Katalin Dittrich

Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome

BACKGROUND In patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available. METHODS We performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m(2) given weekly for one to four courses). Long-term follow-up data (>2 years, median 36, range 24-92.8 months) are available for 29 patients (12 boys). RESULTS Twenty-six of 37 (70.3%) patients remained in remission after 12 months. Relapses occurred in 24 (64.8%) patients after a median of 9.6 (range 5.2-64.1) months. Time to first relapse was significantly shorter in patients receiving one or two compared to three or four initial infusions. In the 29 patients with long-term follow-up for >2 years, 12 (41%) patients remained in remission after the initial rituximab course for >24 months, 7 (24.1%) patients without further maintenance immunosuppression. Nineteen children received two to four repeated courses of rituximab increasing the total number of patients with long-term remission to 20 (69%), remission including 14 (48%) patients off immunosuppression. The proportion of patients with long-term remission was not related to the number of initial rituximab applications. No serious side effects were noted. CONCLUSION Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle’s loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P _ 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m2/y; P _ 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P _0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHN

Alteration of neuronal and endothelial nitric oxide synthase and neuropeptide Y in congenital ureteropelvic junction obstruction.

Abstract Problem: We investigated whether deranged nitric oxide synthase (NOS) and neuropeptide Y (NPY) expression is detectable in the stenotic segments of patients with congenital ureteropelvic junction obstruction. Methods: Using real-time reverse transcription-polymerase chain reaction (RT-PCR), we quantified mRNA amounts of NPY, neuronal (n), endothelial (e) and inducible (i) NOS in the stenotic segments of 20 patients with congenital ureteropelvic junction obstruction (aged 5.1 ± 7.0 years) and of 21 unaffected controls (aged 23.5 ± 24.2 years). Additionally, mRNAs of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), smooth muscle alpha-actin (Smactin), endothelial cell marker (CD31), and protein gene product 9.5 (PGP 9.5) were evaluated. Immunohistochemistry was made for NPY, nNOS, eNOS, iNOS, PGP 9.5, and CD 31. Results: The mRNA of nNOS was significantly reduced in the obstructed junctions when related to the mRNAs of Smactin (P < 0.001) or GAPDH (P < 0.05), respectively. A significant reduction was also obtained for eNOS mRNA when standardized to CD31 (P < 0.05), GAPDH or Smactin mRNA (P < 0.05, and P < 0.001, respectively). NPY, PGP 9.5 and iNOS mRNAs were found in comparable quantities in both groups. In the stenotic segments, Smactin mRNA level was about twofold higher than in our control specimens, as shown by the lower CT values for the patients in real-time PCR (16.9 ± 2.0 vs 17.9 ± 2.6, P < 0.05). Furthermore, Smactin, nNOS, iNOS, eNOS, and NPY mRNA levels in specimens of unaffected ureteropelvic junctions were independent of age. Major differences between control and stenotic tissues were detected by immunohistochemistry: There was a dramatic reduction of innervation density as evidenced by nNOS and NPY labeling. Conclusion: Taken together, we found alterations in NOS gene expression and NPY innervation in tissue specimens of patients with congenital ureteropelvic junction obstruction.

Liver cell transplantation in severe infantile oxalosis—a potential bridging procedure to orthotopic liver transplantation?

BACKGROUND The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. METHODS We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. RESULTS Pox decreased from 104.3±8.4 prior to 70.0±15.0 μmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 μmol/L) and after Day 14 of LCT until LKTx (77.3 μmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patients clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. CONCLUSIONS With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Stimulation of neuropeptide Y release in rat pheochromocytoma cells by nitric oxide

Neuropeptide Y and nitric oxide (NO) synthase are colocalized in nervous tissues. We tested the hypothesis whether or not NO might be involved in the release of neuropeptide Y. Neuropeptide Y concentration in the supernatant of PC12 rat pheochromocytoma cells, shown to express NO synthase I by immunohistochemistry, rose threefold in a time- and dose-dependent manner following sodiumnitroprusside and 3-morpholinosydnonimine (SIN-1) incubation. Neuropeptide Y mRNA expression was induced by NO-donors as a function of incubation-time. Neuropeptide Y production rose fivefold with zaprinast, an inhibitor of the phosphodiesterase V and threefold with nerve growth factor (NGF). Combined application of zaprinast and NGF did not further increase neuropeptide Y production while combination of zaprinast and sodiumnitroprusside potentiated the NO effect on neuropeptide Y release. The data suggest that NO regulates neuropeptide Y secretion of PC12 pheochromocytoma cells on the mRNA level.

Transitional Care and Adherence of Adolescents and Young Adults After Kidney Transplantation in Germany and Austria: A Binational Observatory Census Within the TRANSNephro Trial

AbstractTransition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure.We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012.Most centers (73%) confirmed agreements on the transition procedure. Patients’ age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5–36.7). Median serum creatinine increased from 123 to 132 &mgr;mol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007).The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer.

Successful interventional treatment of arteriovenous fistula after kidney biopsy in pediatric patients--a report of three cases.

BACKGROUND With an incidence of up to 16%, arteriovenous fistula (AVF) is a frequent complication after renal biopsy. METHODS We report on three cases, where renal biopsy in pediatric and adolescent patients led to various but clinically significant complications. In each patient two cores of renal parenchyma from the upper pole of the renal transplant or the lower pole of the right native kidney, respectively, were obtained with two attempts. RESULTS Immediate post-bioptic ultrasound did not show any abnormalities. Setting of an AVF was suspected when complications occurred and ultrasound and Doppler studies showed AVF. The diagnosis was confirmed by angiography and occlusion of the fistulae was performed in the same session. CONCLUSION We conclude that persistent AVF is an uncommon but serious complication after renal biopsy. Well-timed angiography when AVF is suspected can prevent loss of function, especially in transplant recipients.

Fast-in, fast-out.

In November, 2007, early afternoon, a 17-year-old unconscious male patient was admitted to our paediatric emergency department. Third-party history from his co-workers and company physician revealed that the young man collapsed suddenly without any obvious triggers while standing at his workbench in a metal processing factory. He had been completely unconscious for about 1 min; later he was still somnolent but reacted when loudly addressed. There had been no suggestion of a seizure, such as convulsions, tongue biting, or enuresis. Medical history was reported to be unremarkable and there was no knowledge of him taking recreational drugs, medication, or alcohol. There was a family history of epilepsy. On arrival at our hospital, he responded to painful stimuli; heart rate, blood pressure, and respiration were normal. His pupils were moderately dilated and reactive to light. Perioral myoclonia was present. Further clinical examination was unremarkable, but a small glass bottle with a clear fl uid and a 1 mL syringe were found in his belongings (fi gure). Laboratory blood test results including blood-gas analysis and ammonia were within normal ranges. Toxicological analysis of urine was negative for common drugs. CT of the head was normal. The somnolence was fi rst suspected to be post-ictal, although an electroencephalogram (EEG) did not show any seizure activity. Without any specifi c treatment, our patient regained consciousness within 3 h after admission. He could not recall the events that had passed, reported feeling well, and denied any recreational drug use. He stated that the bottle of liquid in his bag was used for cleaning work equipment. Toxicological testing supported this explanation as the liquid was found to be a mixture of long-chain alcohol compounds–widely used in cleaning liquids. Further investigations, including MRI of the brain and a sleep-deprived EEG, showed no abnormalities. The next day he had polydipsia and was sweating excessively. We suspected that these were detoxifi cation symptoms. He admitted that immediately before his collapse he had ingested 2·5 mL of the fl uid from the glass bottle diluted in a soft drink; he stated that the fl uid was γ-butyrolactone (GBL). We monitored him for 2 more days; he underwent psychological assessment, and was discharged in good clinical condition. His parents were informed of the events, and further consultation for drug counselling was arranged. GBL, a pro-drug of γ-hydroxybutyric acid (GHB), has emerged as a major recreational drug during the past 10 years. It is used because of its uninhibiting eff ects, but also as a sleep aid, muscle building, and weight-loss agent. Furthermore, GBL and GHB are used as date-rape drugs because the colourless liquids can easily be added to a drink to induce sedation and anterograde amnesia in the victim. Drug users take GBL orally in volumes of only 1 to 2 mL normally measured by a syringe to obtain these small doses and then dilute it in water or other drinks. Accidental overdosage can happen easily and typically causes sudden unconsciousness followed by abrupt awakening after a few hours (‘fast-in, fast-out’), because of prompt drug resorption and short half-life of about 30 min. Toxicity can be confi rmed by gas chromatography-mass spectrometry. GHB is restricted by controlled substances legislation; its precursors can be legally obtained. Information about the prevalence of GBL/GHB abuse is limited. European surveys estimate an ever-in-lifetime use of 3%, increasing to 19% in some groups, such as people attending nightclubs. GBL toxicity should be considered in any patient who presents with rapid onset of coma of unknown cause. Since there is only a short time frame (<12 h) for chemical detection of GBL, blood or urine samples should be analysed as soon as possible. There is no specifi c antidote for GBL/GHB overdose and patients usually recover rapidly. However, fatalities can occur.

Transition structures and timing of transfer from paediatric to adult-based care after kidney transplantation in Germany: a qualitative study

Objectives It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process. Setting In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed. Results This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition. Conclusions While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge. Trial registration number ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).

Leukocytapheresis in a girl with severe ulcerative colitis refractory to corticosteroids, infliximab, and cyclosporine A.

detected an anovaginal fistula. Pelvic magnetic resonance imaging was normal. Colonoscopy revealed erosions in the rectum. The enteroclysis now showed stenosis and multisegment dilatation, especially from the terminal ileum, with fistulous tracts and adhesions between bowel loops. The patient started treatment with antibiotics and azathioprine (2.5 mg/kg/day), becoming asymptomatic after 2 months. Repeated endoanal ultrasound was normal. In December 2001 she again complained of a profuse vaginal fecaloid discharge, and repeated pelvic magnetic resonance imaging and barium examination showed an enterouterine fistula (Fig. 1). At the operation it was found that the terminal ileum formed a hard adhesion with the posterior wall of the uterus with an ileouterine fistula. She underwent ileocecal resection and surgical repair of the uterus. Histological diagnosis was severe active penetrating CD. She had an uneventful postoperative recovery. She remains in remission on maintenance therapy (azathioprine and mesalazine), although she needed a slow reduction of the azathioprine dose due to neutropenia. The last surveillance exams in 2008 did not show any new changes. Although some internal fistulas may be suspected on clinical grounds, they may be difficult to diagnose and are often found incidentally during surgery or radiologic studies. A high index of suspicion of an ileogenital fistula should be aroused by a patient with CD with weight loss, malnutrition, or especially persistent vaginal discharge. Preoperative gastrointestinal and genitourinary evaluation should be used in an attempt to localize the fistulous origin as well as concomitant fistulas to provide the best treatment.3–5