Five things to watch in nephrology
David Sheikh-Hamad, MD
Professor of Medicine, Molecular & Cellular Biology Baylor College of Medicine
Financial Disclosures
David Sheikh-Hamad, MD
In the context of my participation in this CME activity:
There is no conflict of interest to disclose.
The burden of AKI
• Acute kidney injury (AKI; ischemic or septic) is common, and continues to be associated with significant morbidity,
mortality, increased hospital length of stay and cost of care.
• Studies suggest that AKI results in permanent kidney damage and patients who survive AKI have a greater risk of CKD,
ESRD and death after hospital discharge.
Chertow et al. JASN 16: 3365-3370, 2005; Hoste EA et al., , Crit Care Med. 2008
The burden of AKI
• The incidence of mild/moderate AKI is approximately 2,000- 3,000 per million/year, while the incidence of severe AKI requiring dialysis is 200-300 per million/year.
• AKI has been reported in 5 to 7% of hospitalized patients.
• Approximately 2/3rd of ICU patients will develop AKI defined by the RIFLE classification, and 4-5% will require dialysis
therapy.
Chertow et al. JASN 16: 3365-3370, 2005; Hoste EA et al., , Crit Care Med. 2008
AKI is Associated with Increased In-Hospital Mortality, Length of Stay and Costs
An increase in SCr ≥0.5 mg/dl was associated with a 6.5-fold increase in the odds of death, a 3.5-day increase in LOS, and nearly $7500 in excess hospital costs.
Chertow et al. JASN 16: 3365-3370, 2005 Unadjusted
Age and gender adjusted
Multivariable analyses adjusted (age,
gender, DRG weight, CKD, ICD-9-CM codes for respiratory, GI, malignant, and infectious diseases
Remote ischemic preconditioning for organ protection
• Recent data suggest that remote ischemia preconditioning;
induced by cycles of transient limb ischemia and reperfusion using a standard BP cuff is highly effective in reducing AKI
after surgery or contrast exposure.
• It was also shown to improve myocardial salvage after PCI in STEMI, outcomes after cardiac surgery, and recovery after stroke.
Zarbock et al., JAMA. 2015; Sloth et al., European Heart Journal 2014; Davies et al., Circ Cardiovasc Interv.
2013; Er et al., Circulation 2012; Meng et al., American Journal of Neurology 2012.
What is ischemic preconditioning?
• Ischemic preconditioning-mediated protection is a
phenomenon in which tissue, once exposed to a specific type of insult, will be protected from injury during a repeated
similar or sometimes dissimilar insult.
• Moreover, recent data suggest that ischemia in one organ is accompanied with protective changes in distant organs, such as the heart, kidney and brain, a phenomenon known as
remote ischemic preconditioning (RIPC).
Mechanism of RIPC
• The recruitment of mesenchymal stem cells to the kidney in response to “ALARM” signals released by the injured organ, is critical for this protection.
• For cardiac protection, current knowledge suggests that transient limb ischemia releases a factor (<15 kDa) that
protects the myocardium against ischemia/reperfusion injury in a mechanism that requires opioid-receptor activation and modification of mitochondrial function (via K channels).
Protocol for RIPC
Delayed graft function
• Delayed Graft Function (DGF) refers to failure of a kidney to function optimally after transplantation.
• DGF correlates with cold ischemia time; after the kidney is
harvested, perfused with UW solution and stored on ice until transplanted.
• For every 6-hour increment of cold ischemia the risk of DGF increases by 23%.
Epidemiology and mechanism of AKI in DGF
• DGF occurs in up to 50% of primary deceased-donor kidney transplants in the US, independently predicts reduced 1- and 5-year kidney transplant survival, and is a critical barrier to progress in the field of kidney transplantation.
• In mouse and porcine experimental models of AKI induced
by cold ischemia (DGF), RTEC undergo apoptotic/necrotic cell death, due to low level expression of X-linked inhibitor of
apoptosis (XIAP).
Jani A, Epperson E, Martin J, et al., Transplantation 2011
Nature may provide the solution.
• Hibernating 13-lined ground squirrel survives cold ischemia at ~ 4°C for several days without RTEC apoptosis or renal injury, and XIAP is required to protect squirrel RTECs from apoptosis during cold storage at 4°C.
• Ongoing studies are aimed at increasing the expression of XIAP in the transplant kidney to ameliorate DGF.
Tamm-Horsfall protein (El-Ashkar, Tarek)
• Tamm-Horsfall protein (THP) was discovered in 1950 by Igor Tamm and Frank Horsfall Jr.; named “Uromodulin” in 1985 by Muchmore and Decker.
• It is expressed exclusively in cells of the thick ascending limbs (TAL) of Henle, present in the urine in multimeric form (“gel”
that forms the cast) and is one of the most abundant proteins in the urine.
Tamm-Horsfall protein
• A small portion of THP is directed to the interstitium and
plays a crucial role in protecting S3 proximal segments in AKI, establishing a cross-talk between TAL and S3.
El-Achkar, T.M., R. McCracken, Y. Liu, et al., Am J Physiol Renal Physiol, 2013.
Function
• THP Protein suppresses ROS and the inflammatory response triggered by ischemic injury in the corticomedullary junction after AKI, and AKI is a state of THP deficiency.
• Deficiency of THP is associated with release of IL-23/IL-17 from S3 segments, inducing neutrophil production in the
bone marrow and homing to the kidney – aggravating kidney inflammation and injury.
Micanovic R et al., J Am Soc Nephrol. 2015
Take home message
• Delivery of monomeric form of THP is a potential future therapeutic strategy for AKI.
• And, beyond regulating erythropoiesis through
erythropoietin, the kidney regulates BM granulopoiesis.
Micanovic R et al., J Am Soc Nephrol. 2015
Septic AKI (Pierre Dagher)
• The pathophysiology of AKI in sepsis continues to be poorly understood.
• Endotoxins (derived from GNR bacteremia) are thought to play a major role in Septic AKI.
• Endotoxin is readily filtered and internalized by the proximal tubules through TLR4 receptors and endocytosis. It causes oxidative stress and severe tubular injury.
Kalakeche R et al., J Am Soc Nephrol. 2011
Septic AKI
• Exposure of experimental animals to Endotoxin in large
doses causes AKI; however, mild Endotoxemia protects from large dose Endotoxemia or septic AKI.
• The Endotoxin-preconditioned state is characterized by
increased M2 macrophages (protective) within the kidney and clustering around proximal tubules.
• Transfer of macrophages from Endotoxin-preconditioned animal to a different animal, confers protection from septic AKI.
Hato T et al., , J Am Soc Nephrol. 2015
Potential therapeutic applications of Endotoxin preconditioning
• Endotoxin preconditioning is not a state of immune
compromise; rather, it improves bacterial clearance and survival after sepsis.
• May potentially help decrease AKI incidence after abdominal surgery without compromising pathogen clearance if sepsis where to develop.
