Contribution of psychoacoustics and neuroaudiology in revealing correlation of mental disorders with central auditory processing disorders

Background Psychoacoustics is a fascinating developing field concerned with the evaluation of the hearing sensation as an outcome of a sound or speech stimulus. Neuroaudiology with electrophysiologic testing, records the electrical activity of the auditory pathways, extending from the 8th cranial nerve up to the cortical auditory centers as a result of external auditory stimuli. Central Auditory Processing Disorders may co-exist with mental disorders and complicate diagnosis and outcome.
Background
Evaluation of the central auditory nervous system (CANS) is essential in order to obtain information on its anatomical and functional integrity. Both, children and adults may suffer from central auditory processing disorders (CAPD). This fact has been underestimated but as research in this field progresses, it shows that specific mental disorders may be the outcome of a CAPD or that CAPD can co-exist with a neurological or mental disorder [1].
Assessment of the CANS begun at the mid-1950s with the confirmation by Bocca and his colleagues [2] that CANS disorders do exist and that there are sensitive tests to reveal them. However, at that time acceptance of the new diagnostic methods by the audiologists, who were the first to be interested in this field was limited. This can be attributed to the slow acceptance of each new method before it is fully validated. Better understanding of the anatomy and physiology of the CANS was gained by advances concerning the presence and physiology of neurotransmitters and the accumulation of data on the psychoacoustic and electrophysiologic tests [3]. As a result audiologists started applying the new diagnostic tests more often and appreciated their contribution. Other medical specialties became aware and interested in the disorders of the CANS. These were mainly psychiatry and neurology. The assessment of the CANS is also of great value concerning neuropsychology and special education [4-6].
Anatomy and physiology of the CANS
Clinical evaluation of central auditory function requires understanding of the anatomy and physiology of the CANS and appreciation of its complexity. The CANS extends from the anterior and posterior cochlear nuclei which are situated on the surface of the inferior cerebellar peduncle to the auditory cortex. In between important structures through which nerve fibers pass are: the trapezoid body, the lateral lemniscus, the inferior colliculus, the medial geniculate body and the acoustic radiation of the internal capsule. The auditory cortex includes the gyrus of Heschl on the upper surface of the superior temporal gyrus, the planum temporale and the Silvian fissure.
It is essential to point out that nerve impulses from each ear proceed along auditory pathways on both sides of the brainstem. Both ipsilateral and contralateral pathways are important in ensuring interchange of auditory information. The contralateral pathway exhibits dominance as opposed to the ipsilateral one [7]. Thirty thousand afferent auditory nerve fibers with different range of frequency response are responsible for conveying auditory information to the cortex [8]. Many components of the stimulus are analyzed separately. There is an increasing complexity of the whole process in the auditory cortex. One should keep in mind that, understanding of the exact way of processing the auditory information at the level of the auditory cortex, is still incomplete. It is in this understanding that Phychoacoustics helps as it is the science concerned with the evaluation of the sensation of hearing as an outcome of the sound or speech stimulus.
Components of central auditory processing
Central auditory processing occurs prior to language comprehension [9]. It consists firstly of auditory discrimination, which is responsible for the ability to group sounds according to how similarly or differently they are heard. Auditory memory is the component responsible for storing and recalling auditory information. Auditory perception concerns the reception and understanding of sounds and words. It plays a significant part in reading skills, managing verbal information, communication and social relationships. Auditory-vocal association consists of the interaction between what is heard and verbal response. Auditory synthesis is responsible for combining sounds or syllables to formulate comprehensible patterns (words) and de-combining words into separate sounds. Auditory-vocal automaticity is the ability to predict how future linguistic events will be heard by utilizing past experience. Auditory figure-ground plays a role in diminishing sounds which are not important while focusing on others [10]. It is due to this component that someone can listen to another person talking in a railway station, where a lot of environmental noise exists.
Material and methods
The medline research revealed 564 papers when using the keywords 'auditory deficits' and 'mental disorders'. 79 papers were referring specifically to CAPD in connection with mental disorders, as this is a new term for auditory deficits and one mostly used by audiologists. Auditory deficit is a more general term used mostly by psychiatrists. Both terms refer to the same disorder. It is essential to point out that 25 of the 79 papers are published between 2000 – 2003.
Schizophrenia is found related to CAPD in 175 papers, 49 of them are published between 2000 – 2003 showing the research focus of the last three years. Learning disabilities were found related to CAPD in 126 papers. Parkinson's disease was related to CAPD in 29 papers. Dyslexia is related to CAPD in 88 papers, 37 of them are between 2000–2003. Alzheimer's disease and auditory deficits are connected in 39 papers. The remaining articles are on depression, alcoholism, anorexia and childhood mental retardation, all being related to some extend to CAPD.
Assessment of the CANS is carried through a great variety of tests that fall into two main categories: psychoacoustic and electrophysiologic testing. Psychoacoustic tests are considered more subjective. Electrophysiologic ones are more objective with the exception of P300 component.
Results
psychoacoustic tests
Learning disabilities, attention deficit disorders and dyslexia are assessed through a great variety of psychoacoustic tests. Age limitations have to be considered [11] and specially designed tests are used for different age groups. When evaluating children who are less than 12 years old an important step is the Pediatric Speech Intelligibility (PSI) Test. This consists of single words and sentences presented with a competing message at varying levels of difficulty [12]. In this test it is essential that performance is adjusted for language age according to previously determined normative data [13]. Evaluation of this test may provide the cause of learning disabilities including dyslexia [14,15].
Children older than 12 years old are assessed through a more complex test battery that contains several tests. These tests are based on the stimulation of the auditory system with tones, numbers, syllables, words and sentences. Evaluation is made according to the different components of the auditory processing. One widely used test is that of the dichotic digits which consists of different pairs of numbers presented simultaneously to each ear [16]. The person under examination has to repeat all four numbers regardless of order. This test is easy to use in order to detect the auditory deficit of dyslexia particularly since it does not contain language and phonological parameters [17].
The Staggered Spondaic Word Test (SSW) consists of two-syllable spondaic words that are presented simultaneously to each ear [18]. This involves the diagnosis of auditory deficits in attention disorders, autism, learning disabilities and chronic alcoholism [19,20].
A series of experiments were planned by Nielzen and Olsson on the basis of psychoacoustic handling of auditory stimulation. The results of these psychacoustic experiments show significant differences between a group of schizophrenic patients and a group of reference subjects thus indicating central auditory processing disorders even in a phase of illness remission or during treatment with neuroleptics [21].
electrophysiologic tests
In all mental disorders assessed with the suspicion of CAPD an objective measure of the peripheral auditory system is mandatory. The Auditory Brainstem Responses (ABR), measure the electrophysiologic activity from the 8th cranial nerve to the medial geniculate body of the brainstem [22]. A very important element of ABR evaluation is the morphology and synchronization of the waveform. One should always begin his evaluation while observing waveform changes on real time [23].
The Auditory Middle Latency Responses (AMLRs) provide an electrophysiologic measure of the primary auditory cortex function [24]. The AMLRs can diagnose central auditory processing disorders in children with learning disabilities [25], patients with Alzheimer's disease [26], adult autistic subjects [27,28] patients with Schizophrenia [29] The Auditory P300 Response, which consists of the measure of the hippocampal and auditory cortex function again from an electrophysiological point of view [30]. The P300 response has been considered an endogenous event-related potential. Endogenous responses depend both on the context within which the auditory stimuli are presented and the psychologic condition and attention of the subject. P300 has been used in diagnosing CAPD in patients with dementia of the Alzheimer type [31], in monitoring long-term effects of donepezil in patients with Alzheimer's disease [32], in anorexic patients [33], in children with mental retardation during a selective attention task to auditory stimuli [34] and in first episode and chronic schizophrenia [35]. Mismatch Negativity Response (MMN) is an event-related evoked potential that measures the electrophysiologic activity of the auditory cortex function [36]. The MMN is always elicited 100–250 msecs from stimulus change onset. Its application is in detecting CAPD in alcoholism [37], in Schizophrenia [38-43], in attention deficit and in developmental dyslexia [44].
psychoacoustic and electrophysiologic testing according to type of lesion
In the selection of tests for the evaluation of brainstem lesions the examiner should keep in mind that all psychoacoustic tests have been reported to aid in the diagnosis. According to the studies of Kartz [45] the Staggered Spondaic Words Test may help differentiating brainstem from cortical lesions and upper from lower brainstem lesions. Musiek et al [46] concluded that Auditory Brainstem Responses in combination with either Masking Level Differences or Dichotic Digits Test may be as sensitive in evaluating a group of patients suffering from multiple sclerosis as a seven test battery. Jerger et al [47] reported that for patients suffering from multiple sclerosis the best test battery was a combination of stapedial reflex measures and speech audiometry.
The usual finding in central auditory tests regarding cortical lesions is a deficit or impairment in the ear contralateral to the side of lesion. Psychoacoustic tests such as Dichotic Digits and SSW in patients with well documented cortical and hemispheric lesions demonstrate primarily contralateral ear deficits and impairments [48]. Two exceptions that the examiner should always keep in mind are when frequency and duration tests are applied and when compromise of auditory fibers of the corpus callosum has occurred [49].
Regarding interhemispheric dysfunction, test results may be difficult to evaluate. Representation of auditory information at the cortical level is mostly contralateral as is clearly depicted in dichotic listening situations. When speech responses are required by the subject auditory information from the right ear are projected through to the left hemisphere without the participation of the opposite hemisphere for the production of a speech response. On the contrary auditory stimuli from the left ear must cross the midline through the corpus callosum for the production of a speech response. Patients with split brain disorders subjected to dichotic testing have interestingly demonstrated decreased scores regarding the left ear and enhanced scores in the right ear [50,51].
Considerable evidence has been reported that indicates a relation between various learning disabilities, including dyslexia, attention deficit hyperactivity disorder and poor performance scores on central auditory tests Learning disabilities in children might be the expression of various underlying central auditory disorders such as maturational, developmental or neurological as depicted by abnormal CAPD test results [52].
Conclusions
CANS assessment represents a fascinating field. Cooperation of professionals in psychiatry, neurology, neuropsychology and pediatric psychology, with the otolaryngologist-audiologist is a prerequisite. Central auditory processing disorders may co-exist with various mental disorders such as: learning disabilities, attention deficit hyperactivity disorder, dyslexia, autism, chronic alcoholism, Alzheimer's disease, adult autistic disorder, Schizophrenia, anorexia and mental retardation. Assessing these disorders is difficult due to the complex anatomy and physiology of the CANS. This explains the great variety of existing methods of testing with two main categories: those of psychoacoustic methodology and those based on electrophysiologic measures. Physiology of CANS is still not completely understood and further research is needed on development of new tests and validation of their clinical applicability.
Conflict of interest
none declared

psychoacoustics
mental disorders
central auditory processing disorders


The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders.
Background
Autoimmunity is widely believed to be fundamental to the development and progression of many rheumatic diseases—rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) being the best-known examples. The function of B cells in autoimmunity is still not fully understood, although evidence is mounting that they play an essential role in the process. In addition to their well-known function in synthesizing antibodies, B cells act in antigen presentation and as critical regulators of the development and function of T cells [21]. B cells are also the source of rheumatoid factor, levels of which are strongly correlated with disease severity in RA [103]. These and other lines of evidence provided the rationale for testing whether B cell depletion would be an effective strategy for treating rheumatic diseases. The availability of rituximab (RITUXAN®; Genentech/Biogen-IDEC, South San Francisco, CA, USA), a genetically engineered monoclonal antibody directed against the B cell-specific antigen CD20 [60], enabled this hypothesis to be tested. The first results, demonstrating sustained clinical responses coupled with B cell depletion in 5 RA patients treated with rituximab [30], ignited intense interest in the wider potential of B cell depletion therapy in autoimmune diseases.
A full-scale clinical trial program led to the approval of rituximab in 2006 for the treatment of RA in patients with an inadequate response to anti-tumour necrosis factor (TNF) therapy. A number of other B cell-directed agents are currently in clinical development. Among the most advanced is epratuzumab, a humanized monoclonal antibody directed against CD22, another B cell-specific marker [90]. Epratuzumab has been tested in patients with Sjögren’s syndrome (SS) [89] and results were published recently of an open-label clinical trial involving patients with SLE [29]. Another strategy under investigation is the neutralization of B cell survival factors. BAFF (also known as B lymphocyte stimulator, BLyS) is essential for the survival of B cells and is involved in many other aspects of B cell biology, including germinal center maintenance, isotype switching, and regulation of B cell-specific markers [48]. Belimumab is an anti-BAFF monoclonal antibody that has reached Phase II trials in SLE and RA [27], while atacicept (previously known as TACI-Ig), a recombinant fusion protein that neutralizes both BAFF and APRIL (a related B cell survival factor) [41], has undergone Phase I evaluation in SLE. A more in-depth review was published recently of current B cell-targeted approaches that are being developed to treat autoimmune disorders [31].
The aim of this review is to discuss the potential utility of B cell-directed therapy in the management of autoimmune disorders. As the first of these agents to be approved for clinical use, rituximab will be the focus of this article. In addition, since several excellent reviews have been published recently covering the use of rituximab in RA [25, 31, 58], this review will discuss results from the clinical testing of rituximab in autoimmune disorders other than RA. Information from case reports, clinical trials, and other studies was gathered from a search of the Medline database up to and including June 2007.
Clinical use of rituximab
Rituximab has been tested in a wide range of autoimmune conditions, with clinical trials being most advanced in SLE and SS. A summary of the published clinical data in these and other autoimmune disorders is presented in Table 1.
Table 1Summary of published data from clinical studies of rituximab in autoimmune disorders other than RADisorder/study typeNo. of ptsTreatment regimenSummary of clinical resultsSystemic lupus erythematosusPhase I/II dose escalation [59]18Single RTX infusion of 100 mg/m2 (low dose [n = 6]) or 375 mg/m2 (intermediate dose [n = 6]), or 4 weekly RTX infusions of 375 mg/m2 (high dose [n = 6]) Improved SLAM score at 12 months in 11/17 (65%) evaluable pts Open-label pilot [84]10aRTX (375 mg/m2) once weekly for 4 weeks + prednisolone (0.5 mg/kg/day for 10 weeks, tapered by 4 mg every 2 weeks thereafter)Partial remission (improvement in renal parameters) in 8/10 pts within a median (range) of 2 (1–4) months; of these, 5 pts had complete remission at 3 months (median); this was sustained for ≥12 months in 4 ptsOpen-label pilot [55]24RTX (1,000 mg) + CyP (750 mg): two infusions, 2 weeks apart Improvements in global and all 8 individual BILAG scores at 6 months in 23/24 pts (96%) Open-label pilot [85]11RTX (375 mg/m2) once weekly for 4 weeks + CyP (500 mg) co-administered at first infusion; immunosuppressive therapy at baseline had been unchanged for ≥3 months prior to study and was continued until Month 6, following which dose reduction was allowed 6 complete and 5 partial responses (follow-up through 2 yrs) (overall, significant reduction in median BILAG scores) Sjögren’s syndromeSingle-centre, open-label Phase II [73]15RTX (375 mg/m2) once weekly for 4 weeksImprovements in subjective and objective parameters of disease activity (salivary and lacrimal gland function) in all 14 pts who completed the study. Of the 7 pts with MALT-type lymphoma, 3 had complete remission, while disease was stable in 3 pts and progressive in 1 pt. Retrospective [83]16RTX (375 mg/m2) once weekly for 4 weeks (6 weeks in 1 pt with lymphoma); 1 pt with systemic manifestations received RTX 2 × 1,000 mg. All pts received methylprednisone (100 mg) and either oral certirizine (20 mg) or dexchloropheniramine (5 mg) before the RTX infusionEfficacy observed in 9/11 pts with systemic manifestations (improvement in systemic symptoms) and in 4/5 pts with lymphomas (disease remission) Open-label pilot [26]16RTX (375 mg/m2) once weekly for 2 weeksSignificant improvement in mean VAS scores for fatigue and dryness, tender point count, and quality of life (at Week 12) and for all 4 VAS scores, tender joint count, tender point count, and quality of life (at Week 36) VasculitisCase series [34]9bRTX (500 mg [375 mg/m2 in 1 patient]) once weekly for 2 weeks (n = 3) or 4 weeks (n = 6)Remission (BVAS = 0) in 8 pts and partial remission (BVAS = 1) in 1 pt at 6 monthsCase series [50]11cRTX (375 mg/m2) once weekly for 4 weeks + prednisone (≤1 mg/kg/day, tapering once disease activity improved)Remission (BVAS/WG = 0) in all 11 pts (10 pts within 6 months); tapering of prednisone dose (median = 0; range 0–1.5 mg/kg/day) in all ptsOpen-label pilot [51]10dRTX (375 mg/m2) once weekly for 4 weeks + prednisone (≤1 mg/kg/day, tapering once disease activity improved)Remission (BVAS/WG = 0) in all pts within 3 months; tapering of prednisone dose to 0 in all pts by 6 monthsCase series [88]10eRTX (375 mg/m2) once weekly for 4 weeks + prednisone (≤2 mg/kg/day, tapering once disease activity improved)Complete response (BVAS/WG = 0) in 9 pts and partial response (BVAS/WG = 1) in 1 pt at 6 months. Follow-up (median 34 months; range 26–45 months): 3 pts relapsed but had new sustained response following re-treatmentOpen-label [85]11cRTX (375 mg/m2) once weekly for 4 weeks + CyP (500 mg) co-administered at first infusion; immunosuppressive therapy at baseline had been unchanged for ≥3 months prior to study and was continued until Month 6, following which dose reduction was allowedRemission in 9/11 pts (BVAS = 0) and partial remission in 1 pt (BVAS = 2); 6/10 pts subsequently relapsed but had new sustained response following re-treatment with RTX (2 × 1000 mg, 2 weeks apart)Case series [8]8dRTX (375 mg/m2) once every 4 weeks for 4 cycles + standard treatment (CyP 2 mg/kg once daily or 15–20 mg/kg every 18–21 days or methotrexate 0.3 mg/kg once weekly) Remission (BVAS = 0) in 2 pts, partial remission in 1 pt, unchanged disease activity in 3 pts, and progression in 2 pts 1 month after final cycleMyositisOpen-label pilot [56]7fRTX (375 mg/m2) once weekly for 4 weeks + standard treatment (included azathioprine, corticosteroids, CyP, and intravenous immunoglobulin)Clinical improvement (increased muscle strength relative to baseline [assessed using dynomometry]) in all 6 evaluable pts Idiopathic thrombocytopenic purpuraOpen-label pilot [87]25RTX (375 mg/m2) once weekly for 4 weeksClinical response (rise in platelet counts) at end of therapy without need for further treatment in 13/25 (52%) pts. Responses were sustained for ≥6 months in 7 ptsPooled data from two pilot trials [22]57RTX (375 mg/m2) once weekly for 4 weeks; 17 pts received prednisone (60 mg with Infusion 1 and 20 mg with Infusion 2)Clinical response (rise in platelet counts) at end of therapy without need for further treatment in 31/57 (54%) pts; 29/31 responses occurred within 8 weeks of initiating RTX therapy. 15/16 pts with complete clinical response (rise in platelet counts to normal levels) maintained response for ≥12 months Retrospective national multicenter [13]35RTX (375 mg/m2) once weekly for 4 weeks + prednisone; 6 pts received a fixed dose of 500 mg supplemented by 100 mg methylprednisone or 50–100 mg prednisone + antihistamine prior to RTX infusionClinical response (rise in platelet counts) within 3–8 weeks for 17/39 (44%) treatments (4 pts received 2 cycles); pts with complete or partial responses had been in remission for a median of 47 weeksRetrospective national multicenterg [71]89RTX (375 mg/m2) once weekly for 4 weeks (n = 77) or for 1–6 weeks (n = 12); 31 pts received RTX with other therapies (corticosteroids [n = 20], IVIG [n = 2], corticosteroids + IVIG [n = 3], others [n = 6]) Clinical response (rise in platelet counts) in 49/89 (55%) pts; 31 pts maintained response for a median (range) of 9 (2–42) months, 12 pts for >12 months Thrombotic thrombocytopenic purpuraOpen-label prospective multicenter [35]11RTX (375 mg/m2) once weekly for 4 weeks + premedication with IV steroids (30 mg), IV dexchlorpheniramine (10 mg), and IV paracetamol (1 g). Patients with acute TTP (n = 5) continued plasma infusions for ≥3 weeks followed by tapering at the onset of remissionClinical remission (regression of visceral ischemic signs and normalization of blood parameters) in all patients with acute TTP; continued remission in patients with disease remission at enrolment (6–11 months’ follow-up). Biologic remission (≥10% recovery of ADAMTS-13 activity and disappearance of anti-ADAMTS-13 antibodies) in all pts Open-label prospective multicenter [82]25RTX (375 mg/m2) once weekly for 4 weeks + premedication with IV hydrocortisone (100 mg), IV dexchlorpheniramine (10 mg), and oral paracetamol (1 g) immediately following PEX; PEX was continued until clinical remission was achievedAll patients achieved clinical remission (sustained normal platelet count, absence of clinical manifestations of TTP, and cessation of PEX) in a median of 11 days after initiating rituximab. ADAMTS-13 activity returned to normal levels in 21/25 pts; anti-ADAMTS-13 antibodies disappeared in 23/25 pts Retrospective comparative 2-center [45]15RTX (375 mg/m2) once weekly for 1–8 weeks + standard therapy (PEX + corticosteroids + various agents added as second-line therapy, if needed) (n = 8) or standard therapy alone (n = 7) Clinical remission (absence of clinical manifestations of TTP and normalization of blood parameters): 100% (RTX group) vs. 66% (standard therapy group) (p = 0.0025)Mixed cryoglobulinemiaOpen-label prospective [80]20hRTX (375 mg/m2) once weekly for 4 weeksComplete response (improvement of clinical signs and decline in cryocrit) in 16/20 (80%) pts; response was maintained for ≥12 months in 12/16 respondersCase series [101]15iRTX (375 mg/m2) once weekly for 4 weeks + prednisone (<0.5 mg/kg/day), if already administered at recruitmentImproved clinical symptoms (including cutaneous manifestations, lymphoma features, neuropathic symptoms) in all 15 ptsCold agglutinin diseaseOpen-label Phase II [11]27RTX (375 mg/m2) once weekly for 4 weeks. Re-treatment (if required): RTX (same regimen) plus interferon-α (5 million units three-times weekly for 20 weeks) Clinical response (improvement in anaemia, clinical symptoms, and histopathology) in 14/27 (52%) pts after first treatment and in 6/10 pts after re-treatment; median (range) time to response was 1.5 (0.5–4) monthsPhase II multicenter [81]20jRTX (375 mg/m2) once weekly for 4 weeksOne pt showed a complete response (normalization of hemoglobin levels, absence of signs of hemolysis, and loss of clinical symptoms), 8 pts had a partial response (increase in hemoglobin levels ≥1.0 g/dl for ≥1 month, no need for erythrocyte transfusions, improvement in clinical symptoms); of the 9 responders, 8 relapsed and 1 remained in remission at 48 weeksaProliferative lupus nephritis, bANCA-positive microscopic polyangitis (n = 2) and ANCA-positive Wegener’s granulomatosis (n = 7), cANCA-associated vasculitisdANCA-positive refractory Wegener’s granulomatosis, eANCA-positive microscopic polyangitis (n = 2) and ANCA-positive Wegener’s granulomatosis (n = 8), f Dermatomyositis, g Clinical results were obtained from physicians via a questionnaire (original patient data were not analyzed), h HCV-positive type II or type III mixed cryoglobulinemia, i Type II mixed cryoglobulinemia (HCV-positive [n = 12]; associated with SS [n = 1]; “essential” disease [n = 2]), j Idiopathic CAD (n = 13) and CAD associated with malignant B-cell lymphoproliferative disease (n = 7)ADAMTS-13 a disintegrin-like and metalloproteinase with thrombospondin-like type I motif 13, ANCA anti-neutrophil cytoplasmic antibody, BILAG British Isles Lupus Assessment Group, BVAS Birmingham vasculitis activity score, BVAS/WG BVAS modified for Wegener’s granulomatosis, CAD cold agglutinin disease, CyP cyclophosphamide, HCV hepatitis C virus, IVIG intravenous immunoglobulin, MALT mucosa-associated lymphoid tissue, PEX plasma exchange, pts patients, RTX rituximab, SLAM systemic lupus activity measure, VAS visual analog scale
Systemic lupus erythematosus
Traditional treatments for SLE include nonsteroidal anti-inflammatory drugs, antimalarials, corticosteroids, methotrexate, mycophenylate, and cytotoxic drugs such as cyclophosphamide (often in combination). However, these therapies are associated with many potential side effects and are usually only partially effective in the long term [46]. The wide body of evidence indicating that B cells play a central role in the etiopathology of SLE has focused attention on the potential benefits of rituximab and other B cell-targeted therapies in the disease [33, 57, 78].
Individual case reports and case series, together with encouraging results from early phase clinical trials, indicate that rituximab is likely to provide significant clinical benefit for at least a subset of SLE patients. For example, in a dose-escalation study involving 17 patients, significant improvements in the systemic lupus activity measure (SLAM) score were observed in those patients (11/17) who achieved concomitant profound B cell depletion; efficacy persisted for 12 months and no significant adverse events were reported [59]. Analysis of some of the patients in this trial revealed that clinical response to rituximab correlated closely with the FcγIIIa genotype of individual patients [6], as observed previously in studies involving the rituximab responses of patients with follicular lymphoma [96]. In another open-label study, 23/24 patients achieved depletion of B cells following treatment with rituximab (two 1,000 mg infusions of rituximab separated by 2 weeks); depletion lasted for 3–8 months—except in 1 individual, who remained depleted after 4 years [55]. Clinical improvements observed in this study occurred in each of the 8 organs/systems assessed using the British Isles Lupus Assessment Group (BILAG) system. A recent update from the same group—covering a total of 41 patients with a mean (range) follow-up period of 37 (6–79) months—reported that one-third of patients remained well following B cell depletion, without the need for immunosuppressive agents [64]. Thirteen patients had been re-treated with rituximab. Three serious adverse events (1 pneumococcal sepsis, 1 severe serum sickness-like reaction, and 1 seizure related to hyponatremia) and 2 deaths (1 involving varicella pneumonitis and the other involving pancarditis) had occurred in this cohort over the 7-year observation period.
In another trial involving patients with active or refractory SLE, with a follow-up period of 2 years, all 11 patients in the study responded to a single course of rituximab, with 6 achieving a full response and 5 a partial response; although relapse was common (64%), re-treatment was rapidly effective [85].
In a recently reported case series of six patients with aggressive refractory SLE, rituximab therapy (doses of rituximab and use of combination drugs varied between patients) resulted in partial clinical improvements in five cases [40]. Rituximab has also shown effectiveness in pilot studies involving patients with the common severe complication lupus nephritis [42, 84, 95] and in patients with refractory SLE involving the central nervous system [92].
Although most studies to date indicate that B cell depletion therapy is likely to be useful in SLE, the variability of responses to rituximab therapy observed in SLE trials published to date remains to be explained. Ongoing Phase II/III randomized controlled trials should provide some insight into this question. In addition, although the overall tolerability of rituximab in SLE appears to be good, the Food and Drug Administration recently issued an alert concerning two spontaneous fatal cases of progressive multifocal leukoencephalopathy (PML) due to JC polyomavirus reactivation in two patients with SLE who had received rituximab therapy [38]. It is unclear whether these cases were related to rituximab treatment, since only two cases have been reported and PML has also been reported in >20 SLE patients not treated with rituximab.
Sjögren’s syndrome
Sjögren’s syndrome is a chronic autoimmune disorder of the exocrine glands affecting approximately 1% of the adult US population. The syndrome often occurs in the presence of another autoimmune disorder such as RA or SLE [37]. The etiopathology of SS is not fully understood; however, disturbances in B cell biology are considered to play an important role [43].
A number of case reports and pilot studies have been published that describe the successful treatment of SS with rituximab [2, 73, 76, 93]. In a recent trial involving 16 female patients with systemic complications of primary SS, rituximab therapy led to B cell depletion and decreased levels of various B cell markers; with a median follow-up period of 14.5 months, clinical efficacy was observed in 4/5 patients with lymphomas and in 9/11 patients with other systemic manifestations [83].
Another recent study investigated the effects of rituximab (two infusions of 375 mg/m2 separated by 1 week) in 16 patients with primary SS [26]. Rituximab therapy, which was administered using a slow initial rate of infusion without steroid premedication, was well tolerated and overall improvements were observed in subjective parameters of disease activity and in quality of life after both 12 and 36 weeks’ follow-up.
Results were presented recently from the first double-blind, randomized, controlled study of rituximab in SS [24]. In this 20-patient pilot study, subjects received either rituximab (two 1,000 mg infusions separated by 2 weeks) or placebo. Although patient responses were highly variable and there was a marked placebo effect, a higher proportion of patients in the rituximab group achieved improvement in fatigue (the primary efficacy endpoint) than in the placebo group (48 vs. 20%); this difference was not statistically significant. Significantly greater improvements with rituximab over placebo in the social functioning aspect of the quality of life assessment were also noted.
Vasculitis
Vasculitis refers to a collection of rare inflammatory diseases that involve the blood vessel walls and surrounding interstitium. A subset of these diseases, including Wegener’s granulomatosis (WG), microscopic polyangitis, and Churg–Strauss syndrome, is characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) [97]. The mainstay of current therapies in vasculitis involves glucocorticoids, cyclophosphamide, and—more recently—methotrexate and azathioprine [54]. However, these approaches are not always effective and are often limited by significant toxicity. B cells have been implicated in the pathogenesis of ANCA-associated vasculitis [20], indicating that rituximab may be an effective treatment option.
In addition to a number of individual case reports, results have been published recently from several small open-label trials of rituximab in vasculitis. In a report of a series of nine individual cases of ANCA-positive vasculitis resistant to conventional therapy in which rituximab therapy was attempted, eight patients achieved complete responses, while the other patient showed a partial response [34]. Keogh and colleagues have conducted small, prospective, open-label trials in both ANCA-associated vasculitis and WG. The vasculitis trial involved 11 patients whose disease was either refractory to cyclophosphamide or in whom cyclophosphamide was contraindicated [50]. Following infusions with rituximab, circulating B cells became undetectable in all patients and ANCA titers decreased significantly. Clinical remission was achieved in all patients and was maintained while B cells were undetectable. In ten patients with refractory WG treated with prednisone (1 mg/kg/day) plus rituximab (four consecutive weekly infusions of 375 mg/m2) [51], therapy was well tolerated and—after 3 months—all patients had achieved clinical remission (reduction in disease activity score to 0); in addition, all patients were able to stop glucocorticoids by 6 months. Following the recurrence of raised ANCA titers, five patients in the trial were successfully re-treated with rituximab. Results were also recently published of long-term follow-up of ten patients with ANCA-associated vasculitis who had been treated with rituximab [88]: patients had received four consecutive weekly doses of rituximab (375 mg/m2) and all experienced rapid clinical improvement at 6 months. Although three patients subsequently relapsed, re-treatment was effective. In addition, ANCA titers decreased significantly in all patients. Of 11 patients with refractory ANCA-associated vasculitis who were treated with rituximab in another recently published pilot study, 10 showed either complete or partial responses to a course of rituximab together with a single dose of cyclophosphamide [85].
In contrast to the above findings, one recent study found that rituximab was less effective in a cohort of eight patients with refractory WG [8]. In this trial, rituximab was given every fourth week. Interestingly, all patients in this study had particular granulomatous manifestations, consisting of retro-orbital granulomata (n = 5), nodules of the lungs (n = 1), and subglottic stenosis (n = 2). Although three patients experienced some clinical improvement, ANCA titers were not affected by rituximab therapy (except in a single patient). A smaller Norwegian study had also previously found only temporary responses to rituximab in three patients with WG, two of whom had granulomatous masses [68].
In a recent review of published studies in this area, it was concluded that rituximab may be an effective treatment in patients with refractory ANCA-associated vasculitis (with the probable exception of WG patients with retro-orbital granulomas, who tended to be less responsive to rituximab therapy) [98]. Since then, however, case reports have appeared describing the successful use of rituximab in patients with granulomatous involvement [79, 91]. In addition, results from a recent case series of eight WG patients indicated that, while vasculitis symptoms tended to disappear relatively quickly, granulomatous manifestations usually regressed more slowly (sometimes over several months) [14].
With regard to other forms of ANCA-associated vasculitis, two individual case reports have been published recently detailing the successful treatment of Churg–Strauss syndrome with rituximab [49, 52].
Thrombocytopenic purpura and other hematologic disorders
A number of autoimmune disorders of hemostasis, most notably idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP), have been examined for their potential responsiveness to rituximab in several small trials.
In a study involving a cohort of 25 patients with chronic ITP that had proved resistant to conventional therapies [87], patients received weekly rituximab at a dose of 375 mg/m2 for 4 weeks. The overall response rate (comprising those with complete, partial, and minor responses) was 52%; responses were sustained for at least 6 months in 7 patients. Complete and partial responses were associated with rapid normalization of platelet concentrations. A similar initial response rate (54%) was reported from a larger follow-up trial involving 57 patients; sustained responses were observed in 32% of the study participants [22]. Other reports include a multicenter trial in 35 adults with refractory ITP conducted in Denmark, which resulted in a 44% overall success rate based on predefined rises in platelet concentrations [13]. An indirect retrospective survey of findings from 89 ITP patients treated at multiple centers in Spain indicated that rituximab therapy led to sustained responses in 35% of patients with a median follow-up of 9 months (range 2–42 months) [71].
A review was published recently of the clinical outcomes of patients with chronic ITP who were re-treated with rituximab following an initial response to therapy [72]. All 9 second responses recorded in this report were classified as complete. An interesting additional finding was the higher female:male ratio of the nine re-treated patients compared with the population of patients originally treated across the published studies identified, suggesting that female ITP patients are more likely than male patients to respond to rituximab therapy. In a recently published letter, early administration of rituximab was reported to be associated with a higher response rate in chronic ITP [102].
The efficacy and safety of rituximab in adults with ITP were the subject of a recently published systematic review [9]. Based on 19 reports (313 patients) deemed eligible for the analysis up to April 2006, rituximab therapy was associated with mean complete response (platelet count >150 × 109 cells/l) and overall response (platelet count >50 × 109 cells/l) rates of 44 and 63%, respectively. Significant toxicities including death occurred in 3% of included cases, although the deaths were not necessarily attributable to rituximab therapy. The authors noted the lack of randomized controlled studies of rituximab therapy in ITP.
A number of studies have also been conducted in patients with refractory or relapsing TTP. In addition to several case reports and small case series [3, 17, 69, 70, 74, 99], results from the first prospective trial have been published [35]. This study recruited 11 patients (6 enrolled during an acute refractory phase and 5 during a remission phase); following rituximab therapy (375 mg/m2 once weekly for 4 weeks), clinical remission was observed in all 6 acute cases, while all 5 patients enrolled during remission remained in clinical remission during the 6–11 month follow-up period. Biologic remission (disappearance of anti-ADAMTS-13 [a disintegrin and metalloproteinase with thrombospondin motif 13] antibodies, which occur in the great majority of patients with acquired TTP [75]) was achieved in all patients 7–24 weeks after the final rituximab infusion.
Another more recent study involved 25 patients with acute refractory/relapsing idiopathic TTP, who were given rituximab in conjunction with plasma exchange (PEX) because of progressive clinical disease [82]. It was reported that all 25 patients in this trial achieved complete clinical and laboratory remission (sustained normal platelet count, absence of clinical manifestations of TTP, and cessation of PEX) in a median of 11 days following the initiation of rituximab therapy. Restoration of ADAMTS-13 activity and disappearance of anti-ADAMTS antibodies occurred in the vast majority of cases. At the time of publication, it was stated that none of the patients had clinically relapsed, with a median (range) follow-up of 10 (1–33) months.
In another recent retrospective study, the clinical outcome of patients who had received rituximab (375 mg/m2 once weekly for a maximum of 8 weeks) together with standard therapy (PEX + corticosteroids) was compared with that of patients who had received standard therapy alone [45]. The remission rate in the rituximab group was significantly greater than that observed in the standard therapy group (100 vs. 66%; P = 0.0025). Interestingly, all three of the TTP studies described above reported good tolerability to rituximab therapy.
There have also been sporadic case reports describing the successful use of rituximab in a number of other rare hematologic disorders, including Evans’ syndrome [61, 65], mixed type II cryoglobulinemia [15, 80, 101], and cold agglutinin disease [11, 81]. In addition, we have recently reported on the successful use of rituximab in RA patients with life-threatening hemorrhage due to the presence of Factor VIII inhibitor [67]. By contrast, a case report describing the failure of rituximab therapy in a hemophiliac patient with Factor VIII inhibitor has also been published [18]. A recent analysis of published case reports of patients with acquired antibodies to Factor VIII indicated that rituximab therapy was associated with a similar rate of clinical remission (approximately 80%) compared with the standard treatment modality (cyclophosphamide + prednisolone) [86].
Myositis
Myositis comprises a group of inflammatory myopathies, of which polymyositis, dermatomyositis, and inclusion body myositis are the best defined clinically. The etiopathologies of this group of diseases are currently poorly understood, although autoimmunity is thought to play an important role [19].
The aim of a recent open-label pilot study involving seven patients with dermatomyositis was to test the hypothesis that B cells play a critical role in this disease [56]. The results of this trial, in which patients received four infusions of rituximab (375 mg/m2) at weekly intervals, showed that rituximab therapy was well tolerated and led to significant clinical improvements in the six evaluable patients who completed 1 year of follow-up. A number of other small pilot studies and case reports have also appeared recently detailing the generally successful use of rituximab in patients with dermatomyositis or polymyositis [7, 12, 16, 28, 53, 62, 66].
Antiphospholipid syndrome
Antiphospholipid syndrome (APS), a rare disorder mostly affecting young adults, is defined by the presence of autoantibodies against phospholipids; the main clinical manifestations are venous or arterial thrombosis and obstetric complications, although the link between antiphospholipid antibodies and these clinical features has not been firmly established [39]. The traditional approach to treatment mainly involves the use of anticoagulation therapies. However, data indicating a link between raised circulating CD5+ B cells and high levels of antiphospholipid antibodies in APS patients [100] suggest that APS may be amenable to B cell-directed therapies.
To date, only a small number of case reports have been published which detail attempts to manage APS with rituximab. Three of these studies [5, 77, 94] reported successful clinical outcomes following rituximab therapy, while the other [4] reported only a limited effect of rituximab on thrombocytopenia and anticardiolipin antibodies in a patient with primary APS. Although the data are currently limited, the striking clinical successes seen in some patients suggest that pilot studies with rituximab in APS should be conducted in the near future.
Still’s disease
Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology. Traditional therapies include NSAIDs, corticosteroids, and—more recently—disease-modifying anti-rheumatic drugs [47]. A number of trials have also been conducted with biologic agents (including TNF inhibitors), with some promising results [32].
One case report was published recently that described the successful use of rituximab in a patient with AOSD [1]. This report, together with the author’s unpublished observations of two patients with AOSD refractory to cytotoxic agents who benefited from repeated rituximab infusion therapy, suggests that rituximab may be a future treatment option for this disease.
Neurologic disorders
As reviewed recently by Finsterer [36], rituximab has been tested in a number of immune-mediated peripheral neuropathies with promising results. Its potential clinical utility in neurological diseases of the central nervous system such as multiple sclerosis (MS) remains to be explored. Encouragingly, pilot studies have shown that rituximab therapy results in partial depletion of B cells from the cerebrospinal fluid of patients with progressive MS [23, 63]. The results of the first Phase I and II trials of rituximab in progressive MS were presented recently [10, 44]. In the placebo-controlled Phase II study [44], involving 104 patients with relapsing remitting MS, a single course of rituximab (two infusions of 1,000 mg given 2 weeks apart) resulted in significantly fewer inflammatory brain lesions and relapses over the 6-month observation period compared with placebo. Rituximab treatment was reported to have been well tolerated.
Conclusions
Recent advances in our understanding of autoimmunity have opened up new avenues for exploring novel targeted therapies in a wide range of diseases. The role of B cells in many autoimmune disorders is now widely accepted, in many cases through the demonstration that B cell depletion using rituximab can often be very effective clinically. The potential utility of rituximab and other B cell-directed therapies is currently being studied in several of these diseases, including SLE, SS, and vasculitis. Although to date most of the findings have been encouraging, a significant proportion of the information derives from case reports and small case series. Together with the lack of randomized controlled trials in most of the diseases discussed in this review, it is likely that there has been a degree of positive reporting bias. Therefore, until large-scale clinical trial data are available, it would be prudent to proceed with caution regarding the use of rituximab outside its approved indications. Although rituximab tolerability was generally reported as favorable in most of the studies covered in this review, the true incidence of associated adverse events (e.g., serious infections, serum sickness-like reactions, and PML) will only become clear when larger numbers of patients have been treated in each disease entity. Important questions also remain regarding the optimal rituximab dosing modalities for each disease (for example, the dose and frequency of treatment, when re-treatment should be considered, and whether to use combination therapies). Nevertheless, based on the information published to date, it seems likely that B cell depletion therapy, using rituximab and—in the future—agents currently under development, will offer an effective new approach for the management of many of these burdensome and difficult-to-treat conditions.

biologic therapies
rituximab
cd20
lupus
sjögren’s syndrome
vasculitis
thrombocytopenic purpura
b-lymphocytes


Chronic kidney disease in children: the global perspective

In contrast to the increasing availability of information pertaining to the care of children with chronic kidney disease (CKD) from large-scale observational and interventional studies, epidemiological information on the incidence and prevalence of pediatric CKD is currently limited, imprecise, and flawed by methodological differences between the various data sources. There are distinct geographic differences in the reported causes of CKD in children, in part due to environmental, racial, genetic, and cultural (consanguinity) differences. However, a substantial percentage of children develop CKD early in life, with congenital renal disorders such as obstructive uropathy and aplasia/hypoplasia/dysplasia being responsible for almost one half of all cases. The most favored end-stage renal disease (ESRD) treatment modality in children is renal transplantation, but a lack of health care resources and high patient mortality in the developing world limits the global provision of renal replacement therapy (RRT) and influences patient prevalence. Additional efforts to define the epidemiology of pediatric CKD worldwide are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired.
Introduction
Most epidemiological information on chronic kidney disease (CKD) originates from data available on end-stage renal disease (ESRD), the terminal stage of CKD when treatment with renal replacement therapy (dialysis or transplant) becomes necessary to sustain life. Little information is available on the prevalence of earlier stages of CKD, as patients are often asymptomatic. The epidemiological studies that have been performed provide evidence that ESRD represents the “tip of the iceberg” of CKD and suggest that patients with earlier stages of disease are likely to exceed those reaching ESRD by as much as 50 times [1]. Worldwide, the number of patients with CKD is rising markedly, especially in adults, and CKD is now being recognized as a major public health problem that is threatening to reach epidemic proportions over the next decade [2]. In North America, up to 11% of the population (19 million) may have CKD [1], and surveys in Australia, Europe, and Japan describe the prevalence of CKD to be 6–16% of their respective populations [3, 4]. In North America alone, more than 100,000 individuals entered ESRD programs in 2003 (adjusted incidence rate: 341 new cases per million population), with a prevalence count of more than 450,000 as of December 2003 (prevalence rate: 1,509 per million population) [5]. Not surprisingly, the cost of treating patients with ESRD is substantial and poses a great financial challenge. The economic cost of North American ESRD programs reached $25.2 billion in 2002, an 11.5% increase over the previous year, and is expected to reach $29 billion by 2010 [2]. Two factors, aging and the global epidemic of type-II diabetes mellitus, are primarily responsible for the increasing incidence of CKD in adults.
In contrast, pediatric ESRD patients (<20 years of age) constitute a very small proportion of the total ESRD population. However, they pose unique challenges to providers and to the health care system, which must address not only the primary renal disorder but the many extrarenal manifestations that affect growth and development as well. In North America, children younger than 20 years of age account for less than 2% of the total ESRD patient population, and the prevalence of patients aged 0–19 years has grown a modest 32% since 1990. This is in contrast to the 126% growth experienced by the entire ESRD population over the same time period [5]. Nonetheless, CKD in children is a devastating illness, and the mortality rate for children with ESRD receiving dialysis therapy is between 30 and 150 times that of the general pediatric population [6, 7]. In fact, the expected remaining lifetime for a child 0–14 years of age and on dialysis is only 20 years [6]. Therefore, the diagnostic and therapeutic approach to CKD must emphasize primary prevention, early detection, and aggressive management. Knowledge of the epidemiology of CKD and its associated clinical manifestations is a crucial component of this effort by helping to target key patient populations at risk, by quantifying the extent of the problem, and by facilitating an assessment of the impact of intervention.
Classification of CKD
There is limited information on the epidemiology of CKD in the pediatric population. This is especially true for less advanced stages of renal impairment that are potentially more susceptible to therapeutic interventions aimed at changing the course of the disease and avoiding ESRD. As CKD is often asymptomatic in its early stages, it is both underdiagnosed and, as expected, underreported. This is in part the result of the historical absence of a common definition of CKD and a well-defined classification of its severity. The current CKD classification system described by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) has helped remedy the situation. According to the K/DOQI scheme, CKD is characterized by stage 1 (mild disease) through stage 5 (ESRD) (Table 1) [8]. By establishing a common nomenclature, staging has been helpful for patients, general health care providers, and nephrologists when discussing CKD and anticipating comorbidities and treatment plans. The classification system has, however, been subject to debate, as it is argued that stages 1 and 2 would be better defined by the associated abnormalities (e.g. proteinuria, hematuria, structural anomalies) rather being classified as CKD, whereas more advanced stages (3 and 4) should be characterized by the severity of the impaired renal solute clearance [9]. Furthermore, and with particular reference to children, the normal level of glomerular filtration rate (GFR) varies with age, gender, and body size and increases with maturation from infancy, approaching adult mean values at approximately 2 years of age (Table 2). In turn, GFR ranges that define the five CKD stages apply only to children 2 years of age and older. Finally, although the threshold of GFR reduction where chronic renal failure (CRF) and chronic renal insufficiency (CRI) begins is a matter of opinion, many registries have operationally defined this as a GFR below 75 mL/min per 1.73 m2 [10]. Hence, populations with CRI or CRF are now categorized as those that comprise CKD stages 2–4.
Table 1National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) stages of chronic kidney disease [8]StageDescriptionGFR (mL/min/1.73 m2)1Kidney damage with normal or increased GFR>902Kidney damage with mild decrease in GFR60–893Moderate decrease in GFR30–594Severe decrease in GFR15–295Kidney failure<15 or dialysisGFR glomerular filtration rateTable 2Normal glomerular filtration rate (GFR) in children and adolescents [8]AgeMean GFR±SD (mL/min/1.73 m2)1 week (males and females)41 ± 152–8 weeks (males and females)66 ± 25>8 weeks (males and females)96 ± 222–12 years (males and females)133 ± 2713–21 years (males)140 ± 3013–21 years (females)126 ± 22
Sources of pediatric data
Most of the existing data on the epidemiology of CKD during childhood concentrates on the late and more severe stages of renal impairment [11, 12] and are not population based in nature [13]. In addition, some methodologically well-designed childhood CKD registries are limited by being restricted to small reference populations [14–16]. Finally, direct comparisons of the incidence and prevalence rate of childhood CKD in different geographical areas around the world is difficult due to methodological differences in study age group, characterization of the degree of renal insufficiency, and disease classification.
In the United States, data is primarily available from two sources: the registry of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) organization [10] and the United States Renal Data System (USRDS). NAPRTCS was established as a transplant registry in 1987 with a goal of gathering data from the majority of pediatric renal transplant centers in the United States, Canada, Mexico, and Costa Rica. Its registry was expanded in 1992 to include data from patients receiving maintenance dialysis, and in 1994, data was first collected from patients with CRI characterized by a Schwartz estimated creatinine clearance of ≤75 mL/min per 1.73 m2 [17]. Participation in this registry is voluntary and mandates the involvement of a pediatric nephrologist in the provision of care to those patients entered into the registry. As of December 2005, information had been collected on more than 6,400 patients who entered the registry with a diagnosis of CRI [10].
In contrast to the NAPRTCS, which only receives data voluntarily submitted by pediatric nephrology centers, the USRDS is a national data system that collects, analyzes, and distributes information about all patients with ESRD in the United States. Thus, USRDS data includes information on both adults and children with stage 5 CKD, which is published as an Annual Data Report (ADR) [5, 6]. This source of information is particularly important from an epidemiological perspective, as approximately one third of children and adolescents with ESRD requiring dialysis or transplantation in the United States are cared for in facilities that primarily serve adults, and thus, they are not included in the NAPRTCS database [18].
The recently published data from the ItalKid Project is by far the most comprehensive data on the epidemiology of CKD in children. The ItalKid Project is a prospective, population-based registry that was started in 1990 and includes all incident and prevalent cases of CRF (CCr < 75 mL/min per 1.73 m2) in children (<20 years) from throughout Italy (total population base: 16.8 million children) [19].
The European Dialysis and Transplant Association (EDTA) was established in 1964 to record demographic data and treatment details of patients receiving renal replacement therapy (RRT), including dialysis and renal transplantation. Historically, the EDTA registry gathered data on RRT in children from individual renal units by means of center and patient questionnaires, a process that was subject to underreporting. At the turn of the century, the EDTA office moved to Amsterdam and began collecting data on RRT entirely through national and regional registries and recently reported data on RRT in children from 12 registries located in Europe (vide infra) [20].
Other regional societies, such as the Japanese Society for Pediatric Nephrology (JSPN), have also provided useful epidemiological information. In Japan, children are screened annually by urinalysis in a nationwide program, an approach that has provided invaluable epidemiological information and the opportunity for establishing clinical trials focusing on early detection and intervention. Epidemiological data is also available from Australia and New Zealand [21].
In contrast, epidemiological information from Asia, where 57% of the world’s population resides and a geographic region characterized by a very high proportion of children, is very scant and is primarily based on patients referred to tertiary medical centers [22, 23]. The situation in central and southern Africa or in the Arab countries of North Africa and the Middle East is even more unfortunate, as there are no regional pediatric nephrology societies in place to collect and publish any valid epidemiological data.
Incidence and prevalence of CKD in childhood
Large population-based studies, such as the Third National Health and Nutrition Examination Survey (NHANES III), have made it possible to estimate the incidence and prevalence of CKD in the adult population [1]. According to this report, the prevalence of patients with early stages of CKD (stages 1–4; 10.8%) is approximately 50 times greater than the prevalence of ESRD (stage 5; 0.2%). There is no comparable information available in the United States on the prevalence of the earlier stages of CKD in children and its relationship to ESRD. This is, in large part, due to differences in disease etiology for children and adults. Furthermore, the relationship between the prevalence of earlier stages of CKD and the subsequent development of more severe CKD/ESRD is determined in part by factors unrelated to disease etiology, as was recently shown in a comparison between adult patients in Norway and the United States [4]. Data that do exist on the epidemiology of CKD in children come from a variety of sources.
Population-based data from Italy (ItalKid Project) has reported a mean incidence of preterminal CKD (CCr < 75 mL/min per 1.73 m2) of 12.1 cases per year per million of the age-related population (MARP), with a point prevalence of 74.7 per MARP in children younger than 20 years of age [19]. The national survey performed in Sweden from 1986 until 1994 included children (ages 6 months to 16 years) with more severe preterminal CKD (CCr < 30 mL/min per 1.73 m2) and reported a median annual incidence and prevalence of 7.7 and 21 per MARP, respectively [16]. Similarly, the incidence rate of severe pre-terminal CKD in Lorraine (France) has been estimated as 7.5 per MARP in children younger than 16 years; the prevalence rate ranged from 29.4 to 54 per MARP [15]. In Latin America, the Chilean survey from 1996 reported incidence and prevalence rates of 5.7 and 42.5 per MARP, respectively, in children younger than 18 years of age with CCr < 30 mL/min/1.73 m2, including patients with ESRD [12]. As alluded to above, there are 81.2 million children in the United States younger than 20 years of age [5], but no data on the incidence or prevalence of preterminal CKD is available.
Due to a lack of national registries, any semblance of incidence and prevalence data from developing countries primarily originates as reports from major tertiary care referral centers [22–27]. The nature of the data depends on local referral practices and accessibility to hospital care. The Jordan University Hospital has estimated the annual incidence and prevalence of severe CKD (CCr < 30 mL/min per 1.73 m2) to be 10.7 and 51 per MARP, respectively, based on their hospital admission rate [26]. A 15-year review of admissions from a university teaching hospital in Nigeria estimated the median annual incidence of severe CKD (CCr < 30 mL/min per 1.73 m2) to be 3.0 per MARP, with a prevalence of 15 patients per million children [27]. In a recent report, data from a major tertiary hospital in India revealed that approximately 12% of patients (n = 305) seen by the pediatric nephrology service over a 7-year period had moderate to severe CKD (CCr < 50 mL/min per 1.73 m2), and one quarter of these patients had already developed ESRD, highlighting the late diagnosis and referral pattern [23]. Similar data was reported from another tertiary hospital in India where 50% of 48 patients presenting with CRF over a 1-year period had ESRD [22]. Finally, data from a major Iranian hospital collected over 7 years (1991–1998) reported that 11% of pediatric nephrology admissions (n = 298) were due to severe CKD (CCr < 30 mL/min per 1.73 m2), and one half of the patients advanced to ESRD [25].
The incidence rate of ESRD, adjusted for race and gender, is much higher among adults than among children. Data from the USRDS revealed that in pediatric patients younger than 20 years of age, the annual incidence of ESRD increased marginally from 13 per MARP in the 1988 cohort to 15 per MARP in the 2003 cohort [5]. This is in contrast to the adult incidence rate of 119 per MARP for patients 20–44 years of age and 518 per MARP for those 45–64 years old in the 2003 cohort [5]. As in adults, a higher incidence rate with older patients was also found across the 5-year age groups within the pediatric cohort. The incidence rate was nearly twice as high among children 15–19 years of age (28 per MARP) compared with children 10–14 years of age (14 per MARP), and nearly three times higher than the rate for children 0–4 years of age (9 per MARP). The point prevalence for pediatric patients (adjusted for age, race, and gender) was 82 per million population during 2002–2003 [5].
The EDTA registry recently reported its cumulative data on 3,184 patients (<20 years of age) with ESRD who initiated RRT between 1980 and 2000 in 12 European countries [20]. With a total of 18.8 million children between 0–19 years in the countries surveyed, data revealed that the incidence of ESRD rose modestly from 7.1 per MARP in the 1980–1984 cohort to 9.9 per MARP over the next 15 years. In contrast, the prevalence of patients receiving RRT increased from 22.9 per MARP in 1980 to 62.1 per MARP in 2000, providing evidence of improved long-term survival. As in the United States, the incidence of ESRD was highest in the 15–19 year age group, with the exception of the 0- to 4-year age group in Finland who experienced a high incidence of ESRD (15.5 per MARP) secondary to the large number of infants in that country with congenital nephrotic syndrome. The incidence of ESRD in children (<20 years age) from Australia and New Zealand has remained fairly constant at around 8–10 per million population over the past 25 years, whereas the prevalence of treated ESRD has steadily increased since 1980, from approximately 25 to 50 patients per million population [21].
The 1998 Japanese National Registry data reported comparatively lower ESRD incidence and prevalence rates of 4 and 22 per MARP, respectively, for children 0–19 years of age [28] for reasons that are as yet unexplained. However, as in other countries, the prevalence rate of treated ESRD patients among patients aged 15–19 years of age was not only high (34 per million), but seven times higher than that of patients 0–4 years of age (5 per million).
In the 2005 ADR from the USRDS, data regarding the incidence and prevalence of ESRD in children was simultaneously published from 37 countries to corroborate the information above and to facilitate international comparisons [5]. The highest incidence rates for children were reported from the United States, New Zealand, and Austria, at 14.8, 13.6, and 12.4 per million population, respectively. As mentioned earlier (vide supra), Japan’s rate for pediatric patients was, in contrast, one of the lowest, even though Japan ranks fourth highest in the world for the incidence of ESRD in adults. The prevalence rate for pediatric ESRD patients was reported to be highest in Italy, at 258 patients per million population; however, this may be partially related to the addition of data from patients ages 20–24 to the prevalent group. The second highest prevalence rate for children was reported from Finland, with a rate only 40% of that in Italy but greater than the rates from the United States and Hungary, where they were reported to be 82 and 81 patients per million population, respectively (Fig. 1) [5].
Fig. 1Incidence (left) and prevalence of end-stage renal disease (ESRD) around the world in the 0–19 age group in 2003 [5]
A number of factors influence incidence and prevalence rate variability of childhood ESRD. Factors such as racial and ethnic distribution, type of prevalent renal disease, and quality of medical care available for preterminal CKD patients have a significant impact on patient outcome. As the vast majority of treated ESRD patients come from more-developed countries, which can afford the cost of renal replacement therapy, the huge disparity in the prevalence of ESRD between the more- and less-developed countries probably stems, in large part, from the inadequacy of health-care resource allocation to programs providing renal replacement therapy in underdeveloped countries [29, 30].
Finally, characterization of the patient population with CKD (both preterminal CRF and treated ESRD) reveals that the incidence and prevalence rates are universally greater for boys than for girls [10, 16, 19, 22, 23, 25–27]. Two thirds of patients in the NAPRTCS CRI registry and in the database of the ItalKid Project are males. This gender distribution reflects the higher incidence of congenital disorders, including obstructive uropathy, renal dysplasia, and prune belly syndrome, in boys versus girls. In fact, in the ItalKid Project, males continue to predominate (male:female ratio 1.72) even after excluding patients with posterior urethral valves [19].
As for race, the incidence rate for ESRD in black children in North America is two to three times higher than for white children, irrespective of gender [31]. Likewise, the incidence rate of ESRD for the indigenous people of Australia (Aborigines) and New Zealand (Maoris) is disproportionately higher than that experienced by the remainder of the population [32].
Etiology of CKD
Unlike adults in whom diabetes and hypertension are responsible for the majority of CKD, congenital causes are responsible for the greatest percentage of all cases of CKD seen in children. However, whereas this is the most common reported etiology from developed countries where CKD is diagnosed in its earlier stages, infectious or acquired causes predominate in developing countries, where patients are referred in the later stages of CKD. These generalizations apart, certain disorders giving rise to CKD are, indeed, more common in some countries than in others.
In the CRI registry arm of NAPRTCS, almost one half of the cases are accounted for by patients with the diagnoses of obstructive uropathy (22%), aplasia/hypoplasia/dysplasia (18%), and reflux nephropathy (8%) (Table 3). Whereas structural causes predominate in the younger patients, the incidence of glomerulonephritis (GN) increases in those older than 12 years. Among the individual glomerular causes, only focal segmental glomerulosclerosis (FSGS) accounts for a significant percentage of patients (8.7%), whereas all other glomerulonephritides combined contribute less than 10% of the causes of childhood CKD. For reasons that are as yet not clear, FSGS is three times more common in blacks than in whites (18% vs. 6%) and is particularly common among black adolescents with CKD [10].
Table 3Diagnosis distribution of North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) chronic renal insufficiency (CRI) patients [10]Distributions by diagnosisNumberPercent MalePercent whitePercent blackPercent otherTotal6,40564611920Primary diagnosis Obstructive uropathy1,38586612117 Aplastic/hypoplastic/dysplastic kidney1,12562621721 Other91358631621 FSGS55757403921 Reflux nephropathy5365374620 Polycystic disease25755741115 Prune belly18597622315 Renal infarct15553661321 Unknown16852472032 HUS1345881711 SLE nephritis9625274132 Cystinosis97489235 Familial nephritis9986611227 Pyelo/interstitial nephritis8739642016 Medullary cystic disease82508497 Chronic GN7650432928 MPGN-type I6761481933 Berger’s (IgA) nephritis6463641620 Congenital nephrotic syndrome6846461243 Idiopathic crescentic GN4648522424 Henoch-Schönlein nephritis406578320 MPGN-type II297279317 Membranous nephropathy3348303930 Other systemic immunologic disease2532403228 Wilms tumor2854572121 Wegener’s granulomatosis17769406 Sickle cell nephropathy13620928 Diabetic GN1150364518 Oxalosis66783017 Drash syndrome610067033FSGS focal segmental glomerulosclerosis, HUS hemolytic uremic syndrome, SLE systemic lupus erythematosus, GN glomerulonephritis, MPGN membranoproliferative GN, IgA immunoglobulin A
Data from the ItalKid Project revealed that hypoplasia with or without urological malformations accounts for as many as 57.6% of all cases of CKD in Italy, whereas glomerular diseases account for as few as 6.8% of cases of CKD in children [19]. Interestingly, when the analysis was restricted to the patient population that had reached ESRD, the relative percentage of glomerular diseases increased from 6.8% to 15.2%, whereas that of hypoplasia decreased from 57.6% to 39.5%, underscoring the discrepancy between the rates of progression of these two entities. Observations from this study have also prompted questions regarding the commonly accepted cause–effect relationship between vesicoureteral reflux (VUR) and kidney disease (reflux nephropathy) and support the hypothesis that both hypoplasia and VUR may be related to similar developmental factors causing congenital disorders of the kidney and urinary tract [33].
In the ESRD population reported by the EDTA registry, hypoplasia/dysplasia and hereditary diseases were the most common causes for ESRD in the 0- to 4-year age group, whereas GN and pyelonephritis became progressively more common with increasing age in the majority of reporting countries [20]. The exception is Finland, where congenital nephrosis (Finnish type) remains the most common cause of ESRD in children younger than 15 years of age [34]. Somewhat different is the data reported by the Japanese National Registry, which reflects a very high proportion (34%) of cases secondary to GN [FSGS 60% and immunoglobulin A (IgA) nephropathy 17%] in their pediatric ESRD population [28]. Similarly, the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry reported GN to be the most common cause of ESRD in children and adolescents from Australia and New Zealand (42%) [21].
Comprehensive information on the etiology of ESRD from many less-developed countries is unavailable owing to poor data collection and the absence of renal registries. In addition and in contrast to the experience within developed countries, many of these countries continue to suffer from the burden of infectious diseases such as hepatitis C, malaria, schistosomiasis, and tuberculosis, with resultant infection-related GN. One such example is Nigeria, from which a publication on pediatric CKD reported various glomerulopathies as the cause of renal failure in one half of their patients, a third of whom also had nephrotic syndrome [27]. Human-immunodeficiency-virus (HIV)-associated nephropathy in children is another entity that is underreported, and it is a disorder that is likely to increase along with the increasing incidence of HIV in Africa and Asia. Familial Mediterranean fever leading to amyloidosis has been found to be responsible for up to 10% of cases of CKD in Turkish children (n = 459) [24].
Hereditary disorders are more prevalent in countries where consanguinity is common. One third of Jordanian children with CKD have been diagnosed with hereditary renal disorders such as polycystic kidney disease, primary hyperoxaluria, and congenital nephrotic syndrome [26]. Similarly, one fifth of Iranian children with CKD have been reported to have hereditary disorders such as cystinosis, cystic kidney disease, Alport syndrome, and primary hyperoxaluria [25].
Progression of CKD
Although the stages of CKD are now reasonably well defined, the natural history of the early stages is variable and often unpredictable. However, most available data demonstrates a slower progression toward ESRD in patients with congenital renal disorders compared with patients with glomerular disease. For this reason, and as alluded to previously, the relative proportion of glomerular diseases increases in groups of patients with more advanced stages of CKD. The progression of established CKD is also influenced by a variety of risk factors, some of which (e.g., obesity, hypertension, and proteinuria) may be modifiable [35–37], whereas others, including genetics, race, age, and gender, are not.
Obesity is associated with hypertension, albuminuria, and dyslipidemia, all of which can potentially influence the progression of CKD. The incidence of certain glomerulonephritides, such as FSGS, is higher in obese than in lean individuals [38, 39]. Hypertension together with proteinuria has been shown to be an important risk factor for progression of primary renal disease in children and adults [40, 41], and the renoprotective efficacy of renin angiotensin system (RAS) antagonists, which is in part independent of blood pressure, has been clearly demonstrated in animal models and adults with acquired nephropathies [42–46]. Whereas both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have been shown to reduce proteinuria in children with CKD, the renoprotective efficacy of these medications in children and their potential impact on the epidemiology of CKD still needs to better delineated, as is currently being addressed by the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial [47, 48].
The clustering of CKD in families is strongly suggestive of a genetic or familial predisposition in some cases [49]. Studies have suggested the presence of links between CKD and various alterations or polymorphisms of candidate genes encoding putative mediators, including the renin–angiotensin system. Additionally, racial factors may play a role in susceptibility to CKD, as there is a strong concordance of renal disease in the families of African Americans with hypertensive ESRD [49]. Not only may there be an increased susceptibility to disease, but there is evidence that the rate of progression of CKD is faster among African American males [50]. Low birth weight in some ethnic communities might be associated with a reduction in the number of nephrons and a subsequent predisposition to hypertension and renal disease in later life [51].
Irrespective of the underlying kidney disease or presence of additional risk factors, it is clear that the risk of progression to ESRD in childhood is inversely proportional to the baseline creatinine clearance [10, 19]. Additionally, regardless of the initial level of renal insufficiency, puberty seems to be a critical stage for patients with renal impairment, as a steep decline in renal function often occurs during puberty and the early postpuberty period [19]. Whereas the specific reasons are yet to be determined, it is speculated that this pattern of progression may be attributable to an adolescent-specific pathophysiological mechanism, possibly related to sex hormones and/or the imbalance between residual nephron mass and the rapidly growing body size. Data collected by NAPRTCS has also revealed that patients whose baseline serum albumin was below 4 g/dl, inorganic phosphorus above 5.5 mg/dl, calcium below 9.5 mg/dl, blood urea nitrogen (BUN) above 20 mg/dl, or hematocrit below 33% had a significantly higher risk of reaching ESRD (p < 0.001) [10]. Data pertaining to a variety of risk factors potentially associated with the progression of CKD, including those noted above, is being collected by the Chronic Kidney Disease in Children Study (CKiD), a prospective, multicenter initiative funded by the National Institutes of Health designed to follow the course of 540 children with CKD for 2–4 years [52].
Outcome for children with CKD
The outcome of children with severe CKD is highly dependent upon the economy and availability of health care resources. Approximately 90% of treated ESRD patients come from developed countries that can afford the cost of RRT [29]. Despite comparable incidence rates, high mortality in countries that lack resources for RRT results in a low prevalence of CKD patients in those countries. In one of the tertiary care hospitals in India, for example, up to 40% of the ESRD patients opted out of further therapy because of a lack of financial resources [22], and of the 91 patients with ESRD in another hospital, only 15 underwent renal transplantation, 63 received hemodialysis, and the remainder opted out of dialysis or transplantation care secondary to financial constraints [23]. Similar results were recently published from South Africa where only 62% of children (<20 years of age) with ESRD were accepted by an “Assessment Committee” for RRT as part of a rationing program [30].
In countries where RRT is readily available, the most favored renal replacement modality is transplantation in all pediatric age groups. Sixteen percent of children newly diagnosed with ESRD in North America receive a preemptive transplant, and three fourth of children receive a transplant within 3 years of RRT initiation [5]. Similar figures are reported by the ANZDATA registry [21]. Among Western countries, Spain/Catalonia has the highest pediatric transplant rate, reaching 15 patients per million population, followed by a rate of 12 patients per million population in the United States and Finland (Fig. 2) [5]. In the United States, white pediatric patients are more likely to receive a renal transplant than are patients from other racial groups.
Fig. 2Percent distribution of prevalent dialysis modality (left) and transplant rates in the 0–19 age group in 2003 [5]
The distribution of dialysis modalities varies among countries (Fig. 2) [5]. Peritoneal dialysis (PD) in children is highest in Finland, New Zealand, and Scotland, accounting for 73%, 71%, and 67% of prevalent dialysis patients, respectively. Whereas PD is still the favored mode of dialysis in young children, there has been an increase in hemodialysis (HD) utilization since the early 1990s, and HD is now the most common form of dialysis overall for prevalent patients <19 years of age (Fig. 2) [5]. In the United States, PD is the most frequently used dialysis modality (60% of dialysis patients) according to the NAPRTCS registry [10], whereas HD is more common according to data collected by the USRDS [5]. Once again, this discrepancy reflects in part the fact that many adolescent patients are cared for in adult dialysis units where there is often a preference for HD [18]. Whereas automated PD (APD) is the most frequently used PD modality in children [53], continuous ambulatory PD (CAPD) is commonly used in countries that lack finances and technical support, as reflected in the recent report of the Turkish Pediatric Peritoneal Dialysis (TUPEPD) registry. [54].
Mortality rates remain significantly lower in pediatric patients with ESRD compared with their adult counterparts. Nevertheless, an assessment of the causes of death reflect the excess risk of cardiac and vascular disease and the high prevalence of left ventricular hypertrophy and dyslipidemia among children treated with RRT [55–57]. Pediatric patients with glomerulonephritis or those with cystic/hereditary/congenital disease have the greatest probability of surviving 5 years, in contrast to patients who have developed ESRD as a result of secondary GN or vasculitis [5]. Infants on dialysis have a higher mortality rate than do older children, which is likely, at least in part, to be a result of coexisting morbidities [58]. Although substantial improvement has occurred in the long-term survival of children and adolescents with ESRD over the past 40 years, the overall (dialysis and transplantation) 10-year survival remains at only 80%, and the age-specific mortality rate is still 30–150 times higher than among children without ESRD [6, 7]. It is noteworthy that dialysis is associated with an appreciably higher risk of death compared with renal transplantation; therefore, patients who experience a longer wait for transplantation are more likely to have a worse overall outcome. Not only is the benefit of transplantation evident when one compares transplant recipients to patients deemed “medically unsuitable” for transplantation, it has also been substantiated in a recent longitudinal study of 5,961 patients ≤18 years of age, all of whom were placed on the kidney transplant waiting list in the United States [59]. In that study, transplanted children had a lower estimated mortality rate (13.1 deaths/1,000 patient years) compared with patients on the waiting list (17.6 deaths/1,000 patient years). Similarly, the 2005 ADR reported that approximately 92% of children initiating therapy with a transplant survive 5 years compared with 81% of those receiving HD or PD [5]. Finally, the expected remaining lifetime for children 0–14 years of age and on dialysis is only 18.3 years, whereas the prevalent transplant population of the same age has an expected remaining lifetime of 50 years [5].
Conclusion
Children with CKD comprise a very small but important portion of the total CKD population. Whereas disorders associated with its development are well delineated, the availability of valid and widespread information regarding the epidemiology of CKD in children requires additional efforts, such as the ItalKid Project, in which early identification and longitudinal follow-up are key practices. This information will, in turn, serve as the basis upon which to judge the impact that observational trials such as CKiD and interventional trials such as ESCAPE have on the evolution of CKD during childhood [48].

chronic kidney disease
children
epidemiology
end-stage renal disease
renal replacement therapy