Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators’ assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI.
Introduction
Patients with malignant hematological diseases receiving remission-induction chemotherapy are at a high risk of contracting severe and sometimes lethal invasive fungal infections, especially invasive pulmonary aspergillosis (IPA) [1–4].
Voriconazole follows itraconazole as the second triazole-antifungal agent with an enhanced spectrum of activity against numerous clinically important fungi. This activity is achieved by inhibition of fungal cytochrome P450-mediated 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis. Subsequent loss of ergosterol in the fungal cell wall and accumulation of 14α-methyl sterols are the primary mode of action of voriconazole.
Among the properties of voriconazole are in vitro fungistatic activity against most Candida spp., including those resistant to fluconazole [5–7], fungicidal activity against several Aspergillus spp. [8–10] as well as profound activity against Fusarium spp. [8–13], Scedosporium spp. [14], Cryptococcus spp. [7] and other rare yeasts, molds and dermatophytes, such as Trichosporon spp., Blastomyces spp., Histoplasma capsulatum and Coccidioides immitis [14, 15]. In a controlled clinical trial, voriconazole proved superior efficacy and improved survival when compared with amphotericin B deoxycholate in the treatment of invasive aspergillosis [16]. Voriconazole has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) for treatment of invasive aspergillosis, invasive candidiasis in non-neutropenic patients, esophageal candidiasis as well as serious infections caused by Scedosporium apiospermum and Fusarium spp. in cases refractory to or intolerant of first line treatment [17]. Availability of oral (tablets, suspension) and intravenous preparations along with a favorable safety profile make voriconazole a popular drug among clinicians in cases of suspected or proven invasive fungal infection alike. Voriconazole has become a well-accepted treatment option in probable and proven IFI [18].
Controlled clinical trials are an imperative tool for testing drug efficacy and safety in an idealized study population. To allow comparison between clinical trials, the European Organisation for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) have established criteria for the diagnosis of IFIs [21]. These criteria classify IFIs as possible, probable, or proven according to diagnostic test results. Basically, these criteria demand major clinical signs in combination with host factors for a possible diagnosis. For a probable diagnosis, certain microbiological criteria (e.g. serum galactomannan) must be fulfilled, while a proven diagnosis demands histopathological findings or positive culture from a primary sterile site. However, trial results do not always translate into everyday clinical practice. We therefore conducted a multi-centre survey to evaluate efficacy and safety as well as common treatment indications and prescribed dosing of voriconazole outside clinical trials.
Methods
Participating investigators were asked to document all patients receiving voriconazole via online electronic data capture. Data were collected retrospectively after treatment completion. Collected data comprised demographic information, underlying disease, indication for treatment, earlier antifungal treatment, risk factors for invasive fungal infection, clinical outcome (including results of diagnostic imaging, microbiology, lab results, vital signs and survival), occurrence of adverse events, concurrent medication, and evaluation of response. Treatment outcome was evaluated by the investigator. Data were monitored electronically and manually for plausibility and completeness and queries were raised to the investigators in cases that were unclear or incomplete.
An analysis was conducted after submission of 100 episodes. The objective of the analysis was the evaluation of drug safety and efficacy as well as dosing habits and indications for voriconazole therapy by means of descriptive analysis. All episodes were registered in the period from September 2004 to November 2005. Drug toxicities were evaluated applying common toxicity criteria (CTC) [19].
Results
One-hundred patient courses from the hematological units of five different centers (43 from Frankfurt am Main, 42 from Oldenburg, 10 from Cologne, 4 from Frankfurt an der Oder and 2 from Mainz) were successfully enrolled in the survey. All relevant data concerning the survey objectives were present. The most frequent underlying disease was hematological malignancy (94%). A total of 15 patients underwent stem cell transplantation, 12 of these were allogeneic and 8 showed signs of acute or chronic graft-versus-host disease (GvHD). The five patients with other hematological diseases were two patients with aplastic anemia, two with myelodysplastic syndrome and one with osteomyelofibrosis. Almost half of the patients (N = 48) were isolated by means of reverse isolation, 27 patients had air conditioning with high-efficiency particulate air filters (HEPA). Only 14 patients were accommodated with no isolation at all (Table 1).
Table 1Patient characteristics at baseline and subsequent voriconazole exposure (N = 100)Age (years)a
59 (24–84)Female37 (37%)Mean weight in kg (±SD)76.2 (±14.7)Underlying diseaseb
Acute myeloid leukemia72 Acute lymphoblastic leukemia9 Low grade non-Hodgkin lymphoma4 Other hematological malignancy9 Other non-malignant hematological disease5 Solid tumors3Stem cell transplantation15 Unrelated donor8 Sibling donor4 Autologous3Graft-versus-host disease8Isolation Reverse isolation48 HEPAc
27 No isolation14 LAF9 HEPAc + reverse isolation2Treatment indication Primary prophylaxis3 Empirical therapy21 Suspected or proven IFI57 Secondary prophylaxis19Days on voriconazole (±SD)26.7 (±43.3)
aMedian
bTwo patients with multiple cancers
cHigh efficiency particulate air filter
The most common indication for voriconazole treatment was suspected or proven IFI by assessment of the investigator (N = 57), 21 patients received voriconazole as empirical treatment for an episode of fever of unknown origin (FUO) while considered at risk for an IFI. Other treatment indications were prophylaxis of IFI (N = 22), 19 of which were considered as secondary prophylaxis after an earlier episode of IFI. On average, treatment duration was 27 days (Table 1). Fifteen patients died during the observation period. Causes of death were severe sepsis with multi-organ failure (N = 6), progression of the underlying disease (N = 4), progression of IFI (N = 4) and severe arrhythmia with cardiac arrest (N = 1). The investigator attributed the lethal arrhythmia to hypokalemia several days after switching antifungal therapy from voriconazole to liposomal amphotericin B.
For the 57 patients receiving voriconazole for treatment of suspected or proven IFI, the lung was the most common site of infection (N = 55). Microbiological evidence was obtained in two cases of candidemia, one invasive pulmonary aspergillosis and one Geotrichum capitatum fungemia. All other patients had suspected invasive pulmonary aspergillosis by the investigator’s assessment. Frequent risk factors were exposures to dust due to nearby construction sites (N = 47), leukopenia (N = 43), indwelling central venous catheters (N = 39), immunosuppressive therapy (N = 35) and mucositis (N = 25). The initial daily voriconazole dose averaged 6.8 mg/kg. Almost half of the patients were treated orally from the beginning (N = 27). In 21 of the remaining 30 patients, therapy was later switched to oral administration. Treatment success was rated by the investigators as complete or partial response in 35 (61.4%) patients. Disease remained stable in another 11 (19.3%) patients. Progressive disease was diagnosed in the remaining 11 patients (19.3%). Fifteen (26.3%) patients were switched to a different antifungal class (Table 2).
Table 2Characteristics of patients with suspected or proven IFI by assessment of the investigator (N = 57)Site of infectiona
Lung55 (96.5%) Blood (fungemia)2 (3.5%) Sinus2 (3.5%) CNS1 (1.8%) Liver1 (1.8%)Risk factors Diabetes mellitus4 (7%) HIV1 (1.8%) Leukopeniab
43 (75.4%) Mucositis25 (43.9%) Prior IFI7 (12.28%) Central venous catheter39 (68.4%) Dust exposure47 (82.5%) Surgery1 (1.8%) Cytarabine14 (24.6%) Purine analogues7 (12.3%) Steroids10 (17.5%) Other immunosuppressant4 (7%)Days with fever (±SD)7.6 (±6.54)Total days on antibiotic treatment (±SD)29.3 (±18.30)Days on voriconazole (±SD)26.6 (±26.76)Average initial voriconazole mg/kg (range)6.8 (3.125 – 13.559)Route of administration Oral only27 (47.4%) Switch to oral21 (36.8%) Switch to intravenous4 (7.0%)Outcomec
Complete response19 (33.3%) Partial response16 (28.1%) Stable disease11 (19.3%) Progressive disease11 (19.3%)Switch to other antifungal15 (26.3%) Liposomal amphotericin B8 (14.0%) Caspofungin5 (8.8%) Other2 (3.5%)
aSuper additive because of patients with multiple infection sites
bAs defined as less than 1,000 leukocytes/μl
cAs assessed by investigator
An evaluation of the investigators’ adherence to EORTC/MSG criteria showed a discrepancy between the softer criteria used in recent clinical trials [16, 20] and the official 2002 criteria [21]. While recent trials allowed the investigator to rate evidence as probable without microbiological findings, the official criteria demand at least one microbiological criterion. Thus, 35 of the 57 cases with suspected or proven IFI had probable IFI according to the softer criteria, but only four patients had probable IFI when applying the official EORTC/MSG criteria. Independent of the applied edition of the EORTC/MSG criteria, 19 patients did not meet the requirements for classification of evidence even as possible (Table 3).
Table 3Evidence rating for patients with IFI suspected or proven by the investigator (N = 57)Investigator assessmentAccording to criteria from recent clinical trials [16, 20]According to EORTC/MSG 2002 [21]Proven3/57 (5.3)2/57 (3.5)2/57 (3.5)Probable26/57 (45.6)35/57 (61.4)4/57 (7.0)Possible14/57 (24.6)1/57 (1.8)32/57 (56.1)Not defined14/57 (24.6)19/57 (33.3)19/57 (33.3)Values in parenthesis are in percentage
In the 21 patients, where voriconazole was given as empirical therapy, oral administration was preferred (N = 16). Average duration of fever was higher than in those with suspected or proven IFI, averaging 11.6 days. Treatment duration averaged 9.7 days, markedly shorter than the other subgroups. Eleven patients improved under empirical treatment, six were stable while four showed signs of progressive infection. There was a frequent switch of therapy to antifungals of different classes, i.e. liposomal amphotericin B (N = 3), caspofungin (N = 4) or their combination (N = 1) (Table 4).
Table 4Voriconazole dosing and treatment outcomeEmpirical treatment (N = 21)Secondary prophylaxis (N = 19)Average initial voriconazole dose in mg/kg (range)5.7 (2.469–10.870)5.7 (3.3–7.5)Route of administration Oral only16 (76.2%)18 (94.7%) Switch to oral2 (9.5%)0 Switch to intravenous–1 (5.3%)Days with fever (±SD)11.6 (±11.17)n. a.Days on antibiotic treatment (±SD)29.8 (±13.55)n. a.Days on voriconazole (±SD)9.7 (±6.94)48.8 (±84.31)Breakthrough IFIn. a.4 (21.1%)Outcomea
Progressive disease4 (19.1%)n. a. Stable disease6 (28.6%)n. a. Partial response1 (4.8%)n. a. Complete response10 (47.6%)n. a.Switch to other antifungal8 (38.1%)7 (36.8%) Liposomal amphotericin B3 (14.3%)2 (10.1%) Caspofungin4 (19.1%)5 (26.3%) Liposomal amphotericin B + caspofungin1 (4.8%)0
Almost all patients on voriconazole as secondary prophylaxis (N = 19) received their treatment orally (N = 18). Mean treatment duration was 48.8 days. Four breakthrough IFIs were reported. Therapy was switched to other antifungals in seven cases, most often to caspofungin (N = 5) (Table 5).
Table 5Other adverse events (N = 100)Visual disturbance6Nausea3Rash3Hallucination2Vomiting2Diarrhea1Drug fever1Edema1Adverse events at least possibly related to voriconazole by judgment of the investigator
The most frequent adverse events at least possibly related to voriconazole treatment by the investigators were visual disturbances (N = 6), nausea (N = 3) and rash (N = 3) (Table 6). At least one liver function test showed grade 3–4 toxicity, applying the common toxicity criteria in 15 cases, seven of which were attributed to voriconazole by the investigators. In this survey, gamma glutamyl transpeptidase was the most sensitive marker for voriconazole toxicity, showing a marked elevation in 12 cases of investigator attributed toxicity. However, no definite preference could be detected for any of the liver parameters assessed. None of the four patients with grade 3–4 nephrotoxicity were attributed to voriconazole (Table 6).
Table 6Highest grade of treatment-emergent renal and hepatic adverse eventsCTC-toxicity [19]Grade-1 (%)Grade-2 (%)Grade-3 (%)Grade-4 (%)
N evaluableLiver GOT (AST)29 (31.5)5 (5.4)2 (2.2)2 (2.2)926 (6.5)a
1 (1.1)a
1 (1.1)a
1 (1.1)a
GPT (ALT)20 (20.2)4 (4)1 (1)1 (1)993 (3)a
3 (3)a
0 (0)a
1 (1)a
GGT14 (15.7)14 (15.7)11 (12.4)0 (0)893 (3.4)a
4 (4.5)a
5 (5.6)a
0 (0)a
AP17 (19.5)4 (4.6)2 (2.3)0 (0)877 (8)a
1 (1.2)a
1 (1.2)a
0 (0)a
Bilirubin10 (11)5 (5.5)4 (4.4)2 (2.2)913 (3.3)a
3 (3.3)a
3 (3.3)a
1 (1.1)a
Kidney Creatinine11 (11)6 (6)2 (2)2 (2)1002 (2)a
1 (1)a
0 (0)a
0 (0)a
Values given in parenthesis are in percentage
aToxicity judged at least possibly attributable to voriconazole treatment by the investigator
Discussion
In our survey, voriconazole was efficacious in 61.4% of patients treated for suspected or proven IFI (by assessment of the investigator). Favorable response was documented for 52.4% of patients receiving voriconazole as empirical therapy. This observation is comparable to prior results. For the treatment of suspected or proven IFI, especially IPA, investigator assessed favorable results defined as complete or partial responses were obtained in 61.4% as compared to 52.8% in Herbrecht’s trial [16]. In the empirical setting, favorable response was reported in 52.4%, while only a 26% overall response was reported previously [22]. However, the outcome evaluation was supposedly far more rigid in the clinical trials than the self-assessment of the registry contributors.
When compared to earlier prospective controlled clinical trials [16, 22], adverse events were less common. Visual disturbances were only reported in 6% and hallucinations in 2% as compared to 44.8 and 6.6%, respectively, in aspergillosis [16] and to 21.9 and 4.3%, respectively, in febrile neutropenia [22]. However, adverse event reporting is naturally less stringent in a survey than in controlled clinical trials.
Analysis of survey data did not reveal yet unknown toxicities of voriconazole. Treatment-related grade 3 or 4 hepatotoxicity was observed in 15 patients. Further frequent adverse events were visual disturbances (6%), rash (3%) and nausea (3%).
Significant elevations of serum alkaline-phosphatase activities (>3× baseline value) occurred in 2.9% compared to 2.3% of grade 3–4 CTC toxicity in our study, aspartate aminotransferase (>3× baseline value) in 8.9 versus 4.4%, alanine aminotransferase (>3× baseline value) in 7.2 versus 2% and bilirubin (≥1.5× baseline value) in 27.2 versus 6.6% [22].
Our survey demonstrates that clinical reality regularly strays from approved indications and evidence based choice of treatment. A total of 43% of the reported patients received voriconazole prophylactically or empirically. One third of the 57 patients with voriconazole for treatment of actual IFI lacked sufficient evidence of IFI according to EORTC/MSG criteria [21]. Thus, a rate of as much as 62% may be considered as off-label use. Furthermore, all randomized controlled clinical trials on voriconazole used the intravenous formulation as initial treatment. Despite this, 39.5% of patients with at least possible IFI were started on oral voriconazole. Looking at these figures, one could claim that only 23% of the patients reported were treated as approved by the German health administration and according to best scientific evidence. But does this mean patients were not treated in their best interest?
The difficulty of proving IFI remains a dilemma in choosing adequate treatment. There is still no sensitive and specific non-invasive method for detection of invasive pulmonary aspergillosis (IPA) [21, 23–25]. Controlled clinical trials on antifungal agents normally use the current EORTC/MSG criteria with or without modifications, while the consensus committee clearly discourages from clinical decision-making based on their guideline [21]. Additionally, especially in palliative situations, long-term inpatient treatment with intravenous antifungals is often undesirable. Finally, no antifungal has yet been approved for secondary prophylaxis of IPA.
In the above clinical situations, voriconazole offers a flexible and tolerable treatment option. Still, the many difficulties in the diagnosis and treatment of invasive fungal infections should not be used as a carte blanche in clinical decision making. Physicians should strive towards establishing the most accurate diagnosis possible and then treat according to current evidence.

fungal infection
voriconazole
antifungals
prophylaxis
aspergillosis
candidiasis
drug therapy


Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children

The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) is variable (~30%) The incidence of recurrence is less in African-Americans than in whites and Hispanics Graft survival rates are decreased in recipients with FSGS, especially if remission of the NS is not achieved in those with recurrence Although controversial, the use of living donor (LD) transplants are not contraindicated; however, obligatory heterozygote parental grafts with a podocin mutation should be used with caution Optimal treatment to induce a remission post-transplant has not been delineated Pre-transplant and/or prophylactic post-transplant pre-operative plasmapheresis (PP) for high-risk patients—especially those with recurrence in a previous graft—may be promising An international multicenter controlled study is required to delineate the optimal approach to prevent and/or treat the recurrence of NS/FSGS
Introduction
Focal segmental glomerulosclerosis (FSGS) is a histologic (pathologic) diagnosis that encompasses numerous specific clinical entities with potential varied etiologies. Steroid-resistant nephrotic syndrome (SRNS) is a specific clinical phenomenon that may vary histologically from minimal change nephrotic syndrome (MCNS) to FSGS, but it also may be associated with other specific histological diagnoses.
The most frequently acquired disease resulting in end-stage renal disease (ESRD) in children is FSGS, accounting for 8.3% of the chronic renal insufficiency (CRI) patients, 14.3% of the dialysis patients, and 11.4% of the transplant recipients included in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry [1].
In 1972, Hoyer et al. [2] from Minnesota described the recurrence of NS in 3/4 pediatric renal allograft recipients whose original disease was FSGS. At post-mortem examination, the lesion of FSGS was present in the grafts of two recipients [2]. An editorial accompanying the publication of this article in Lancet stated that “renal transplantation may be contraindicated (in patients with FSGS) leaving dialysis as probably the only means of prolonging life” [3].
The purpose of this teaching review article will be to address the factors that influence the incidence of recurrence of NS/FSGS in renal allografts, establish the known risk factors for recurrence, and delineate the current preventive and therapeutic approaches to the recurrence of NS/FSGS in pediatric renal allograft recipients.
What is the incidence of recurrence of post-transplant NS/FSGS?
The general consensus is that 30–40% of recipients whose original disease was NS/FSGS will clinically manifest recurrence [4]. In most instances, recurrence is clinically apparent in the immediate post-transplant period, frequently with substantive proteinuria in the initial 24 hours following transplantation. However, the onset of clinical recurrence has been reported to occur at more than one year following transplantation. The delay in initial clinical manifestations may be coincident to the occurrence of acute tubular necrosis (ATN), which occurs more frequently in live donor (LD) and deceased donor (DD) recipients with FSGS [5]. It has been proposed that the “immediate fulminate recurrence of NS/FSGS post-transplant likely predisposes such grafts to ATN and explains the increased incidence of ATN in this patient population [5].
What is the incidence of subsequent recurrence in a patient who manifested clinical recurrence in a previous graft?
Re-transplantation of a recipient with recurrence of NS/FSGS in a previous graft has been associated with a ~80% recurrence rate [4]. Recently, a 100% recurrence rate has been reported in ten recipients of a second (6), third (3), and fourth (1) transplant [6]. Therefore, proceeding with a subsequent transplant in a patient who manifested previous recurrence has been discouraged. Recently, pre-operative plasmapheresis (PP) was successful in preventing clinical recurrence in 3/6 patients whose initial graft was lost in association with clinical recurrence [7].
What is the incidence of recurrence in recipients with mutations of genes that encode for podocin?
The association of mutations impacting on the structure of the foot processes in the region of the slit diaphragm of the glomerular basement membrane in patients with sporadic and familial NS has potentially delineated the pathophysiology of the NS in such patients [8]. Initial publications indicated that the incidence of recurrence of NS/FSGS in patients with podocin mutations was similar to that reported for all patients with NS/FSGS [9]. However, a recent analysis of 73 patients with either homozygous/compound heterozygous (65) or heterozygous (8) mutations revealed a 7.7% incidence in the former and a 62.5% incidence in the latter recipients [10]. If these data are confirmed, it would seem advantageous to test all potential recipients with ESRD secondary to NS/FSGS for such mutations in order to delineate an optimal transplant strategy.
Do patients with the glomerular tip lesion who receive a renal allograft manifest recurrence of the NS?
Howie et al. [11] reported that 12 of 14 recipients whose native kidney manifested the glomerular tip lesion had clinical recurrence of the NS post-transplant. In all 12 recipients, the glomerular tip lesion was the only histologic abnormality on graft biopsy. These data support the concept that the glomerular tip lesion may be the earliest histologic abnormality in the NS/FSGS spectrum of disease. Precise incidence and outcome data await subsequent reports.
Does race impact on the recurrence of NS/FSGS?
Although the disease process appears more virulent in African-American (AA) children with NS/FSGS [12], it is interesting that the incidence of recurrence following transplantation in this ethnic population is decreased. At least three studies [5, 13, 14] have shown that the incidence of recurrence in the AA recipient was <50% of that in the Caucasian recipient. Hispanic recipients had an incidence similar to that of Caucasians. The precise reason for this disparity in incidence has not been delineated.
Has the incidence of recurrence changed with the introduction of new immunosuppressive regimens?
Since the initial publication in 1972 of Hoyer et al. [2], there has been a significant change in the available immunosuppressive agents and regimens to both prevent and treat rejections. Despite these regimens, which have substantially reduced the incidence of acute rejection episodes and markedly improved short-term allograft survival rates, the incidence of recurrent NS/FSGS has remained unaffected [14]. Bartosh et al. [14] reviewed the NAPRTCS database for the period 1998–2003 and found the incidence of recurrence was 31%, which was similar to the incidence in the initial NAPRTCS report for the period 1987–1990 [4].
What are the risk factors for the recurrence of NS/FSGS?
Three factors identified in the 1970s to be associated as risk factors for recurrence were: (1) the rapid progression to ESRD in a period of <3 years; (2) the presence of mesangial hypercellularity on biopsy; and (3) the age at onset of the clinical NS of >6 years. More recently, the presence of a circulating permeability factor [15], the use of induction therapy in the immunosuppressive regimen [16], and native kidney nephrectomy either prior to or at the time of transplantation [17] have been reported to be associated with an increased risk of recurrence.
Does the presence of an identified circulating factor predispose to the recurrence of NS/FSGS?
Savin et al. [15] showed that the presence of a permeability factor (Palb) with an activity of ≥0.50 was associated with a recurrence rate of 86% (6/7), whereas an activity of <0.50 was associated with a recurrence rate of 17% (4/23). Plasmapheresis was associated with both a reduction in the Palb activity and in urinary protein excretion.
Is induction therapy a risk factor for the recurrence of NS/FSGS?
Raafat et al. [16] noted a recurrence rate of NS/FSGS of 43% between 1968 and 1997. However, it was only 11% (1/9) in those who did not receive induction, whereas it was 53% (15/28) in those receiving some form of antilymphocyte serum (ALS). Conversely, Gagnodoux [17] reported an incidence of recurrence of 31% prior to 1985 when no induction therapy with antilymphocyte globulin/antithymocyte globulin (ALG/ATG) was used compared to 30% following the introduction of induction therapy. Both Sheth et al. [18] and Hubsch et al. [19] noted a significant increase in the incidence of recurrence (17.6% vs 37.5% and 38% vs 83%, respectively) with the use of anti-IL2 receptor antibody as induction therapy. In the most recent analysis of NAPRTCS for the period 1998–2003, Bartosh et al. [14] noted an overall incidence of recurrence of 31% (51/165), which was similar to no induction (30%) or the use of polyclonal antibody (27%) or monoclonal antibody (33%). Therefore, advocating the restriction of induction therapy to reduce the incidence of recurrence awaits the performance of a multicenter prospective randomized controlled study.
Is native nephrectomy a risk factor for the recurrence of NS/FSGS?
Analysis of the recent NAPRTCS database [14] indicated a significant (p < 0.001) difference in the incidence of recurrence in recipients who had undergone prior native kidney nephrectomy (50%) compared to those whose native kidneys were not removed prior to or at the time of transplantation (22%). A possible explanation for this phenomenon was that the native kidneys provided a “sponge” for any circulating putative antibody and that native nephrectomy facilitated a sufficient level of circulation of such antibodies which were deposited in the graft precipitating recurrence. Other reports [20] have come to the same conclusion.
Does the recurrence of NS/FSGS impact on the allograft survival rate?
Baum et al. [21] in 2002 and Bartosh et al. [14] in 2004 reviewed the NAPRTCS database, which indicated inferior long-term graft survival rates in both recipients of LD and DD grafts whose original disease was FSGS. Analysis of the UNOS database demonstrated a similar disadvantageous graft survival rate for recipients whose original disease was FSGS compared to recipients with other primary renal diseases [22].
A consensus is that 50% of the grafts with the recurrence of NS/FSGS are lost, presumably as a result of the recurrent pathologic process. However, data from Schachter and Harmon [23] noted that long-term survival rates significantly (p = 0.002) improved in those recipients with recurrence who achieved remission with some therapeutic intervention compared to those who failed to go into remission and had persistent NS.
Does age at the time of transplantation impact on graft survival in recipients with FSGS?
Adolescent recipients (13–17 years of age) with FSGS have a significantly poorer graft survival rate with both LR and DD grafts compared to younger recipients (0–12 years of age) [21]. In actuality, the 0–12 year-old recipient DD graft survival rate was similar in the FSGS and no FSGS groups. The specific reason for this phenomenon is not known. However, Scientific Registry of Transplant Recipients (SRTR) data have consistently demonstrated that adolescent recipients have substantially poorer long-term graft survival rates, which approach that of recipients >65 years of age at transplantation [24].
Should an LD graft be utilized in children with ESRD secondary to FSGS?
At least five reports from 1989 to 1999 [4, 25–28] concluded that recipients with FSGS had a greater risk of allograft failure from an LD graft than from a DD graft. A precise reason for this phenomenon was not delineated.
In 2001, Baum et al. [5] reviewed the NAPRTCS database and showed that the 5-year LD graft survival rate was 69% for recipients with FSGS compared to 82% with no FSGS (p < 0.001), whereas it was 60% and 67%, respectively, in the DD groups. The authors concluded that the long-term advantage of LD grafts was lost in recipients with FSGS.
Conversely, Huang et al. [22] proffered that, although the LD advantage was not observed in AA pediatric recipients, the authors recommend that LD transplantation be considered for all racial groups with FSGS.
With this potential excellent outcome with newer preventative and therapeutic regimens for recurrence to be detailed subsequently, the previous concerns regarding the use of an LD graft may not be appropriate. However, the recurrence of NS/FSGS in two recipients with a homozygous podocin mutation who received an LD graft from their obligatory heterozygote mother indicates that the obligatory heterozygote parental donor may not be ideal [29, 30]. Similarly, the development of FSGS and ESRD in three donors [28, 31] at some point following donation also indicates that appropriate informed consent should be obtained prior to utilizing an LD graft in recipients with FSGS.
What are the therapeutic options available to produce a remission following the recurrence of NS in recipients with FSGS?
In 1988, Laufer et al. [32] reported the remission of NS in two pediatric recipients following nine sessions of PP at 3 and 6 months post-transplant. Both recipients manifested prolonged ATN. This led to the general use of PP in patients with recurrence. However, no randomized control trial was ever performed and the rate of remission has been variable.
Ingulli et al. [33] in 1990 reported the success in inducing a remission with high-dose cyclosporine in three pediatric recipients. The rationale for the increased dosage was that hyperlipidemia bound the cyclosporine and higher doses were required to achieve adequate bioavailability. The precise dose and length of treatment with the “high-dose” regimen were never delineated in a controlled trial. However, this report led to the general approach of using a higher maintenance dosage of cyclosporine once a remission was obtained.
Recently, Raafat et al. [34] reported a recurrence rate of 67% (16/24) in recipients with FSGS between 1991 and 2003. The oral dose of cyclosporine was increased to 24 mg/kg/day until either remission was achieved or renal toxicity was evident. Complete remission was achieved in 69% (11/16) within 14 days to 19 months (10/11 within 3 months) and 12% (2/16) had a partial remission. Concomitant PP was administered to 7/16 recipients with recurrence.
Cochat et al. [35] in 1993 introduced a regimen of PP and cyclophosphamide in three patients who remitted within 12–24 days. This regimen has been adopted by some centers, especially for patients who failed to remit with PP alone. However, again, no controlled trial has been performed.
Plasma protein absorption was introduced by Dantal et al. [36] in 1994 for recipients with an identified circulating factor. Although proteineuria was reduced in the eight patients treated, it was permanent in only one patient following discontinuation of the procedure. Subsequent reports utilizing this technique in pediatric recipients are limited.
Recently, Salomon et al. [37] reported an 82% (14/17) remission rate utilizing IV Cyclosporine at 3 mg/kg/day to reach a cyclosporine level of 250–350 mg/dl. These data add to the potential utility of high-dose cyclosporine in inducing a remission following the recurrence of NS/FSGS.
With the use of angiotensin-converting enzyme/angiotensin receptor blocker (ACE/ARB) therapy to reduce proteinuria in patients with various forms of renal disease, it would seem logical to extend the use of these agents to recipients with the recurrence of NS/FSGS. However, there has been no controlled study of the use of these drugs either alone or as adjunctive to other therapeutic regimens.
Can pre-operative PP reduce the risk of recurrence of NS/FSGS?
Ohta et al. [38] in 2001 reported the recurrence of NS/FSGS in 9/21 grafts. Pre-operative PP was performed in 15 and recurrence developed in five, whereas 4/6 without pre-operative PP developed recurrence. The authors concluded that pre-operative PP was effective in preventing the recurrence of NS/FSGS.
At the International Pediatric Transplant Association (IPTA) Congress in August 2005, Rainthavorn et al. [39] from the UCLA reported a recurrence rate of 100% in three recipients of DD grafts who received one session of pre-operative PP, whereas it was 57% (4/7) in recipients of LD grafts who received <5 pre-operative PP and 0% in three recipients who received >5 pre-transplant PP sessions. The authors concluded that >5 pre-operative PP sessions prevented the recurrence of NS/FSGS.
Kawamura et al. [40], at the same IPTA congress, reported a recurrence rate of 15.4% (2/13) in LD recipients who received 1–2 pre-operative PP sessions, as well as native kidney nephrectomy. Recurrence was evident at 6 days and 8 months post-transplant, respectively, and remitted with post-transplant PP.
A recent publication involving primarily adult recipients (9/10 were adult) utilized a combination of pre- and post-operative PP in high-risk patients—six with recurrence in a prior graft and four with rapid progression to ESRD (<3 years) [7]. The LD recipients received eight courses of PP over a two-week period—one week prior to and one week following transplantation. The DD recipients initiated PP within 24 hours of transplantation and continued for two weeks post-transplant. There was no recurrence in the four recipients with rapid progression to ESRD and 3/6 recipients with a recurrence in a prior graft had no recurrence.
Certainly, the utilization of pre-operative and prophylactic post-operative PP appears promising in high-risk patients. Controlled multicenter trials are warranted to delineate the optimal preventative and therapeutic approaches.
Conclusions
The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) has remained at ~30% for the past four decades, despite the introduction of newer and more potent immunosuppressive regimens. Multiple risk factors have been identified to predispose or precipitate clinical recurrence. However, no prospective multicenter studies have validated the relationships. Mutations of the gene encoding for podocin may identify a population of patients with NS/FSGS who are at a lower risk for clinical recurrence. Because of the potential for an increased incidence of recurrence and/or graft loss, living donor (LD) grafts should be used with constraint. Graft survival rates in recipients with NS/FSGS are decreased. However, if a remission can be induced, the outlook for long-term graft survival is substantially improved.
Various therapeutic regimens, including pre-operative plasmapheresis (PP), high-dose cyclosporine, IV cyclosporine, and adjunctive cyclophosphamide, have proven to be effective. However, there have been no multicenter controlled studies to delineate the optimal therapeutic approach. Recent use of pre-operative and/or post-operative prophylactic PP to prevent the recurrence of NS/FSGS is exciting. Controlled trials are required to validate efficacy and delineate a precise preventative regimen.
Questions (Answers appear following the references)The incidence of recurrence of FSGS is:
Comparable in whites and African-AmericansLess in whites than HispanicsLess with re-transplants than with primary graftsNot influenced by pre-transplant plasmapheresisBetween 30% and 40%The use of a deceased donor is mandatory in a patient with FSGS when:
A living donor graft is not availableThe initial graft was lost as a result of recurrenceThe parental donor is not an obligatory podocin heterozygoteThe potential live-donor is a haplotype mismatchThe potential live-donor is a B-antigen mismatchGraft survival following the recurrence of NS in a patient with FSGS is dependent upon:
A reduction in the magnitude of proteinuria to 3.0 g/kg/dayThe lack of histologic evidence of FSGS during the initial post-transplant monthInducing a complete remission of the NSThe immediate use of post-transplant plasmapheresisThe use of a one haplotype-matched live-related donorThe optimal approach to prevent the recurrence of NS in patients with FSGS:
Includes cyclophosphamide and plasmapheresisIncludes one week of pre-transplant plasmapheresisIncludes post-operative tacrolimus and plasmapheresisIncludes post-operative sirolimus and plasmapheresisHas not been delineatedThe recurrence of NS in patients with congenital nephrotic syndrome:
Has not been reported with the “Finnish” typeIs >80% in recipients with diffuse mesangial sclerosisIs uniform with Fin-major/Fin-minor genotypeIs associated with the development of antinephrin antibodiesIs associated with anti-podocin antibodiesWhich of the following does not impact on the recurrence of NS in patients with FSGS:
RaceNative kidney nephrectomyRecurrence in a prior graftPodocin mutationNone of the above

recurrent focal segmental glomerulosclerosis (fsgs)


Microsurgical third ventriculocisternostomy as an alternative to ETV: report of two cases

Objective To describe a microsurgical alternative to endoscopic third ventriculocisternostomy.
Introduction
In the last two decades, endoscopic third ventriculocisternostomy (ETV) via a precoronal burr hole and transfrontal approach became a good therapeutic alternative to shunt placing and in non-communicating hydrocephalus, ETV has become the first choice of treatment [29]. Also, ETV is more and more offered to patients with shunt at the time of shunt malfunction or in case of slit-ventricle syndrome (SVS) as a means to become shunt independent. However, in a subpopulation of patients, ETV is technically not feasible due to small ventricular system or slit ventricles. Patients with such small ventricles and multiple shunt malfunctions possess a highly therapeutic challenge.
Other means of internal shunting, as an alternative to ventriculoperitoneal or ventriculoatrial shunting, have been described in the decades before ETV became a routine procedure. Third ventriculocisternostomy (TVS) has been performed by subtemporal craniotomy [5], anterior subfrontal approach [6, 7, 24], Torkildsen ventriculocisternostomy [26, 27], microsurgical ventriculocisternostomy [17, 20], stereotactic ventriculocisternostomy [4, 13, 19], fluoroscopic ventriculocisternostomy [10–12], microsurgical opening of the lamina terminalis [21], reconstruction of or stent placement in the aqueduct [15], and endoscopic aqueductoplasty [22].
TVS by lamina terminalis fenestration is still a routine procedure in aneurysm surgery for subarachnoid hemorrhage, especially in case of anterior communicating artery aneurysms. However, the possibility of a microsurgical TVS (MTV) for obstructive hydrocephalus seems to be lost to oblivion by the widespread use of ETV.
In this report, we describe two patients in whom an ETV could not be performed because of slit ventricles and who became shunt independent after MTV by a minimally invasive supraorbital approach.
Case reports
Case 1
This eight-year-old boy was born with an occipital meningocele and a thoracolumbar myelomeningocele. Both of these congenital abnormalities were operated upon 1 day after birth. Within several days, the patient developed a hydrocephalus which was treated with a ventriculoperitoneal shunt. One month later, a Chiari type II malformation was treated by a suboccipital craniotomy and a duraplasty. Since then, the patient experienced multiple drain infections and both proximal and distal drain dysfunctions. Ventriculoperitoneal shunting and ventriculoatrial shunting with different types of valves were implanted but none of them led to problem-free shunting, largely due to stiff slit ventricles. In March 2003, the patient experienced another drain dysfunction with an intracranial pressure (ICP) of 50 cm H2O while maintaining slit ventricles followed by infection necessitating external ventricular drainage and antibiotics treatment. In search for a more definitive treatment of his recurrent drain dysfunctions, we considered to perform an ETV. However, the very narrow slit-like lateral ventricles and third ventricle did not allow a safe execution of this procedure (Fig. 1a–c). As an alternative, a microsurgical fenestration of the lamina terminalis and Liliequist’s membrane was performed via a right-sided eyebrow incision and a small supraorbital craniotomy (Fig. 2). The postoperative course was uneventful. The patient did not experience any symptoms suspect for hydrocephalus or raised intracranial pressure during a follow-up of 3 years. MRI control examination did not reveal a significant increase in the size of the ventricular system (Fig. 1d–f).
Fig. 1Case report 1. a, b Axial T1 MRI depicting very small slit-like lateral and third ventricles, c sagittal T2 MRI showing small third ventricle and lamina terminalis, d, e postoperative axial T1 MRI showing minimal increase in size of the lateral ventricles; f postoperative sagittal T2 MRI shows a minimal increase of the third ventricle, but no flow void phenomenon at the lamina terminalisFig. 2Postoperative photograph of case 1 showing the hardly visible scar of the eyebrow incision
Case 2
This 16-year-old boy, born with a lumbosacral meningocele and shunt dependent from birth on, developed with 13 years of age an increasing overdrainage syndrome with positional headaches. In another hospital, many valve revisions were performed in order to solve this problem and to rule out underdrainage. The original differential pressure valve was exchanged over a period of 3 years for several different Delta valves and a Codman Medos programmable valve, with which practical all settings were tried. Also, a shunt explantation was tried but after initial improvement, this led to a secondary increase of headaches and papilledema within several weeks, after which again, a Codman Medos valve was inserted. From this procedure, we obtained the security that the patient was still shunt dependant at that age. A new ICP monitoring was performed in the other hospital which showed negative intracranial pressures in upright sitting position and an ICP of 5–10 cm H2O in the supine position. The headache continued, even seemed to increase and became also chronic with positional increase of headaches in the upright position. The largest problem, however, became the frequent absenteeism from school because of these headaches. Chronic consultation of a pediatric neurologist and conservative treatment measures did not alter the symptoms either.
At this time, he was referred to our department. As a first measure, a PaediGav 9/29 gravitational valve was applied because we had gained good experience with this type of valve but without any positive effect on the headaches. Although the patient did not improve after many shunt upgrading, it was felt that his headaches most likely were to be attributed to chronic overdrainage. Therefore, we sought for a means to have the patient shunt independent (after proven shunt dependency at the time). Because an ETV was considered to be impossible, a right supraorbital craniotomy with a lamina terminalis fenestration and fenestration of Liliequist’s membrane was executed and the shunt was completely removed, except for the ventricular catheter that was fixated and therefore left behind. Again, no significant change of the headache could be observed. A 24-h continuous ICP monitoring, performed after 6 weeks because of unchanged symptoms, revealed a normal ICP in supine and upright positions with a maximum nightly increase to 13 mm Hg. Two years after surgery, the patient is still shunt independent with chronic headaches, no papilledema (contrary to the first shunt explantation before MTV), and in a rehabilitation program. A computed tomography (CT) scan 1.5 years after surgery shows a minimal increase in the size of the ventricles (Fig. 3).
Fig. 3Case report 2. a, b Preoperative CT scan depicting slit-like ventricles; c, d postoperative CT scan with minimal increase of ventricle size and a residual ventricular catheter that could not be removed
Discussion
There are many complications related to shunt dependency. In 10.9–29% of cases complications (other than mechanical obstruction) occur, the majority of which is a shunt infection [9, 14, 18]. Mechanical complications in shunts including late shunt malfunction may even occur in up to 45.9% in the first postoperative year and up to 81% of patients at 12 years follow-up [8, 9, 18]. Also, the long-term shunt-related mortality rate of the shunt-treated patient, despite many improvements in shunt technique, diagnostics, and follow-up, remains high (2.9% to 12.4% at 10 years follow-up) [10, 16, 30]. Therefore, the ultimate goal in hydrocephalus therapy is to get the patient shunt free.
Since the first experience by Guiot [10], transcortical or transventricular endoscopic third ventriculocisternostomy has proved to be a valid alternative in the treatment of obstructive hydrocephalus. Also, several studies have shown that ETV is an effective treatment in patients with obstructive hydrocephalus who had undergone previous shunting procedures [1, 23, 25]. It can provide a definitive cure for patients with difficult-to-manage shunt dysfunction.
The potential advantages of ETV over conventional shunting are clear. However, ETV requires a certain degree of lateral and third ventricle dilatation to be performed safely. In case of small ventricles, the potential risks of this procedure (injuring fornix, thalamostriate or internal cerebral veins, hypothalamus) outweigh the advantages. One might consider to enlarge the ventricles and, thus, to facilitate an ETV. This has been safely and successfully performed by Butler and Khan [2] with an external ventricular drain and by Chernov et al. [3] by using a programmable valve of which the pressure was increased in a stepwise fashion. In our department, we have practised both techniques for ventricular dilatation successfully, but we also encountered serious complications from this strategy.
In both cases described here, we already knew from previous shunt malfunctions that the ventricles hardly dilate with increased intracranial pressure. A shunt revision in case 1 for proximal catheter obstruction only several months before the MTV revealed an intracranial pressure of 50 cm H2O with only minimal ventricular dilatation. Therefore, in our two patients, we opted to perform an open microsurgical TVS by opening the lamina terminalis via a small supraorbital craniotomy and did not consider achieving ventricular expansion. Both patients became shunt independent.
Open surgical TVS once was a popular therapeutic technique for the treatment of obstructive hydrocephalus before the advent of VP shunt systems. The idea of third ventricular communication into the chiasmatic cisterns was initially proposed by Dandy [7] in 1922 as a surgical procedure to alleviate obstructive hydrocephalus. It was first performed by Dandy via a subfrontal approach and frequently required the sacrifice of one optic nerve and elevating the chiasm. Later, Dandy [5] described the alternative subtemporal approach.
In 1936, Stookey and Scarff [24] described a subfrontal anterior approach for TVS through the lamina terminalis and the hypothalamus to the lumen of the third ventricle. Scarff [21] published a review of 527 patients subjected to this operation by both the subfrontal and subtemporal procedures, as reported by many authors. The over-all operative mortality was 15% and the permanent arrest of the hydrocephalus was obtained in 70% of the survivors.
Open surgical TVS for obstructive hydrocephalus was then abandoned due to better and reliable shunting systems and because the advent of endoscopic techniques of this procedure is not reported to be in widespread use. Nevertheless, it remained a routine procedure during aneurysm surgery in order to get more slack ventricles and to prevent, or decrease the number of, posthemorrhagic hydrocephalus. To the best of our knowledge, MTV, by opening the lamina terminalis for the treatment of hydrocephalus, was last reported in 1988. In this report from Reddy et al. [17], five shunted patients with aqueduct stenosis and slit ventricle syndrome described are treated successfully with MTV via opening of the lamina terminalis. The lamina terminalis was approached in all patients via a classic pterional craniotomy. Since then, reports on ETV dominate the literature.
Operative technique
Many neurosurgeons consider craniotomy and MTV too large and risky a procedure. However, the procedure described in this report is a truly minimally invasive procedure. The operation time is about 1 h, the wound and scar are minimal, recuperation is very fast, and the potential risks are very low. One might even suggest that this procedure is safer than an ETV because it has an extracerebral approach, in contrast to ETV, and that surgery is better controlled with more opportunities for hemostasis.
The supraorbital craniotomy with eyebrow incision has been described previously [28]. The Sylvian fissure needs not to be dissected. The ipsilateral optic nerve and the optic chiasm, the ICA and the ipsilateral ACA as well as the ACoA are exposed after which the lamina terminalis is reached. Lamina terminals fenestration is a standard procedure easily performed with the bipolar forceps or an arachnoid diamond knife. This, however, is not sufficient. It is essential to open Liliequist’s membrane to allow free and sufficient CSF communication between the posterior fossa and the suprasellar and frontobasal cisterns.
Recovery of this operative procedure is fast and without major side-effects. Usually, hospitalization time is 2 to 3 days.
Conclusion
In conclusion, open microsurgical third ventriculocisternostomy by opening the lamina terminalis should be kept in mind as an alternative technique for treating patients with multiple shunt failures and small ventricles not accessible for an endoscopic approach in an effort to make these patients shunt independent.

third ventriculocisternostomy
lamina terminalis
minimally invasive
supraorbital approach
microsurgery
neuroendoscopy


Effect of renal Doppler ultrasound on the detection of nutcracker syndrome in children with hematuria

To assess the detection rate of nutcracker syndrome in children with isolated hematuria, renal Doppler ultrasound examinations were routinely performed on 216 consecutive children (176 microscopic hematuria and 40 gross hematuria). Renal Doppler ultrasound was also performed on 32 healthy normal children. The peak velocity (PV) was measured at the hilar portion of the left renal vein (LRV) and at the LRV between the aorta and the superior mesenteric artery. The PV at the aortomesenteric portion (P=0.003) and the PV ratios of the LRV (P=0.003) were significantly higher in children with hematuria than in normal children, while the PV at the hilar portion was not different. If a PV ratio of the LRV of at least 4.1 (the cut-off level set at the mean ±2 SD of the value for the normal children) was defined as abnormal, 72 cases (33.3%) in children with hematuria and no cases in normal children were diagnosed as having nutcracker syndrome. The prevalence of nutcracker syndrome is relatively high in children with isolated hematuria, and the inclusion of renal Doppler ultrasound as a screening examination has a substantial effect on the detection of nutcracker syndrome.
Introduction
Hematuria is a common urinary abnormality with a prevalence of 0.5–2.0% among school-aged children [5]. In South Korea, mass urinary screening was started in school-aged children in 1998, and therefore the incidence of patients with asymptomatic microscopic hematuria has been increasing. When routine diagnostic tests for hematuria are used, approximately 40% of children with isolated hematuria are classified as being idiopathic [14, 17].
The prevalence of nutcracker syndrome in children with hematuria is unknown, because evaluation of nutcracker syndrome has not been routinely performed in children with isolated hematuria. This might be due to the absence of both reliable and easily applicable diagnostic methods in diagnosing nutcracker syndrome in children. Recently, however, renal Doppler ultrasound has been developed to diagnose nutcracker syndrome, and it is now possible to apply this diagnostic method to children [10–12].
Therefore, we carried out a prospective study of routine renal Doppler ultrasound in children presenting with isolated hematuria at our Nephrology Unit. The main aim was to assess the detection rate of nutcracker syndrome by renal Doppler ultrasound as a screening examination.
Methods
Patients
All consecutive 221 children with isolated hematuria (gross and microscopic) who visited our Nephrology Unit between 1 January 2002 and 31 December 2004 were routinely offered a renal Doppler ultrasound to detect cases of nutcracker syndrome in addition to a complete blood cell count, electrolytes, biochemistry, coagulation profile, serology for hepatitis B, antinuclear antibody, anti-streptococcal O titer, complement C3 and C4, urine culture, urinary calcium/creatinine, two-dimensional ultrasonography and excretory urography.
Hematuria was defined as the presence of at least five red blood cells (RBCs) in a centrifuged specimen. A urine sample from each parent and sibling was examined for hematuria, and a family history of urolithiasis was considered positive if a sibling, parent, grandparent, or parental sibling had a history of renal-stone disease. We excluded proteinuria by urinalysis in most patients, but also collected 24-h urine collections if proteinuria was suspected by urinalysis in some patients with gross hematuria. We collected 24-h calcium and creatinine if the urinary calcium/creatinine ratio was more than 0.2. Hypercalciuria was defined when 24-h calcium excretion was more than 4 mg/kg. Children with a documented urinary tract infection (n=2), Henoch-Schoenlein purpura (n=1), and systemic lupus erythematosus (n=2) were excluded, because the causes of hematuria were evident in these patients.
Therefore, 216 patients were included in this study: 176 showed microscopic hematuria on several examinations (170 through mass urinary screening and 6 through routine urinalysis during admission due to other diseases) and 40 gross hematuria. The hematuria was intermittent in 19 patients and permanent in 197. Blood pressure was normal in all patients. Also, 32 age- and sex-matched normal healthy children with no evidence of renal disease or other chronic diseases were selected for comparison. This study was approved by the institutional review board and the research ethics committee of Yonsei Severance Hospital.
Renal Doppler ultrasound
Renal Doppler ultrasound was performed at the first visit by one experienced radiologist, not knowing whether the subjects had hematuria or were control subjects. A HDI 5000 sonography system with 5- to 8- and 4- to 6-MHz convex transducers (Philips, Ultrasound, Bothell, Wash.) was used, and the Doppler spectrum could be successfully obtained in most cases, except in one with a retroaortic left renal vein.
After the patients had fasted for 6 to 8 h, renal Doppler ultrasound was performed with the patients in the supine position. Peak velocity (PV) was measured in the transverse plane at two points in the LRV, one at the lateral portion of the LRV near the hilum (PV1) and the other where the LRV courses between the aorta and the superior mesenteric artery (aortomesenteric portion, PV2).
Doppler spectra of the LRV at the hilum were obtained with the transducer placed on the middle of the upper abdomen. Doppler spectra of the LRV at the aortomesenteric angle were obtained with the transducer placed on the right or left subcostal area for keeping the Doppler angle of the LRV less than 60°. It was relatively easy to obtain the PV at the hilar portion of the LRV with the Doppler angle of less than 60°, but there were some patients in whom the measurements of the PV at or beyond the aortomesenteric portion of the LRV were somewhat difficult with the Doppler angle of 60°. The median Doppler angle was 60° (range 32–66°) at the hilar portion and 60° (range 56–70°) at the aortomesenteric portion of the LRV. Ratios of the PV of the LRV between the two portions (Aortomesenteric PV/Hilar PV, PV2/PV1) were calculated.
Statistical analysis
Statistical analysis was performed with Student’s t-test and chi-square test, using SPSS for Windows (version 11.0). The mean ±2 SD of PV2/PV1 ratios was calculated for normal controls and was used as the cut-off value for diagnosing nutcracker syndrome. A P value of 0.05 or less was defined as significant.
Results
Figure 1 shows Doppler images of a patient with nutcracker syndrome (a, b) and a normal child (c, d). Color Doppler imaging of all LRVs showed blood flow from the renal hilum to the aortomesenteric portion.
Fig. 1Renal Doppler ultrasound of the left renal vein in a patient with nutcracker syndrome (a, b) and a normal child (c, d). (a) The peak velocity was 194.8 cm/s in the aortomesenteric entrapped portion. (b) The peak velocity was 21.3 cm/s in the hilar portion (c). The peak velocity was 49.3 cm/s in the aortomesenteric portion. (d) The peak velocity was 23.8 cm/s in the hilar portion
Doppler velocimetric findings in children with hematuria and the control subjects are summarized in Table 1. In children with hematuria, the median PV2 and PV1 were 75.4 (range 23.9–288.0) cm/s and 23.8 (range 7.3–40.7) cm/s, respectively. In normal children, the median PV2 and PV1 were 60.2 (range 20–133.7) cm/s and 23.9 (range 10.7–36.8) cm/s, respectively. There were no differences in the PV1, PV2, and PV2/PV1 ratios between children with gross hematuria and those with microscopic hematuria. The median PV2/PV1 ratio was 3.14 (range 1.18–16.44) in children with hematuria and 2.56 (range 1.21–3.87) in normal children. The PV2 (P=0.003) and PV2/PV1 ratios (P=0.003) were significantly higher and had a wider distribution (Fig. 2) in children with hematuria than in normal children. On the basis of these data, we set the cut-off levels of the PV2/PV1 ratios for diagnosing nutcracker syndrome at the mean ±2 SD of the value for the normal children. The calculated cut-off levels were 4.1. When these Doppler sonographic diagnostic criteria were applied, 72 cases (33.3%) in children with hematuria and no cases in normal children were diagnosed as having nutcracker syndrome. In the 72 children with nutcracker syndrome, the PV2/PV1 ratios were 6.82±2.51 (median 6.46, range 4.1–16.44) as compared with 2.57±0.74 (median 2.56, range 1.21–3.87) in normal children (P<0.0001) (Tables 1, 2). Collateral vessels around the LRV were observed in two patients with nutcracker syndrome. The body mass index was significantly lower in the nutcracker group than in the non-nutcracker group (P=0.006) (Table 2).
Table 1Renal Doppler findings and anthropometric parameters (median values and ranges) Gross hematuria (n=40)Microhematuria (n=176)Total hematuria (n=216)Control (n=32)P-valueDoppler findings PV at AM portion (PV2, cm/s)72.2 (23.9–207)76.2 (30.1–288)75.4 (23.9–288)60.2 (20–133.7)0.003 PV at hilar portion (PV1, cm/s)22.6 (11.5–40.7)24.1 (7.3–38.4)23.8 (7.3–40.7)23.9 (10.7–36.8)NS PV2/PV1 ratio3.06 (1.18–10.34)3.19 (1.2–16.44)3.14 (1.18–16.44)2.56 (1.21–3.87)0.003 PV ratio >4.1*9 (22.5%)63 (35.8%)72 (33%)0 (0%)<0.0001Anthropometric findings Height (cm)132 (72–183)134 (88–171)133 (72–183)133 (109–164)NS Weight (kg)31.5 (13.5–71)30 (12–74)30 (12–74)30 (18–56)NS BSA (m2)1.09 (0.53–1.78)1.06 (0.54–1.86)1.06 (0.53–1.86)1.05 (0.74–1.6)NS BMI (kg/m2)17.24 (12.98–27.23)16.88 (13.13–25.97)17.05 (12.98–27.73)17.09 (15.15–20.82)NS*Data are number (%)PV= peak velocity, AM= aortomesenteric, BSA= body surface area, BMI= body mass index, and NS= not significant (P>0.05)There were no differences between gross and microscopic hematuriaFig. 2The peak velocity ratios of the left renal vein in children with gross (GH) or microscopic hematuria (MH) and normal controlsTable 2Renal Doppler findings and anthropometric parameters in 216 children with and without nutcracker syndrome Nutcracker group (PV ratio >4.1: n=72)Non-nutcracker group (PV ratio <4.1: n=144)P-valueDoppler findings PV at AM portion, PV2 (cm/s)129 (69.8–288)*63.9 (23.9–113)<0.0001 PV at hilar portion, PV1 (cm/s)20.1 (7.3–30.1)26.3 (14.2–40.7)<0.0001 PV2/PV1 ratio6.46 (4.1–16.44)2.45 (1.18–4.0)<0.0001Anthropometric findings Height (cm)137 (72–183)132 (90–171)0.031 Weight (kg)32 (12–67)30 (13–74)NS BSA (m2)1.1 (0.53–1.78)1.05 (0.58–1.86)NS BMI (kg/m2)16.12 (13.42–27.01)17.24 (12.98–27.73)0.006*Median and rangesPV= peak velocity, AM= aortomesenteric, BSA= body surface area, BMI= body mass index, and NS= not significant (P>0.05)
Clinical characteristics and diagnoses of 216 children with hematuria with or without nutcracker syndrome are listed in Table 3. The median age and gender did not differ between the two groups. The incidence of gross hematuria, abdominal or flank pain and a family history of urolithiasis were also similar in both groups. Nutcracker syndrome was present in 60 of the 149 children (40%) in whom no other explanation for hematuria was ascertained, and it was also combined with other causes of hematuria in 12 patients. Among the children with nutcracker syndrome, renal biopsy findings were normal in three, and one had IgA nephropathy.
Table 3Clinical characteristics and diagnoses of 216 children with hematuria with and without nutcracker syndrome PV ratios of the LRVNutcracker group (PV ratio >4.1: n=72)Non-nutcracker group (PV ratio <4.1: n=144)Clinical characteristics* Age (years)9 (2–16)9 (3–15) Sex (M/F)37:3576:68 Gross hematuria**931 Abdominal or flank pain1117 Familial history of urolithiasis410Clinical diagnoses† IgA nephropathy1 (1)1 (1) Thin GBM disease5 (5) Hereditary nephritis with deafness2 Proliferative glomerulonephritis1 (1) Postinfectious glomerulonephritis4 Familial hematuria320 Cystitis3 Trauma1 Hypercalciuria818 Hematuria unexplained60 (3)‡89 (5)‡*There were no differences between the two groups (**P=0.107)†Numbers in parenthesis indicate the number of diagnoses confirmed by renal biopsy‡Results of renal biopsies were normal
The results of the diagnostic studies are included in Table 4. Complete blood count, electrolytes, biochemistry, and the coagulation profile were normal in all patients. Positive antinuclear antibody was detected in 13 patients (1:40 weak positive), but repeat testing and anti-ds DNA showed no evidence of autoimmune diseases. Serum C3 concentrations were low (more than 10% below the lower limit of normal) in four patients. Hypercalciuria was found in 26 patients (12%). Ninety-five percent of the two-dimensional ultrasonography and 97% of the excretory urography showed no abnormal findings. Of the 11 abnormal ultrasounds (2 increased echogenecity, 3 thickened bladder wall, 1 mild dilatation of the renal pelvis, and 5 urolithiasis) and 7 urographic examinations (2 duplications of the ureter, 1 aberrant small right upper calyx, and 4 bifid collecting systems), no finding was clinically significant. The detection rate of nutcracker syndrome by renal Doppler ultrasound was highest among all diagnostic tests for hematuria.
Table 4Diagnostic studiesDiagnostic studyNormal result (no. of patients)Abnormal result (no. of patients)Positive rate (%)Complete blood count21600Electrolytes and biochemistry21600Coagulation profile21600C321241.9C421420.9Anti-streptococcal O titer1793717Antinuclear antibody203136Hepatitis B surface antigen21510.5Urine culture21600Urinary calcium/creatinine1902612Renal/bladder ultrasonography205115Excretory urography20973Renal Doppler ultrasound1447233
Discussion
According to Stapleton et al. [14], the cause of isolated hematuria was defined in only 27% of their patients when routine diagnostic tests for hematuria were performed. However, they found that idiopathic hypercalciuria was the most common cause of hematuria with a prevalence of 26% in children with isolated hematuria by the routine evaluation of urinary calcium excretion. Nevertheless, the cause of hematuria in the remaining 47% of the patients could not be explained.
In the present study, we could not identify the cause of hematuria in 149 (69%) of the 216 patients when renal Doppler ultrasound was not performed, but 40 percent was found to have nutcracker syndrome by renal Doppler ultrasound. Thus, nutcracker syndrome was the most common cause of isolated hematuria in children without urinary tract infection or proteinuria in our study, and we speculate that childhood nutcracker syndrome might have been underestimated in the past.
Compression of the LRV between the aorta and the SMA by a mechanism similar to that of a nutcracker has been recognized by anatomists for about 70 years [6, 8]. However, the prevalence of this syndrome is unknown in both children and adults with hematuria. Even current textbooks of pediatrics rarely describe this syndrome [1, 5]. It is known that nutcracker syndrome is an uncommon cause of gross or microscopic hematuria from non-glomerular origin and may cause orthostatic or variable degrees of proteinuria [4, 9, 12]. Hematuria is believed to be caused by LRV hypertension, which may result in minute rupture of thin-walled collateral veins into the calyceal fornix [9, 10].
Left renal venography with measurement of the pressure gradient between the inferior vena cava and LRV has been used to confirm nutcracker syndrome in selected cases [10]. However, this procedure is invasive, time-consuming, and therefore not indicated if there are no severe symptoms. In addition, there were no reliable and easily-applicable non-invasive diagnostic methods in diagnosing childhood nutcracker syndrome in the past. Consequently, it has been thought that screening nutcracker syndrome in all children with hematuria is unnecessary and irrational, and therefore, the prevalence of nutcracker syndrome has not been evaluated. Recently, however, the introduction of renal Doppler ultrasound with color flow has improved functional diagnostic capabilities by showing the blood flow velocity of the LRV [10–12]. Compression of the LRV between the aorta and the SMA may cause an increase in flow velocity in the LRV at the aortomesenteric angle, and this flow can be measured noninvasively by using Doppler ultrasound. Although anatomical definition of nutcracker syndrome is the compression between the aorta and the SMA, the changes (narrowing at the aortomesenteric portion and dilatation at the hilar portion) in diameters of LRV are variable according to the stage of nutcracker syndrome. This would be the reason that Doppler ultrasound had been developed to detect nutcracker syndrome in both adults and children.
Kim et al. [10] first developed and applied this Doppler technique to adults with nutcracker syndrome confirmed by venography, because the measurements of diameters of the LRV had not been satisfactory [3], and it had been suggested that dilatation in the proximal LRV shown at either 2-dimensional ultrasonography or computed tomography might be a normal variant in both children and adults [3, 18]. Takebayashi et al. also found that nutcracker syndrome can exist in either nondistended or distended LRV, and normal flow also can exist in distended LRV [15]. However, a combination of different parameters might improve the correlation with hematuria [10]. According to the Kim et al.'s study [10], Doppler sonographic findings were comparable to venographic findings, and the sensitivity and specificity of the PV2/PV1 ratios were higher than those of the ratio of LRV diameters (sensitivity 80% vs. 69%; specificity 94% vs. 89%) in adults with nutcracker syndrome. Park et al. [12] had also reported that the mean PV2/PV1 ratios in 26 normal children aged 6–16 years were 2.57±0.70 (range 1.3–3.9), which were similar to those (2.57±0.74, range 1.21–3.87) in our control subjects (4.8–14.5 years). Thus, the Doppler sonographic cut-off value for the PV2/PV1 ratios in our study (4.1) was similar to that of Park et al. [12] (4.0), but lower than that in adults [10] (5.0). Kim et al. [10] reported the PV at the hilar portion in hematuric adults with nutcracker syndrome was significantly lower than that in normal adults, suggesting compression of the LRV at the aortomesenteric portion could change the flow pattern in the hilar portion of the LRV. Similarly, our study also demonstrated that the PV at the hilar portion in the nutcracker group is significantly lower than that of the non-nutcracker group, suggesting the entrapment of the LRV might also influence the PV at the hilar portion.
We agree with the previous reports describing the necessity of limited evaluations in children with microscopic hematuria, because the extensive work-up resulted in a low rate of positive findings [7]. Nevertheless, our data suggest that the detection rate of nutcracker syndrome by renal Doppler ultrasound was highest among many other diagnostic tests. Regarding treatment of nutcracker syndrome, surgery should be considered if the patients have severe symptoms [2], but it has been suggested that childhood nutcracker syndrome might be a transient phenomenon resolving spontaneously with time by physical development [13, 16]. Therefore, renal biopsy should be delayed in children with asymptomatic microscopic hematuria if nutcracker syndrome is detected. However, if hematuria persists despite the improvement of Doppler findings, renal biopsy might be necessary to detect other causes of hematuria.
However, our study has some limitations: (1) We did not perform left renal venography because most of our patients had mild renal symptoms, such as asymptomatic microscopic hematuria, detected through mass urinary screening. It was felt to be unethical to perform such an invasive procedure in these patients. (2) Renal Doppler ultrasound was performed by one pediatric radiologist, and we could not show inter-observer reproducibility. (3) We did not perform the urinary RBC morphology as a routine examination. However, a current textbook of pediatrics [5] describes: “Although urinary RBC morphology may be normal with non-glomerular bleeding and dysmorphic from glomerular bleeding, cell morphology does not reliably correlate with the site of hematuria.” Kim et al. demonstrated the percentage of isomorphic RBC was considerably variable (range 2–90%) in patients with nutcracker syndrome confirmed by venography [10]. Despite these limitations, our data suggested that nutcracker syndrome might be one of the leading causes of isolated hematuria during childhood.

renal doppler ultrasound
nutcracker syndrome
hematuria
screening examination


Position paper on the use of mandibular advancement devices in adults with sleep-related breathing disorders

Custom-made mandibular advancement devices are an effective treatment option for snoring, upper airway resistance syndrome, and obstructive sleep apnea (OSA). Evidence-based data indicates their efficacy, and international sleep societies recommend oral appliance (OA) therapy for patients with sleep-related breathing disorders. The following position paper by the German Society of Dental Sleep Medicine (DGZS) is to guide the interdisciplinary team (sleep physician and sleep disorder dentist) in detail when to prescribe oral appliances. This position paper supports the responsible use of OA as an effective treatment option for patients with sleep-related breathing disorders. The paper advises of proper indication regarding OSA severity, body mass index (BMI), and dentition. It emphasizes the interdisciplinary approach of oral appliance therapy and suggests treatment under the guidance of dentists trained in dental sleep medicine.
Introduction
Various options are available in the treatment of obstructive sleep-related breathing disorders (SRBD):
Continuous or bi-level positive airway pressure (nCPAP/biPAP)Mandibular advancement devices (MADs)Surgical proceduresOther procedures
The use of oral appliances in treating SRBD was first described in 1982 [3]. The first findings, which document the therapeutic effect of MADs, were presented in 1984 [8]. Of the many oral appliances designed for use in the treatment of SRBD, mandibular advancement devices have been the most intensely researched. Progress in the areas of dentistry and appliance technology has lead to fundamental modifications in the design of mandibular advancement devices.
The clinical effectiveness of this treatment option has been documented with varying degrees of evidence in numerous studies. The clinical importance of this form of therapy is constantly being reinforced by the gathering of improved data on the validity of this form of treatment. The effectiveness of mandibular advancement devices in the treatment of SRBD has been documented by the Cochrane Collaboration as the highest level of scientific evidence [5]. The clinical analysis has been reviewed and revised twice since Cochrane’s first evaluation in 2002 [6, 7]. The German Society of Dental Sleep Medicine (DGZS) takes this opportunity to issue its position with regard to this form of therapy and to make recommendations.
The definition of mandibular advancement devices in the treatment of SRBD
A system of laboratory fabricated custom-made adjustable splints manufactured for the individual patient and adjusted to fit the upper and lower jaws. These splints position the lower jaw, tongue, and additional structures more anteriorly, and increase the occlusal vertical dimension, resulting in an opening of the pharynx lumen, which reduces resistance in the airway and mechanically keeps the airway open during sleep.
Guidelines and indication recommendations from professional sleep-medicine societies
As early as 1995, the American Academy of Sleep Medicine (AASM) published recommendations on the indication and application of oral appliances in the treatment of SRBD [1]. These were updated and stated more precisely in 2005 [2]. In 2001, the German Society of Pneumology (DGP) in co-operation with the German Sleep Society (DGSM) published the “S2” guidelines on the diagnosis and treatment of SRBD. These guidelines envisaged the use of mandibular advancement devices as a treatment option [4]. A new description of the significance of mandibular advancement devices was formulated by the “Task Force Apnea of the DGSM” in the year 2006 [9].
Based on scientific appraisals and international guidelines, the DGZS recommends the use of mandibular advancement devices in the treatment of SRBD:
As an initial treatment for
Primary snoringUpper airway resistance syndromeMild to moderate obstructive sleep apnea [apnea hypopnea index (AHI) up to about 25/h] with minor clinical symptoms with a sufficient number of retaining teeth and a body mass index (BMI) of up to 30 kg/m2In cases of SRBD with an approximate AHI of over 25/h, MADs can be used as an alternative after a previous therapeutic trial with nCPAP.Regardless of SRBD severity in patients with CPAP failure and CPAP noncompliance.A special dental, oral, and functional diagnosis is necessary to check the dental requirements for long-term use before prescribing MADs.The procedure should take into account the various interdisciplinary and intradisciplinary treatment flows, particularly the preliminary medical diagnosis and the subsequent medical follow-ups.This service should be delivered by dentists who have specialized training in the field of sleep medicine.
The DGZS supports the specialized training of dentists and physicians in the field of dental sleep medicine. Patients and referring physicians can find the addresses of certified practitioners on the DGZS website at http://www.dgzs.de.

position paper
mandibular advancement device
snoring
upper airway resistance syndrome
obstructive sleep apnea
oral appliance
german society of dental sleep medicine
dental sleep medicine
dgzs