Atypical hemolytic uremic syndrome in the Tunisian population

Background

Hemolytic uremic syndrome consists of a triad of acquired hemolytic anemia, thrombocytopenia and renal failure.

Aim

Our objectives were to determine epidemiology, clinical and laboratory characteristics of patients with atypical hemolytic uremic syndrome (aHUS) to determine the relationship between the complement protein deficit and aHUS in the Tunisian population.

Methods

We studied retrospectively four cases of atypical HUS in adults admitted in the Nephrology Department of Fattouma Bourguiba Universitary Hospital in Monastir between 2000 and 2008.

Results

Three patients had renal failure that required dialysis. One of them received kidney transplantation with no further recurrence of aHUS. Three patients had normal C3, C4, CFH, and FB levels, and in all patients anti-FH autoantibodies were absent. The kidney biopsy of one patient showed in addition to lupus glomerulonephritis histological findings consistent with TMA. A decrease in C3, C4 and CFH levels in this patient was found both before and after the cure.

Conclusion

Nephrologists should be aware of autoimmune conditions and genetic abnormalities of the complement regulatory genes as possible pathogenic mechanisms in atypical HUS patients.     

Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation

Background

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood. It usually occurs after a prodromal episode of diarrhea and it leads to significant morbidity and mortality during the acute phase. However, cases that start as diarrhea-positive HUS whose renal function fail to recover should be screened for genetic disorders of the complement system, which is called atypical HUS (aHUS).

Case-Diagnosis/Treatment

We herein report a 10-year-old girl, who initially came with bloody diarrhea and had features of HUS with delayed renal and hematological recovery despite plasma therapy. Eculizumab (600 mg/week) was initiated on day 15 for atypical presentation and later a complement factor I (CFI) mutation was detected. The girl recovered diuresis within 24 h and after the third eculizumab infusion, hemoglobin, platelet, and C3 levels normalized; renal function improved; and proteinuria completely disappeared in 2 weeks.

Conclusion

It is our belief that eculizumab can be the treatment of choice in children who have plasma exchange-refractory HUS with defective regulation of the alternative complement pathway.     

The challenge of managing hemophilia A and STEC-induced hemolytic uremic syndrome

Background

The hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy leading to acute kidney injury in children. In most cases it is triggered by an infection caused by Shiga-like toxin-producing Escherichia coli (STEC). Endothelial damage plays a central role in the pathogenesis of disease. Hemophilia A is a genetic disorder leading to factor VIII (FVIII) deficiency, an important factor in the coagulation system.

Case

Here we describe a hemophilia A patient who developed HUS due to a STEC O26 infection. The patient developed not only acute kidney injury, but also severe gastro-intestinal and neurological complications. Increased amounts of recombinant FVIII (rFVIII) had to be administered during the acute phase of the disease to reach acceptable blood levels of FVIII, in order to control the hemorrhagic colitis and to prevent severe neurological complications.

Conclusion

The patient’s treatment schedule of rFVIII during the HUS period was a serious challenge, and we cannot exclude that it contributed to the severity of the HUS by enhancing the thrombotic microangiopathic process. The role of factor VIII administration in the severe outcome of this disease is discussed.     

Additive antiproteinuric effect of enalapril and losartan in children with hemolytic uremic syndrome

Background

Angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers decrease postdiarrheal hemolytic uremic syndrome (D + HUS) sequelar proteinuria. However, proteinuria may persist in some patients. In nephropathies other than D + HUS, an additive antiproteinuric effect with coadministration of both drugs has been observed.

Methods

To assess such an effect in D + HUS, 17 proteinuric children were retrospectively studied. After a median period of 1 year post-acute stage (range 0.5–1.9) patients received enalapril alone for a median of 2.6 years (range 0.33–12.0) at a median dose of 0.4 mg/kg/day (range 0.2–0.56). As proteinuria persisted, losartan was added at a median dose of 1.0 mg/kg/day (range 0.5–1.5) during 2.1 years (range 0.5–5.0).

Results

The decrease in proteinuria with enalapril was 58.0 %, which was further reduced to 83.8 % from the initial value after losartan introduction. The percentage of reduction was significantly greater with the association of both drugs (p?=?0.0006) compared with the effect of enalapril exclusively (p?=?0.023). Serum potassium, glomerular filtration rate, and blood pressure remained unchanged.

Conclusions

Our results suggest that adding losartan to persisting proteinuric D + HUS children already on enalapril is safe and reduces proteinuria more effectively. Whereas this effect is associated with long-term kidney protection, it should be determined by prospective controlled studies.     

Characteristics of children with sporadic hemolytic uremic syndrome in a single Northern California center

Purpose

Hemolytic uremic syndrome (HUS) is a frequent cause of acute kidney injury in children. The aim of this study is to describe our experience at a Northern California center.

Methods

Medical records of children suffered from HUS (08/99 to 03/09) at University of California Davis Medical Center were reviewed.

Results

Forty-six children (70% girls) were studied, and their median age was 3.5?years. Diarrhea was a presenting symptom in 42 subjects (91%), and hematochezia was present in 31 children (67%). Escherichia coli 0157:H7 was isolated in 20 patients (44%). Thirteen subjects (28%) underwent dialysis for a median of 7?days during their hospitalization. Follow-up was achieved in 36 patients (78.3%) for a median of 16?months. One patient required angiotensin-converting enzyme (ACE) inhibitor for proteinuria but none was on dialysis.

Conclusions

In our cohort in children with HUS in a single Californian center, long-term complications were uncommon during a median follow-up time of 16?months.     

Use of eculizumab and plasma exchange in successful combined liver–kidney transplantation in a case of atypical HUS associated with complement factor H mutation

Background

Atypical hemolytic uremic syndrome (aHUS) evolves into end-stage renal failure in nearly half of affected patients and is associated with defective regulation of the alternative complement pathway. Patients with a complement factor H (CFH) mutation have a 30–100% risk of graft loss due to aHUS recurrence or graft thrombosis. Since CFH is produced predominantly by the liver, combined liver–kidney transplant is a curative treatment option. One major unexpected risk includes liver failure secondary to uncontrolled complement activation. We report a successful combined liver–kidney transplantation with perioperative plasma exchange and use of the humanized anti-C5 monoclonal antibody eculizumab.

Case Diagnosis/Treatment

An 11-month-old female presented with oliguric renal failure after 3 weeks of flu-like symptoms in the absence of diarrhea. Following the identification of Escherichia coli 0157:H7 in her stool, she was discharged home on peritoneal dialysis with a diagnosis of Shiga toxin-associated HUS. Three months later, she developed severe anemia, thrombocytopenia, and neurological involvement. aHUS was diagnosed and confirmed, and genetic testing revealed a mutation in CFH SCR20. Once donor organs became available, she received preoperative plasma exchange followed by eculizumab infusion with intra-operative fresh frozen plasma prior to combined liver–kidney transplant. At 19 months post-transplant, she continues to have excellent allograft and liver function without signs of disease recurrence.

Conclusion

Perioperative use of eculizumab in conjunction with plasma exchange during simultaneous liver–kidney transplant can be used to inhibit terminal complement activity, thereby optimizing successful transplantation by reducing the risk of graft thrombosis.     

Macrovascular involvement in a child with atypical hemolytic uremic syndrome

Background

Atypical hemolytic uremic syndrome (aHUS) is a disorder of the complement system which leads to thrombotic microangiopathy. It is caused by either acquired or hereditary defects in the activation or regulation of the alternative complement pathway and is therefore considered to be a disease of local complement dysregulation in microvasculature with predominantly renal involvement. However, extrarenal manifestations are observed in approximately one-fifth of aHUS patients, with the myocardium and central nervous system (CNS) being involved most often. Additionally, there have been a few reports of aHUS with cerebral artery stenoses or periphereal gangrene, suggesting the possibility of ‘macrovascular’ involvement in aHUS.

Case-diagnosis/treatment

We present a child with early onset aHUS and a C3 gain-of-function mutation who developed cerebral artery stenoses, leading ultimately to death due to a massive stroke 9 days after successful renal transplantation under prophylactic eculizumab treatment. Similar cases described in the literature are also briefly summarized.

Conclusions

The disease course in our patient with aHUS confirms that dysregulated complement activation can induce arterial steno-occlusive lesions in the absence of acute episodes of HUS. Further studies are required to document the frequency of such macrovascular complications and the role of eculizumab treatment in preventing their development and progression.     

Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab

Background

Atypical hemolytic uremic syndrome (aHUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Neonatal cases are extremely uncommon. Plasma therapy is the first choice therapy in patients with aHUS based on the belief of an underlying complement dysregulation. Alternatively, eculizumab, which targets complement 5, is used to block complement activation.

Case-diagnosis/treatment

Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn. Investigations revealed hemolytic anemia, thrombocytopenia, renal impairment, and a low serum C3, leading to the diagnosis of aHUS. Fresh frozen plasma (FFP) infusions and peritoneal dialysis for acute kidney injury were initiated. This approach yielded full renal and hematological remission. The patient was discharged with FFP infusions, but subsequently developed three life-threatening disease recurrences at 1, 3, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions. After the first dose of eculizumab, his renal and hematological parameters returned to normal and his blood pressure normalized. Genetic screening of the CFH gene revealed a novel homozygous p. Tyr1177Cys mutation.

Conclusion

Eculizumab can be considered as an alternative to plasma therapy in the treatment of specific patients with aHUS, even in infants.     

Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding

Background

Atypical hemolytic uremic syndrome (aHUS) is associated with mutations affecting complement proteins and regulators and with autoantibodies against complement factor H (CFH). Approximately half of the aHUS patients progress to end-stage renal disease. DNA analysis of the risk factor genes is important for prognosis of aHUS recurrence after renal transplantation.

Methods

Mutational screening of C3 encoding the central complement component was performed by Sanger sequencing in 70 aHUS patients. Mutated and wild type recombinant C3b proteins were produced and their affinity to CFH was analyzed by ELISA.

Results

A single novel missense change p.Lys65Gln in C3 was found in 3 aHUS patients. The alteration leads to decreased binding of C3b to CFH in vitro. All three patients acquired the illness as adults and had a first aHUS episode after renal transplantation or suffered recurrence of the disease after transplantation.

Conclusions

The novel C3 change was found in 3 aHUS patients. It results in decreased C3b binding to CFH and thus might lead to impaired C3b inactivation in vivo. The p.Lys65Gln is likely to be associated with aHUS after kidney transplantation and, therefore, might be an important prognostic factor.     

Serum ferritin as an indicator of the development of encephalopathy in enterohemorrhagic <Emphasis Type="Italic">Escherichia coli</Emphasis>-induced hemolytic uremic syndrome

Objectives

To investigate the diagnostic value of serum ferritin levels as a marker of disease activity and the development of encephalopathy in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli.

Methods

Twenty patients with HUS were studied. Serum ferritin levels were compared with clinical features and serum soluble tumor necrosis factor receptor (sTNFR) I and sTNFRII levels. Serum sTNFRI and sTNFRII levels were quantified by enzyme-linked immunosorbent assays.

Results

Serum ferritin levels were significantly elevated at the time of the diagnosis of HUS. Serum ferritin levels were significantly elevated in patients with encephalopathy compared to patients without encephalopathy. HUS patients with serum ferritin levels of >687.5 ng/ml were at high risk of encephalopathy. Serum ferritin levels were significantly positively correlated with serum sTNFRI and sTNFRII levels.

Conclusions

Serum ferritin levels are a promising indicator of the development of encephalopathy in HUS.

     

A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome

Background

Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes.

Case-Diagnosis

Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH.

Conclusions

This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses.     

Successful treatment of DEAP-HUS with eculizumab

Background

Deficiency of complement factor H-related (CFHR) proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) represents a unique subgroup of complement-mediated atypical HUS (aHUS). Autoantibodies to the C-terminus of CFH block CFH surface recognition and mimic mutations found in the genetic form of (CFH-mediated) aHUS. CFH autoantibodies are found in 10–15 % of aHUS patients and occur—so far unexplained—almost exclusively in the background of CFHR1 or CFHR3/CFHR1 deletions.

Methods

As a well-defined role for eculizumab in the treatment of complement-mediated aHUS is becoming established, its role in DEAP-HUS is less conspicuous, where a B-cell-depleting and immunosuppressive treatment strategy is being proposed in the literature.

Results

We here show eculizumab to be safe and effective in maintaining a disease-free state, without recurrence, in a previously plasma-therapy-dependent DEAP-HUS patient, and in another patient in whom, although showing a good clinical response to plasma therapy, the therapy was hampered by allergic reactions to fresh frozen plasma and contend there is a rationale for the use of eculizumab in concert with an immunosuppressive strategy in the treatment of DEAP-HUS. Considering the high rate of early relapse, the possible coexistence and contribution of both known and unknown complement-gene mutations, the probable pathogenic role of CFHR1 as a complement alternative pathway (CAP) regulator, the experimental nature of measuring and using anti-CFH autoantibodies to guide management, and until the positive reports of immunosuppression in addition to plasma therapy are confirmed in prospective studies, we feel that a complement-directed therapy should not be neglected in DEAP-HUS. Serial CFH autoantibody titer testing may become a valuable tool to monitor treatment response, and weaning patients off eculizumab may become an option once CFH autoantibody levels are depleted.

Conclusions

A prospective study of eculizumab treatment in a larger cohort of DEAP-HUS patients is required to validate the applicability of our positive experience.     

Case Series: Hemolytic Uremic Syndrome—Another Cause of Transplant Dysfunction

Background

Renal transplantation is the optimal treatment for suitable patients with end-stage renal disease (ESRD). However, acute graft dysfunction occurs in 5%–35% of patients. This is commonly due to acute rejection, drug toxicity, ureteric obstruction, or infection. Atypical hemolytic uremic syndrome (aHUS), either recurrent or de novo, is uncommon after transplantation.

Cases

We highlight three cases of acute transplant dysfunction in which transplant biopsy revealed HUS without associated clinical or hematologic clues to the etiology. Two cases had recurrent HUS and 1 had de novo HUS secondary to tacrolimus therapy. Screenings for ADAMTS-13 and gene mutations of complement regulatory proteins were negative. Thrombocytopenia and red blood cell fragments on blood film appeared some days later.

Treatment

Treatment comprised a combination of plasma exchange with fresh-frozen plasma and switching immunosuppressive therapy, which led to the recovery of the above hematologic features but salvaged graft function in only 1 case.

Conclusions

Classical hematologic findings of HUS appeared late in these cases. HUS should be considered in cases of allograft dysfunction where there is no obvious cause, and biopsy should be performed. This enables early initiation of therapy to gain rapid recovery of hematologic parameters and potentially of transplant function.     

Atypical hemolytic uremic syndrome: a clinical conundrum

Background

Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. However, STEC identification is limited by the natural history of HUS.

Methods

The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S). A single-center retrospective review (2003–2012) of 42 HUS patients (follow-up 31.3?±?38.7 months) was carried out. HUS was managed clinically with supportive treatments such as dialysis, plasma therapy, and eculizumab.

Results

There was no significant difference in the D+S+ (31 %), D+S? (50 %) and D?S? (19 %) groups in the outcome variables of chronic kidney disease stages I–II (100 % vs 81 % vs 67 %) and proteinuria at follow-up (20 % vs 12.5 % vs 33.3 %), hospitalization duration (16.0?±?8.7 vs 18.1?±?9.5 vs 23.7?±?12.9 days); dialysis requirement (50 % vs 81 % vs 66.7 %), and dialysis duration (10.2?±?1.9 vs 33.3?±?72.8 vs 10.3?±?8.1 days). There was no significant difference in study outcomes in STEC+ (59 %) versus STEC– (41 %) groups. Genetic testing was performed in 12 % of HUS patients based on age, recurrent HUS, familial HUS, persistently low C3, or prolonged dialysis, and 80 % of the patients tested were positive for genetic mutations.

Conclusions

Our study does not show poorer outcomes in STEC? HUS. Indications and the cost-effectiveness of genetic testing, eculizumab, and plasmapheresis in STEC? HUS need to be evaluated further.

     

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.¹ Recent work demonstrates that defects in regulation of the alternative pathway of complement are major risk factors for developing atypical HUS (aHUS), and mutations in numerous complement proteins have been identified in these patients.^2–5 Even in patients with mutations in complement regulatory proteins, however, the disease is episodic and is frequently triggered by a clinical illness or stressor.⁴ Disease flares have been associated with the use of calcineurin inhibitors, infection, pregnancy, and malignant hypertension.⁴ It has been proposed that these insults trigger intrarenal complement activation, but the mechanisms by which these different conditions activate the alternative pathway within the kidney are not known.Microparticles are submicrometer-sized membrane vesicles (0.05–1 μm) that are actively shed from cells in response to activation or injury.^6,7 Complement activation on the cell membrane can induce cells to release microparticles.^8,9 Although complement proteins can be detected on the surface of microparticles released from apoptotic and injured cells,¹⁰ less is known regarding whether microparticles from specific cell types themselves can cause complement activation. We hypothesized that injury of endothelial cells induces the release of complement-activating microparticles into the circulation. Because endothelial cells are in contact with complement proteins in the plasma, the release of complement-activating microparticles by endothelial cells could have a profound effect on intravascular complement activation.Cyclosporine (CsA) is a calcineurin inhibitor used as an immunosuppressive agent for the prevention of organ allograft rejection and as a treatment for autoimmune diseases. However, the use of CsA is associated with the development of vascular injury, nephrotoxicity, and hypertension, and aHUS.¹¹ Because of the association of CsA with renal toxicity, vascular injury, and aHUS, we examined whether exposure of endothelial cells to CsA could induce the release of microparticles, and we examined whether microparticles from CsA-exposed endothelial cells activate the complement system within the kidney.     

Impact of platelet transfusions in children with post-diarrheal hemolytic uremic syndrome

Background

Platelet transfusions should be avoided in children with post-diarrheal hemolytic uremic syndrome (D + HUS) because they might increase microthrombi formation, thereby aggravating the disease. As this possibility has not yet been explored, we investigated whether platelet transfusion in patients with D + HUS would lead to a worse disease course compared to that in patients who did not receive platelet transfusion.

Methods

This was a case–control study in which data from D + HUS children who received platelet transfusions (cases, n? = ?23) and those who did not (controls, n? = ?54) were retrospectively reviewed and compared.

Results

Both patient groups were similar in age (p?=?0.3), gender (p? =? 0.53), weight (p? = ?0.86), height (p? = ?0.45), prior use of non-steroidal anti-inflammatory drugs (p? = ?0.59) or antibiotics (p ?= ?0.45) and presence of dehydration at admission (p? = ?0.79). The two groups also did not differ in initial leukocyte count (p? = ?0.98), hematocrit (p? = ?0.44) and sodium (p? = ?0.11) and alanine aminotransferase levels (p? = ?0.11). During hospitalization, dialysis duration (p? = ?0.08), number of erythrocyte transfusions (p? =? 0.2), serum creatinine peak (p? = ?0.22), presence of severe bowel (p? = ?0.43) or neurologic (p? = ?0.97) injury, arterial hypertension (p? = ?0.71), need for intensive care (p? = ?0.33) and death (p? = ?1.00) were also comparable.

Conclusion

Our findings suggest that platelet transfusion does not aggravate the course of the disease. Conversely, no hemorrhagic complications were observed in the group of patients who did not receive a platelet transfusion. Until these observations are confirmed by further studies, the benefits and risk of platelet transfusion should be thoughtfully balanced on an individual case basis.     

Clinical characteristics and long-term outcome of diarrhea-associated hemolytic uremic syndrome: a single center experience

Objectives

To clarify the clinical characteristics and long-term outcomes of patients with diarrhea-associated hemolytic uremic syndrome (D?+?HUS) with a particular focus on time course.

Methods

We retrospectively analyzed the medical records of 61 patients with D?+?HUS who were admitted to Kobe University Hospital between 1995 and 2015. The onset of D?+?HUS was defined as day 1 of diarrhea.

Results

The age of onset was 4.1 (1.5–13.4) years, and the period between onset and diagnosis of D?+?HUS was 5 (3–18) days. The platelet count was lowest on day 7 (4–24), and the lactase dehydrogenase level was maximal on day 8 (4–25). Twenty-three patients required dialysis for 13 (2–37) days, starting at day 5–9. Seventeen patients showed central nervous system (CNS) symptoms at day 4–18. They were followed up for 3.7 (0–18.4) years. At the final follow-up, estimated glomerular filtration rate was 113.7 (57.9–159.9) ml/min/1.73 m² with five patients having chronic kidney disease. Three patients developed CNS sequelae. The time to diagnosis was significantly shorter in the group of patients receiving dialysis than without dialysis (p?=?0.018) and in the group with CNS complications than without (p?=?0.013).

Conclusion

CNS complications were often apparent after blood examination results improved. Moreover, a shorter period between the onset of diarrhea and a diagnosis of D?+?HUS indicated a more severe clinical course or long-term sequelae, and it should be considered as a risk factor for poor prognosis.

     

Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome

Background

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by chronic uncontrolled complement activation.

Case-diagnosis/treatment

We present a 4-year-old girl with aHUS who had multiple severe clinical manifestations of thrombotic microangiopathy (TMA) including acute kidney injury, dilated cardiomyopathy, and cardiorespiratory arrest. She was managed with intensive plasma exchange and hemodialysis, which could not halt the progression of TMA. The initial single dose of eculizumab only temporarily improved the clinical symptoms of TMA. Sustained improvement of renal, hematological, and cardiac values were only achieved upon institution of chronic treatment with eculizumab. During long-term treatment with eculizumab (>2.5 years), she has had no further clinical manifestations of TMA, and required neither plasma exchange nor hemodialysis.

Conclusion

Chronic eculizumab treatment was associated with control of complement-mediated TMA and sustained long-term improvement in renal and cardiac function.     

Chlamydia pneumoniae and osteoporosis-associated bone loss: a new risk factor?

Summary

We found an association between the presence of Chlamydia pneumoniae DNA both in osteoporotic bone tissue and peripheral blood mononuclear cells (PBMCs) and the increase in circulating resorptive cytokines.

Introduction

Our study was designed to determine whether C. pneumoniae infection may be involved in osteoporosis-associated bone loss.

Methods

The study included 59 women undergoing hip joint replacement surgery for femoral neck fracture: 32 with osteoporosis and 27 with osteoarthritis. A total of 118 tissue specimens (59 bone tissues, 59 PBMCs) were examined for C. pneumoniae DNA by real-time polymerase chain reaction (PCR). Serum levels of soluble receptor activator of nuclear factor kappa B ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 were also measured.

Results

C. pneumoniae DNA was detected in osteoporotic bone tissue whereas it was not found in non-osteoporotic bone tissue (p?<?0.05). A significantly higher rate of C. pneumoniae DNA (p?<?0.05) was found in PBMCs of osteoporotic patients than in those of osteoarthritis patients. Among osteoporotic patients, serum sRANKL, IL-1, and IL-6 concentrations as well as sRANKL/OPG ratio significantly differ between patients with bone tissue and PBMCs positive to C. pneumoniae and C. pneumoniae-negative patients.

Conclusion

The association between the presence of C. pneumoniae DNA, both in bone tissue and PBMCs, and the increase in sRANKL/OPG ratio as well as in IL-1β and IL-6 levels observed in osteoporotic patients suggests C. pneumoniae infection as a new risk factor for osteoporosis.