Caribbean Institute of Nephrology CIN 10 th Annual

Caribbean Institute of Nephrology (CIN) 10 th Annual Conference on Nephrology & Hypertension At the Knutsford Court hotel in New Kingston, Kingston Jamaica on the 19 th and 20 th of January 2018. Avoid acute kidney attack! Stop Chronic Kidney Disease

10 th Annual Conference on Nephrology & Hypertension Acute Kidney Injury in Global Disasters Lawrence Agodoa, M. D. , F. A. C. P. Director, Chronic Kidney Disease and End Stage Renal Disease Programs Director, Office of Minority Health Research Coordination National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health 2 Democracy, Suite 9221 A 6707 Democracy Boulevard Bethesda, Maryland 20892 -5454

10 th Annual Conference on Nephrology & Hypertension Acute Kidney Injury in Global Disasters Lawrence Agodoa, M. D. , F. A. C. P. Disclaimer: I have been employed by the National Institutes of Health. However, with the US government shut down, I am currently furloughed. Therefore, for my presentation today, I am not representing the US government

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS OUTLINE Introduction Types of World Disasters reviewed in this presentation include: Earthquakes Crush Injuries: Rhabdomyolysis Burn Injuries Hurricanes, Tsunamis Crush Injuries Infectious Outbreaks Ebola Virus Disease HIV Epidemics Summary and Conclusion

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INTRODUCTION Natural and man-made disasters seem to have become more frequent as the world population increases and more people become exposed. Because of the magnitude of the number of people impacted with each occurrence, local resources are quickly overwhelmed and external help becomes necessary. A large number of exposed individuals die immediately, but a significant number suffer acute injuries, such as AKI, that may ultimately lead to chronic diseases,

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INTRODUCTION Non-nephrological Acute – Traumatic serious penetrating or blunt trauma to skull, chest, abdomen – leading to bleeding/hypovolemic shock, lacerations, fractures, freezing, burning, etc. Non-traumatic injuries, including increased incidence of acute myocardial infarction, hypertensive crises, diabetic ketoacidosis, asthma attacks, infections, diarrhea, dehydration, PTSD, and other psychiatric problems become prominent Effect on Pre-existing medical problems: diabetes, hypertension, chronic obstructive pulmonary disease, cancer, psychiatric and neurological disorders become magnified.

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INTRODUCTION Nephrological Acutely – Traumatic: crush syndrome, ischemic ATN, hypotension and shock, laceration in the GU system with/without obstruction Non-traumatic: AKI due to nephrotoxicity of antibiotics, contrast agents, NSAIDs, transfusions, infections, and sepsis. Problems in the treatment of existing kidney disease– predialysis CKD, patients on hemodialysis, peritoneal dialysis, and those with renal transplants also need special care in the acute phase of the disaster.

Acute Kidney Injury in Global Disasters EARTHQUAKES • Deadliest Earthquakes from 1900 to present: (from the US Geological Survey) • • • January 12, 2010 - Haiti - 316, 000 killed (magnitude 7. 0). July 27, 1976 - Tangshan, China - 242, 769 killed (7. 5) December 26, 2004 - Sumatra, Indonesia - 227, 898 killed in quake and resulting tsunami (9. 1) December 16, 1920 - Haiyuan, China - 200, 000 killed (7. 8) September 1, 1923 - Kanto, Japan - 142, 800 killed (7. 9) October 5, 1948 - Ashgabat, Turkmenistan - 110, 000 killed (7. 3) May 12, 2008 - Eastern Sichuan, China - 87, 587 killed (7. 9) October 8, 2005 - Pakistan - 86, 000 (7. 6) December 28, 1908 - Messina, Italy - 72, 000 (7. 2) May 31, 1970 - Chimbote, Peru - 70, 000 killed (7. 9) June 20, 1990 - Rasht-Qazvin-Zanjan, Iran - 50, 000 killed (7. 4) March 11, 2011 - A 9. 1 -magnitude earthquake strikes near the east coast of Honshu, Japan. The quake's epicenter was 231 miles away from Tokyo. The total of confirmed deaths and missing was over 22, 000.

Acute Kidney Injury in Global Disasters EARTHQUAKES • Falling objects, including buildings, may lead to immediate death by trauma to the vital organs. However, the crush syndrome is the second most common cause of death in survivors. • The crush syndrome occurs from rapid dissolution of damaged or injured skeletal muscle. The disruption of skeletal muscle integrity (rhabdomyolysis) leads to the release of intracellular muscle components, including myoglobin, creatine kinase (CK), aldolase, and lactate dehydrogenase, as well as electrolytes into the blood stream and extracellular space. The crush syndrome includes extreme elevations in CK, electrolyte imbalances, acute renal failure (ARF), and disseminated intravascular coagulation (DIC).

Mechanism of Rhabdomyolysis (Patrick Torres et al: Ochsner J, 2015 15: 58 -69) ATP = adenosine triphosphate; ATPase = adenosine triphosphatase; DNA = deoxyrobonucleic acid; PLA = polylactic acid; ROS = reactive oxygen species. 1. During normal muscle physiology at rest, ion channels (including N+/K+ pumps and Na+/Ca 2+ exchangers located on the plasma membrane maintain low intracellular Na+ and Ca 2+ concentrations and high K+ concentrations within the muscle fiber. 2. When muscle injury or ATP depletion occurs, the result is an excessive intracellular influx of Na+ and Ca 2+. 3. The increase in the intracellular Na+ draws water into the cell and disrupts the integrity of the intracellular space. 4. The prolonged presence of high Ca 2+ levels intracellularly leads to a sustained myofibrillar contraction that further depletes ATP, and also activates Ca 2+-dependent proteases and phospholipases, promoting lysis of the cellular membrane as well as further damage to the ion channels. 5. The end result of these alterations within the muscle cell milieu is an inflammatory, self-sustaining myolytic cascade that causes necrosis of the muscle fibers and release of the muscle contents into the extracellular space and into the bloodstream. The figure illustrates this process, showing how a wide array of insults can ultimately coalesce upon a final common effector pathway to initiate the rhabdomyolysis cascade.

Acute Kidney Injury in Global Disasters BURN INJURIES Burn injuries can result from: • Earthquakes • Arsons • War

Acute Kidney Injury in Global Disasters: AKI in Critically Burned Patients Study Authors N Mean % TBSA Mean Age, yrs. Sanchez-Sanchez 2016 184 30 49 Béchir 2010 HES group 16 40 Béchir 2010 Control 14 Béchir 2013 HES group Béchir 2013 Control Chung 2012 AKI (RIFLE) RRT Resuscitation Protocol 21% 9. 1% Low dose HES 49 25% HES 200/0. 5/10% 37 35 7. 1% 23 31 49 26% 22 32 47 27. 3 1973 16 36 Chung 2012 > 20 % Noshad 2013 100 Lopes 2007 126 Palmieri 2010 60 36% Mosier 2010 221 42 Brusselaers rev 2010 2111 25% (33% AKIN criteria) 62% (77% AKIN criteria 45 76% 36% Parkland 43 32% Parkland 40 49% 11. 2 18. 4 – 47, 4 3. 2% Crystalloid (RIFLE = Risk, Injury, Failure, Loss End-stage Kidney; AKIN = Acute Kidney Injury Network; HES = Hydroxyethyl Starch; Parkland – crystalloid followed by colloids) 1. AKI is a common complication in burn patients, but the exact incidence seems to vary from study to study. 2. AKI is higher in patients with TBSA burn > 20%. 3. The use of the AKIN criteria usually shows a higher incidence of AKI than using the RIFLE. 4. AKI is associated with increasing age, TBSA burned, need for mechanical ventilation and need for vasopressors 5. The type of resuscitation protocol used seems to influence AKI outcome. 6. The use of low dose hydroxyethyl starch (HES), a relatively inexpensive alternative to human albumin in correcting hypovolemia, does not seem to adversely affect the outcome of AKI. 7. The presence of DM, HTN, heart failure, or the etiology of burn do not seem to increase the incidence of AKI.

Acute Kidney Injury in Global Disasters HURICANES 1. Hurricane is a storm in which winds attain speeds greater than 74 mi (119 km) per hr. Wind speeds gust over 200 mi (320 km) per hour in some hurricanes. The term is often restricted to those storms occurring over the N Atlantic Ocean; the identical phenomenon occurring over the W Pacific Ocean is called a typhoon; around Australia and over the Indian Ocean it is referred to as tropical cyclone. Hurricanes have a life span of 1 to 30 days. 2. The Saffir-Simpson scale is the standard scale for rating the severity of a hurricane as measured by the damage it causes. It classifies hurricanes on a hierarchy from category 1 (minimal), through category 2 (moderate), category 3 (extensive), and category 4 (extreme), to category 5 (catastrophic). A super typhoon is equivalent to a category 4 or 5 hurricane. 3. Only three category-5 storms have hit the United States since record-keeping began—the 1935 Labor Day hurricane, which devastated the Florida Keys, killing 600; Hurricane Camille in 1969, which ravaged the Mississippi coast, killing 256; and Andrew in 1992, which leveled much of Homestead, Fla. The deadliest U. S. hurricane was the 1900 Galveston storm, which killed 8, 000– 12, 000 people and destroyed the city. Hurricane Katrina (2005), one of the worst natural disasters in U. S. history, was economically the most destructive U. S. storm, devastating the SW Mississippi and SE Louisiana coasts, flooding New Orleans, killing some 1, 200 people, and leaving hundreds of thousands homeless. 4. Hurricane Katrina in 2005 was a category-5 storm at peak intensity over the central Caribbean, Mitch in 1998 was a category-5 storm at its peak over the W Caribbean, and Gilbert in 1988 was a category-5 storm at its peak. Gilbert was the strongest Atlantic storm of record until Wilma in 2005, which, at its peak over the W Caribbean, was a category-5 storm. 5. The 1970 Bay of Bengal tropical cyclone killed some 300, 000 persons, mainly by drowning, and devastated Chittagong (now Bangladesh); some 130, 000 died when the cyclone struck Myanmar along the Andaman Sea in 2008. High winds are a primary cause of hurricane-inflicted loss of life and property damage. Another cause is the flooding resulting from the coastal storm surge of the ocean and the torrential rains, both of which accompany the storm. Most deaths from hurricanes are from drowning. The Crush Syndrome is responsible for AKI following hurricanes/cyclones/typhoons.

Acute Kidney Injury in Global Disasters TSUNAMI 1. A tsunami is a series of ocean waves that sends surges of water, sometimes reaching heights of over 100 feet (30. 5 meters), onto land. These walls of water can cause widespread destruction when they crash ashore. 2. Most tsunamis–about 80 percent–happen within the Pacific Ocean’s “Ring of Fire, ” a geologically active area where tectonic shifts make volcanoes and earthquakes common. [The Ring of Fire is an arc of mountains, volcanoes, and oceanic trenches that stretch from New Zealand northward along the eastern edge of Asia, then east across the Aleutian Islands of Alaska, and then south along the western coasts of North and South America. ] 3. Tsunamis race across the sea at up to 500 miles (805 kilometers) an hour—about as fast as a jet airplane. At that pace, they can cross the entire expanse of the Pacific Ocean in less than a day. And their long wavelengths mean they lose very little energy along the way. Most deaths occur from drowning. AKI results from the Crush Syndrome.

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INFECTIOUS OUTBREAKS

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INFECTIOUS OUTBREAKS I. EBOLA VIRUS DISEASE

Historical Context of Ebola Virus Disease (CDC) • The Ebola and Marburg viruses are the sole members of the Filoviridae family of viruses. They are characterized by a long filamentous form that is unique in the viral world. Filoviruses are among the most virulent pathogens currently known to infect humans. They cause fulminating disease characterized by acute fever followed by generalized hemorrhagic syndrome that is associated with up to 90% mortality in the most severe forms. • Since their discovery in 1967 (Marburg) and 1976 (Ebola), thousands of cases and deaths have been reported. Ebola viruses are found in several African countries. Ebola first emerged in 1976 as the causative agent of two simultaneous outbreaks in southern Sudan and northern Zaire near the Ebola River in what is now the Democratic Republic of the Congo. Since then, outbreaks have appeared sporadically in Africa. • Ebola virus (family Filoviridae, genus Ebolavirus) comprises five identified Ebola virus species, four of which are known to cause disease in humans: Ebola virus (Zaire ebolavirus); Sudan virus (Sudan ebolavirus); Taï Forest virus (Taï Forest ebolavirus, formerly Côte d’Ivoire ebolavirus); and Bundibugyo virus (Bundibugyo ebolavirus). The fifth, Reston virus (Reston ebolavirus), has caused disease in nonhuman primates, but not in humans. • The natural reservoir host of Ebola virus remains unknown. However, on the basis of evidence and the nature of similar viruses, researchers believe that the virus is animal-borne and that bats are the most likely reservoir. • Four of the five virus strains occur in an animal host native to Africa.

MAP OF EBOLA OUTBREAKS 1976 -2014 (CDC)

Transmission of Ebola virus • The virus is thought to be initially acquired by exposure to body fluids or tissue from infected animals, such as bats and non-human primates; however, the natural reservoir and mode of transmission to humans has not been confirmed. • Animal to human transmission may occur during hunting and consumption of the reservoir species or infected non-human primates. • The practice of butchering or eating bush meat or food contaminated with bat feces (three species of tree roosting bats have been implicated as a reservoir) is also thought to contribute. • Most cases of human to human transmission result from direct physical contact or contact with body fluids (such as sweat, blood, feces, vomit, saliva, genital secretions, urine, and breast milk) of infected patients through broken skin or mucus membranes. • A person infected with Ebola is not contagious until symptoms appear • Infection through inhalation is possible in non-human primates but there is no evidence for airborne transmission in humans.

Acute Kidney Injury in EVD

ACUTE KIDNEY INJURY IN EBOLA VIRUS DISEASE Frequency – It is a common complication in patients with severe Ebola infection. It is usually accompanied by severe volume depletion, severe metabolic acidosis, profound electrolyte derangement, shock and multi-organ failure, including respiratory failure and liver failure. In the West Africa epidemic, the severity of acute kidney injury has a positive correlation with mortality.

ACUTE KIDNEY INJURY IN GLOBAL DISASTERS INFECTIOUS OUTBREAKS II. HIV EPIDEMICS

Acute Kidney Injury in Global Disasters II. HIV EPIDEMICS • Approximately 36. 7 million people live with HIV infection worldwide. In 2015, 2. 1 million cases were incident. 75% of HIV-infected persons live in Sub. Saharan Africa. • Although 18. 2 million people worldwide were receiving antiretroviral therapy by 2016, only 40% of HIV-infected persons in Sub-Saharan Africa received antiretroviral therapy as of 2014. • Kidney Disease is a common complication of HIV infection and its treatment.

HIV infection and Kidney Disease (Cohen SD et al; NEJM 377; 24: 2363 -2374) Acute Kidney Injury Chronic kidney disease Prerenal azotemia Acute tubular necrosis Rhabdomyolysis Antiretroviral therapy–associated acute kidney injury • Tubulointerstitial nephritis Immune reconstitution syndrome • HIV-associated nephropathy • HIV immune-complex kidney disease Ig. A nephropathy Post-infectious glomerulonephritis Mesangial proliferative glomerulonephritis Lupus-like glomerulonephritis Membranoproliferative glomerulonephritis Cryoglobulinemic glomerulonephritis Other glomerulonephridites • Thrombotic microangiopathies • Urinary tract obstruction Bladder outlet obstruction Ureteral obstruction Intrinsic: fungus balls, blood clots • • • Extrinsic: retroperitoneal fibrosis, lymphadenopathy • HIV-associated nephropathy HIV immune-complex kidney disease Antiretroviral therapy– associated chronic kidney disease Tubulointerstitial nephritis Crystal nephropathy Tenofovir disoproxil fumarate-induced nephrotoxicity • Tubulointerstitial renal disease Diffuse infiltrative lymphocytosis syndrome Opportunistic infections of the kidney parenchyma • Viral infections Cytomegalovirus Parvovirus Herpes simplex Other infections • • • Fungal infections Mycobacterial infections, typical and atypical Mycoplasma Microsporidia Bacterial pyelonephritis Infiltrative lesions of the kidney • • Lymphoma Kaposi’s sarcoma

Pathogenesis of HIV-Associated Nephropathy. • Host factors • Genetics – APOL 1 variants • Other possible factors • Pathogen characteristics Environmental and behavioral factors • • • Nephrotoxins Coinfections Nutrition • • Access and adherence to combination antiretroviral therapy • Increased likelihood of HIV-associated nephropathy Decreased likelihood of HIV-associated nephropathy The pathogenesis of HIV-associated nephropathy involves the complex interaction of host and environmental factors, pathogen characteristics, and patient access to antiretroviral therapy. HIV-associated nephropathy is unique in that treatment plays a key role in mediating expression of nephropathy. Increased APOL 1 gene expression, stimulated by interferon, may be sufficient to induce glomerulopathy. Additional factors may synergize with APOL 1 variants, in which case APOL 1 variants could be seen as susceptibility factors. Other factors, such as environmental factors, coinfections, coexisting medical illnesses, or treatment effects influence development and sustained kidney damage. APOL 1 variants probably damage podocytes and other renal cells. Although injury mechanisms are not well understood, evidence points to alterations in ion flux across the plasma membrane; altered endo-lysosomal, mitochondrial, and autophagic function; and increased cellular inflammatory pathways, including activation of protein kinase R and effects of interferon as key pathogenic factors.

Acute Kidney Injury in Global Disasters Summary and Conclusion • Many new AKI patients emerge after global disasters. In addition, predialysis CKD patients, those on dialysis, and kidney transplants patients suffer from serious problems which can ultimately affect their survival. • Support from national and international organizations is necessary for the local responders to be able to handle affected individuals.