if currentID = 1 or currentID = 11 then%>
Watts, RA, Scott DG. Epidemiology of the vasculitides. Semin Respir Crit Care Med. 2004;25:455-464.
Nahar A, Akom M, Hanes D, Briglia A, Drachenberg CB, Weinman EJ. Pyelonephritis and acute renal failure. Am J Med Sci 2004;328:121-123.
Klenzak J, Himmelfarb J. Sepsis and the kidney. Crit Care Clin. 2005;21:211-222.
Wan L, Bellomo R, Di Giantomasso D, Ronco C. The pathogenesis of septic acute renal failure. Curr Opin Crit Care. 2003;9:496-502.
Ortiz A, Justo P, Sanz A, Lorz C, Efgido J. Targeting apoptosis in acute tubular injury. Biochem Pharmacol. 2003 Oct 15;66:1589-1594.
Sobel JD, Kaye D. Urinary Tract Infections. In: Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases – Fourth Edition, edited by Churchill Livingstone Inc., 1995: 662-690.
Majd M, Nussbaum Blask AR, Markle BM, Shalaby-Rana E, Pohl HG, Park JS, Chandra R, Rais-Bahrami K Pandya NPatel KM, Rushton HG. Acute Pyelonephritis: Comparison of Diagnosis with 99mTc-DMSA SPECT, Spiral CT, MR Imaging, and Power Doppler US in an Experimental Pig Model.Radiology; 2001;218:101-108.
Robert W. Schrier, M.D., and Wei Wang, M.D. Acute Renal Failure and Sepsis. NEJM 2004;351:159-169.
Goyette RE, Key NS, Ely EW. Haematologic changes in sepsis and their therapeutic implications. Semin Respir Crit Care Med. 2004;25:645-659.
Aird WC. The haematologic system as a marker of organ dysfunction in sepsis. Mayo Clin Proc. 2003;78:869–881.
Mavrommatis AC, Theodoridis T, Orfanidou A. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2000;28:451–457.
Warkentin TE Aird WC Rand JH. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Haematology (Am Soc Haematol Educ Program). 2003;:497-519.
Mayer SA, Aledort LM. Thrombotic microangiopathy: differential diagnosis, pathophysiology and therapeutic strategies. The Mount Sinai Journal of Medicine 2005;72:166-175.
Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, Tratchman H. Non-enteropathic hemolytic uraemic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43:976-982.
Pène F, Papo T, Brudy-Gulphe L, Cariou A, Piette JC, Vinsonne. Septic shock and thrombotic microangiopathy due to Mycobacterium tuberculosis in a non-immunocompromised patient. Arch Intern Med 2001;161:1347-1348.
Chand DH, Brady RC, Bissler JJ. Hemolytic uraemic syndrome in an adolescent with Fusobacterium necrophorum bacteraemia. Am J Kidney Dis. 2001;37:E22.
Mulder AH, Gerlag PG, Verhoef LH, van den Wall Bake AW. Hemolytic uremic syndrome after capnocytophaga canimorsus (DF-2) septicemia. Clin Nephrol. 2001;55:167-170.
Kanj NA, Mikati AR, Kfoury EM. Early relapse of thrombotic thrombocytopenic purpura during therapeutic plasma exchange associated with Acinetobacter anitratus bacteraemia. Ther Apher Dial. 2003;7:119-121.
Mayer SA, Aledort LM. Thrombotic microangiopathy: differential diagnosis, pathophysiology and therapeutic strategies. Mt Sinai J Med. 2005;72:166-175.
Brilliant SE, Lester PA, Ohno AK, Carlon MJ, Davis BJ, Cushner HM. Hemolytic-uraemic syndrome without evidence of microangiopathic haemolytic anemia on peripheral blood smear. South Med 1996;89: 342-345.
AB, an 84 year-old woman, body mass index 22 kg/mq, was submitted in September 1999 to hemicholectomy because of carcinoma of sigma; at that period renal function was normal (serum Creatinine -SCr- 0.6 mg/dl, GFR according to the MDRD formula 82 ml/min).
On the 13th of December 1999 she presented fever (38 °C) and right flank pain. On December 15th she was conducted to the Emergency Department: blood pressure was 130/80 mmHg, heart rate 95 beats/min, respiratory rate 18/min, Oxygen saturation 98%, temperature 39.5°C.
Laboratory investigations disclosed renal failure (SCr 4.8 mg/dl), haemoglobin 8 g/dl, leukocytosis (24400/mm3), thrombocytopenia (73000/mm3), increased LDH (1935 U/l), AST (95U/l) and ALT (93 U/l).
In the following days renal failure worsened (SCr 6.5 mg/dl) and the patient was admitted to our Department of Nephrology.
Physical examination was regular, except for positive Giordano sign at the right flank. Blood pressure was 170/90 mmHg.
Other examinations showed: SCr 7.4 mg/dl, K+ 6.2 mEq/l, Na+ 134 mEq/l, calcemia 7.5 mg/dl, haemoglobin 7.7 g/dl, platelets 40.000/mm3, leukocytes 24.000/mm3 (neutrophils 90%), INR 0.9, PTT 36”, D-Dimero 9.5 mcg/ml, ATIII 76%, total proteins 5 g/dl, albumin 1.9 g/dl, glucose 86 mg/dl, AST 132 U/l, ALT 52 U/l, alkaline phosphatase 186 U/l, gammaGT 38 U/l, LDH 900 U/l, CPK 43 U/l, bilirubin 0.9 mg/dl, C Reactive Protein -CRP- 36 mg/dl, haptoglobin 5 mg/dl (normal values 30-200 mg/dl). Schistocytes were absent.
No monoclonal component was evident in serum or urine.
In the urinary sediment 10-15 RBC/hmf, 8-10 WBC/hmf were found. Proteinuria was 1.2 g/24h, with an exclusive tubular pattern.
Ultrasound examination of the abdomen showed normal sized kidneys, hyperechogenic cortex, and small parapyelic cysts. In the left kidney a cortical hyperechogenic area with a diameter of 4 cm was detected. Liver, gall bladder, biliary ways, spleen, pancreas, aorta and bladder were regular.
Chest X-Ray did not reveal pathologic abnormalities.
Question 1) - Which diagnoses could be hypothesized?
(Only ONE answer is correct)
> a) Acute tubular necrosis
> b) Vasculitis or rapidly progressive glomerulonephritis
> c) Acute pyelonephritis
<%if currentID = 11 then%>
> d) Hemolytic-uraemic syndrome
if Answer1 = RightAnswer1 then
Answer to question n. 1 is right! "
Response.Write " Answer to question n. 1 is wrong! "
Response.Write " The right answer is the checked one! "
An infectious disease was suggested by fever, leukocytosis and elevated CRP. However, microscopic poliangiitis and crescentic glomerulonephritis could be an alternative hypothesis as they may have a similar presentation and the peak age of onset is from 65 to 74 years (1).
In this case, the most probable localization of the infection was the urinary tract, because of right flank pain, negative chest X-Ray and absence of other pathologic physical signs. Hyperechogenic areas at ultrasound examination are frequently found in acute pyelonephritis. Pyelonephritis is a focal disease, which is accompanied by renal failure only in anecdoctal cases (2). For this reason, a diffuse localization of the infection in the renal interstitium could be more likely.
Acute tubular necrosis can accompany severe infections. Its pathogenesis could be ischemic or toxic, but some studies point to the possibility that septic acute renal failure is more likely to be an immune condition in which apoptosis is a central mechanism (3,4,5).
Haemolytic-uraemic syndrome (HUS) could be hypothesized on the basis of the association of thrombocytopenia and anaemia, in spite of the absence of schistocytes. Haemolytic anaemia superimposed on anaemia secondary to renal failure could be suspected on the basis of elevated LDH and reduced haptoglobin. The patient’s age and the incomplete haematologic parameters made this hypothesis not convincing.
newID = 2
newID = 11
if currentID = 2 or currentID = 22 then%>
Urine culture was found to be positive for Enterococcus faecalis 106 cfu/ml.
The association of positive urine culture, fever and flank pain indicates that the patient was suffering from urinary tract infection. The patient complained of right flank pain whilst echographic examination showed a hyperechogenic area in the left kidney. However, it was not clear whether it was an acute pyelonephritis or an acute tubular interstitial nephritis due to bacteria infiltration.
Treatment with ceftriaxone 2 g/day had been started at admission. This antibiotic was replaced on the 5th day with amoxicillin-clavulanate based on an antibiogram.
Other examinations showed negative ANCA, HbsAntigen, HBs and HBc Antibodies, HCV and HIV. C4 and C3 were in the normal range, ANA and antiDNA were negative; cryoglobulins were absent.
A central vein catheter was positioned and dialysis was performed.
if currentID = 3 or currentID = 33then%>
if currentID = 4 or currentID = 44 then%>
This patient had moderate sepsis: body temperature was 39.5°C, heart rate 95 beats/min, leukocytes >12.000/mm3 and there was evidence of infection.
Question 4) - Can thrombocytopenia be justified by infection?
> a) Yes
<%if currentID = 44 then%>
> b) No
if Answer4 = RightAnswer4 then
Answer to question n. 4 is right! "
Response.Write " Answer to question n. 4 is wrong! "
Response.Write " The right answer is the checked one! "
“The most common abnormalities of the haematologic system in patients with sepsis are anaemia, leukocytosis, thrombocytopenia and activation of the haemostatic system. Dysfunction of the haematologic organ system is an early manifestation of severe sepsis and is seen in virtually all patients with this disease”(9).
Sepsis is a clear risk factor for thrombocytopenia, with an estimated incidence of 35%–59% (10).
There is an inverse relationship between the severity of sepsis and the platelet count (11). Hence, sepsis-associated thrombocytopenia is a surrogate marker for the severity of the host response.
Pathophysiology of thrombocytopenia is illustrated in the diagram in Fig. 3 (12). The monocyte/tissue macrophage binds lipopolysaccharide (or some other bacterial wall components), resulting in the activation of inflammatory and coagulation cascades. Once activated, these pathways communicate with one another to further amplify host response.
Figure 3. Schematic of the innate immune response.
LPS, lipopolysaccharide; TF, tissue factor; PAF, platelet activating factor; NO, nitric oxide; ROS, reactive oxygen species.
From Warkentin TE et al. Hematology (Am Soc Hematol Educ Program). 2003;:497-519 (12).
In sepsis, circulating platelets are surrounded by inflammatory mediators and activated coagulation factors. Once activated, platelets aggregate, provide a phospholipid-rich surface for coagulation complexes, and release mediators including proinflammatory molecules such as IL-1ß. In addition, platelets may generate procoagulant-rich microparticles, which contribute to a prothrombotic state (12). Finally, platelets interact with activated endothelial cells, resulting in an amplification of host response through positive feedback loops (12).
In the interaction with other cell types, platelets are sequestered at the level of the endothelium. Sequestered platelets may be irreversibly activated, destroyed, and/or prevented from returning to the circulating pool. Platelets may become entrapped by evolving fibrin clots (12).
Moreover, patients with sepsis may develop de novo ethylenediaminetetraacetic acid (EDTA)-dependent antibodies, which cause platelet clumping in the test tube. A subset of patients with platelet-associated antibodies has auto-antibodies directed against glycoprotein IIb/IIIa (12).
Moreover, the bone marrow of septic patients with thrombocytopenia may show hypocellularity with reduced numbers of megakaryocytes (12).
newID = 5
newID = 44
if currentID = 5 or currentID = 55 then%>
Therefore, in our patient we could suppose that thrombocytopenia was related to sepsis, but severe anaemia with elevated LDH and consumed haptoglobin, even in the absence of schistocytes, could alternatively suggest HUS. Moreover, diffuse bacterial interstitial infiltration and tubular damage secondary to sepsis could also be lesions responsible for renal failure.
if currentID = 6 or currentID = 66 then%>
In this patient, the main problem related to renal biopsy was thrombocytopenia and platelet dysfunction due to uraemia.
As platelets increased, secondary to an improvement of infection and repeated dialytic treatments, the patient could be submitted to renal biopsy.
The tissue obtained for histologic examination included 7 glomeruli. Two presented collapsed basement membranes. In the others, capillary lumina were dilated and they often contained thrombi. Some areas of fibrinoid necrosis were found. Endothelium was somewhere necrotic. Pre-glomerular arterioles were occluded by thrombi. Two crescents were evident. The interstitium was enlarged, oedematous and infiltrated by inflammatory cells. Tubuli showed haematic casts and some of them had necrotic epithelial cells (Fig. 4).
Fig. 4. Necrosis of tubules; one vessel has a fibrin thrombus; the glomeruli are congested.
The renal histologic examination showed thrombotic microangiopathy (TMA) together with tubular interstitial damage. Some areas of fibrinoid necrosis were found, capillary lumina were dilated and they often contained thrombi and the endothelium was necrotic. The interstitium was enlarged, oedematous and infiltrated by mononuclear inflammatory cells. Areas of tubular necrosis were probably secondary to sepsis.
In conclusion, this patient had TMA associated with acute tubular necrosis and no signs of direct interstitial bacterial infiltration.
TMA defines a microvascular alteration with detachment or swelling of the endothelium, amorphous material in the subendothelial space (13).
It can be idiopathic or due to known etiologic factors.
Etiologic factors can be:
-drugs (quinine, ticlopidine, clopidogrel, CyA, FK506, cisplatin, carboplatin)
-autoimmune diseases (SLE, ankylosing spondylitis, polyarteritis nodosa Sjogren, Graves disease, sclerodermia, polymyositis)
-bone marrow transplantation
-Shiga-toxins-producing E. coli
-idiopathic enzyme deficiency
The most prominent diseases associated with TMA are thrombotic thrombocytopenic purpura (TTP) and HUS.
The two thus far elucidated pathomechanisms leading to endothelial damage in HUS are inappropriate activation of complement system by deficient Factor H and toxin production by bacteria.
if currentID = 7 or currentID = 77 then%>
Question 7) - Is it possible to define the clinical condition of this patient as “HUS”?
> a) Yes
<%if currentID = 77 then%>
> b) No
if Answer7 = RightAnswer7 then
Answer to question n. 7 is right! "
Response.Write " Answer to question n. 7 is wrong! "
Response.Write " The right answer is the checked one! "
In this patient the etiologic agent was atypical for HUS. From a clinical point of view diagnosis of HUS was also doubtful, due to the absence of schistocytes.
This topic has already been discussed by Brilliant (20), who describes the case of a young man with histologically ascertained HUS without evidence of microangiopathic haemolytic anaemia by peripheral blood smear. Indirect evidence of haemolysis was suggested, as in our case, by LDH elevation and mild anaemia. This Author postulates that the inability to detect schistocytes could reflect a low degree of haemolysis. The same Author underlines that the observation that schistocytes are not always present in HUS has received little attention in the literature.
In spite of these speculations, it is difficult to know whether this histologic pattern was to be referred to HUS or whether it may represent aspecific lesions occurring in course of sepsis. Literature about renal involvement in course of sepsis does not report lesions like TMA, which could be due to the interaction between activated platelets and endothelium.
In conclusion, the patient was affected with severe urinary tract infection due to Enterococcus faecalis, which determined moderate sepsis. Infection was responsible for acute tubular necrosis and for thrombotic microangiopathy lesions where in a clinical context differentiation from HUS is difficult.
All clinical parameters improved and the patient was discharged after one month with improved renal function (SCr 2.7 mg/dl), normalization of infectious parameters, platelets and leukocytes.
newID = 8
newID = 77