Symposium. Acute Kidney Injury with Thrombocytopenia. Lalitha A V*, Suryanarayana G**, Sumithra S***

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1 Symposium Acute Kidney Injury with Thrombocytopenia / Lalitha A V*, Suryanarayana G**, Sumithra S*** *Associate Professor, Head,PICU **, Fellow in PICU, *** Assistant Professor, PICU, Division of Pediatric Critical care, St John s Medical college and Hospital Received: 20-Feb-18/Accepted: 10-Mar-18/Published online: 30-Apr-18 ABSTRACT Pediatric AKI presents with a wide range of clinical manifestations from a minimal elevation in serum creatinine to anuric renal failure, arises from multiple causes and occurs in a variety of clinical settings. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Thrombocytopenia is one of the most common laboratory findings in the ICU. The causes of acute kidney injury associated with thrombocytopenia are very few. This chapter gives an overview of etiology, incidence, diagnosis, conservative treatment, of various causes of AKI associated with thrombocytopenia in children beyond the newborn period in the context of advances made in this field. Key words: Renal Replacement Therapy, Thrombocytopenia, Intensive Care Units, Pediatric, Hemolytic-Uremic Syndrome Acute kidney injury (AKI) is a frequent complication in patients admitted to the intensive care unit (ICU) and is associated with high mortality rates, particularly when renal replacement therapy (RRT) is required. 1 Acute renal failure (ARF) is associated with adverse outcomes, especially in children admitted to the pediatric intensive care unit (PICU). 2 AKI is a syndrome comprising multiple clinical conditions, and outcomes are influenced by underlying disease. In a prospective obseravational study on clinical profile of acute kidney injury by Sriram Krishnamurthy et,al. they found the common etiologies were infections, (62.9%), acute glomerulonephritis (7.6%), snake envenomation (5.7%), hemolytic uremic syndrome (3.8%) and congestive cardiac failures (3.8%). 3 Thrombocytopenia is one of the most common laboratory findings in the ICU. In AKI, however, a low PC has been recognized as a prognostic marker. 4 Moreover, severe thrombocytopenia at the beginning of RRT has been associated with hospital mortality. 4 Sepsis-associated AKI (SA-AKI) is the most common cause of AKI with thrombocytopenia in critically ill patients and an independent predictor of morbidity and mortality. In this article we have discussed HUS and TTP as causes of AKI associated with thrombocytopenia. Correspondence: Lalitha A V, Associate Professor, Head, PICU St John s Medical college and Hospital, Bangalore Phone , drlalitha03@gmail.com Hemolytic uremic syndrome (HUS) Introduction - The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. 5 It is one of the main causes of acute kidney injury and thrombocytopenia in children. Classification - Traditionally, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. The former, also referred to as typical HUS, primarily resulted from Shiga toxin-producing Escherichia coli (STEC) infections, and less frequently from Shigella dysenteriae type 1 infection. All other causes of HUS were referred to as atypical HUS or assigned to the diarrhea-negative HUS. Clinical manifestations - After 3-8 days of incubation, the first symptom is watery diarrhea, followed by bloody diarrhea and abdominal cramps. Nausea and vomiting are also present. Fever is less commonly observed. The most important factors as- sociated with HUS evolution are the use of anti-motility agents, antibiotics, bloody diarrhea, leukocytosis, young age and female gender. Recovery is often spontaneous, but 26% of patients develop renal failure, with 3%-5% of deaths. 6,7 Hematological and renal symptoms, including hemolytic anemia, low platelet counts, fragmentocytes, increased lactate dehydrogenase (LDH) and very low haptoglobin levels and various degrees of renal failure may all be present. Other symptoms may arise due 42

2 to the involvement of other organs such as the brain, pancreas and myocardium. 8,9 Factors triggering vasular damage Shiga toxin Viruses Immunecomplex Drugs Figure 3:Pathogenesis of Thrombotic micoangiopathies Etiologies of HUS: Etiology identified HUS infectioninduced (1) Shiga and shiga-like toxin producing bacteria, Enterohemorrhagic Escherichia Coli, Shigella dysenteriae type 1 (2) Streptococcus pneumoniae HUS induced by disorders of complement regulation (1) Genetic (2) Acquired ADAMTS13 de ciency (1) Genetic (2) Acquired Defective cobalamin metabolism Endothelial cell damage Thrombotic microangiopathy Favoring factors C3 low levels Factor H reduced activity Anti Factor H autoantibodies Factor I reduced activity Reduced MCP vwf reduced activity Etiology unknown Malignancy, cancer chemotherapy, ionizing radiation Calcineurin inhibitors and transplantation Pregnancy, HELLP syndrome, contraceptive pill, Systemic lupus erythematosus, antiphospholipid antibody syndrome Glomerulopathy Drug induced Diagnosis - The diagnosis of hemolytic uremic syndrome (HUS) is clinically based on the presence of the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, The MAHA is established by a hemoglobin level less than 8 g/dl with a negative Coomb s test and a peripheral blood smear demonstrating a large number of schistocytes (up to 10 percent of red cells) and helmet cells Thrombocytopenia is characterized by a platelet count below 140,000/mm 3 and is usually approximately 40,000/mm 3. Despite the low platelet count, there is typically no purpura or active bleeding. The degree of thrombocytopenia is unrelated to the severity of renal dysfunction. Acute kidney injury - The severity of renal involvement ranges from hematuria and proteinuria to severe renal failure (usually identified by abnormally elevated serum creatinine and blood urea nitrogen [BUN] levels) and oligoanuria. Most patients have microscopic hematuria on urinalysis, although macroscopic hematuria may be observed. Development of Shiga-toxin-associated hemolytic uremic sydrome Pathogenetic steps Clinical Ingestion of Escherichia Colonization of the gut Coli through contaminated food or patient to patient transmission or transmission from animal to man Diarrhoea Local tissue damage Bloody diarrhoea Systemic toxinemia Generation of host cytokines Endothelia cell damage, and chemokines activation of local thrombosis in kidneys and in other organs. Renal involvement HUS Renal Insufficiency Damage to glomerular endothelial cells, arteriolar damage, mesangial cell activation/damage, podocyte injury, tubular damage Acute renal failure Chronic renal failure Arterial hypertension, proteinuria, hematuria Differential Diagnosis - The differential for hemolytic uremic syndrome (HUS) includes several conditions that may also present with concomitant findings of anemia, thrombocytopenia, and acute kidney injury. Disseminated intravascular coagulation (DIC) is distinguished from HUS by the presence of abnormal coagulation studies, including prolonged prothrombin time and activated partial thromboplastin time, and elevated levels of fibrin degradation products and D-dimer. In general, DIC occurs in pediatric patients who are seriously ill, such as those in septic shock or who have undergone massive tissue injury or breakdown. 43

3 Thrombotic thrombocytopenic purpura (TTP) - described below Systemic vasculitis - Patients with vasculitis typically have other systemic symptoms (such as arthralgias and rash) and do not have a prodromal diarrheal illness. Treatment Overview - The initial management of hemolytic uremic syndrome (HUS) is supportive. The approach is as follows: Red blood cell transfusions for anemia when clinically indicated (eg, hemoglobin level reaches 6 to 7 g/dl or hematocrit <18 percent). Platelet transfusion for patients who have significant clinical bleeding. Appropriate fluid and electrolyte management to maintain adequate intravascular volume and correct/avoid electrolyte abnormalities. Stopping nephrotoxic drugs or those that are implicated in the etiology of HUS. Initiation of dialysis therapy in patients with symptomatic uremia, azotemia,severe fluid overload, or electrolyte abnormality that is refractory to medical therapy. Provision of adequate nutrition. The use of other interventions is dependent on the underlying cause of HUS. Thrombotic thrombocytopenic purpura (TTP) It is a thrombotic microangiopathy (TMA) similar to HUS, is a rare but life-threatening disease in children, characterized by MAHA, and organ involvement. 10,11 The brain, heart, and kidneys are likely to be affected 12 and intensive care unit (ICU) management is often required to manage organ dysfunction. The basic pathology in TTP is the widespread formation of von Willebrand factor (vwf)-rich platelet thrombi in the microcirculation leading to multiorgan ischemia (causing renal and/or neurological dysfunction), MHA, and thrombocytopenia. 13 Summary of differential diagnosis of AKI with thrombocytopenia: Clinical findings Important laboratory values Urinary findings Sepsis Systemic inflammatory response syndrome C-reactive protein, procalcitonin, leukocytosis Uric acid (Leukocyturia) Thrombotic microangiopathy TTP STEC-HUS ahus neurologic symptoms, bleeding signs diarrhoea, bleeding signs, renal failure bleeding signs, renal failure Thrombopenia Hb, haptoglobin, LDH, ADAMTS13 activity Thrombopenia, Hb, haptoglobin, LDH, Shiga toxin in stool Thrombopenia, Hb, haptoglobin, LDH, complement abnormalities Systemic autoimmune diseases ANCA vasculitis Systemic lupus erythematosus IgA vasculitis IgA Vasculitis arthralgia, purpura, sinusitis, epistaxis, haemoptysis arthralgia, (butterfly) rash, alopecia, oral ulcerations arthralgia, abdominal pain, purpura,bloody stool Inflammation, ANCA, anti- PR3/-MPO Inflammation, leukopenia, thrombopenia, C3, C4, ANA, anti-dsdna Inflammation Glomerular erythrocyturia, proteinuria 44

4 Clinical Feature The historical clinical pentad of fever, thrombocytopenia, MHA, neurological symptoms (range from headache and confusion to stroke, coma, and seizures), and renal insufficiency that used to define TTP appears obsolete, as several cohort studies have clearly demonstrated that these 5 symptoms were present in less than 10% of patients with an acute TTP. 14 Renal involvement - Proteinuria and hematuria are common in TTP. In contrast, acute renal failure with marked azotemia, fluid overload, hypertension, and need of dialysis, is much less common. 15 Microangiopathic Hemolytic Anemia (MAHA) is a major diagnostic criterion for TTP and it is defined by the presence of schistocytes in the peripheral smear along with evidence of hemolysis. More than 1% schistocytes, in the absence of other causes of thrombotic angiopathies, is highly suggestive of TTP- HUS The measurement of ADAMTS 13 is necessary in the work up for TTP but it is not a diagnostic criterion because the levels may be normal in many patients that otherwise have all the features of TTP. 11 Treatment The cornerstone of TTP therapy is PE(Plasma Exchange), which has reduced the mortality in TTP from 90 % to <10%. High-dose plasma infusion may be an alternative treatment for TTP in patients who cannot have early PE with the caveat that large volumes of plasma may result in fluid overload. 16 Rituximab, corticosteroids, and splenectomy are reserved for refractory cases. Conclusions: Acute kidney injury (AKI) is characterized by the abrupt failure of the kidneys to regulate water and electrolyte homeostasis. AKI with thrombocytopenia often in critically ill children usually associated with SA-AKI, HUS and rarely TTP. Early recognition and appropriate intervention will help early recovery and reduces progression to chronic renal failure. Source of Funding - Nil Conflict of Interest - Nil References: 1. Metnitz PGH, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30(9): Cerdá J, Bagga A, Kher V, Chakravarthi RM. The contrasting characteristics of acute kidney injury in developed and developing countries. Nat Clin Pract Nephrol 2008 ;4(3): Krishnamurthy S, Narayanan P, Prabha S, Mondal N, Mahadevan S, Biswal N, et al. Clinical profile of acute kidney injury in a pediatric intensive care unit from Southern India: A prospective observational study. Indian J Crit Care Med Peer- Rev Off Publ Indian Soc Crit Care Med 2013;17(4): Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM. Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 1995;155(14): Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol JASN 2005;16(4): Ahn CK, Klein E, Tarr PI. Isolation of patients acutely infected with Escherichia coli O157:H7: low-tech, highly effective prevention of hemolytic uremic syndrome. Clin Infect Dis Off Publ Infect Dis Soc Am 2008;46(8): Verweyen HM, Karch H, Brandis M, Zimmerhackl LB. Enterohemorrhagic Escherichia coli infections: following transmission routes. Pediatr Nephrol Berl Ger 2000 ;14(1): Richardson SE, Karmali MA, Becker LE, Smith CR. The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections. Hum Pathol 1988;19(9): Siegler RL. Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr 1994;125(4): Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998;339(22): Tsai H-M. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost 2003;1(4): Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347(8): George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006;354(18): Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008;142(5): Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during Intern Med Tokyo Jpn 45

5 2010;49(1): Coppo P, Bussel A, Charrier S, Adrie C, Galicier L, Boulanger E, et al. High-dose plasma infusion versus plasma exchange as early treatment of thrombotic thrombocytopenic purpura/ hemolytic-uremic syndrome. Medicine (Baltimore) 2003;82(1): How to cite this article: Lalitha AV, Suryanarayana G, Sumithra S. Acute Kidney Injury with Thrombocytopenia. J Pediatr Crit Care 2018;5(2): How to cite this URL: Lalitha AV, Suryanarayana G, Sumithra S. Acute Kidney Injury with Thrombocytopenia. J Pediatr Crit Care 2018;5(2): Available from: 46