Thrombotic microangiopathy with hypertension and acute renal failure in children (a typical hemolytic uremic syndrome).
All India Institute of Medical Sciences, New Delhi., India
U N Bhuyan
All India Institute of Medical Sciences, New Delhi.
Thus I would like to conclude by saying that an idiopathic form of obliterative renal arteriopathy account for the rare presentation of severe hypertension and progressive renal failure with or without overt hemolytic anemia and thrombocytopenia in children. It can be labelled as primary malignant nephrosclerosis (NScl) or atypical HUS, based on primary thrombotic angiopathy. This, essentially intimal changes, is seen in diverse conditions and appears to result from primary endothelial injury followed by intimal exudation, thrombosis, and repair by fibrosis. Persistent or recurrence of this process form the basis of progressive obliterative arteriopathy. The result is renal ischemia and renin-angiotensin mediated hypertension. Establishment of a vicious circle would further accelerate HT and lead to end stage renal failure. Early recognition and prompt therapeutic intervention might prove beneficial.
|How to cite this article:|
Bhuyan U N. Thrombotic microangiopathy with hypertension and acute renal failure in children (a typical hemolytic uremic syndrome). J Postgrad Med 1994;40:120-2
|How to cite this URL:|
Bhuyan U N. Thrombotic microangiopathy with hypertension and acute renal failure in children (a typical hemolytic uremic syndrome). J Postgrad Med [serial online] 1994 [cited 2023 Sep 21 ];40:120-2
Available from: https://www.jpgmonline.com/text.asp?1994/40/3/120/545
Acute renal failure is quite common in children. Its cause is well elicited in the majority and can be treated effectively. This is particularly true of frequently occurring prerenal and infrequently observed post renal failure. Prerenal ARF is haemodynamically mediated and is due to functional failure following "renal shut down". Post-renal ARF is also functional failure in the early stages due to urinary tract obstruction. Both are rapidly reversible on appropriate therapy. On the other hand, renal failure, which is associated with structural renal damage, shows a very variable response to therapy. Some respond favorably, others remain refractory. The last group, which forms a very small proportion of refractory ARF in childhood, poses formidable problems in diagnosis and management. Here I shall discuss our observations in 13 such children who had presented with severe ARF, accelerated hypertension (HT) and appeared distinct from the usual cases of ischemic ARF. They formed 5% of a total of 265 cases of ARF seen during the last decade at the AlIMS.
The ARF was of insidious onset, of prolonged duration, 0.3 3.0 months, not preceded by diarrhoeal or respiratory symptoms. The HT was very marked and associated with papilloedema in 8 patients. Other features included mild to moderate fever, seizure, bleeding, anemia, thrombocytopenia, reticulocytosis, raised fibrin degradation products (FDP), marked proteinuria (PU) and gross hematuria (HU) in about 1/3 of the children. A tentative diagnosis of atypical hemolytic uremic syndrome (HUS) was made in 4. It was uncertain in others. The following differential diagnoses were entertained Rapidly Progressive (Crescentic) GN, Malignant Nephroselerosis (NSci), Atypical Hemolytic Uremic Syndrome (HUS, Thrombonecrotic Polyarteritis (PAN), Acute Cortical Necrosis (ACN).
Renal biopsies were performed during the ARF period (17 94 days). These were processed for light, immunofluorescent and electron microscopic assessment. Histologically, crescentic GN was excluded in all cases. Only in 2, < 10% glomeruli revealed segmental cellular crescents. In the majority, they showed variable shrinkage, congestion and/or segmental necrosts. In 5 biopsies, features of mixed thrombotic microangiopathy (TMA) affecting glomeruli and arteries were seen. In the glomeruli, endothelial swelling, fibrillar mesangium, luminal thrombosis and mural splitting were observed. Focal acute tubular ne crosis (ATN) was seen but ACN was not observed. In 8 patients, the most striking changes were seen in the inteflobular arteries and arterioles, which looked like choked pipes with very marked intimal thickening and luminal stenosis. In addition, fresh thrombi in the lumen and fibrinoid necrosis of the wall were seen without appreciable inflammatory reaction. This was what could be termed as obliterative or occlusive TMA. IF did not reveal significant immunoglobulin or complement deposits, but the arterioles and glomeruli stained intensely for fibrin. EM revealed endothelial degeneration and subendothelial electron lucent deposits in the glomeruli.
Similar changes along with medial necrosis were seen in arteries and arterioles. The patients were managed with standard supportive measures and received fresh blood transfusion, anti hypertensive drugs and/or peritoneal or haemodialysis when indicated. No anticoagulant was administered. No plasma exchange was performed. They were followed for 2 months to 6 years. Three prognostic categories were observed.
Death or end stage renal failure was seen within 18 months in 5 with arterial TMA and 3 with mixed TMA accounting for 70% of all cases. Persistent proteinuria and HT was seen in 1 each with arterial TMA.
A rebiopsy done after 4 years of persistent HT, showed marked arterial and glomerular sclerosis along with moderate tubular atrophy and fibrosis. Renal recovery was observed in 23 months in 2 with mixed TMA.
I have presented a clinicopathologic analysis of primary thrombotic arteriopathy manifesting as primary malignant nephroscierosis and ARF without apparent hemolysis and thrombocytopenia and a high mortality (70%). This can be labelled as enteritis negative or atypical HUS observed in older children and adults. A poor prognosis with arterial TMA, in contrast to glomerular TMA has already been reported in the literature. Such obliterative arteriopathic changes have been observed in diverse conditions e.g, infections, various drugs, systemic lupus erythematosus, systemic vasculitis, systemic sclerosis, radiation injury, allograft rejection, malignant neoplasia and essential and secondary hypertension e.g. glomerulonephritis and interstitial nephritis and familial and idiopathic HUS. This is essentially a diffuse intimal disease of medium sized muscular arteries, comparable to localized atherosclerosis in large elastic arteries. It points towards a unifying mechanism in the evolution and progression of obliterative arteriopathy.
The most obvious starting point or the first step appears to be endothelial injury by diverse mechanisms e.g. cytopathic, immunologic, pressure, hypoxia and / or intrinsic cellular defect. Any of these singly or in combination may be operative in a subclinical or covert manner in idiopathic cases. Endothelial injury is associated with increased procoagulant activity. This result in the next important step in pathogenesis e.g. exudation of plasma including fibrin and broken erythrocytes into intima and mural thrombosis which eventually get incorporated into the intima. The third inevitable step is intimal repair. Myointimal cells, essentially muscle cells, migrate from media to intima, proliferate and produce mucin and fibres sequentially. This is facilitated by cytokines and growth factors liberated by endothelial calls. The intima looks thickened with mucinous edema initially. This is followed by "onion skin" cellular proliferation and finally production of fibrosis/fibroelastosis.
Persistence or recurrence of endothelial injury thrombosis and intimal fibrosis lead to progressive obliterative arteriopathy. After a certain critical stage is attained e,g. more than 70% luminal stenosis, renal ischemia would ensue comparable to myocardial ischemia in obliterative coronary angioscierosis. Renal ischemia would in turn start off a vicious circle by way of increased reninangiotensin production, accelerated HT and progressive renal failure. Early recognition and breakdown of this vicious mechanism by prompt therapeutic intervention, including plasma exchange, might prove very helpful. It is possible that in the patients 1 presented, mild diarrhoeal episodes could have been overlooked and progressive obliterative arteriopathy would have developed slowly and insidiously and finally accelerated by angiotensin mediated vasospasm and vasoocclusion. But these are at best reasonable guesses and the truth must be established from further factual observations.
Thus I would like to conclude by saying that, an idiopathic form of obliterative renal arteriopathy account for the rare presentation of severe hypertension and progressive renal failure with or without overt hemolytic anernia and thrombocytopenia in children. It can be labelled as primary malignant nephrosclerosis (NScl) or atypical HUS, based on primary thrombotic angiopathy. This essentially intimal changes, is seen in diverse conditions and appears to result from primary endothelial injury followed by intimal exudation, thrombosis, and repair by fibrosis. Persistent or recurrence of this process, form the basis of progressive obliterative arteriopathy. The result is renal ischemia and reninangiotensin mediated hypertension. Establishment of a vicious circle would further accelerate HT and lead to end stage renal failure. Early recognition and prompt therapeutic intervention might prove beneficial.
Moschehowiltz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: An undescribed disease. Arch IntMed l 925; 36:8993.|
|2||Symmers WSt C. Thrombotic microangiopathic hemolytic anemia (TMA). Br Med J 1952; 2:897903.|
|3||Gasser C. HUS. SchweizMed Woschenschr 1955; 85:905909.|
|4||Habib R, Mathieu H, Royer P. Le syndrome hemolytique et uremique de Penfant. Nephron 1967; 4:139172.|
|5||Robson JS. Irreversible postpartum renal failure Quart J Med 1968; 37:423.|
|6||Linton AL. Microangiopathic hemolytic anemia and the pathogenesis of malignant hypertension. Lancet 1969; 1:12771282.|
|7||Vitsky B. The HUS. Am J Path 1969; 57:627.|
|8||Hammond D, Liberman E. The HUS. Renal cortical thrombotic microangiopathy. Arch Int Med 1970; 126:816-822.|
|9||Rielle MC. Renal Microangiopathy of the HUS in childhood. Nephron 1976; 17:188203.|
|10||Sinclair RA, Antonovych TT. Mostofi PK. Renal pioliferative arteriopathies and associated giomerular changes. Human Path 1976; 7:565588.|
|11||Bohle A. Malignant Nephrosclerosis in patients with HUS Curr Top Path 1977; 65:81113.|
|12||MorelMaroger L. Prognostic importance of vascular lesions in ARF with microangiopathichaemolytic anemia. Kidney Int, 1979; 15:548558.|
|13||Segonds N. Postpartum HUS: A study of 3 cases with a review of literature. Clin Nephrol 1979; 12:229-242|
|14||Fong JS. HUS: current concepts and management. Ped Clin NA 1982; 29:835856.|
|15||Trompeter RS. HUS: an analysis of prognos tie features. Arch Dis Child 1983; 58:101105.|
|16||Kaplan BS, Presmans W. The HUS of childhood and its variants. Semin Hematol 1987; 24:148160.|
|17||Remuzzi G. HUS & TTP: Variable expression of a single entity. Nephrology Forum. Kidney Int 1987; 32:292308|
|18||Srivastava RN, Bagga A, Moudgil A. ARF in North Indian Children. Ind J Med Res 1990; 92:404408|
|19||Newild GH. HUS. Nephron 1991; 59:194205. |
|20||Bhuyan UN, Bagga A. Srivastava RN. ARF and severe HT in children with TMA. Nephron 1994; 66:302306.