompensated Heart Failure.

In a prospective, double-blind, randomized trial, 308 patients with acute decompensated heart failure were assigned to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustmen

ts after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.

In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.

Reference: Felker Gm at al. N Engl J Med. 2011 Mar 3;364(9):797-805.

Rituxan in ANCA-associated vasculitis

Wegener’s granulomatosis and microscopic polyangiitis are classified as antineutrophil cytoplasmic antibody (ANCA)−associated vasculitides as most patients have antibodies against proteinase 3 or myeloperoxidase.The ANCA-associated vasculitides affect small-to-medium-size blood vessels, with a predilection for the respiratory tract and kidneys. Without treatment mortality is very high and mostly the norm.

Cyclophosphamide and glucocorticoids have been the standard therapy for remission induction for decades. While this treatment is effective in controlling the disease and inducing temporary remission in a majority of the patients, the side effects of cyclophosphamide (leucopenia, infertility, bladder cancer) are very severe and limiting. And, a search for a suitable alternative to cyclophosphamide for inducing disease remission in these patients with fewer side effects is ongoing.

In the following slides I have summarized two landmark studies that evaluated Rituxan in ANCA associated vasculitis as an alternative to cyclophosphamide:

Virological Synapses Allow HIV-1 Uptake and Gene Expression in Renal Tubular Epithelial Cells.

Authors:
Chen P, Chen BK, Mosoian A, Hays T, Ross MJ, Klotman PE, Klotman ME.

Reference:
J Am Soc Nephrol. 2011 Mar;22(3):496-507. Epub 2011 Feb 18.

Abstract:
In animal models of HIV-associated nephropathy, the expression of HIV regulatory genes in epithelial cells is sufficient to cause disease, but how the CD4-negative epithelial cells come to express HIV genes is unknown. Here, we co-cultured T cells infected with fluorescently tagged HIV with renal tubular epithelial cells and observed efficient virus transfer between these cells. The quantity of HIV transferred was much greater than that achieved by exposure to large amounts of cell-free virus and occurred without a requirement for CD4 or Env. The transfer required stable cell-cell adhesion, which could be blocked by sulfated polysaccharides or poly-anionic compounds. We found that the internalization of virus could lead to de novo synthesis of viral protein from incoming viral RNAs even in the presence of a reverse transcriptase inhibitor. These results illustrate an interaction between infected T cells and nonimmune cells, supporting the presence of virological synapses between HIV-harboring T cells and renal tubular epithelial cells, allowing viral uptake and gene expression in epithelial cells.

HIV Entry Into Renal Tubular Epithelial Cells Through Cell–Cell Adhesion

Using live confocal imaging, Chen et al followed interactions between renal tubular epithelial cells (RTECs) and co-cultured fluorescently-tagged-HIV infected CD4+ T cells and recently demonstrated that the viral RNA was directly transferred from the infected CD4+ T cells into RTECs. The virus transfer required cell surface heparin sulfate proteoglycans (which serve as attachment receptors for HIV-1 on macrophages and dendritic cells) and stable cell–cell adhesion and was independent of HIV Env expression. Interestingly, the quantity of viral RNA transferred through cell–cell adhesion was much higher than that achieved by exposure large amounts of cell-free virus.

The authors also demonstrated that the HIV virus acquired via cell–cell contact results in de novo synthesis of viral proteins in the infected RTECs. Furthermore, reverse transcriptase, protease and integrase inhibitors seem to block gene expression in the RTECs that acquired the infection from cell-free virus but not in the RTECs that acquired the virus via cell–cell contact.

In summary, it seems that direct transfer of virus from infected T cells to RTECs is possible in vitro on cell–cell contact via a highly efficient mechanism that is independent of Env. The extent to which this happens in vivo and contributes to the pathogenesis of HIV-associated nephropathy remains to be seen.

Reference: chen et al. J Am Soc Nephrol. 2011 Mar;22(3):496-507. Epub 2011 Feb 18.

Is peritoneal dialysis a viable option in patients with cirrhosis and ascites ?

Theoretical disadvantages of PD when compared to HD?
1. Increased risk of peritonitis.
2. Ongoing and higher protein losses in dialysate may aggravate malnutrition. And, with excessive protein supplementation there may be worsening of hepatic encephalopathy.
3. More hypokalemia – can worsen encephalopathy by increasing ammonia production in PT and also results in impaired motility of the gut -> increased bacterial colonization and peritonitis risk.
4. Intrabdominal bleeding from catheter trauma.
5. Might adversely affects transplantation rates or increase peri-transplant morbidity secondary to adehesions, etc.

Theoretical advantages of PD when compared to HD?

1. Avoids hypotension episodes and better preserves residual renal function.
2. Rapid drop in plasma osmolality with HD can results in cerebral edema and AMS.
3. Dialysate can serve as source of calories in malnourished patients.
4. Avoids risk of bleeding with cannulation that is associated with HD.
5. Increased intra-abdominal pressure opposes portal & splanchnic hypertension and less formation & accumulation of ascites.
6. Ultrafiltration capacity augmented with respect to non-cirrhotic patients (as ascites is removed) – making use of hypertonic bags unnecessary.
7. PD removes endotoxins (part of GNB cell walls) and Nitric Oxide in the ascitic fluid.
8. Peritonitis is detected much earlier & non-invasively as cloudiness of the fluid is readily noticeable.

*Pertitonitis rates reported in literature are varied and inconclusive:
Chow et al (Hongkong):
Compared 25 patients with HBV with cirrhosis on PD vs. 36 HBV patients without cirrhosis on PD.
Mean follow-up: 4 years
Peritonitis rate: 1 episode/19.2 months in cirrhotics vs. 1/20.5 months in non-cirrhotics (NS).
No difference in time to first peritonitis between groups.
None of the patients were on antibiotic prophylaxis.
Significant increase in alpha hemolytic strep infections.
No increase in enterobacteriacea peritonitis.

*DeVecchi et al (Italy):
Compared 21 cirrhotics on PD vs. 41 non-cirrhotic PD patients.
Mean follow-: 3 years
Peritonitis rate lower in cirrhotic group. 1/39 months vs. 1/22 months.
Unclear whether pateints were on antibiotic prophylaxis.

*Selgas et al (Spain):
Case series with 8 cirrhotics.
Peritonitis rate: 1 episode/9 months (2.5x higher than their average rate).
Unclear whether patients were on antibiotic prophylaxis.
Peritonitis due to S. faecalis, E.coli and gram negative bacilli significantly higher.

Suggested management strategies for PD in patients with ascites:
*At PD initiation:
A. Initial large volume paracentecis thorugh newly placed PD catheter with IV albumin support for hemodynamic stability to alleviate pressure at suture site and promote healing of catheter site and reduces chances of a leak.
B. Initial PD regimen should be low-volume supine regimen with no ambulatory dialysis – to reduce chance of leak.
C. Controlled paracentecis/drain restricted exchanges (limit to 2400-2500 ml/drain) with low dextrose concentration: Allows for eventual slow removal of ascites.

*Ongoing stratergies:

A. Prevention & treatment of peritonitis episodes.

1. Consider oral prophylactic antibiotics for SBP.
2. Topical gentamycin ointment for exit site care.
3. Chronic lactulose therapy – metabolized by colonic bacteria into pyruvate and lactate which acidify the stool and reduce bacterial colonization.
4. Avoid hypokalemia – can worsen intestinal motility and bacterial overgrowth.
5. PD itself, by removing endotoxins (component of GNB cell walls) and Nitric Oxide in the ascitc fluid, may reduce inflammation fo the peritoneal membrance. It can also reduce portal pressure gradient and reduce bleeding from varices.
6. Intraperitoneal antibiotics effective.
7. Initial regimen should provide broad spectrum coverage and include ampicillin.
8. Rx with intraperitoneal antibiotics + IV albumin reduced morbidity, mortality rate and prevented subsequent deterioration of renal function in one study. In addition to providing colloidal osmotic pressure, albumin also binds cytokines produced during peritonitis.

B. Protein losses in dialysate.

1. Several studies have shown that peritoneal protein losses are high initially but diminish over time. Monitor nutritional parameters closely.
2. Non-restricted diet is recommended
3. Oral protein supplements as needed.

C. Transplantation rates.

1. None of the large studies list transplantation rates.

References:
1. Chow et al. Peritoneal Dialysis International, Vol. 26, pp. 213–217.
2. DeVecchi et al. American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: pp 161-168.
3. Steven Guest. Advances in Peritoneal Dialysis, Vol. 26, 2010
3. Selgas et al. Peritoneal Dialysis International, Vol. 28, pp. 118–122.

Publication alert: HIV-associated nephropathy: pathogenesis.

AUTHORS:
Raj Kiran Medapalli, MD, MPH, John Ci-jiang He, MD, PhD and Paul E. Klotman, MD.

REFERENCE:
Curr Opin Nephrol Hypertens. 2011 Feb 23. [Epub ahead of print]

ABSTRACT:
PURPOSE OF REVIEW: HIV-associated nephropathy (HIVAN) is characterized histologically by a collapsing form of focal segmental glomerulosclerosis (FSGS), microcystic tubular dilation, interstitial inflammation and fibrosis. In this review, we provide a summary of the current state of knowledge about the mechanisms involved in the pathogenesis of HIVAN.
RECENT FINDINGS: Two variants in the ApoL1 gene have been identified as the susceptibility alleles that account for a majority of the increased risk of FSGS and nondiabetic end-stage renal disease in blacks. HIVAN1 and HIVAN2 are the other host susceptibility genes that have been identified in animal models for HIVAN. HIV infects renal tubular epithelial cells likely through direct cell-cell transmission. Both in-vivo and in-vitro evidence suggests that Nef and Vpr are the key viral genes mediating HIVAN. Nef induces podocyte dysfunction, whereas Vpr induces renal tubular epithelial cell apoptosis.
SUMMARY: HIVAN results from direct infection by HIV-1 and expression of viral genes, especially Nef and Vpr, in renal epithelial cells in a genetically susceptible host. The infected renal epithelium acts as a separate viral compartment from the blood and facilitates evolution of strains distant from blood. Dysregulation of several host cellular pathways, including those involved in cell cycle and apoptosis, ultimately results in the unique histopathological syndrome of HIVAN.

Publication alert: Expert opinion on pharmacotherapy of kidney disease in HIV-infected patients.

Authors:
Zygimantas C. Alsauskas, MD, Raj Kiran Medapalli, MD, MPH, Michael J. Ross, MD.

Reference:
Expert Opin Pharmacother. 2011 Apr;12(5):691-704. Epub 2011 Jan 21.

Abstract:
Introduction: Human immunodeficiency virus (HIV) infection is associated with the development of a wide spectrum of kidney diseases. HIV-associated nephropathy (HIVAN) is the most common cause of chronic kidney disease (CKD) in HIV-infected individuals and predominantly affects patients of African ancestry. HIVAN is a leading cause of end-stage renal disease (ESRD) among African-Americans. Areas covered: An overview of the spectrum of kidney disease in patients with HIV is given. Current pharmacologic interventions to treat kidney disease in HIV are discussed. This review will enhance knowledge regarding the most common causes of kidney disease in HIV-infected patients. An understanding of the principles related to pharmacotherapy in HIV-infected patients with kidney disease will also be gained.
Expert opinion: Kidney disease is an important cause of morbidity and mortality in HIV-infected patients. The most common cause of chronic kidney disease in this population is HIV-associated nephropathy, which is caused by viral infection of the renal epithelium. Several medications that are commonly used in HIV-infected patients can have adverse effects on the kidneys and the doses of many antiretroviral medications need to be adjusted in patients with impaired renal function.

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Amelioration of Metabolic Acidosis and Progression of CKD (Journal Club)

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Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club)

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Preeclampsia and the Risk of ESRD (Journal Club)

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