Key summary points

1. Tubulointerstitial nephritis is often diagnosed late, so clinical suspicion is necessary for early identification and possible intervention (or removal of the offending agent).

2. Presenting signs and symptoms of TIN can include nonspecific systemic symptoms (fatigue, weight loss, headache, flank pain), fever, rash, eosinophilia/eosinophiluria, and evidence of elevated creatinine and Fanconi’s syndrome (glucosuria, aminoaciduria, acidosis).

In this population-based prospective cohort study, we evaluated the associations of fetal first trimester crown–rump length with kidney growth and function in childhood. We did not observe consistent associations of fetal first trimester growth with kidney outcomes in childhood.

Some methodological issues need to be addressed. We used a subgroup of a large population-based prospective cohort study to examine the kidney consequences of fetal first trimester growth restriction. Only mothers with a first trimester crown–rump measurement and a reliable first day of their last period were eligible for entry into the study, and women meeting these criteria represented only a small subgroup of the full study. We used the first day of the last menstrual period in women with a regular menstrual cycle to date gestational age since we could not measure the timing of ovulation and implantation. It is therefore possible that a misclassification of gestational age could have occurred [25]. Of the eligible subgroup, blood samples had been collected from 67 % of all children. Our results would be biased if the results differed between children with and without follow-up measurements at the age of 6 years. Although this possibility seems unlikely, we cannot exclude it. Children for whom no blood samples were available had a lower mean birth weight than their counterparts for whom blood samples were available. Our results would be biased if the associations of first trimester growth with childhood kidney function differed between children with and without blood samples. Since smaller numbers of blood samples were available in children with lower birth weight, our observed effect estimates may be underestimated. Glomerular number cannot be evaluated in vivo, but kidney size and glomerular number correlate in pathological studies in childhood and adulthood [26, 27, 28]. We estimated the GFR using the Schwartz formula [20], which is based on serum creatinine levels, and the Zappitelli formula [21], which is based on serum cystatin C levels; both formulas have been validated in pediatric populations. The eGFR was higher when calculated based on creatinine concentrations than on cystatin C concentrations, a difference which is in line with previous studies [29]. However, no difference in results were observed when we used eGFR based on creatinine concentrations compared to cystatin C concentrations, and we found no differences in outcomes between those formulas. It has been suggested that serum cystatin C levels may be the superior biomarker for evaluating kidney function compared to serum creatinine levels [30]. However, to date it is not clear which formula provides the best estimation of the GFR [30]. We used a random urine sample to determine the albumin to creatinine ratio to evaluate microalbuminuria. Since intra-individual variation in urinary albumin secretion may be large, the variability would probably have been lower if we collected first morning void samples [31]. Finally, although we adjusted for several potential confounders, residual confounding might still be a problem because of the observational design of the study.

Pelger–Huët anomaly (PHA) is a very rare, multi-factorial disorder of granulocytopoiesis that manifests itself in reduced nuclear segmentation and excessive chromatin condensation in neutrophils [1, 2, 3, 4]. The disease may be hereditary or acquired. The cause of congenital PHA is probably a mutation in the lamin B receptor (LBR) gene [1]. Presumably, in the acquired form of PHA, the pseudo-Pelger–Huët anomaly (PPHA), etiological factors reversibly suppress expression of the LBR gene and block the functions of the LBR protein [5]. PPHA may occur after the use of certain medications and in patients who suffer from hematological or infectious disorders [5]. Owing to the fact that dysgranulopoiesis may be a marker of a myelodysplastic or myeloproliferative process, the emergence of granulocyte abnormalities in peripheral blood in a child who has been treated for many years using immunosuppressive drugs, should raise great concern regarding neoplastic processes. In differentiating between proliferative disorder and iatrogenic forms of PPHA, the key elements are: clinical data, reversibility of the process, assessment of peripheral blood smear and bone marrow biopsy [5]. It was impossible for us to establish a final diagnosis without extensive tests. Initially, both the myelogram and the BCR mutation genetic test allowed us to reject suspicions of a myeloproliferative process and myelodysplastic syndrome (MDS). Most of the reported cases of PPHA refer to patients after vascularized organ transplantation who receive immunosuppressive polytherapy (mainly mycophenolate mofetil (MMF) as a basic drug in the prevention of transplant rejection) [5, 6]. At the time of the occurrence of dysgranulopoiesis, our patient was at a critical moment of immunosuppressive therapy conversion. In the regimen, the patient was receiving a full dose of MMF. Two weeks prior to the manifestation of PPHA, Rtx was administered due to the high frequency of nephrotic syndrome relapses. Nephrotic syndrome additionally had features of severe steroid and cyclosporine A (CsA) toxicity apparent both clinically and microscopically. The dose of MMF was immediately reduced and subsequently withdrawn after the occurrence of PPHA, which caused the normalization of complete blood count (CBC). It is essential to point out the fact that MMF used in monotherapy did not lead to any morphological granulocyte changes. Perhaps an explanation of the observed phenomenon is the pharmacological potentialization of the effect of given drugs. It may also suggest that MMF, as an inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), has a myelosuppressive activity [6]. Presumably, the mechanism leading to the occurrence of PPHA may be associated with drug interactions or impairment of the function of enzymes that are involved in the transport and metabolism of drugs. There are many hypotheses that suggest a possible mechanism of an impaired process of granulocyte nuclei segmentation in PPHA, e.g., individual variation of IMPDH activity, which has an influence on adverse effects of MMF [6]. However, the most probable cause of PPHA seems to be multi-drug interactions [1, 2, 3, 4, 5]. Determination of a main role for one of the drugs in particular is almost impossible. The majority of patients described in publications received polytherapy. Despite the fact that in recent brief reports there is some information regarding the possibility of PPHA occurrence after Rtx administration, the most probable cause of the PPHA in this patient was the MMF interactions, since only total withdrawal of MMF resulted in normalization of hematopoietic cells.

This clinical quiz highlights the importance of careful evaluation of all multiorgan symptoms occurring in the described patient to prevent further complications.

In 1980, Neufeld and Blizzard proposed the first classification of autoimmune polyendocrine syndromes on the basis of clinical criteria and defined four types of APS [9]. Of these four types, polyglandular autoimmune syndrome type 1, also known as APS1, autoimmune polyendocrinopathy–candiasis–ectodermal dystrophy or Whitaker syndrome, is a rare genetic disease which is autosomal recessive, inherited in a monogenic pattern and caused by a mutation in the gene of autoimmune regulation (AIRE) localized on the long arm of chromosome 21 (21q22.3) [OMIM 240300] [10, 11]. It was described for the first time in 1946 by Leonard [12]. The prevalence of this syndrome in the Polish population was set at 1:129 000 people. APS1 occurs in both sexes. The suggested role for AIRE is to induce expression of peripheral antigens in the thymus, thereby mediating negative selection of autoreactive T cells and cause toleration [13]. The main components of APS1 are hypoparathyroidism, adrenal insufficiency and candidiasis of mucous membranes (oral, anal area, external genitals) and/or of the skin and nails. A necessary condition for the diagnosis of APS1 is the simultaneous occurrence of two of the three above-mentioned diseases. APS1 is accompanied by other diseases with an autoimmune origin [14, 15, 16]. The first symptom is usually candidiasis of the oral mucosa, which occurs before the age of 5 years. Autoimmunity in APS1 is also the responsible factor for the CYSTATIN salivary antigen1 deficiency, which causes impaired protection against Candida albicans infections [17]. The first endocrinopathy is an autoimmune hypoparathyroidism, which occurs before the age of 10 years, and the second is adrenal insufficiency, which usually develops before the age of 15 years [9, 18].

DOI: 10.1007/s00467-017-3620-9