Pediatr Nephrol (2000) 14:1137–1144
© IPNA 2000
D E V E L O P M E N TA L B I O L O G Y R E V I E W
Thierry Gilbert · Claudie Merlet-Bénichou
Retinoids and nephron mass control
Received: 10 January 2000 / Revised: 17 March 2000 / Accepted: 22 March 2000
Abstract Advances in the molecular biology of retinoids have provided evidence that vitamin A profoundly influences the differentiation of the whole embryo. In addition to its well-characterized role in primary body axis and central nervous system formation, vitamin A is also required for the ad hoc development of numerous tissues and organs, including the kidney. This review will focus on the emerging evidence that the development of the urogenital tract depends on retinoids. In order to understand the role of vitamin A during kidney development, the mechanisms and sites of retinoic acid production are presented. In addition, an overview of the molecular targets that may be regulated by retinoic acid is included. Together, these elements support the concept that control of vitamin A homeostasis during renal organogenesis might control nephrogenesis via specific gene expression. The clinical impact of variations in vitamin A status during pregnancy is discussed. Key words Vitamin A · Nephron number · Organogenesis · Retinoids · Gene expression
Introduction During embryonic development, tissues and organs form as a result of coordinate interactions between cell populations whose identity and differentiation state are dependent on an adequate supply of nutrients, growth factors, and vitamins. Among these, naturally occurring retinoids (vitamin A or retinol and its active metabolites) are acknowledged as regulatory signals during vertebrate T. Gilbert (✉) INSERM U319, “Développement normal et pathologique des fonctions épithéliales”, Université Paris 7-Denis Diderot, 2 place Jussieu, Tour 33–43, 75251 Paris Cedex 05, France e-mail:
[email protected] Tel.: +33-1-43250470, Fax: +33-1-43256789 T. Gilbert · C. Merlet-Bénichou INSERM U319, Université Paris 7-Denis Diderot, 75005 Paris, France
organogenesis, controlling the differentiation of numerous cells via activation of a multitude of transcription factors [1]. For example, retinoid signalling is essential in axial determination of the main body axis, central nervous system morphogenesis, and limb patterning. Several lines of evidence now point to the central role of retinoids during renal organogenesis. The role for vitamin A in kidney development was first identified by the pioneering work of Wilson and Warkany in the late 1940s [2]. When pregnant rats are fed a diet lacking in vitamin A, the development of the kidney is severely impaired. The abnormalities range from hypoplastic or ectopic ureters and horseshoe kidneys to renal hypoplasia. The reversibility of these features with vitamin A treatment at the onset of renal organogenesis was suggestive of the direct involvement of vitamin A in kidney development [3]. In the last decade, dissection of the nuclear machinery of retinoid signalling has revealed that all renal phenotypes associated with embryonic vitamin A deficiency can be recovered by combining mutations of at least two retinoid nuclear receptors [4]. Some double null mutations lead to unilateral or bilateral renal agenesis or severe hypoplasia [5]. In addition, genetic studies on the enzymes involved in retinoic acid (RA) synthesis demonstrates that embryonic RA synthesis is required for renal organogenesis [6]. Table 1 summarizes these findings. However, despite dramatic illustrations of the impact of retinoids on kidney development, the underlying mechanisms are far from understood. Recent in vitro and in vivo data from our laboratory provide new insights into the role of retinoids in kidney development [7, 8, 9]. In particular, we have demonstrated that the number of nephrons is closely modulated by the vitamin A environment and we propose that fetal vitamin A status may be responsible for most of the variations in nephron number found in the general population [10]. This review will support an integrated model of retinoid-controlled nephron induction.
1138 Table 1 Renal abnormalities linked to impaired retinoid signalling Experimental approach
Abnormalities
References
Agenesis
Hypoplasia
Hydronephrosis
Vitamin A deficiency Severe? Moderate
– –
+ +
+ –
[2] [9]
Nuclear receptor loss of function RARα/RARβ2 RARα/RARγ RARβ2/RARγ RARα/RARα RARα/RXRαaf2° RARβ/RXRαaf2° RARγ/RXRαaf2° RXRαaf2°/RXRβ
– + – + + – – –
+ – – – + – + +
+ – + – – + – –
[5, 30] [5] [5] [16] [17] [17] [17] [17]
Lack of enzyme activity Raldh2-/-
No nephric duct
[6]
Fig. 1 Retinoid metabolism and signalling. Major metabolic routes of intracellular vitamin A and translocation to the nucleus to initiate gene transcription via specific nuclear receptors. In this diagram, occupancy of retinoic acid receptor (RAR) and heterodimerization with retinoid X receptor (RXR) induces gene expression through binding to a RA response element (RARE). Numbers represent enzymes involved in retinoid metabolism. 1, Lecithin or acyl-CoA retinol acyltransferase; 2, retinyl ester hydrolase; 3, alcohol or retinol dehydrogenase; 4, retinal dehydrogenase; 5, cytochrome P450 (CYP26); 6, β-carotene dioxygenase. Isomerization of all-trans RA into 9-cis RA may not be enzymatic
Retinoid metabolism and action Vitamin A or retinol is necessary for the development of the mammalian embryo [11]. Since animal cells cannot manufacture de novo retinoids, they rely on diet to provide a minimal amount of vitamin A. β-Carotene from plants and retinyl esters from animal sources are the main precursors of vitamin A derivatives. Due to the hydrophobic nature of retinoids, a complex machinery has been developed in order to transport and convert retinoids into hormonally active metabolites. A storage pathway develops to prevent insufficient supply and to insure
the bioavailability of active retinoids on demand. Among active retinoids, RAs are acknowledged as the major signalling molecules and Fig. 1 presents an overview of their synthesis and action. In the liver, but also in extrahepatic tissues such as the adult kidney, retinyl esters represent the most-abundant storage form. Following hydrolysis of retinyl esters, released retinol undergoes a reversible oxidation step to form retinal that is then converted into RA in an irreversible manner. Each step of this double-oxidation process is catalyzed by specific enzymes, retinol dehydrogenases and retinal dehydrogenases, respectively. Although not depicted in Fig. 1, two
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families of retinoid-binding proteins serve as partners in retinoid function : the cellular retinol-binding proteins and the cellular RA-binding proteins. Their high specificity and affinity for their respective specific retinoid not only reduces free retinoid concentrations and protects them from massive turnover, but also directs them towards specific metabolic pathways [12]. Recently, cellular retinol-binding protein 1 has been shown to be essential for vitamin A homeostasis [13]. For an up-to-date description of RA biosynthesis and metabolism, readers should consult reference [14]. To transduce the retinoid signal by RA, two classes of nuclear receptors have been characterized: the RA receptors (RARs) and the retinoid X receptors (RXRs). Both classes display three isotypes (α, β, γ) and various isoforms [4, 15]. These receptors belong to the superfamily of steroid/retinoid/thyroid/ vitamin D/orphan receptors. All-trans RA binds specifically RAR, whereas 9-cis RA can interact with either type of receptor. Following heterodimerization, DNA interaction through specific response elements and ligand binding, the RAR/RXR/ligand complex activates transcriptional responses [16]. The integrity of the RXRα ligand-dependent activating function 2 (RXRαaf2) is important for mouse development [17]. An additional degree of complexity in RA metabolic homeostasis relies on the ability of RA to induce or repress, in a nuclear receptor subtype-specific manner, many of its metabolic enzymes. For example, upon increasing the concentration of RA, RA regulates the storage pathway through upregulation of the lecithin:retinol acyltransferase, an enzyme involved in retinyl ester formation [18, 19]. Or, RA may favor upregulation of cytochrome P-450 transcripts to convert excess of RA into inactive metabolites [20]. However, since these storage or degradative pathways may not yet be effective in undifferentiated or newly formed cells, RA is efficient in downregulating retinaldehyde dehydrogenase 2 activity, an enzyme involved in its own production [21]. In addition, both expression of retinol and RA-binding proteins are inducible by RA [22].
Retinoids and determination of the number of nephrons In the mammalian embryo, kidney development relies on a series of sequential and reciprocal inductive interactions between mesodermal derivatives [23]. Besides the formation of two transient renal structures, the pronephros and the mesonephros, which appear quite early in development (day 22 in humans, day 10 in rats, day 8 in mice), the metanephros is the permanent kidney of amniotes. The pronephric duct, which is the central component of the excretory system throughout development, forms from the intermediate mesoderm. Its progression through surrounding mesenchymes induces primitive pronephric and mesonephric tubules. A single bud (ureteric bud) from the caudal end of the nephric duct then emerges and invades the caudal part of the mesenchymal nephric cord (metanephric blaste-
Fig. 2 In vitro stimulation of nephrogenesis by retinoids. Metanephros was explanted from embryonic day 14 rat embryos and grown on polycarbonate filters floating on a serum-free culture medium. Without retinoid in the medium, about 80 nephrons are formed over a 6-day culture period. Addition of various retinoid, all-trans RA (open circles), 9-cis RA (open squares), 13-cis RA (closed squares), or all-trans RE (closed circles) increases this number up to threefold, corresponding to a 200% nephrogenic stimulation. This effect plateaus in the micromolar range of concentrations. Higher concentrations exert a negative effect on in vitro nephron formation, consistent with the known toxic effects of retinoids at these doses
ma) to form the metanephros. Interactions between the tips of the developing ureter, which is an epithelial tissue, and the undifferentiated nephrogenic mesenchyme lead to branching morphogenesis of the ureter and to conversion of mesenchymal cells into pre-tubular cell aggregates. These latter undergo epithelial differentiation to generate the nephrons. Branching of the ureter and nephron formation are dependent on each other, which means that as nephrogenesis proceeds, new branches of the growing ureteric tree form within the peripheral mesenchymal mass leading the new tips to induce new nephrons. Therefore successive generations of nephrons appear in a centrifuge pattern. At the end of this reciprocal induction period, a definite number of nephrons has been induced and the highly branched ureteric duct forms the collecting system. In humans nephrogenesis ends after 34 weeks of gestation, and on average one million nephrons per kidney have been formed. In the rat and mouse, nephrogenesis is completed a few days after birth and about 36,000 and 14,000 nephrons, respectively, are present in each kidney [10]. Utilizing the willingness of embryonic kidneys to grow and differentiate in organ culture, it was first shown that exogenous retinoids can modulate the number of nephrons in a dose-dependent manner [7]. This result obtained from rat metanephros organ cultures was made possible by the use of quantitative approaches that allowed the counting of nephrons in the entire metanephros and the analysis of the branching pattern of the ureteric bud [24, 25]. As shown in Fig. 2, both retinol and
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all-trans RA are potent stimulators of in vitro nephrogenesis, increasing the number of nephrons up to threefold over a 6-day culture period. It is noteworthy that the order of potency of both compounds is consistent with their positions in the vitamin A oxidative pathway; the curve for retinol is shifted by two orders of magnitude towards higher concentrations compared with the effect of all-trans RA. The increase in nephron number results from the effect of retinoids upon ureteric bud branching capacity [7]. A more-extensive branching results in more inductive tips facing the metanephric blastema and therefore more nephrons being formed. Interestingly, both 9cis and 13-cis RA exert the same nephrogenic stimulation as the all-trans isomer. This indicates a potent role for both isomers in in vitro nephron induction. However, much remains unknown about the physiological significance of 9-cis and 13-cis RA in mammalian embryos. The role of vitamin A in renal organogenesis was further demonstrated by showing that a 50% reduction of circulating vitamin A in pregnant rats induced a mild renal hypoplasia in term fetuses [9]. The number of nephrons was also closely correlated to the circulating vitamin A level in term fetuses. This may account for much of the variation in nephron number in the human kidney.
Retinoid machinery and kidney development Despite the recent demonstration that the pronephric duct requires the conversion of retinaldehyde into RA in order to allow renal organogenesis in the intermediate mesoderm [6], very few studies have investigated RA synthesis in the developing metanephros. In collaboration with C. Mendelsohn at Columbia University, Department of Urology, the presence or absence of endogenous RA was investigated at the first stage of metanephros formation in the rat, when the emerging ureteric bud interacts with the metanephric blastema. When embryonic day 13 (E13) rat metanephros (equivalent to E11 mouse embryo) was cultured on top of the RA reporter cell line F9-RARE-lacZ, β-galactosidase activity was detected in the surrounding reporter cells [26]. This demonstrates that significant amounts of RA were present in the newly formed definitive kidney, which were able to diffuse locally to turn on transcription of the lacZ gene. Following isolation of the metanephric blastema and of the ureteric bud, each tissue proved to be a potent supplier of RA. By combining either the undifferentiated mesenchyme or the unbranched ureteric bud on top of those cells with the presence of retinol in the medium, in situ detection of β-galactosidase activity was even more intense, suggesting that RA synthesizing enzymes were expressed in both embryonic renal tissues. The local generation of RA from retinol confirms an underlying cellular requirement for this signal molecule. In addition, as revealed by in situ hybridization, two retinaldehyde dehydrogenases are expressed in the metanephros in a complementary pattern. Retinaldehyde dehydrogenase 1 is exclusively localized in the ureteric bud and retinalde-
hyde dehydrogenase 2 in the nephrogenic mesenchyme [26]. This suggests that the local RA availability in these tissues might be controlled differentially. Differences in retinal affinity for both enzymes have been reported [14]. This indicates that at sites of interaction of ureteric bud ends with the nephrogenic mesenchyme, leading to nephron induction, two enzymes are present to ensure RA synthesis. Of interest, this is the place where the expression of the Ret tyrosine kinase receptor, a crucial determinant in renal organogenesis is restricted and controlled by RA. During the postnatal development of the kidney, changes in retinal dehydrogenase expression have also been reported, suggesting that modulating RA levels in different cell types is of importance for kidney maturation [27]. In mouse embryos, alcohol dehydrogenase 1, which catalyzes the oxidation of retinol to retinal, is first detected in the primitive genitourinary tract (mesonephros, E10.5) before being restricted to metanephric collecting tubules in E16.5 embryos [28]. At this stage of renal development, high RA levels in the kidney are detected, far exceeding those found in other embryonic tissues such as the liver [28]. This high retinoid synthesis seems to be necessary in order to compensate for dietary fluctuations in retinoid intake, especially during pregnancy, in order to ensure an optimal number of nephrons to be formed. Moreover both binding protein families are expressed in the cortex of developing metanephros to control retinol and RA biopotencies [29]. Although the involvement of retinoid nuclear receptors in renal development is well characterized (Table 1), the localization of the various isotypes in the renal cell populations is not fully understood. Recent re-examination of the RARα/RARβ2 double-mutant animals that exhibit small kidneys at birth has provided significant insight into the mechanism of the observed oligonephronia [30]. In these animals, the development of the collecting duct system was severely impaired. Since in the metanephros the stromal cells are the only ones to express these two nuclear receptors, this is evidence that signalling from stromal cells mediates retinoid-dependent ureteric bud branching morphogenesis. Molecular analysis of downstream genes expressed in the ureteric bud revealed that the proto-oncogene c-ret was downregulated in these mutants. RA-responsive genes Among the plethora of genes involved in kidney organogenesis that have been characterized (for details the reader is invited to consult the kidney development database at www.ana.ed.ac.uk/anatomy/database/kidbase), the expression of many is potentially regulated by retinoids. Such candidates are summarized in Table 2. Although this is far from complete, it shows that numerous transcription factors known to be regulated by retinoid signalling are expressed during kidney organogenesis. The Hox homeogenes are the most interesting, since they
1141 Table 2 Genes expressed during renal organogenesis and potentially regulated by retinoic acid Gene encoding for
References
Transcription factors Hox A3, A4, A5, A6, A7, A11, A13 Hox B3, B4, B5, B7, B8 Hox C4, C6, C8, C9 Hox D9, D10, D11, D13 HNF 1, 3α, 4 lim-1 RARα2, β2
[57, 58, 59, 60] [61, 62, 63, 64] [65, 66, 67] [68, 69] [35, 70, 71, 72, 73] [34, 74, 75] [36, 37, 38]
Growth factor receptors c-ret EGFR Transferrin receptor
[8, 40, 76] [44, 46, 77] [45, 47]
may provide a link between pattern formation and the effects of RA on embryonic development [31]. Of the 39 members of the Hox family, 20 genes specify regional information for mammalian kidney development. However, none of the single Hox mutations has lead to renal anomalies. Only two double Hox mutant animals for the most 5' groups (Hox 11–13) exhibit renal dysmorphogenesis: Hoxa-13+/-/Hoxd-13-/- compound mutants display hydronephrosis [32] and Hoxa-11-/-/Hoxd-11-/- mice exhibit severe renal hypoplasia, with some animals lacking one or both kidneys [33]. In the latter, it has been proposed that Hoxa-11 and Hoxd-11 regulate mesenchymalepithelial interactions that control branching morphogenesis of the ureteric bud, therefore providing a new function of the Hox family. Since endogenous RA plays a major role in the transcriptional regulation of Hox genes, we would expect the machinery used to synthesize RA in the metanephros to be expressed in a complementary pattern. A typical feature of the Hox family is that not only Hox genes at the 5' ends of the chromosome clusters are expressed at later times in embryogenesis, and in more-posterior regions than the Hox genes at the 3' ends, but also their expression requires higher levels of endogenous retinoids than the 3' end paralogs [31]. Another gene primarily activated by RA and encoding an homeodomain protein is lim-1 [34]. However, despite its clear role in renal organogenesis (knock-out mice lack kidney), no information is available on the renal transcripts it regulates. Transcription factors belonging to the hepatocyte nuclear factors (HNF) are also expressed in the developing kidney. Downregulation following RA treatment has been reported for HNF 1 and 4 [35]. Finally, involvement of transcription factors of the retinoid nuclear receptor family in kidney organogenesis is perhaps the best characterized, as shown in Table 1. At least two members, RARα2 and RARβ2, are transcriptionally regulated by RA [36, 37, 38]. However, few data on the cellular distribution of RAR and RXR transcripts during kidney development are available [29, 30, 39]. Future work is therefore needed to firstly clarify their cellular pattern of expression, since these transcription factors
are usually expressed in a limited number of cells and at a specific time during renal organogenesis, and secondly to identify the gene expressions they regulate. The second type of potential target for RA we describe in this review is a number of genes encoding cell surface receptors. At present, only one growth factor/ receptor couple is acknowledged as indispensable for metanephros formation: the glial cell line-derived neurotrophic factor/Ret receptor. This mesenchyme-derived secreted molecule binds a cell surface-associated protein to interact with the receptor tyrosine kinase Ret encoded by the proto-oncogene c-ret. The expression of this receptor is restricted to the tips of the ureteric bud, where the interactions with the metanephric mesenchyme take place [40]. Targeted mutations in this system profoundly affect kidney development [41, 42]. Using the in vitro model of enhanced nephrogenesis upon RA addition and semiquantitative reverse transcription/polymerase chain reaction, it was recently shown that c-ret mRNA expression was regulated by RA in a dose-dependent manner [8]. Interestingly, this transcriptional response parallels the curve of the nephron number. This provides the first correlation over five orders of magnitude of a gene expression with a dose-dependent renal phenotype. c-ret expression is therefore a key target of retinoids in kidney organogenesis. However, no direct transcriptional activation of c-ret by RA has been reported [43]. This is consistent with recent data indicating that c-ret expression relies on an optimal RARα/RARβ2-dependent stromal cell signalling [30]. Two other receptors are likely to have their expression modulated by RA in the developing kidney, as shown in other models: the epidermal growth factor receptor (EGFR) [44] and the transferrin receptor [45]. Epidermal growth factor stimulates the mesenchymal cells to become stromal cells [46], whereas transferrin is absolutely required to allow the nephrogenic mesenchyme to convert into nephrons [47]. The balance between the expression of both receptors is therefore a key step to ensure optimal nephron mass formation, and could be dependent on the vitamin A environment. Of course potential targets of RA are not restricted to these two categories of genes. Numerous growth factors and extracellular matrix components are also involved in urinary tract formation. For example, it has been demonstrated that the first detectable response of the renal mesenchyme to induction involves a shift in the matrix composition from an intestitial, mesenchymal phenotype to a differentiated, epithelial phenotype [48]. This change involves a shift from type I and type III collagens to type IV collagen. Recently, it has been shown that RA downregulates the promoter activity of the rat pro-α1-collagen type I [49]. Applied to the developing kidney, this may help differentiation of mesenchymal cells into tubular structures. Conclusion It is now well accepted that fetal environmental factors influence the nephron number [10]. The finding that the
1142
nephron number is closely modulated by vitamin A is of particular importance. Until recently, only large changes in vitamin A status have been considered a risk factor for the fetus. The above data allow us to speculate that even moderate changes in vitamin A status may cause developmental renal defects. Slight nephron deficits, which are not recognized at birth, may induce long-term renal failure and increase the incidence of hypertension [10, 50]. Although in industrialized countries vitamin A deficiency is not a major health problem as it is in some developing countries, recent reports indicate that vitamin A intake and plasma retinol of the general population vary widely. A mild vitamin A deficiency may be common in otherwise healthy individuals [51, 52]. Inadequate intakes may occur as a result of dietary practices. Low circulating levels of pro-vitamin A or vitamin A have been reported in several situations, the most common being smoking, alcohol abuse, and uncontrolled weight-reducing diets. This is particularly important for women of child-bearing age, because low vitamin A stores resulting from insufficient intake may not be sufficient to meet the increased demands encountered during pregnancy [53, 54]. In addition, although the plasma retinol concentration of the fetus reflects that of the mother, it is generally 50% lower [55]. This may explain why an inadequate circulating vitamin A level is much more frequent in the fetus than in the mother [56]. These findings provide the rationale for further clinical and epidemiological studies on the consequences of moderate fetal vitamin A deficiency. In addition, further experimental studies should reveal the molecular mechanisms underlying vitamin A control of nephrogenesis and retinoid target genes. Acknowledgements The authors thank Dr José Vilar for critically reading this review. We would like to acknowledge the support of the Institut National de la Santé et de la Recherche Médicale.
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L I T E R AT U R E A B S T R A C T S
N. Yano · M. Endoh · K. Fadden · H. Yamashita · A. Kane H. Sakai · A. Rifai
Comprehensive gene expression profile of the adult human renal cortex: analysis by cDNA array hybridization Kidney Int (2000) 57:1452–1459 Background Profiling of gene expression in healthy and diseased renal tissue is important for elucidating the pathogenesis of renal diseases. Comprehensive information about the genes expressed in renal tissue is unavailable. The recently developed cDNA array hybridization methodology allows simultaneous monitoring of thousands of genes expressed renal tissue. Methods Complex [alpha-33P]-labeled cDNA probes were prepared from histopathologically uninvolved remnants of nine renal tissues obtained by nephrectomy. Each probe was hybridized to a high-density array of 18,326 paired target genes. The radioactive hybridization signals by phosphorimager screens were quantitated by special software. Bioinformatics from public genomic databases were used to assign a chromosomal location of each expressed transcript and gene function. Cluster analysis was used to arrange genes according to the similarity in pattern of gene expression. Results A total of 7563 different gene transcripts was detected in the nine tissue samples. Approximately 870 of these genes were full-length mRNA human transcripts (HT), and the remaining 6693 were expressed sequence tags (ESTs). The full-length transcripts were classified by function of the gene product and were listed with information of their chromosomal positions. To allow a comparison between gene expression in clinical and experimental studies, the mouse genes with known similar function to the human counterpart were included in the bioinformatics analysis. Cluster analysis of 502 full-length genes that are expressed in four or more renal tissues revealed more than 110 genes that are highly expressed in all the renal specimens. Conclusions The presented data constitute a comprehensive preliminary transcriptional map of the adult human renal cortex. The information may serve as a resource for speeding up the discovery of genes underlying human renal disease. The integrated listing of the full-length expressed human and mouse genes is available through e-mail (
[email protected]).
E. Hindie · P. Urena · C. Jeanguillaume · D. Melliere J.M. Berthelot · V. Menoyo-Calonge · D. Chiappini-Briffa A. Janin · P. Galle
Preoperative imaging of parathyroid glands with technetium-99m-labelled sestamibi and iodine-123 subtraction scanning in secondary hyperparathyroidism Lancet (1999) 353:2200–2204 Background Parathyroidectomy is unsuccessful in 10–30% of uraemic patients operated on for secondary hyperparathyroidism. We investigated the usefulness of preoperative radionuclide imaging, with simultaneous recording of the distribution images of iodine-123 and technetium-99m-labelled sestamibi. Methods 11 patients with secondary hyperparathyroidism underwent prospective imaging and parathyroidectomy. Plasma concentrations of intact parathyroid hormone (PTH) were measured in all patients before and 6 months after subtotal parathyroidectomy. Results Preoperative scanning showed 42 hot-spots suggesting enlarged parathyroid glands. 45 glands were discovered at surgery, and the parathyroidectomy was deemed successful in ten patients. Among the latter, one patient had a supernumerary parathyroid gland detected by scanning and resected from the left thymus. Another patient showed ectopic uptake corresponding to a large parathyroid gland in the upper mediastinum, and another had a parathyroid gland well above the thyroid. No false-positive scan findings were documented. In the patient for whom parathyroidectomy failed, preoperative scanning suggested five enlarged parathyroid glands, though the surgeon found only four glands, in their normal positions. Hyperparathyroidism persisted (intact PTH 527 ng/L, 6 months after surgery). A second scan confirmed the preoperative scan, showing a fifth parathyroid gland in the middle of the right thyroid lobe. Conclusions Simultaneous recording of 99mTc-sestamibi and 123I improved the imaging of parathyroid glands in secondary hyperparathyroidism. The technique can identify ectopic and supernumerary parathyroid glands
