Determining the underlying pathology of newly discovered nodules or masses in patients with established CKD represents a diagnostic challenge. Malignancy, despite being relatively rare, is among the top differential diagnosis of those masses. Working-up FPT might expose the patients to prolonged medical, radiologic, interventional workup and psycho-economic burdens before revealing their underlying benign pathology [11, 12, 19]. In this work, we present five pediatric CKD patients who had incidental findings of tumor-like lesions that were suggested to be functional renal tissue by utilizing DMSA imaging with better precision when coupled with SPECT imaging compared to planar DMSA. Those FPTs were later on followed up by US and were stable in size and appearance (Table 1).

All five cases had a history of recurrent episodes of UTI and renal scarring. Four of them had VUR. These findings are in agreement with other case reports with similar presentations of UTI and VUR [9, 20].

Three of the reported cases had established CKD and were followed up regularly in the nephrology clinic. The FPT were not seen early-on in the course of their disease and were only noted on later US scans. Whether FPTs represent newly formed renal tissue (i.e., regenerating nodules) or a rare entity of focal compensatory hypertrophy and whether those two mentioned mechanisms represent a spectrum of renal regeneration is a question that needs further cellular-based investigations.

The mechanism by which the kidney restores acute or chronic lost function has been a debatable topic. Different mechanisms were suggested such as;

The presence of circulating extra-renal stem cells that can differentiate and integrate into the existing renal tissue to restore function [3]. These cells have the ability to go through numerous cycles of cell division while maintaining an un-differentiated state (i.e. self-renewal ability) and to generate a progeny of differentiated cells or their precursors (i.e. multipotent characteristic) [21]

The presence of multipotent intra-renal progenitor cells [1, 4,5,6]. These cells have the ability to differentiate along one or more particular cell lineages, but display a limited self-renewal potential [21].

Mature resident renal cells undergoing de-differentiation, migration into the areas of damage, and re-differentiation to replace the neighboring dead cells [1, 4].

Compensatory kidney hypertrophy (CKH) is a well-described physiologic phenomenon, through which the kidney cells increase in size (hypertrophy) but not in count (hyperplasia) [22]. It contributes to kidney growth and restoration of kidney function in the setting of reduced total nephron mass, such as in a single functioning kidney, or in the remaining kidney tissue following unilateral radical or partial nephrectomy [22,23,24,25,26,27]. While the mechanisms underlying CKH have been well-reported in the literature [22], such compensatory phenomena are debatable and not well-reported in significantly scarred kidneys. Two main mechanisms have been proposed to explain CKH. First, after kidney injury, the remaining functioning renal nephrons increase their activity (hyper-filtration) and undergo hypertrophy. Second, release of a renal specific factor that initiates CRH in response to loss of functioning kidney tissue [22].

Few papers have reported the findings on kidney biopsies of FPT. In one case series, the ultrasound-guided renal biopsies of the FPT showed normal glomeruli and tubules that are double or triple the usual diameter, without fibrosis [7]. Another case report documented a mass lesion that histologically showed a segmental or regional compensatory hypertrophy [8].

All tumor-like lesions were discovered incidentally in our case series with subsequent additional work-up to identify the nature of the lesions. With the advancement and wide availability of different imaging modalities, the number of incidentally discovered kidney masses has significantly increased [28, 29]. Although this has led to early detection of kidney tumors [30], a significant percentage of these masses were benign in nature, leading to unnecessary stress, tests and even unnecessary biopsies and surgeries [11, 12, 19]. Interestingly, studies looking at patients who underwent resection of solitary kidney lesions, 11–30% of the masses showed benign pathology depending on the studied population [19].

The incidence of childhood renal and suprarenal neoplasms depends on the age of presentation. Neuroblastoma may be seen in the perinatal period. Benign renal masses predominate in early infancy. Wilms' tumor is the most common renal malignancy from infancy to adolescence. Renal cell carcinoma becomes more frequent towards adolescence [31]. Less commonly encountered renal neoplasms are medullary carcinoma, angiomyolipoma, and metanephric tumors. Lymphomas are usually multifocal masses, but has also been reported as a solitary mass [32].

A kidney pseudotumor is defined as a mass that mimics the appearance of a neoplasm radiologically but contains normal renal tissue histologically and requires no treatment [10, 15, 33].

Differential diagnosis of renal pseudo-tumors can be classified into:

Congenital causes including hypertrophied column of Bertin, persistent fetal lobulation, spleno-renal fusion and dromedary humps.

Acquired causes in cases of CKD, known in the literature as “regenerating nodules” or “focal nodules of compensatory hypertrophy” which we elect to call FPT.

Some authors include Wegener granulomatosis, renal pelvic hematomas, arteriovenous malformation and infections (such as xantho-granulomatous pyelonephritis, abscess, focal pyelonephritis, fungal and TB pyelonephritis) as a part of the differential diagnosis [15, 33], however those represent unique pathologic entities with secondary renal involvement [10].

The FPTs were not observed on prior US scans of the 3 patients with established CKD who were previously following up in our hospital, which makes congenital causes unlikely. None of the 5 patients had symptoms suggestive of UTI. Urine cultures were negative for bacterial and fungal micro-organisms making the diagnosis of focal pyelonephritis unlikely. The masses all showed significant tracer uptake on DMSA scan which suggests functioning renal tissue and makes other pathological conditions with secondary renal involvement such as hematomas, arteriovenous malformations, granulomas, sarcoidosis, and most importantly neoplasms less likely. All patients were followed-up with kidney US scans or MRI which showed stable appearance and size of the FPT which is not the expected course in malignancy (Table 1).

FPTs represent a diagnostic challenge and necessitate further radiologic work-up. Even after conducting US and non-contrast CT, some lesions still remain indeterminate [14]. In one study on CKD patients, 92.5% of the tumor-like lesions evaluated by conventional MRI remained indeterminate [13]. Contrast-enhanced CT and MRI are frequently unfavorable due to advanced CKD and the potential risk of contrast-induced-nephropathy and nephrogenic systemic fibrosis respectively. Hence, contrast-free and isotope-mediated imaging is plausibly preferable [13].

DMSA scan is non-invasive, non-nephrotoxic, readily available technique that usually does not require sedation [34]. It is specifically a renal cortical imaging modality used in the diagnosis of renal parenchymal disorders, mostly scarring. However, in this case series, we used DMSA scans to pick up normally functioning renal tissue (i.e., the FPTs) in the setting of severely scarred malfunctioning kidneys. The mechanism by which the radiotracer targets the renal cortex is not well established. The most widely accepted theory suggests that the radiopharmaceutical is bound to plasma proteins and freely filtered by the glomeruli and reabsorbed by renal proximal tubular cells accumulating in the kidney cortex. This indicates the need for both functioning glomeruli and cortical tubules for the isotope to be up taken in cortical tubules [14, 35, 36]. This can explain why there is decreased radiotracer uptake in patients with proximal tubular dysfunction despite normal gross anatomy and normal creatinine clearance [35, 37]. Accordingly, we argue that radiotracer uptake will be decreased or absent in any neoplasm even if it was highly differentiated since it lacks function.

Normally, the functioning renal tissue will pick up the radiotracer, while nonfunctioning tissues, such as renal scars, cysts or neoplasms will have decreased or absent uptake, thus appearing photo-penic [10, 14]. DMSA scans of our CKD patients revealed areas of relatively normal or increased uptake corresponding to the FPTs. Historically, DMSA was used more extensively to evaluate renal masses in the late 1970’s and 1980’s [38,39,40,41], however this practice has shifted to ultrasound, CT and MRI characterization. In previous case reports where biopsies of the FPT were done revealing functioning renal tissue, all nodules displayed radiotracer uptake on the scans done preceding excision [7, 8]. More recently Gruning et al. eluded to this concept in a series of 15 patients with renal masses and showed a high accuracy (100%) at excluding malignancy when uptake is present [14].

Three of our patients had undergone SPECT-DMSA imaging which allowed more precision in picking up the FPTs as shown in image 3 (B) and more accuracy in their localization compared to planar DMSA scans, as shown in Fig. 1 (B), 2 (B) and 3 (B). Planar 2D scans lack the ability of demonstrating 3D structures, even if images are taken in different planes [16]. SPECT provides 3D reconstructions, leading to definite localization of the suspected mass which helps in corelating it to the suspected mass seen on the other imaging modalities. Moreover, SPECT images obtained from gamma cameras can be fused with the patient’s corresponding CT or MRI study [16, 17]. In addition, SPECT DMSA increases the sensitivity regarding picking up more abnormalities that might be less detectable on planar images [17, 18]. However, the main disadvantage of SPECT is the increased scanning time which may be an important factor in the pediatric population [34]. This limitation can somewhat be overcome with newer faster scanners.

Other modalities that were similarly proposed as a contrast-free problem-solving tool in cases of pseudo-tumors in scarred kidneys are MRI with diffusion weighted images and contrast-enhanced US. On MRI with diffusion-weighted images, kidney tumors may show restricted diffusion while FPT would not show restricted diffusion [13, 15]. MRI with diffusion weighted images has its own technical and logistical challenges including possible requirement for sedation and requires more robust data. Contrast-enhanced US uses non-nephrotoxic microbubble contrast agents that can help characterize FPTs. However, unlike DMSA, contrast-enhanced US is not widely available and clinical expertise is still limited [42, 43].

In conclusion, FPTs can be picked up on routine imaging of pediatric patients with CKD. Although larger cohort studies are needed to confirm these conclusions, our case series supports the evidence that DMSA scans showing uptake at the site of a renal mass can be a useful tool to suggest the diagnosis of FPTs, and that SPECT DMSA scan adds more precision in picking up and accurately localizing and characterizing FPT compared to planar DMSA.