We are in the midst of a worldwide epidemic of diabetes and hypertension. In the United States, t... more We are in the midst of a worldwide epidemic of diabetes and hypertension. In the United States, the overall incidence of end-stage kidney disease (ESKD) is increasing at an alarming rate due to this epidemic. Recently, the incidence of ESKD was estimated at 336 per million per year (1), such that the number of patients with ESKD may approach 2.24
Shiga toxin-producing Escherichia coli (STEC) is among the common causes of foodborne gastroenter... more Shiga toxin-producing Escherichia coli (STEC) is among the common causes of foodborne gastroenteritis. STEC is defined by the production of specific toxins, but within this pathotype there is a diverse group of organisms. This diversity has important consequences for understanding the pathogenesis of the organism, as well as for selecting the optimum strategy for diagnostic testing in the clinical laboratory. This review includes discussions of the mechanisms of pathogenesis, the range of manifestations of infection, and the several different methods of laboratory detection of Shiga toxin-producing E coli.
L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has bee... more L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has been shown to induce analgesia in rodents by up-regulating the expression of metabotropic glutamate receptor 2 (mGlu2) in dorsal root ganglia (DRG). We now report that LAC-induced upregulation of mGlu2 expression in DRG cultures involves transcriptional activation mediated by nuclear factor-kappaB (NF-kappaB). A single application of LAC (250 muM) to DRG cultures induced a transient increase in mGlu2 mRNA, which was observable after 1 hour and was no longer detectable after 1 to 4 days. In contrast, LAC treatment had no effect on mGlu3 mRNA expression. Pharmacological inhibition of NF-kappaB binding to DNA by caffeic acid phenethyl ester (CAPE) (2.5 microg/ml for 30 minutes) reduced the constitutive expression of mGlu2 and mGlu3 mRNA after 1-4 days and reduced the constitutive expression of mGlu2/3 protein at 4 days. This evidence combined with the expression of p65/RelA and c-Rel in DRG ne...
The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in youn... more The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in young children. Most patients recover from the acute phase of the illness but they may develop arterial hypertension (AH) after many years, even in the absence of signs of renal impairment during short-term follow-up. In this study, we performed casual blood pressure (BP) measurement, 24-h blood pressure monitoring (ABPM), and a Bruce walking treadmill study (ET) in 24 children (aged 5-15 years, 13 males, 11 females) with a history of HUS and normal renal function during follow-up (median 5.8 years, range 1.8-12.4 years). There were 22 children (91%) with prodromal diarrhea associated with HUS and 20 (83%) underwent dialysis during the acute illness. All children had normal casual BP measurement. Of 13 children (54%) with normal ABPM, 5 patients (38%) had an abnormal BP response during the ET study. There were 4 (58%) of the 7 patients with AH by ABPM (29%) and an abnormal BP response during ET. These findings suggest that ET could be a useful means of identifying children with a history of HUS that could be at risk of future AH even if they had normal renal function, casual BP, and ABPM during long-term follow-up. These results should be confirmed with a large prospective clinical study.
Verocytotoxin-producing Escherichia coli(VTEC) infections cause most cases of hemolytic uremic sy... more Verocytotoxin-producing Escherichia coli(VTEC) infections cause most cases of hemolytic uremic syndrome (HUS); 10-30% of patients, however, are negative for VTEC infection. The etiology of HUS in VTEC-negative cases remains poorly understood. Before the association between VTEC infection and HUS was recognized, sporadic cases of HUS with enterovirus infection were reported in the literature. Since May 1988, most cases of HUS in Italy have been reported to the Italian surveillance system, and in 73% of these, evidence of VTEC infection was demonstrated. The aim of this study was to determine whether the frequency of enteroviral infections was different in the acute phase of VTEC-positive and VTEC-negative HUS. Eighty-nine patients were investigated for enteroviral infection, of whom 58 were VTEC positive and 31 VTEC negative. Two serum samples from each patient were examined for seroconversion to enterovirus (coxsackie, echovirus, and picornavirus) by a complement fixation test. Serological evidence of acute infection with non-polio enterovirus was found in 33 patients (37%) [20/58 (34.5%) VTEC positive and 13/31 (41.9%) VTEC negative]. There was no statistically significant difference between the two groups. These results demonstrate that there are no significant differences for enteroviral infection in VTEC-positive and VTEC-negative patients and, therefore, enteroviral infections should not be considered a cause of HUS in VTEC-negative children.
The molecular pathogenesis of diabetic glomerulosclerosis remains unknown, but recent studies sug... more The molecular pathogenesis of diabetic glomerulosclerosis remains unknown, but recent studies suggest that podocyte damage may play a role. Bone morphogenetic protein 7 (BMP-7) is physiologically expressed in podocytes and tubular epithelial cells. Our previous studies show that BMP-7 reverses glomerular and tubulointerstitial damage in diabetic rats, but there is little known about possible effects of BMP-7 on podocytes. We postulate that high glucose may injure the podocyte by altering structural proteins such as synaptopodin and podocin. This study investigates the effect of high glucose on mouse podocytes, expression of synaptopodin and podocin under normal and high glucose and the treatment effect of BMP-7 on these molecules. Human diabetic glomeruli are studied in parallel. Conditionally immortalized mouse podocytes were exposed to media containing normal (NG) or high (HG) glucose for 2 weeks. Synaptopodin, podocin and BMP-7 gene transcription and protein were assayed with real-time PCR, Western blot or immunohistochemistry, respectively. Synaptopodin and podocin mRNA and protein was evaluated using podocytes incubated in HG for 1 week, in the presence of low (10 ng/ml) and high (300 ng/ml) dose recombinant BMP-7 (rhBMP-7). Human diabetic glomeruli were excised from renal biopsies by laser capture micro-dissection (LCM) and endogenous BMP7 and synaptopodin and podocin were determined by RT-PCR and/or immunohistochemistry. Culture of podocytes in HG decreases synaptopodin, podocin and BMP-7 transcription and protein synthesis compared to NG. Treatment with rhBMP-7 restores synaptopodin and podocin mRNA and protein. Decreased BMP-7 and synaptopodin is also observed in human diabetic glomeruli both at the transcription and protein level. BMP-7 may confer resistance to hyperglycaemic injury via synaptopodin and podocin suggesting novel BMP7 therapies for diabetic glomerulosclerosis.
Onset and correction of hypernatraemia constitute major hypertonic stresses for mammalian cells. ... more Onset and correction of hypernatraemia constitute major hypertonic stresses for mammalian cells. Cells respond by activating specific osmoregulatory mechanisms allowing to preserve their volume and to adapt to their new environmental conditions. These processes have major implications in the management of hypernatraemia. In particular, cells chronically exposed to hypertonic conditions progressively accumulate organic osmolytes to maintain optimal intracellular electrolyte concentrations. During treatment of hypernatraemia, elevated intracellular organic osmotic content exposes cells to cellular oedema if sodium concentrations are rapidly corrected. In addition, circulating ions equilibrate slowly across the blood-brain barrier during acute changes in plasma osmolality. This can generate major brain water shifts and severe cerebral lesions related to brain shrinking or cerebral oedema. The basic mechanisms involved in brain ion and water transport are reviewed. A proper understanding of these processes is essential to develop appropriate treatment strategies in managing children with hypernatraemia.
Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic ... more Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.
We are in the midst of a worldwide epidemic of diabetes and hypertension. In the United States, t... more We are in the midst of a worldwide epidemic of diabetes and hypertension. In the United States, the overall incidence of end-stage kidney disease (ESKD) is increasing at an alarming rate due to this epidemic. Recently, the incidence of ESKD was estimated at 336 per million per year (1), such that the number of patients with ESKD may approach 2.24
Shiga toxin-producing Escherichia coli (STEC) is among the common causes of foodborne gastroenter... more Shiga toxin-producing Escherichia coli (STEC) is among the common causes of foodborne gastroenteritis. STEC is defined by the production of specific toxins, but within this pathotype there is a diverse group of organisms. This diversity has important consequences for understanding the pathogenesis of the organism, as well as for selecting the optimum strategy for diagnostic testing in the clinical laboratory. This review includes discussions of the mechanisms of pathogenesis, the range of manifestations of infection, and the several different methods of laboratory detection of Shiga toxin-producing E coli.
L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has bee... more L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has been shown to induce analgesia in rodents by up-regulating the expression of metabotropic glutamate receptor 2 (mGlu2) in dorsal root ganglia (DRG). We now report that LAC-induced upregulation of mGlu2 expression in DRG cultures involves transcriptional activation mediated by nuclear factor-kappaB (NF-kappaB). A single application of LAC (250 muM) to DRG cultures induced a transient increase in mGlu2 mRNA, which was observable after 1 hour and was no longer detectable after 1 to 4 days. In contrast, LAC treatment had no effect on mGlu3 mRNA expression. Pharmacological inhibition of NF-kappaB binding to DNA by caffeic acid phenethyl ester (CAPE) (2.5 microg/ml for 30 minutes) reduced the constitutive expression of mGlu2 and mGlu3 mRNA after 1-4 days and reduced the constitutive expression of mGlu2/3 protein at 4 days. This evidence combined with the expression of p65/RelA and c-Rel in DRG ne...
The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in youn... more The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in young children. Most patients recover from the acute phase of the illness but they may develop arterial hypertension (AH) after many years, even in the absence of signs of renal impairment during short-term follow-up. In this study, we performed casual blood pressure (BP) measurement, 24-h blood pressure monitoring (ABPM), and a Bruce walking treadmill study (ET) in 24 children (aged 5-15 years, 13 males, 11 females) with a history of HUS and normal renal function during follow-up (median 5.8 years, range 1.8-12.4 years). There were 22 children (91%) with prodromal diarrhea associated with HUS and 20 (83%) underwent dialysis during the acute illness. All children had normal casual BP measurement. Of 13 children (54%) with normal ABPM, 5 patients (38%) had an abnormal BP response during the ET study. There were 4 (58%) of the 7 patients with AH by ABPM (29%) and an abnormal BP response during ET. These findings suggest that ET could be a useful means of identifying children with a history of HUS that could be at risk of future AH even if they had normal renal function, casual BP, and ABPM during long-term follow-up. These results should be confirmed with a large prospective clinical study.
Verocytotoxin-producing Escherichia coli(VTEC) infections cause most cases of hemolytic uremic sy... more Verocytotoxin-producing Escherichia coli(VTEC) infections cause most cases of hemolytic uremic syndrome (HUS); 10-30% of patients, however, are negative for VTEC infection. The etiology of HUS in VTEC-negative cases remains poorly understood. Before the association between VTEC infection and HUS was recognized, sporadic cases of HUS with enterovirus infection were reported in the literature. Since May 1988, most cases of HUS in Italy have been reported to the Italian surveillance system, and in 73% of these, evidence of VTEC infection was demonstrated. The aim of this study was to determine whether the frequency of enteroviral infections was different in the acute phase of VTEC-positive and VTEC-negative HUS. Eighty-nine patients were investigated for enteroviral infection, of whom 58 were VTEC positive and 31 VTEC negative. Two serum samples from each patient were examined for seroconversion to enterovirus (coxsackie, echovirus, and picornavirus) by a complement fixation test. Serological evidence of acute infection with non-polio enterovirus was found in 33 patients (37%) [20/58 (34.5%) VTEC positive and 13/31 (41.9%) VTEC negative]. There was no statistically significant difference between the two groups. These results demonstrate that there are no significant differences for enteroviral infection in VTEC-positive and VTEC-negative patients and, therefore, enteroviral infections should not be considered a cause of HUS in VTEC-negative children.
The molecular pathogenesis of diabetic glomerulosclerosis remains unknown, but recent studies sug... more The molecular pathogenesis of diabetic glomerulosclerosis remains unknown, but recent studies suggest that podocyte damage may play a role. Bone morphogenetic protein 7 (BMP-7) is physiologically expressed in podocytes and tubular epithelial cells. Our previous studies show that BMP-7 reverses glomerular and tubulointerstitial damage in diabetic rats, but there is little known about possible effects of BMP-7 on podocytes. We postulate that high glucose may injure the podocyte by altering structural proteins such as synaptopodin and podocin. This study investigates the effect of high glucose on mouse podocytes, expression of synaptopodin and podocin under normal and high glucose and the treatment effect of BMP-7 on these molecules. Human diabetic glomeruli are studied in parallel. Conditionally immortalized mouse podocytes were exposed to media containing normal (NG) or high (HG) glucose for 2 weeks. Synaptopodin, podocin and BMP-7 gene transcription and protein were assayed with real-time PCR, Western blot or immunohistochemistry, respectively. Synaptopodin and podocin mRNA and protein was evaluated using podocytes incubated in HG for 1 week, in the presence of low (10 ng/ml) and high (300 ng/ml) dose recombinant BMP-7 (rhBMP-7). Human diabetic glomeruli were excised from renal biopsies by laser capture micro-dissection (LCM) and endogenous BMP7 and synaptopodin and podocin were determined by RT-PCR and/or immunohistochemistry. Culture of podocytes in HG decreases synaptopodin, podocin and BMP-7 transcription and protein synthesis compared to NG. Treatment with rhBMP-7 restores synaptopodin and podocin mRNA and protein. Decreased BMP-7 and synaptopodin is also observed in human diabetic glomeruli both at the transcription and protein level. BMP-7 may confer resistance to hyperglycaemic injury via synaptopodin and podocin suggesting novel BMP7 therapies for diabetic glomerulosclerosis.
Onset and correction of hypernatraemia constitute major hypertonic stresses for mammalian cells. ... more Onset and correction of hypernatraemia constitute major hypertonic stresses for mammalian cells. Cells respond by activating specific osmoregulatory mechanisms allowing to preserve their volume and to adapt to their new environmental conditions. These processes have major implications in the management of hypernatraemia. In particular, cells chronically exposed to hypertonic conditions progressively accumulate organic osmolytes to maintain optimal intracellular electrolyte concentrations. During treatment of hypernatraemia, elevated intracellular organic osmotic content exposes cells to cellular oedema if sodium concentrations are rapidly corrected. In addition, circulating ions equilibrate slowly across the blood-brain barrier during acute changes in plasma osmolality. This can generate major brain water shifts and severe cerebral lesions related to brain shrinking or cerebral oedema. The basic mechanisms involved in brain ion and water transport are reviewed. A proper understanding of these processes is essential to develop appropriate treatment strategies in managing children with hypernatraemia.
Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic ... more Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.
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Papers by Laura Petris