Acquired Pial and Dural Arteriovenous Fistulae following Superior Sagittal Sinus Thrombosis in Patients with Protein S Deficiency: A Report of Two Cases

Two patients with protein S deficiency with acquired multiple pial and dural arteriovenous fistulae (AVFs) following superior sagittal sinus (SSS) thrombosis are reported. Case 1 is a 38-year-old male with protein S deficiency who developed generalized seizure due to SSS thrombosis. Local fibrinolysis was achieved in the acute stage. His 10-month follow-up angiogram revealed an asymptomatic acquired dural AVF arising from the middle meningeal artery and the anterior cerebral artery with drainage to the thrombosed cortical vein in the right frontal lobe. Furthermore, his 2-year follow-up angiogram revealed a de novo pial AVF from the middle cerebral artery in the Sylvian fissure with drainage to the cortical vein initially thrombosed. However, this asymptomatic pial AVF caused bleeding in the ipsilateral cerebral hemisphere 12 years after onset, whereas the dural AVF spontaneously disappeared. Surgical disconnection was successfully performed to eliminate the source of hemorrhage. Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure. His angiogram showed a cortical dural AVF in the left parietal lobe and a sporadic dural AVF involving the right sigmoid sinus. The parietal lesion was eliminated by transarterial embolization followed by craniotomy. However, a de novo pial AVF emerged from the middle cerebral artery adjacent to the previously treated lesion. Of four cortical AVFs in two patients, thrombosis of cortical veins caused by protein S deficiency might play an important role in their formation. Long-term follow-up is required because this peculiar disorder has an unusual clinical course.     

Successful vaccination against varicella zoster virus prior to kidney transplantation

BACKGROUND: In recent years we have observed a number of severe complications of primary varicella-zoster virus (VZV) infections after adult kidney transplantation. We questioned how many patients on the waiting list for kidney transplantation had not been protected against VZV and whether patients with renal insufficiency would be able to develop a specific immune response upon VZV vaccination. METHODS: We examined the VZV antibody titer of 280 patients on the kidney transplant waiting list. Seronegative kidney transplant candidates were vaccinated twice with a live attenuated varicella vaccine at an interval of 6 weeks. CONCLUSIONS: Approximately 3% of patients on the waiting list were seronegative for VZV. Vaccination induced no side effects and resulted in a positive serologic response in most patients.     

Asymmetric dimethylarginine: a new player in the pathogenesis of renal disease?

PURPOSE OF REVIEW: This review summarizes current knowledge on asymmetric dimethylarginine, renal function in health and disease, and renal disease progression and examines interventions that may modify the plasma concentration of this methylarginine. RECENT FINDINGS: Nitric oxide deficiency may occur in patients with chronic kidney disease and may contribute to accelerate progression of chronic kidney disease, hypertension and cardiovascular complications. An increase of endogenous nitric oxide inhibitors like asymmetric dimethylarginine seems to play a major role in this process. The kidneys are crucial in both, in re-absorbing and generating L-arginine as well as in eliminating asymmetric dimethylarginine primarily by the enzyme dimethylarginine dimethylaminohydrolase and to a minor degree by urinary excretion. Asymmetric dimethylarginine accumulation predicts both accelerated renal function loss and death in patients with chronic kidney disease and incident cardiovascular complications in patients with end stage renal disease. SUMMARY: Asymmetric dimethylarginine is a new risk factor potentially implicated in the progression of renal insufficiency and in the high rate of cardiovascular complications of patients with chronic kidney disease.     

Spontaneous tibial artery thrombosis associated with varicella pneumonia and free protein S deficiency

Pneumonia is the most common serious complication of varicella infection in adults. A variety of thrombotic complications including purpura fulminans and disseminated intravascular coagulation have been reported in children with varicella but not in adults. Two men with varicella pneumonia who had profound lower extremity ischemia caused by thrombosis of the profunda femoris and tibial arteries are reported. Both patients had free protein S deficiency and vascular thrombosis in association with varicella pneumonia without overt evidence of disseminated intravascular coagulation or purpura fulminans. Antiphospholipid immunoglobulin G and immunoglobulin M antibodies were present in one, whereas the other had evidence of the lupus anticoagulant. The proposed pathogenesis and management options including intraarterial thrombolytic therapy with urokinase and the need for long-term anticoagulation are discussed. (J Vasc Surg 1998;27:563-7.)     

Ceftriaxone-related hemolysis and acute renal failure

A 5-year-old girl with no underlying immune deficiency or hematologic disease was treated with a combination of ceftriaxone and ampicilline-sulbactam for pneumonia. On the ninth day of the therapy, she developed oliguria, paleness, malaise, immune hemolytic anemia (IHA) and acute renal failure (ARF). Laboratory studies showed the presence of antibodies against ceftriaxone. Acute interstitial nephritis (AIN) was diagnosed by renal biopsy. The patient’s renal insufficiency was successfully treated with peritoneal dialysis without any complications. The patient recovered without any treatment using steroids or other immunosuppressive agents.     

Varicella vaccination in children with chronic renal failure

Children with kidney disease are at risk for serious varicella-related complications. To evaluate the safety and immunogenicity of a two-dose regimen of varicella vaccine in children (aged 1-19 years) with chronic renal insufficiency and on dialysis, the Southwest Pediatric Nephrology Study Group (SPNSG) undertook an open-label, multi-center, prospective 3-year clinical trial. Ninety-six patients without history of varicella were enrolled. Fifty (mean age 4.2 years) had no detectable varicella zoster virus (VZV) antibody; 98% seroconverted after the two-dose regimen. At 1, 2, and 3 years' follow-up, all patients studied maintained VZV antibody, including 16 who received a transplant. No significant vaccine-associated adverse events were seen. One subject developed mild varicella (10-50 maculopapular lesions) 16 months post transplant. In multivariate regression analysis, patients vaccinated after age 6 years had VZV antibody levels 73% (95% confidence interval 33%-89%) lower than patients vaccinated before age 6 years after controlling for gender, estimated glomerular filtration rate, and dialysis treatment. Adjusted analysis also showed that VZV antibody levels were lower after kidney transplantation, but this appeared to be a transient phenomenon. In this study, varicella vaccination with a two-dose regimen of varicella vaccine was generally well tolerated and highly immunogenic in children with chronic kidney disease.     

Relationship of transforming growth factor-beta(1) with tumour necrosis factor-alpha and endothelial activation in patients with stable renal transplantation

Aim: To evaluate whether or not transforming growth factor‐beta₁ is related to inflammation markers and to intercellular and vascular cell adhesion molecules in patients with stable renal transplantation. Methods: Serum concentrations of transforming growth factor‐beta₁, tumour necrosis factor‐alpha, C‐reactive protein and adhesion molecules were analysed in 33 renal transplanted patients, 33 patients with chronic renal insufficiency (matched to the transplanted group for level of renal function), and 33 hypertensives with normal renal function. anova , Student's t‐test and simple regression analysis were used to analyse the data. Results: Transplanted patients showed higher values than hypertensives of transforming growth factor‐beta₁, tumour necrosis factor‐alpha, C‐reactive protein and adhesion molecules (P < 0.0001 for all). Renal insufficiency group exhibited higher concentrations of transforming growth factor‐beta₁, tumour necrosis factor‐alpha, C‐reactive protein and adhesion molecules than hypertensives (P < 0.0001 for all). Transplanted and renal insufficiency patients had similar blood pressure and renal function levels, and transforming growth factor‐beta₁, tumour necrosis factor‐alpha, C‐reactive protein and adhesion molecules were not significantly different. In transplanted and in renal insufficiency groups transforming growth factor‐beta₁, adhesion molecules and tumour necrosis factor‐alpha correlated significantly each other and with glomerular filtration rate (P < 0.001 for all). Conclusion: In long‐term renal transplantation inflammation and endothelial activation biomarkers, the pro‐fibrotic cytokine transforming growth factor‐beta₁ and kidney function are interrelated. Because of the relevant role that inflammation, organ fibrosis and graft dysfunction may play against renal and cardiovascular survival of graft recipients, a better comprehension of the interactions between these variables is needed.     

'Endotoxin tolerance': TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state

The term 'endotoxin tolerance' defines a state in which prior endotoxin (lipopolysaccharide (LPS)) exposure induces resistance to subsequent LPS attack. However, its characteristics within kidney have not been well defined. Hence, this study tested the impact of LPS 'preconditioning' (LPS-PC; 18 or 72 h earlier) on: (i) selected renal inflammatory mediators (tumor necrosis factor (TNF)-alpha, interleukin-10 (IL-10), monocyte chemotactic protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), Toll-like receptor 4 (TLR4); protein or mRNA); (ii) cholesterol homeostasis (a stress reactant); and (iii) isolated proximal tubule (PT) vulnerability to hypoxia or membrane cholesterol (cholesterol oxidase/esterase) attack. Two hours post LPS injection, LPS-PC mice manifested reduced plasma TNF-alpha levels, consistent with systemic LPS tolerance. However, in kidney, paradoxical TNF-alpha hyper-reactivity (protein/mRNA) to LPS existed, despite normal TLR4 protein levels. PT TNF-alpha levels paralleled renal cortical results, implying that PTs were involved. LPS-PC also induced: (i) renal cortical iNOS, IL-10 (but not MCP-1) mRNA hyper-reactivity; (ii), PT cholesterol loading, and (iii) cytoresistance to hypoxia and plasma membrane cholesterol attack. A link between cholesterol homeostasis and cell LPS responsiveness was suggested by observations that cholesterol reductions in HK-2 cells (methylcyclodextrin), or reductions in HK-2 membrane fluidity (A2C), blunted LPS-mediated TNF-alpha/MCP-1 mRNA increases. In sum: (i) systemic LPS tolerance can be associated with renal hyper-responsiveness of selected components within the LPS signaling cascade (e.g., TNF-alpha, iNOS, IL-10); (ii) PT cytoresistance against hypoxic/membrane injury coexists; and (iii) LPS-induced renal/PT cholesterol accumulation may mechanistically contribute to each of these results.     

Protein S deficiency and skin necrosis associated with continuous ambulatory peritoneal dialysis.

Skin necrosis associated with protein C deficiency has recently been reported to occur in hemodialysis patients. The clinical presentation and course of this syndrome appears indistinguishable from skin necrosis (purpura fulminans) seen in other settings with inherited or acquired deficiency of the naturally occurring anticoagulant proteins, protein C and S. Patients on maintenance hemodialysis may have low levels of these factors. However, patients on peritoneal dialysis have normal or elevated levels of these proteins despite documented peritoneal losses. We report two patients in whom the occurrence of protein S deficiency and subsequent skin necrosis can be related to demonstrated peritoneal dialysis-associated losses. We suggest that these losses may become critical under appropriate conditions and suggest caution in peritoneal dialysis patients requiring warfarin therapy.     

Renalase Protects against Ischemic AKI

Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalase-deficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wild-type mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.Ischemic AKI is a major problem for patients subjected to major surgical procedures involving the kidney, liver, heart, or aorta.¹ Renal ischemia reperfusion (IR) injury is a frequent cause of clinical AKI, with the incidence of AKI exceeding 50% after major cardiac, hepatobiliary, or aortic surgery.^2,3 Furthermore, ischemic AKI is frequently complicated by multi-organ dysfunction, systemic inflammation, sepsis, and death.⁴ Unfortunately, there are no proven therapies to prevent or treat AKI in the perioperative setting.⁵Renalase is a 38-kD, flavin adenine dinucleotide–dependent amine oxidase synthesized and secreted by the renal proximal tubules.⁶ Renalase degrades circulating catecholamines and regulates systemic BP in rodents and humans.⁷ Plasma catecholamines and systemic BP are elevated in patients with chronic kidney dysfunction or end stage renal insufficiency.⁸ Recent studies suggest that renalase deficiency in patients with chronic renal insufficiency leads to increased plasma catecholamine levels and systemic BP.^7,9–11 However, the effect of ischemic AKI on kidney renalase and plasma catecholamine levels remains to be determined.In addition to regulating BP, renalase may protect against inflammatory tissue injury by metabolizing catecholamines. Catecholamines via activation of leukocyte α-adrenergic receptors directly cause inflammation in sepsis and multi-organ dysfunction.^12,13 Indeed, patients with chronic renal insufficiency show increased markers of inflammation that contribute directly to increased morbidity and mortality.¹⁴ In mice, renalase deficiency resulted in exacerbated cardiac IR injury and exogenous renalase administration reduced myocardial necrosis.¹⁵In this study, we hypothesized that ischemic AKI in mice leads to renalase deficiency and this renalase deficiency directly exacerbates ischemic AKI. We performed experiments to test the following: (1) whether ischemic AKI leads to reduced kidney and plasma renalase levels, (2) whether ischemic AKI-induced renalase deficiency leads to elevated plasma catecholamine (NE) levels, (3) whether renalase-deficient mice exhibit increased renal IR injury, and (4) whether exogenous administration of recombinant human renalase directly protects against ischemic AKI in mice.     

Obesity-related focal and segmental glomerulosclerosis: normalization of proteinuria in an adolescent after bariatric surgery

Obesity-related glomerulopathy (ORG) is a secondary form of focal and segmental glomerulosclerosis (FSGS) occurring in severely obese patients. A significant percentage of individuals with ORG will develop renal insufficiency or end stage renal disease. We report here a 17-year-old girl with morbid obesity (body mass index 56.8 kg/m²) and ORG presenting with nephrotic range proteinuria, who failed to improve following treatment with diet, exercise and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) therapy. Laparoscopic gastric bypass surgery was performed, and within 2 weeks following the surgery, the patient had lost 5.7 kg body weight and showed a remarkable decrease in protein excretion to one tenth of pre-surgery levels. More than 1 year after surgery, the patient’s urine protein and kidney function have remained normal while off renin–angiotensin system inhibition therapy. This is the first report of successful use of gastric bypass surgery for obesity-related glomerulopathy in an adolescent. We propose that gastric bypass surgery be considered for patients with ORG.     

Immunization in children with chronic renal failure

Infections jeopardize children on immunosuppression after organ transplantation. Immunization is protective in healthy children. The aims of this study were to analyze the rate and efficacy of immunization in 62 children undergoing dialysis and renal transplantation (RTPL) between 1987 and 2000. The analysis was based on clinical findings, vaccination certificates, and measurement of specific serum antibodies. A member of the renal unit administered vaccinations. All 62 patients were immunized against diphtheria, tetanus, pertussis, poliomyelitis, measles, mumps, rubella, and hepatitis B. Since introduction in 1991 and 1995, 44 and 42 children were also vaccinated against influenza and Hemophilus influenzae type b, respectively. Of 16 patients with a negative history, 14 were given varicella vaccine; 16 children on peritoneal dialysis (PD) or with nephrotic syndrome were immunized against Streptococcus pneumoniae. All vaccinated patients had detectable serum antibodies against measles, mumps, rubella, varicella, hepatitis B, H. influenzae, and S. pneumoniae. There were 3 infections despite vaccination; 1 patient developed varicella after RTPL and 1 patient on PD had 2 episodes of peritonitis caused by H. influenzae and S. pneumoniae. In conclusion, monitoring and administration of the vaccines by the renal team enabled a high immunization rate. Whether vaccines, as documented by antibody titers, or by the low prevalence in the general population promoted the low prevalence of infections remains open, as there were at least a few vaccination failures.     

Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome

Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab'2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FH-specific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.     

Retroperitoneoscopic radiofrequency ablation of a solid renal mass.

PURPOSE: To report a new technique for radiofrequency (RF) ablation of a solid renal mass. PATIENT AND METHODS: An 83-year-old man with a history of chronic renal insufficiency was found to have solid mass in the right kidney. Retroperitoneoscopic localization of the renal mass was accomplished using intraoperative ultrasonography. The lesion was treated with a 14-gauge RITA Starburst XL probe (Rita Medical Systems, Inc., Mountain View, CA). RESULTS: The total treatment time included two cycles of 5.5 minutes. There were no intraoperative complications. Tissue desiccation was noted during treatment. A CT scan 48 hours after ablation showed a decrease in the density of the lesion suggestive of coagulation necrosis. The postoperative hospital course was uneventful. CONCLUSION: The retroperitoneal laparoscopic technique is a feasible approach to performing RF ablation of a solid renal mass. It facilitates direct insertion of the RF probe, allows viewing and avoidance of adjacent structures such as bowel, and permits better staging by enabling biopsy of perirenal fatty tissue.     

Vitamin K<Subscript>2</Subscript> Improves Renal Function and Increases Femoral Bone Strength in Rats with Renal Insufficiency

Renal insufficiency induces cortical bone loss in rats. The present study examined the influence of vitamin K₂ on renal function, cortical bone mass, and bone strength in rats with renal insufficiency. Thirty male Sprague-Dawley rats (8 weeks old) were randomized by the stratified weight method to the following three groups of 10 animals each: sham operation (control), 5/6 nephrectomy, and 5/6 nephrectomy + oral vitamin K₂ (menaquinone-4, menatetrenone, 30 mg/kg, 5 days/week). Treatment was initiated 10 days after surgery. After 6 weeks of treatment, samples of serum, urine, and bone (femur and tibia) were obtained. Renal function was evaluated, bone histomorphometric analysis was performed on the tibial diaphysis, and the bone mineral density (BMD) and mechanical strength of the femoral diaphysis were determined by peripheral quantitative computed tomography and a three-point bending test, respectively. Nephrectomy induced renal dysfunction, as indicated by increased levels of serum creatinine and urea nitrogen along with a decrease of creatinine clearance; and it also decreased BMD without significantly affecting bone strength at the femoral diaphysis. Vitamin K₂ improved renal function parameters but did not significantly influence BMD at the femoral diaphysis. However, vitamin K₂ decreased the bone marrow area of the tibial diaphysis and increased the stiffness of the femoral diaphysis. These findings suggest that administration of vitamin K₂ improves renal function and increases cortical bone strength without altering BMD in rats with renal insufficiency.     

Unusual renal sarcoma in a young adult: its similarities to clear cell sarcoma of the kidney

We report an unusual case of renal sarcoma in a young adult. Histological examination demonstrated many similarities to the histopathological features of clear cell sarcoma of the kidney. Immunohistochemically, none of the intrinsic tumor cells showed positive staining with the antibodies against the intermediate filament proteins, epithelial membrane antigen, S100 protein, neuron-specific enolase, Leu-7 or myoglobin. The clinical course of this tumor was that of high grade malignancy, resulting in death with generalized metastases 13 months after tumor resection.     

The Insulin-Like Growth Factor–I Axis in Acute Renal Failure

We have examined the response of the renal insulin-like growth factor (IGF-I) axis to acute ischemic injury in the rat Key findings. included a de-crease in IGF-I mRNA and peptide levels, a decrease in GH receptor gene plus protein expression and a decrease in the IGF binding proteins except for IGF binding protein 1. Administration of GH to compensate for the reduced GH receptor binding corrected the IGF-I mRNA levels suggesting a relative GH deficiency. Interestingly, IGF-I receptor mRNA levels were unchanged while plasma membrane IGF-I receptor number increased two fold. This appeared to be due to a redistribution of receptors to a membrane location. IGF-I receptor autophosphorvlation and tyrosine kinase activity were intact despite severe uremia for up to 6 days. We propose that this increase of functional IGF-I receptors following acute tubular necrosis will sensitize the kidney to the administration of exogenous IGF-I.     

Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity

Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 (PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor-κB, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild-type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-α axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin-induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity.     

Late diagnosis of primary hyperoxaluria after failed kidney transplantation

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.