Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

Similar renal outcomes in children with ADPKD diagnosed by screening or presenting with symptoms

Autosomal dominant polycystic kidney disease (ADPKD) in children is sometimes considered to be a benign condition, with morbidity manifesting in adulthood. Therefore, diagnostic screening of children at risk is controversial. The aim of our study was to to compare the manifestations of ADPKD in children diagnosed by postnatal ultrasound (US) screening versus those presenting with symptoms. This was a retrospective chart review of children with ADPKD assessed in a single centre between 1987 and 2007. Age and reason for diagnosis were noted, and children were separated into two groups: (1) those diagnosed on the basis of family-based screening; (2) those presenting with a symptom. The two groups were compared for renal size, number of cysts, estimated glomerular filtration rate (eGFR), the presence of hypertension and microalbuminuria. In the 47 children with ADPKD (21 females) from 33 families who satisfied the enrollment criteria, mean (standard deviation) age at referral and last follow-up was 7.2 (4.4) and 12.9 (5.1) years, respectively, and the mean follow-up duration was 5.7 (3.6) years. Diagnosis was based on postnatal US screening in 31 children, whereas 16 were diagnosed after presenting with symptoms. The proportions of children with nephromegaly, hypertension, microalbuminuria and decreased eGFR, respectively, were similar in both groups. Based on these results, we conclude that renal-related morbidities, including hypertension and microalbuminia, do occur in children with ADPKD and at a similar frequency in those diagnosed after presenting with symptoms and those diagnosed upon postnatal screening. We suggest that at-risk children should have regular checks to detect hypertension. Moreover, affected children may benefit from novel therapies to minimise cystic disease progression.     

Postnatal trends in creatinemia and its covariates in extremely low birth weight (ELBW) neonates

To document trends and covariates of creatinemia (Scr) in extremely low birth weight (ELBW, < 1,000 g) neonates, maternal characteristics [betamethasone, premature preterm rupture of membranes (PPROM), pre-eclampsia, maternal Scr], characteristics at delivery [gestational age (GA), birth weight (BW), small for GA (SGA), Apgar, intubation] and during neonatal stay [ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, intraventricular hemorrhage, retinopathy of prematurity (ROP), phototherapy] were linked with Scr observations. Data were reported by median and range or incidence. Characteristics in ELBW neonates with raised peak Scr (>P75) were compared to controls (<P75). In 151 ELBW neonates, an initial increase in Scr was observed, resulting in a peak Scr on day 3 or 4 of 99.9 (46.8–221.8) μmol/l with subsequent decrease. In cases (n  = 37) with a peak Scr >P75 (112.3 μmol/l), Scr remained elevated until day 28. Mothers of cases received less betamethasone, neonates had a lower GA, lower BW, lower Apgar, and needed more often intubation. Postnatal ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, ROP, and intraventricular hemorrhage were different. GA and ventilation or Apgar were independent factors for raised peak Scr. ELBW neonates display trends similar to heavier neonates, but peak Scr is higher, and the subsequent decrease slower. Raised creatinemia in ELBW neonates reflects immaturity (GA) and morbidity (ventilation, Apgar).     

Cystatin C in newborns: a promising renal biomarker in search for standardization and validation

Objective: Neonatologists still commonly use creatinine as a proxy for renal clearance, despite issues related to neonatal (patho)physiology and methodology (assay variability). Cystatin C (CysC) has been suggested to be a more reliable biomarker, but assay related differences have also been reported in children and adults. We are unaware of any review on the assay related impact on CysC reference values in newborns.

Methods: A structured literature search was performed on published CysC values in (pre)term neonates.

Results: The extensive range (>5-fold) in serum CysC observations in neonates in part relates to the fact that CysC concentrations are higher at birth with subsequent decrease and that CysC concentrations are higher in preterm compared to term neonates. The CysC assay matters while disease characteristics also affect CysC values, but not always in the predicted direction.

Conclusions: Similar to creatinine, the extensive CysC range in neonates is only in part explained by renal (patho)physiology. Its applicability in neonatal medicine can be further improved by use of assay specific reference values, adapted to neonatal renal physiology (e.g. weight, age) and should be compared to a gold standard such as inulin clearance.     

Long-Term Outcome of Infants with Severe Chronic Kidney Disease

Background and objectives: In 2000, we reported the outcome of 101 children with a GFR <20 ml/min per 1.73 m² at 0.3 yr of age (range 0.0 to 1.5 yr). Long-term data on such young children are scarce.Design, setting, participants, & measurements: Mortality, treatment modalities, and growth were reanalyzed 9.9 yr later.Results: Of the 101 patients, 28 died and three were lost to follow-up during 13.90 yr (range 0.03 to 22.90 yr). One-, 2-, 5-, 10-, 15-, 20-, and 22-yr survivals were 87, 81, 77, 75, 73, 72, and 64%, respectively. Fifty-one children had comorbidities. Sixty-six percent were tube fed for 1.7 yr (range 0.1 to 6.9 yr), 37% had a gastrostomy, and 13% had a Nissen fundoplication. Mean height SD score (SD) was −0.42 (2.33) at birth (n = 40), −2.07 (1.34) at 0.5 (n = 62), −1.93 (1.38) at 1 (n = 72), −1.14 (1.14) at 5 (n = 67), −1.04 (1.15) at 10 (n = 62), −1.84 (1.32) at 15 (n = 40), and −1.68 (1.52) at age ≥18 yr (n = 32). Comorbidities adversely influenced growth (P < 0.01) and final height (P = 0.02): Mean height SD score (SD) was −1.16 (1.38) in otherwise normal adults.Conclusions: Growth and final height in infants with severe chronic kidney disease are influenced by comorbidity. Intensive feeding and early transplantation resulted in a mean adult height within the normal range in patients without comorbidities. Overall mortality is comparable to that of older children.In the past 25 yr, renal replacement therapy (RRT) for infants who have other challenging treatment issues, such as prematurity and comorbid conditions, has become increasingly accepted. Medium-term data demonstrate satisfactory outcomes for growth, development, and transplantation (1–3), although comorbidity is recognized as a factor that affects success of treatment (1,4–6). Long-term outcome is unknown for infants who are treated from the inception of such programs. In 2000, we published the survival and growth of 101 children who were aged <2 yr and had severe chronic kidney disease (CKD) after up to 13 yr of follow-up (1). We present the outcome of these patients after up to 22.9 yr of follow-up. We hope that these unique data will help doctors inform families about the prognosis for similarly affected infants.     

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1–15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0–19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3–5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.     

Evaluation of quality of life by young adult survivors of severe chronic kidney disease in infancy

Background

The health related quality of life (HRQoL) of young adults treated for chronic kidney disease (CKD) stage 4/5 from infancy is unknown.

Methods

A HRQoL questionnaire was sent to all 41 patients aged >16 years from a previously characterised cohort of infants with CKD stage 4/5 born between 1986 and 1997. Patient scores were compared with a previously reported cohort of patients who needed renal replacement therapy (RRT) in mid childhood and in the normal population.

Results

All patients (11 women) completed the questionnaire at a median (range) age of 19.2 (16.3–23.4) years. At the time of the survey, 5 (12.5 %) were on dialysis, 35 (85.5 %) had a functioning kidney transplant, one (2 %) was still conservatively treated and 22 (54 %) had comorbidities; 68 % were either studying or in paid employment, with 17 % actively seeking employment. Although patients described a lower HRQoL than a healthy, age-matched UK group, in some aspects, scores were comparable with patients needing RRT in later childhood. Lower scores were associated with comorbidities, dialysis at last follow-up, more than one treatment modality change and short stature.

Conclusions

Our survey demonstrates very encouraging results for long-term HRQoL of infants with severe CKD and highlights the negative impact of comorbidities. These data will help clinicians to counsel and inform families.