Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD)

BACKGROUND: ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived. METHODS: We examined the clinical course of 164 neonatal survivors (126 unrelated families) over a mean observation period of 6 years (range 0 to 35 years). PKHD1 mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) for the 66 exons encoding the 4074 aa fibrocystin/polyductin protein. RESULTS AND CONCLUSION: This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.     

Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology

BACKGROUND: Inflammatory reactions and other events in early life may be part of the etiology of late-onset diseases, including cerebral palsy, autism, and type 1 diabetes. Most neonatal screening programs for congenital disorders are based on analysis of dried blood spot samples (DBSS), and stored residual DBSS constitute a valuable resource for research into the etiology of these diseases. The small amount of blood available, however, limits the number of analytes that can be determined by traditional immunoassay methodologies. METHODS: We used new multiplexed sandwich immunoassays based on flowmetric Luminex xMAP technology to measure inflammatory markers and neutrophins in DBSS. RESULTS: The high-capacity 25-plex multianalyte method measured 23 inflammatory and trophic cytokines, triggering receptor expressed on myeloid cells-1 (TREM-1), and C-reactive protein in two 3.2-mm punches from DBSS. It also measured 26 cytokines and TREM-1 in serum. Standards Recovery in the 25-plex method were 90%-161% (mean, 105%). The low end of the working range for all 25 analytes covered concentrations found in DBSS from healthy newborns. Mean recovery of exogenous analytes added at physiologic concentrations in DBSS models was 174%, mean intra- and interassay CVs were 6.2% and 16%, respectively, and the mean correlation between added and measured analytes was r2 = 0.91. In DBSS routinely collected on days 5-7 from 8 newborns with documented inflammatory reactions at birth, the method detected significantly changed concentrations of inflammatory cytokines. Measurements on DBSS stored at -24 degrees C for >20 years showed that most cytokines are detectable in equal concentrations over time. CONCLUSIONS: The method can reliably measure 25 inflammatory markers and growth factors in DBSS. It has a large potential for high-capacity analysis of DBSS in epidemiologic case-control studies and, with further refinements, in neonatal screening.     

Differential diagnosis of low-attenuation splenic lesions on computed tomography

A retrospective computed tomography evaluation of proved low-attenuation splenic lesions in nontraumatic cases was done. Computed tomography was able to distinguish cystic from solid lesions. Although computed tomography examination is sensitive in the detection of low-attenuation lesions, the computed tomography findings alone are not helpful in differentiation of different low-attenuation lesions. Associated computed tomography findings in other organs and clinical findings are more helpful than the size, shape, and computed tomography attenuation of the lesions. Splenic lesions may be the only metastatic manifestation in some cancer patients. A thin needle aspiration may be done to document the nature of the pathologic lesion in problematic cases.     

Magnetic resonance imaging of discrete and conglomerate retroperitoneal lymph node masses

In the identification of discrete and conglomerate retroperitoneal lymph node masses, MRI and CT performed equally well. No specific MRI characteristics were identified.     

Biomarkers for the prediction of preterm delivery

This structured review discusses the current literature on selected biomarkers and their ability to predict preterm delivery (PTD). Among symptomatic women, the likelihood ratio (LR+) for the prediction of PTD was found to be greater than 10 using amniotic fluid (AF) interleukin-6 (IL-6), AF Ureaplasma urealyticum, as well as a multi-marker consisting of cervical IL-6, cervical IL-8, and cervical length (CL). The LR+ was found to be between 5 and 10 for serum C-reactive protein (CRP). An LR+ between 2.5 and 5 was recorded for serum corticotropin-releasing hormone (CRH), cervical fetal fibronectin (fFN), cervical IL-6, serum relaxin, and a multi-marker consisting of fFN and CL. CL and bacterial vaginosis (BV) both predicted PTD in women with preterm labor with an LR+ of less than 2.5. In asymptomatic women, AF U. urealyticum and a multimarker consisting of five individual markers [fFN, CL, serum alpha-fetoprotein (AFP), serum alkaline phosphatase, and serum granulocyte colony-stimulating factor (G-CSF)] predicted PTD with an LR+ greater than 10. The LR+ was between 5 and 10 for serum relaxin and CL. LRs+ recorded for serum alkaline phosphatase, salivary estriol, serum CRH, serum G-CSF, cervical IL-6, AF IL-6, cervical fFN, AFP, and Chlamydia all ranged between 2.5 and 5. Finally, an LR+ below 2.5 has been documented for serum ferritin, serum CRP, BV, and cervical ferritin.     

Medical and surgical aspects of pediatric renal transplantation using living donors

The outcomes of 19 consecutive living-donor renal transplants (LD-RTx) was compared with 41 cadaveric grafts (CD-RTx) performed at our institution using basiliximab, cyclosporine, and prednisone as standard immunosuppression. LD-RTx significantly shortened the waiting time on dialysis. However, patient survival (100% in both groups), 1-year graft survival (94.7% vs 90%), and rejection-free graft survival (76.9% vs 73.5%) was not significantly different. LD-RTx showed better glomerular filtration rates in the early phase after transplantation, a difference that faded with time. Graft function was similar after 1 and 2 years. LD grafts with double renal arteries were used successfully in four cases; heparin therapy was administered to avoid graft thrombosis. A significantly greater number of lymphoceles was observed with LD grafts (7/19 vs 1/41, P < .01). In conclusion with improved immunosuppression producing better results with CD grafts, the advantages of LD-RTx have vanished. LD grafts with double arteries may be used successfully and LD-RTx allows a shorter dialysis period. The high incidence of lymphoceles in our series awaits further evaluation.     

Pseudotumor cerebri following cyclosporine A treatment in a boy with tubulointerstitial nephritis associated with uveitis

An 11-year-old boy with recurrent nephritis due to tubulointerstitial nephritis associated with uveitis (TINU syndrome) was treated with cyclosporin A (CSA) to induce sustained remission. CSA was introduced as a steroid-sparing drug because of extreme obesity (body mass index 32 kg/m²). Although the boy did not complain of any clinical symptoms, eye inspection after 7 months revealed bilateral disk edema with retinal bleeding and the patient developed cerebrospinal hypertension. Pseudotumor cerebri was diagnosed by measuring the intracranial pressure (31 cmH₂O) and normal computer tomography and brain magnetic resonance imaging. Cessation of CSA therapy and treatment with mycophenolate mofetil led to resolution within 12 weeks.Supported by Forschungsunterstützungskreis Kindernephrologie e.V. Essen