Sharon P. Andreoli

Aluminum Intoxication from Aluminum-Containing Phosphate Binders in Children with Azotemia Not Undergoing Dialysis

Aluminum intoxication developed in three infants with azotemia who were not undergoing dialysis and who had been treated with aluminum hydroxide from the first month of life. Biopsies of the iliac crest demonstrated the presence of severe osteomalacia and massive deposition of aluminum in the bone. Serum aluminum levels were significantly (P less than 0.001) higher in these 3 infants and in 1 other, all of whom received more than 100 mg of elemental aluminum per kilogram of body weight per day (mean +/- S.D., 371.0 +/- 178.9 ng per milliliter [13.75 +/- 6.6 mumol per liter] ) than they were in 8 older children with azotemia who were not undergoing dialysis and who received less than 100 mg of elemental aluminum per kilogram per day (27.0 +/- 18.6 ng per milliliter [1.0 +/- 0.68 mumol per liter] ), 7 such children who did not receive aluminum hydroxide (20.28 +/- 9.2 ng per milliliter [0.75 +/- 0.34 mumol per liter] ), and 16 children with normal renal function (21.04 +/- 4.9 ng per milliliter [0.78 +/- 0.18 mumol per liter] ). In all the children with azotemia who were treated with aluminum hydroxide, there was a positive correlation (r = 0.90; P less than 0.01) between the serum aluminum level and the daily dose of elemental aluminum. These studies indicate that gastrointestinal absorption of aluminum can lead to aluminum intoxication in children with azotemia, and that infants may be particularly susceptible to this complication of therapy.

Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS)

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood and the reason for chronic renal replacement therapy. It leads to significant morbidity and mortality during the acute phase. In addition to acute morbidity and mortality, long-term renal and extrarenal complications can occur in a substantial number of children years after the acute episode of HUS. The most common infectious agents causing HUS are enterohemorrhagic Escherichia coli (EHEC)-producing Shiga toxin (and belonging to the serotype O157:H7) and several non-O157:H7 serotypes. D+ HUS is an acute disease characterized by prodromal diarrhea followed by acute renal failure. The classic clinical features of HUS include the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS mortality is reported to be between 3% and 5%, and death due to HUS is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with HUS require dialysis therapy, and about one third have milder renal involvement without the need for dialysis therapy. General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy if necessary, and initiation of renal replacement therapy when appropriate. The prognosis of HUS depends on several contributing factors. In general “classic” HUS, induced by EHEC, has an overall better outcome. Totally different is the prognosis in patients with atypical and particularly recurrent HUS. However, patients with severe disease should be screened for genetic disorders of the complement system or other underlying diseases.

Acute kidney injury in children

Acute kidney injury (AKI) (previously called acute renal failure) is characterized by a reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. The incidence of AKI in children appears to be increasing, and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Genetic factors may predispose some children to AKI. Renal injury can be divided into pre-renal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The pathophysiology of hypoxia/ischemia-induced AKI is not well understood, but significant progress in elucidating the cellular, biochemical and molecular events has been made over the past several years. The history, physical examination, and laboratory studies, including urinalysis and radiographic studies, can establish the likely cause(s) of AKI. Many interventions such as ‘renal-dose dopamine’ and diuretic therapy have been shown not to alter the course of AKI. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have suffered AKI from any cause are at risk for late development of kidney disease several years after the initial insult. Therapeutic interventions in AKI have been largely disappointing, likely due to the complex nature of the pathophysiology of AKI, the fact that the serum creatinine concentration is an insensitive measure of kidney function, and because of co-morbid factors in treated patients. Improved understanding of the pathophysiology of AKI, early biomarkers of AKI, and better classification of AKI are needed for the development of successful therapeutic strategies for the treatment of AKI.

Treatment of severe IgA nephropathy in children

We treated ten children with severe IgA nephropathy (IgAN) [proteinuria > 1g/day, hypertension, renal insufficiency, segmental sclerosis, crescent formation and/or glomerular basement membrane (GBM) deposition of IgA] with prednisone and azathioprine for 1 year. Following the year of therapy, seven of the ten children underwent a repeat kidney biopsy. All biopsies were scored for activity (percentage of glomeruli demonstrating crescent formation, degree of mesangial proliferation and interstitial infiltrate; maximum score = 9) and chronicity (percentage of glomeruli demonstrating fibrous crescents, segmental sclerosis, global sclerosis, and degree of tubular atrophy and interstitial fibrosis; maximum score = 12). After 1 year of therapy, the protein excretion of all the children decreased significantly (P<0.01) from 4052±3190 mg/day to 1692±1634 mg/day. The activity score decreased significantly (P<0.01) from 4.35±0.94 prior to therapy to 2.28±0.75 after therapy while the chronicity score was unchanged (5.42±1.7 vs 5.85±2.0). The percentage of glomeruli demonstrating cellular crescents decreased (P<0.05) from 21.2±21.7% prior to therapy to 0.94±2.4% after therapy. Mesangial deposition of IgA persisted but GBM deposition of IgA was less prominent after therapy. During the follow-up period (mean 2.6 years, range 9 months–7.5 years), one child required brief retreatment for biopsy-confirmed recurrence of active disease, two children have developed renal insufficiency due to progressive scarring in the absence of inflammation, while the remaining seven are stable. We suggest that treatment with prednisone and azathioprine may be beneficial in children with severe IgAN and that a controlled clinical trial is warranted.

Reactive oxygen molecules, oxidant injury and renal disease.

Oxidant injury has been implicated in the pathogenesis of inflammotory, metabolic and toxic insults, in ischemic-reperfusion injury, and in carcinogenesis, aging and atherosclerosis. Oxidant injury is initiated by free radicals and reactive oxygen molecules which are generated by activated neutrophils, monocytes, and mesangial cells, during normal and abnormal metabolic processes, and from the metabolism of exogenous drugs and toxins. When cells and organs are exposed to oxidant stress, several different antioxidant defense mechanisms operate to prevent or limit oxidant injury. When antioxidant defense mechanisms are decreased, or when the generation of reactive oxygen molecules is increased, oxidant injury results from the shift in the oxidant/antioxidant balance. Oxidant-induced alterations of proteins, membranes, DNA, and basement membranes leads to cell and organ dysfunction. Several renal diseases including glomerulonephritis, vasculitis, toxic nephropathies, pyelonephritis, acute renal failure, and others are likeky to be mediated at least in part by oxidant injury. In the future, mechanisms to decrease the generation of reactive oxygen molecules and/or antioxidant therapy may develop into new avenues of therapeutic intervention.

Hemolytic uremic syndrome: epidemiology, pathophysiology, and therapy

Shiga toxin (Stx)-producing Escherichia coli (STEC) were first linked to human disease in 1982 [1]. At that time an E. coli serotype (O157:H7) that had not previously been linked with human disease was found to be associated with outbreaks of hemorrhagic colitis [1]. Subsequent studies demonstrated that E. coli O157:H7 produced potent toxins that were genetically and physically very similar to Stx from Shigella dysenteriae type 1 [2]. The link between STEC infections and hemolytic uremic syndrome (HUS) was established in the 1980s in Canada by Karmali et al. [3] when they found that infection with various serotypes of STEC was strongly associated with the subsequent development of HUS. The most common E. coli serotype identified to cause hemorrhagic colitis and HUS in the United States was the single serotype – O157:H7. The reason this serotype is most commonly identified in STEC infections is that it is relatively easy to identify in clinical microbiology laboratories due to its inability to ferment sorbitol. Since the first description of O157:H7 as a human pathogen in 1983, it has become apparent that E. coli O157:H7 is but one of a much larger family of STEC whose primary virulence characteristic is the ability to produce Stxs [2, 3, 4]. STEC are clinically associated with both bloody and non-bloody diarrhea as well as systemic complications such as HUS [4]. It is now clear that there are at least 200 different types of STEC, of which approximately 60 have been associated with disease in humans [2, 4, 5]. Non-O157 STEC, especially E. coli O111, have been the cause of major outbreaks in both the United States and other parts of the world [6, 7]. However, apart from the occasional outbreak of nonO157 in the United States, the association of nonO157:H7 STEC with disease in this country is largely undetermined. Of note, the majority of laboratories do not routinely look for non-O157 STEC [8], suggesting that lack of diagnosis of non-O157:H7 disease is a failure of use of appropriate diagnostic techniques. Compatible with this hypothesis are at least two small studies in which non-O157:H7 STEC were routinely found in patients submitting stools for microbiological analysis in the United States. [9, 10]. Recent work from our laboratory in collaboration with multiple sites in the United States has attempted to determine the prevalence of both O157 and non-O157 STEC in selected sites in the United States. We have performed multi-site surveillance studies to determine the prevalence of O157 and non-O157 STEC in stool samples submitted to clinical microbiology laboratories for S.P. Andreoli is the editor of the Proceedings and H. Trachtman the associate editor. D.W.K. Acheson is the author of the section Microbiology and epidemiology of Shiga toxin-induced hemolytic uremic syndrome, R.L. Siegler is the author of the section Animal models of Stx-mediated HUS, T.G. Obrig is the author of the section Mechanisms of Stx-mediated cell injury, and H. Trachtman is author of the section New and future therapies for diarrhea-associated HUS.

Purine excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: Relationship to acute renal failure*

We measured serial urine levels of hypoxanthine, xanthine, and uric acid in 19 children with acute lymphocytic leukemia (ALL) receiving allopurinol therapy during tumor lysis; four of these children developed acute renal failure. The urinary excretion of uric acid rose moderately from 447 +/- 251 micrograms/dl glomerular filtrate before chemotherapy to 778 +/- 463 micrograms/dl glomerular filtrate during tumor lysis (P less than 0.05) whereas the urinary excretion of hypoxanthine (17.9 +/- 15 to 292 +/- 213 micrograms/dl glomerular filtrate) and xanthine (74 +/- 62 to 1091 +/- 1085 micrograms/dl glomerular filtrate) rose dramatically (P less than 0.001). The urinary excretion of uric acid, hypoxanthine, and xanthine per deciliter of filtrate was significantly higher (P less than 0.001) in those who developed acute renal failure than in those who did not, but the highest urine concentration of these purine metabolites did not differ in the two groups. In all 19 children, the highest urine concentration of uric acid and hypoxanthine during tumor lysis did not exceed the solubility limit of each in an alkaline urine specimen. In contrast, the peak urine concentration of xanthine exceeded its solubility limit in an alkaline urine specimen in 16 of 19 children. The urine sediment during the period of tumor lysis was examined by diffuse reflectance infrared spectroscopy; precipitated xanthine was found in sediment from eight of the 19 children, was significantly (P less than 0.001) associated with a urine xanthine level greater than 350 mg/dL, and occurred with equal frequency in those who did or did not develop acute renal failure. We conclude that urinary excretion of hypoxanthine and xanthine increases dramatically whereas uric acid excretion rises moderately in children undergoing tumor lysis while receiving allopurinol, that acute renal failure occurs in children with a higher purine load per deciliter of glomerular filtrate, but that factors other than tubular precipitation of purine metabolites are likely to be involved in the pathogenesis of renal failure during tumor lysis.

Chronic Kidney Disease: Common, Harmful, and Treatable—World Kidney Day 2007

Thursday, March 8, 2007, is World Kidney Day! World Kidney Day was proposed by the International Society of Nephrology and International Federation of Kidney Foundations in 2006 to broadcast a message about kidney diseases to the public, government health officials, general physicians, allied health

Radiation nephritis following total-body irradiation and cyclophosphamide in preparation for bone marrow transplantation

Two children prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide developed hypertension, microscopic hematuria, proteinuria, diminished renal function, and anemia six months after transplantation. Light microscopy of the kidneys revealed mesangial expansion, glomerular capillary wall thickening, and lumenal thrombosis. Electron microscopy demonstrated widening of the subendothelial space due to the deposition of amorphous fluffy material. In one patient, immunofluorescence microscopy revealed glomerular capillary wall deposition of fibrin and immunoglobulins. The clinical and histologic findings support the diagnosis of radiation nephritis. Patients prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide should be followed closely after transplantation for the development of hypertension, proteinuria, and renal insufficiency.

IgA nephropathy in children: significance of glomerular basement membrane deposition of IgA

Seventeen children with IgA nephropathy were grouped according to the absence (group I, n = 10) or presence (group II, n = 7) of glomerular basement membrane (GBM) deposition of IgA to determine whether GBM deposition of IgA correlated with laboratory or pathologic data at diagnosis or clinical status at follow-up. Children in group II had significantly (p less than 0.01) more proteinuria at diagnosis than children in group I. The percentage of glomeruli demonstrating crescent formation was significantly (p less than 0.05) higher in group II biopsies. Chronic changes of fibrous crescents, segmental sclerosis, global obsolescence, tubular atrophy, and interstitial fibrosis were also significantly (p less than 0.001) more common in group II biopsies. After a mean follow-up period of 2 years, all children in group II have persistent proteinuria of more than 1 g/24 h, and 3 of 5 have renal insufficiency (2 require dialysis). In contrast, 2 of 9 group I children have proteinuria exceeding 1 g/24 h, and only 1 has renal insufficiency. We conclude that, as compared to children with IgA localized to the mesangium, children with IgA nephropathy and GBM deposition of IgA have a higher urinary protein excretion at the time of diagnosis, more severe histologic alterations including a greater percentage of glomeruli demonstrating crescent formation, more chronic changes of segmental or global sclerosis, tubular atrophy, and interstitial fibrosis. Such children usually have persistent proteinuria and are more likely to develop progressive renal disease.