Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson’s disease and other neurological and psychiatric disorders. Electrodes are chronically implanted in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism.In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of deep brain stimulation across scales of observation, including micro-, meso- and macroscale circuit alterations. et al. provide a critical review of competing theories of the mechanisms of action of deep brain stimulation. By integrating findings from neurophysiological studies across different spatiotemporal resolutions, they derive a potential explanation for how deep brain stimulation exerts its effects.Neumann  To dissect the effects of DBS, we must consider the affected circuits to which stimulation is applied. In Parkinson’s disease, loss of dopaminergic innervation leads to an imbalance of activity of the basal ganglia’s direct and indirect pathways , which exhibits widespread mono- and polysynaptic connections with distributed cortical and subcortical networks  is a neurosurgical treatment that uses implanted electrodes and pulsatile electrical stimulation  to treatnetworks . In addinetworks .11 We ai12; a procedure currently being revived through the opportunity to perform lesions without opening the skull using magnetic resonance-guided focused ultrasound.14 The comparable clinical effects of DBS to pallidal and subthalamic lesions in human and animal studies led to the primary hypothesis that DBS causes reversible functional deafferentation of the neural target populations.15 An early study in patients with Parkinson’s disease showed that intraoperative microinjections of lidocaine  or muscimol (GABA agonist) to the STN led to a rapid reversal of parkinsonian symptoms in parallel with local suppression of neuronal firing in all three studied patients.16 These acute intraoperative effects resembled the subsequent therapeutic effects of high-frequency STN-DBS in these patients. Beyond the STN in Parkinson’s disease, suppression of local activity was also suggested as a primary mechanism of DBS in the pallidum and thalamus.17–19 The suppression of somatic firing had been hypothesized to be mediated by GABAergic activation,20 synaptic depression21 or depolarization blockade.22 The distant consequences of DBS in downstream subcortical nuclei were not easily accessible in patients, as neurophysiological recordings in structurally connected brain regions would require additional stereotactic trajectories beyond the therapeutic target. However, in addition to thorough characterizations of the cortical network effects of DBS in patients , a large body of computational modelling and preclinical animal work has focused on potential distant neural modulation by orthodromic and antidromic axonal activations.24 These works have often found more complex DBS effects than expected  and STN can alleviate motor signs of Parkinson’s diseaseexpected , which h6 Similarly, short durations of pallidal DBS lead to decreased firing of thalamic neurons,25 as opposed to the expected inactivation of GABAergic pallidothalamic projections. While DBS appeared to reduce somatic firing , these studies suggest that the efferent axons and their synaptic terminals could in fact be reliably activated by DBS pulses. This led to the decoupling of axon and soma hypothesis,26 and an adaptation of the local suppression hypothesis: the idea of an informational lesion27—an accepted yet relatively unspecific DBS mechanism, reminiscent of a new appreciation of the complexity of electrical stimulation effects on neural circuits. In recent neurophysiological works , this complexity has been attributed to synapse-specific dynamics of short-term synaptic plasticity, in that afferent and efferent synapses can have unique functional properties (e.g. resilient versus vulnerable synaptic transmission fidelities). Recent studies have shown that local and antidromic firing can be increased in the short-term, but suppressed after longer stimulation periods,5 and it is therefore possible that high-frequency DBS cannot chronically sustain the high rate of activation associated with clinically effective stimulation over longer durations.28 This is further supported by in vitro studies that have reported that HFS of thalamocortical axons can lead to a rapid sigmoidal decrease of efferent layer 4 neuron firing through short-term synaptic transmission failure.29In non-human primates rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), short trains of subthalamic high-frequency stimulation (HFS) were reported to increase pallidal firing, which was incompatible with the hypothesis that STN-DBS suppresses all synaptic connections .30–33 Low latency antidromic evoked potentials have also been reported in patients using invasive and non-invasive electrophysiology.34–36 However, the causal or mechanistic role of antidromic cortical activation in the clinical effect of DBS has been challenged by an important non-human primate report suggesting that antidromic activation is unstable over time, can shift to synaptic depression, and is only present during therapeutically effective STN but not GPi stimulation.5 Given that both STN and GPi DBS are effective for the alleviation of Parkinson’s disease motor signs, these findings are difficult to integrate with an important role of antidromic activation of cortex for the clinical treatment of Parkinson’s disease. Of note, short latency cortical evoked responses have been reported for GPi-DBS but were attributed to direct stimulation of the corticospinal tract instead of specific subcortical pathways, whereas long latency cortical evoked responses during GPi-DBS are thought to reflect feedforward/downstream basal-ganglia-thalamo-cortical network interactions rather than direct antidromic activation of cortico-basal ganglia fibres.34 Furthermore, one study showed that the effects of direct motor cortical stimulation have elicited improvements in the motor signs of patients with essential tremor, but not Parkinson’s disease,37 while other studies have shown only modest symptom alleviation in patients with Parkinson’s disease38 or transient beneficial effects in parkinsonian non-human primate models.39A series of rodent studies has suggested that antidromic activation of motor cortex may play a particularly important role in producing anti-parkinsonian effects in animal models.24 axonal activations may also ‘invade’ axonal branches of afferent and efferent projections, leading to neurotransmitter release at various terminal locations , then the A-B synapse can be activated via ‘invasion’ of the axonal collateral projection  and inhibit GPi or SNr [by way of invading the axon collaterals of afferents from the globus pallidus externus (GPe)].40It must also be considered that axonal projections may be polysynaptic, with axonal branches terminating at different neural targets. Thus, in addition to ‘jamming’ incoming information through action potential collisions ,in vivo with unprecedented, millisecond precision, enabling mechanistic studies of potential DBS effects in rodents.41 In 2009, Gradinaru et al.30 published a seminal report that optogenetic activation of cortico-subthalamic hyperdirect pathway axons in the acute 6-OHDA mouse model of Parkinson’s disease was necessary for therapeutic benefit, while direct inhibition of local STN neurons was not. However, stimulation of the hyperdirect pathway was not entirely dissociated from the inhibition/suppression of STN firing (as seen in their fifth figure). This may have been a result of activating both excitatory hyperdirect and inhibitory indirect pathway projections, or perhaps a result of inactivation/depression of excitatory cortico-subthalamic inputs. Nevertheless, more refined channel rhodopsins  supported the therapeutic role of hyperdirect pathway axons in a mouse model of Parkinson’s disease.31 However, more elaborate behavioural analyses  have also shown a direct beneficial effect of optogenetic inhibition or inactivation of the STN43 using the same opsin as Gradinaru et al.30 Similarly, next generation ultrafast opsins (i.e. Chronos) have provided evidence that optogenetic stimulation of STN neurons that resulted in bidirectional neuronal responses  could in fact also improve parkinsonian symptoms in rodents.44 Moreover, optogenetic interventions in GPe have produced long-lasting motor recovery in parkinsonian rodents, achieved by stimulating a subpopulation of parvalbumin-expressing GPe cells that preferably project to the STN.46 These studies have therefore provided evidence that activation of indirect pathway pallido-subthalamic projections may also hold therapeutic potential.Optogenetics is a powerful neuroscientific tool that allows for the manipulation of neuronal circuits 47 While optogenetics has provided a powerful means of circuit-level interrogation of the mechanisms of DBS, the results of such studies have similarly produced mixed insights, and it is moreover important to consider that these studies are putatively limited in translational value due to the level of invasiveness and manipulation required for further validation in humans. As such, the remainder of this article is focused on recent mechanistic insights gained from intraoperative and perioperative neurophysiological studies in DBS patients, highlighting the most recent mechanistic insights from the literature across various spatiotemporal resolutions.Ultimately, the mechanisms elicited by DBS have historically been considered as complex and varied; with effects that are parameter-dependent, site-specific, synapse-specific and likely more. Future studies investigating neural effects over longer time periods, with simultaneous recordings from multiple structurally and/or functionally connected regions, together with related clinical information, will have significant impact on our understanding on underlying brain network interactions.48–50 an integrated computational framework51 has recently been developed that is capable of reproducing experimental results of stimulation induced local neuronal firing rate changes in human STN,53 SNr53 (or GPi54), and thalamic ventral intermediate nucleus (Vim)55 at various stimulation frequencies. The framework suggests that individual DBS pulses simultaneously activate the presynaptic terminals of all afferent axons terminating49 at the target structure. The consequent neuronal responses are thereby dependent upon the relative distributions of excitatory and inhibitory afferent inputs converging50 upon the target site  and neurophysiological (short-term plasticity) properties into consideration to reproduce site-specific and frequency-dependent responses to DBS.Building upon previous modelling studies,get site . These n55 In stimulation targets with predominantly GABAergic inputs , individual DBS pulses lead to a net hyperpolarization and stimulus-locked inhibition of target neuron firing.57 STN has a more balanced distribution of glutamatergic (i.e. hyperdirect pathway) and GABAergic (i.e. indirect pathway) inputs, leading to weaker net inhibitory responses compared to SNr or GPi.58 These single-pulse phenomena (evoked fields and associated single neuron responses) are visualized in 59In targets with predominantly glutamatergic excitatory inputs , individual stimuli lead to a net postsynaptic depolarization and resultant stimulus-locked generation of action potentials.60 This resiliency of inhibitory synaptic transmission to STN has now also been confirmed in patients with Parkinson’s disease.58 Importantly, this new empirical work emphasizes that differences in susceptibility to synaptic depression are not neurotransmitter-specific, but are in fact synapse-specific. While inhibitory synaptic transmission to STN (mediated by GPe) was partially sustained during subthalamic HFS, inhibitory synaptic transmission to SNr (mediated primarily by striatum) was rapidly depressed by SNr HFS.58 This potent depression of inhibitory synaptic fidelity during SNr HFS resulted in the return of spontaneous neuronal firing in SNr after several seconds, compared to sustained inhibition as seen in STN with STN HFS , it has recently been suggested that the modulations of short-term synaptic dynamics differ across synapse types. In naïve rodent STN slices, DBS-like extracellular HFS rapidly and reliably depressed excitatory cortico-subthalamic synaptic currents; however, inhibitory GPe-STN synaptic transmission efficacy was maintained over time, after an initial weakening. STN HFS .61 furthermore emphasize that it may be possible to achieve more selective control of neural activity than anticipated with extracellular stimulation,63 particularly when strategically leveraging neurophysiological readouts to titrate stimulation location and parameter settings.64 Therefore, such functional readouts should be considered in the development of new and emerging DBS paradigms and indications.Ultimately, it can now be empirically supported that the effects of DBS are anatomy-dependent and synapse-specific; adding explicit mechanistic details to the otherwise unspecific claims of complexity. When taking each of these nuances into consideration (which synapses are engaged and how they behave), it is possible to conceive a generalizable theory as to how DBS may modulate neuronal activity. Mechanistic studies demonstrating the target- and circuit-specific effects of DBS55 these studies do not rule out the clinical importance of broader network-level effects. To this end, from a mechanistic standpoint, the aforementioned theoretical framework can be expanded upon to capture the simultaneously evoked (synapse-specific) up- and downstream responses at structurally connected targets  represents a summation of presynaptic transmembrane voltage fluctuations, ion flux and local action potential firing.66 Thus, with LFP, synchronized neural population activity can be recorded that likely reflects pre- and postsynaptic currents from thousands of neurons surrounding the DBS electrode directly in the target region. Increased oscillatory power in the beta frequency band (13–35 Hz) was demonstrated to be related to the parkinsonian hypodopaminergic state,67 both in the STN and GPi,68 and the amplitude of these oscillations was shown to be correlated with parkinsonian motor sign severity in the dopaminergic OFF state.70Beyond firing patterns, access to intracranial field potentials from DBS electrodes has defined research into disease and symptom specific pathological oscillatory patterns.71–78  are particularly detrimental to the parkinsonian state.86–88 Conversely, antiparkinsonian medications and adaptive closed-loop DBS were retrospectively shown to shorten prolonged beta episodes, implying that short duration beta episodes may be of a more physiological nature.89Importantly, DBS was demonstrated to cause a local suppression of this pathological activity pattern71–78 , with th90–92 After each DBS pulse, a transient evoked phenomenon is visible, which typically contains two positive-going peaks in the 7 ms interstimulus window during 130 Hz stimulation, and remains observable for a short time period after cessation of stimulation [94 ERNA has been postulated to be the result of entraining the inhibitory-excitatory reciprocal connections between GPe and STN.95 An ERNA substrate has now also been detected in the context of intraoperative microelectrode recordings, and it has been confirmed that each peak of the interstimulus waveform is associated with temporally-locked neuronal inhibition [96 Mechanistically, it is hypothesized that the first ERNA peak is the result of a net inhibitory response from activating the afferent inputs to STN, while the resonant peak is the result of concurrent activation of STN efferents, which excite GPe, resulting in feedback inhibition to STN [96 While this theory is dependent upon the unique ability of GPe afferent synapses to maintain a high rate of activation,58 the same would need to be true for STN efferent synapses. To this end, it has indeed been shown that STN HFS results in persistent upregulation of GPe firing, albeit decaying over a slow time course.6 Connecting insights, it can now be confirmed that patterned interstimulus inhibitions of neuronal activity in STN  [6; further corroborating the reciprocal mesocircuit activation hypothesis. Moreover, through the use of a recently published expert anatomist-derived subcortical fibre atlas,97 it was shown that the ERNA hot spot in STN is in fact associated predominantly with the activation of reciprocal fibres between STN and GPe.96In addition to the suppression of pathological beta activity, a novel stimulation-evoked LFP marker of DBS response has recently been described, termed evoked resonant neural activity (ERNA).98 and these observations have also been confirmed intraoperatively [93 Since various studies have shown that ERNA amplitude scales with therapeutic benefit of both STN-92 and GPi-DBS,98 ERNA may represent a convergent subcortical mechanistic signature, orchestrated by persistent GPe-mediated inhibition, that is able to explain the common efficacy of these two interventions. Given that hyperdirect pathway activation is not able to explain the common efficacy,5 ERNA may therefore impose a downstream influence on the greater basal-ganglia-thalamo-cortical network, which could explain the common cortical functional connectomic anti-correlation , which co-localizes the predictive efficacy of STN- and GPi-DBS to the M1 region.99Most recently, observations of ERNA have also been recorded by macrocontacts of the DBS electrode during GPi-DBS,90 and the emergence of each of these signatures has been attributed to the same mesocircuit network.100–102 From an integrative standpoint, studies of these aggregate-level LFP markers therefore seem to imply that DBS replaces spontaneous pathological activity (i.e. increased beta oscillatory power) with evoked high-frequency activity by way of increased efficacy of GPe-mediated inhibition . Both of these mesoscale signatures are presently under investigation in closed-loop DBS applications.104Intriguingly, ERNA amplitudes have been found to correlate with amplitudes of beta oscillations,106 To this end, it was shown that the suppression of beta activity can be observed not only in target nuclei (STN or GPi), but also in distant cortical sensorimotor networks.107 Several studies using EEG, magnetoencephalography (MEG) and electrocorticography (ECoG) have independently replicated findings that cortical beta is modulated by STN-DBS in Parkinson’s disease.109 Beyond beta suppression, it was further shown that more complex neurophysiological phenomena can be observed in response to DBS. Namely, ECoG and EEG studies have shown that cortical beta-gamma cross-frequency coupling was increased in Parkinson’s disease111 and suppressed with DBS.112 It was moreover reported that cortical broadband activity was coupled to specific phases of the beta oscillation.112 Later, some of these observations were explained by a change of waveform shape of beta itself. Cycle-by-cycle waveform investigations114 have revealed that particularly sharp signal deflections are shorter and therefore less likely to nest broadband signals during DBS. Thus, increased sharpness asymmetry of trough and peak of the beta oscillation in Parkinson’s disease was shown to be smoothed during therapeutic DBS.116 In fact, specifically sharp single cycle discharges in the beta oscillation could be isolated in the parkinsonian motor cortex and associated with the hypodopaminergic OFF state.117 More recently, altered cross-frequency coupling in patients with Parkinson’s disease undergoing STN-DBS was also described using ECoG and EEG.118 Namely, coupling of finely tuned cortical gamma to the stimulation frequency and lower harmonics can be observed during DBS and may reveal underlying mechanisms of symptom alleviation.119 These effects have been hypothesized to be the result of a dynamic entrainment mechanism of neural populations to the stimulation frequency described in regions of a cortical  and subcortical (STN and cerebellum) network. In particular, implementation of a Wilson-Cowan model  was able to be replicate these gamma entrainment responses120; however, empirical neuronal/synaptic underpinnings are yet to be established, though these observations are perhaps reminiscent of the mechanistic underpinnings of ERNA (described earlier).In addition to intracranial recordings from subcortical structures, it is possible to record broader network level cortical activity during DBS .105,106 121–123 The most comprehensive account of this was reported in a study in subthalamic DBS for Parkinson’s disease using combined MEG-LFP recordings.79 During DBS, it was shown that beta-band coherence (a measure of frequency specific correlation of phase and power between two recordings) can be suppressed by DBS, an effect that localizes to the medial frontal cortex overlapping with the supplementary motor area (SMA).79 In addition to synchrony, oscillatory networks can also be investigated for directionality of information flow, e.g. using Granger causality-based metrics. In patients with Parkinson’s disease, subthalamic beta activity is hypothesized to be driven by cortex. The most recent multi-modal work124  suggests that cortical high-frequency beta oscillations (20–35 Hz) are propagated to STN, where they are subsequently converted to the more pathological low-frequency (13–20 Hz) rhythm126 by the reciprocal connectivity of the STN-GPe network; a phenomenon that may be exacerbated in the hypodopaminergic state.123 Importantly, while DBS modulates synchrony between cortex and STN, it does not change directionality of this network that follows the neuroanatomical/axonal orientation of the hyperdirect pathway.124Network-level studies demonstrate that modulation of one node in the circuit can lead to distinct neurophysiological alterations recorded in other nodes of the same network. But beyond local subcortical or cortical changes in oscillatory activity, neurophysiology also allows for the investigation of functional oscillatory connectivity.127 Achievement of this optimal network profile can in fact result in the restoration of neurocircuit function that closely resembles that of age-matched healthy controls,11 which represents the ultimate goal of DBS as a neuromodulatory intervention.Finally, through recent functional connectomic works , widespread changes to brain circuitry have been shown to converge on a common network that can be remarkably predictive of therapeutic success; with a particular emphasis on the functional anticorrelation between subcortical targets (STN and GPi) and primary motor cortex.51 the unique functional properties of engaged synapses seem to govern the response at high frequencies of stimulation58; underscoring the importance of understanding the short-term synaptic dynamics of engaged synapses on a structure-by-structure basis. In the case of STN-DBS, HFS seems to depress/abolish the cortical excitatory influence on STN, while promoting/persistently eliciting GPe-mediated inhibition.60 The suppression of cortical inputs could explain aggregate-level observations of the attenuation of pathological beta frequency oscillations, which are hypothesized to be dependent on cortical influence of the STN via the hyperdirect pathway projections.124 Conversely, the persistent supraharmonic entrainment of GPe-mediated inhibition (i.e. ERNA) may prove to be an important therapeutic mechanism, which seems to be able to explain the common clinical efficacy of STN- and GPi-DBS98; which cannot otherwise be explained by antidromic activation of the hyperdirect pathway.5 To this end, it is perhaps subcortical alterations that give rise to broader, downstream basal-ganglia-thalamo-cortical network level changes, which functionally co-localize the predictive efficacy of STN- and GPi-DBS to the M1 region .99 Meanwhile, invasion of the cortico-subthalamic hyperdirect pathway may explain faster timescale functional readouts such as the disruption of excessive oscillatory power124 and cortico-cortical coupling112 achieved by STN-DBS in Parkinson’s disease.The effects of DBS are dependent upon the therapeutic target and the specific synapses that are present within the vicinity of the electrical field that are engaged by the stimulation pulses. While the distribution of GABAergic versus glutamatergic afferent inputs may determine the net neuronal response to individual pulses (i.e. selective excitation versus inhibition),awad239_Supplementary_DataClick here for additional data file.


This comprehensive systematic review provides valuable insights into the landscape of biomarkers in clear cell renal cell carcinoma (ccRCC) and their potential applications in the prediction of treatment response, prognosis, and therapeutic monitoring. One of the major challenges in ccRCC is determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy. This review aims to provide a comprehensive overview of biomarkers in ccRCC and their utility in the prediction of treatment response, prognosis, and therapeutic monitoring in patients receiving systemic therapy for metastatic disease. The findings underscore the importance of incorporating biomarker assessment into clinical practice to guide treatment decisions and improve patient outcomes in ccRCC.Background: Challenges remain in determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy in renal cell carcinoma. The objective of this review is to provide a comprehensive overview of biomarkers in metastatic renal cell carcinoma (mRCC) and their utility in prediction of treatment response, prognosis, and therapeutic monitoring in patients receiving systemic therapy for metastatic disease. Methods: A systematic literature search was conducted using the PubMed database for relevant studies published between January 2017 and December 2022. The search focused on biomarkers associated with mRCC and their relationship to immune checkpoint inhibitors, targeted therapy, and VEGF inhibitors in the adjuvant, neoadjuvant, and metastatic settings. Results: The review identified various biomarkers with predictive, prognostic, and therapeutic monitoring potential in mRCC. The review also discussed the challenges associated with anti-angiogenic and immune-checkpoint monotherapy trials and highlighted the need for personalized therapy based on molecular signatures. Conclusion: This comprehensive review provides valuable insights into the landscape of biomarkers in mRCC and their potential applications in prediction of treatment response, prognosis, and therapeutic monitoring. The findings underscore the importance of incorporating biomarker assessment into clinical practice to guide treatment decisions and improve patient outcomes in mRCC. In 2023, there will be an estimated 76,080 new cases and 13,780 new deaths due to kidney cancer in the US . The curHistorically used chemotherapy and radiation therapy lacked sensitivity in ccRCC ,7, and tDespite the advances that have been made, there are many challenges to treating ccRCC. In particular, pure anti-angiogenic trials (which have been largely negative) and pure immune-checkpoint monotherapy trials have been applied  to the adjuvant setting with continued uncertainty as to who would benefit from adjuvant therapy or neoadjuvant therapy and for how long . The advPrior reviews have broached this topic but have not provided a comprehensive review of the vast variety of biomarkers that exist in ccRCC or have focused on a specific form of therapy. For example, Gulati et al. aim to evaluate validated biomarkers that are being utilized to guide treatment choices and help identify pathways of resistance in other tumor types, and do this by organizing their paper by biomarker  . SimilarThe protocol of the present systematic review and meta-analysis was following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PRISMA checklist was shown in Two authors independently searched relevant studies from the PubMed Advanced Search Builder literature database. The retrieval time ended on 31 December 2022. The systematic searching was restricted to the English language and human subjects. The following search strategy was employed in PubMed: ((biomarker) OR (prognostic marker) OR (gene expression)) AND ((immunotherapy) OR (immune checkpoint inhibitor) OR (ICI) OR (targeted therapy) OR (tyrosine kinase inhibitor) OR (TKI) OR (VEGF inhibitor)) AND ) OR (ccRCC) OR (clear cell RCC)) AND ((metastatic) OR (metastasis) OR (metastases) OR (stage 4) OR (stage IV) OR (adjuvant) OR (neoadjuvant)) NOT (“case report”[Title]) NOT (“case reports”[Publication Type]) NOT (review [Publication Type]).Two authors independently screened the literature according to the following criteria: (1) studies including patients who were diagnosed with primary or metastatic RCC after cytology or pathology; (2) studies that were Phase I, II, III, or IV or retrospective studies; (3) studies that focused on systemic therapies to treat adjuvant, neoadjuvant, or metastatic disease; (4) studies that used IO, TKI, VEGFi, or a combination of these therapies; and (5) articles that were published in English. For repeatedly published studies, we only chose the latest literature or the literature with the largest sample size. The articles were excluded based on the following reasons: (1) without the normal control group data; (2) review articles, editorials, comments, letters, case reports, etc.; (3) duplicated data; and (4) animal experiment. Only articles published between January 2017 and December 2022 were included, given that RCC treatment protocols have frequently changed. A standardized data collection form was employed to extract the following information by 2 authors independently: the first author’s name, publication year, title, DOI, abstract, paper methodology, sample size, marker name, marker purpose, marker class, type of maker, drug, drug class, major findings, and limitations. These data can be found in The Newcastle–Ottawa quality (NOS) assessment scale was used to evaluate the quality of the included studies by the 2 authors independently. The full mark of the scale was 9. Scores with 0–3, 4–6, and 7–9 were regarded as low quality, moderate quality, and high quality, respectively.https://public.flourish.studio/visualisation/14189718/ (accessed on 22 July 2023). The purpose of this review is to systematically identify biomarkers that have the potential to diagnose, predict, prognose, and track therapeutic monitoring in ccRCC patients receiving systemic therapy with ICI, TKI, VEGFi, or a combination for treatment of adjuvant, neoadjuvant, and metastatic disease. This review organizes our findings first by marker class, then drug class, and finally paper methodology . VariousImmunologic markers are those that serve as surrogate markers for cellular activation and play an important role in the function of the immune system. These includes serum cytokines, chemokines, adipocytokines, soluble forms of cell receptors, and immune activation markers .Immune checkpoint inhibitors are monoclonal antibodies that boost anticancer immune responses by targeting various immune receptors. These agents have been successfully used to treat RCC in clinical trials and/or are being studied in several prospective and retrospective studies. There are few clinically proven predictive and prognostic biomarkers for ccRCC treated with first-line therapies, but novel drugs and biomarkers have been emerging from clinical trials. The safety and efficacy of rocapuldencel-T, a type of immunotherapy prepared from mature dendritic cells, was explored in a Phase III study in combination with standard of care sunitinib as a first-line therapy for mRCC. When compared to the standard of care, Rocapuldencel-T produced immune responses in 70% of patients and the strength of the response correlated with OS. High baseline numbers of T regulatory cells are associated with improved outcomes in patients treated with rocapuldencel-T, but were associated with worse outcomes in patients receiving SOC treatment . PD-1 is a receptor found on T-cells which binds to PD-L1, a receptor often upregulated on cancer cells. This binding interaction prevents T-cells from destroying cancer cells, enabling the tumor to escape the immune system. Clinical trials have proven the efficacy of anti-PD1 therapies as a mainstay systemic treatment in ccRCC patients ,19,20,21By contrast, Mahoney et al. examined soluble PD-L1 (sPD-L1) as a biomarker within serum, rather than from tumor tissue. They found that sPD-L1 is a marker of nivolumab-refractory disease in RCC and is more complex than just a substitute for PD-L1. This is because aggressive disease produces sPD-L1, but there may be a distinct secondary pathway by which some patients with some or complete response to nivolumab produce sPD-L1. Therefore, a comparison of baseline and on-therapy sPD-L1 levels in RCC may be able to predict progressive disease in patients taking nivolumab . IncorvaRoss-Macdonald et al. found that non-response to nivolumab was correlated with tumors highly infiltrated with T-cells. The degree of infiltration was measured at baseline and on day 28 by a T-cell receptor “CD3TCR” expression score using a gene set of the CD3-γ, CD3-δ, CD3-ε, CD3-ζ, TCR-α, and TCR-β subunits . They alOther predictive markers being explored include circulating endothelial cells. García-Donas et al. found that, when given antiangiogenic treatments (sunitinib and/or pazopanib), the detection of higher CEC levels, defined as DAPI+, CD105+, and CD45−, was associated with progression-free survival in ccRCC. The study also found that CEC levels did not change significantly despite tumor progression compared with baseline, which suggests that CECs could be determined at any time during treatment, remaining a stable predictive biomarker . 2, and age ≥ 70 years independently predicted overall survival. SII changes at 3 months also predicted OS [Prognostic liquid biopsy biomarkers have been explored prospectively as well. Bootsma et al. examined circulating tumor cell abundance and HLA I to PD-L1 (HP) ratio as prognostic markers in RCC and demonstrated that both markers can be used to monitor treatment response Specifically, the direction in which CTC enumeration changes was strongly associated with OS and increases in the HP ratio over time collated with worse outcomes . Billon icted OS . A study by Saal et al. aimed to evaluate the prognostic value of the modified Glasgow prognostic score (mGPS) in patients with mRCC treated with ICIs, specifically in the context of the IMmotion151 trial, which compared atezolizumab plus bevacizumab to sunitinib. The mGPS assigns points based on elevated serum C-reactive protein (CRP) and decreased serum albumin levels. Patients are categorized as low, intermediate, or high risk. The results demonstrated that the mGPS outperformed the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, the current standard for risk stratification in mRCC. The mGPS had a higher concordance index and identified a larger proportion of patients as low risk while maintaining comparable survival rates. This study suggests that the mGPS could replace the IMDC score as a simple and effective prognostic tool in the era of immuno-oncology for mRCC patients .Retrospective studies disclose even more unique biomarkers that have both predictive and prognostic value when studying effects of immunologic treatments. Many biomarkers have been studied, the most common of which are C-reactive protein (CRP), NLR, and immune-related adverse events (irAEs). Many other markers were also studied and can be found in One of the most commonly studied predictive and prognostic markers is CRP, which is a nonspecific marker of inflammation found in blood. Kankkunen et al., Roussel et al., and Ito et al. all studied elevated baseline CRP as a marker of poor prognosis in RCC, and found that this marker can predict worse OS and PFS on nivolumab ,35,36. KAbuhelwa et al. also studied CRP as a prognostic maker in ccRCC. They found that CRP could be used to stratify patients into four levels, with CRP levels inversely correlated with OS and PFS . Fukuda Others studied CRP as a predictor of treatment response in RCC. Noguchi et al. found that CRP level at 1 month after treatment with nivolumab may be clinically useful in quickly predicting treatment effect . Fukuda Another commonly studied predictive and prognostic biomarker is NLR, which is a biomarker that links the two parts of the immune system: the innate immune response, mediated by neutrophils, and adaptive immunity, supported by lymphocytes . There iirAEs, a known side effect associated with ICIs, are a set of autoimmune conditions that can affect any organ in the body, which makes them difficult to diagnose and manage . CliniciTKIs are a class of drugs that inhibit signal transduction of protein kinases which in turn critically disrupt cellular signaling . One groVEGFR TKIs form a class of adjuvant therapy used in RCC. Drugs that are approved by the US FDA include sorafenib, sunitinib, axitinib, and pazopanib . These aProspective studies have studied both the predictive and prognostic abilities of angiogenesis markers as well as plasma cytokines in patients treated with VEGFR TKIs. Mauge et al., Jilaveanu et al., Oudard et al., and Xu et al. all studied the prognostic abilities of various angiogenesis markers ,55,56,57Jilaveanu et al. also studied the predictive value of MVD. They also found that high MVD significantly correlated with Fuhrman grade 1–2, clear cell histology, and absence of necrosis but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size, and therefore concluded that MVD was a better potential as a prognostic marker, rather than a predictive marker . Hakimi Other groups have prospectively looked at the predictive and prognostic abilities of various plasma cytokines in patients treated with VEGFR TKIs. IL-6 is a plasma cytokine that is known to play a pathologic role in chronic inflammation as well as RCC ,60. PilsLike Chehrazi-Raffle et al., Bellmunt et al. and Xu et al. all looked at the predictive and prognostic value of plasma cytokines other than IL-6. Bellmunt et al. studied the predictive value of IL-10 levels in mRCC patients receiving second-line pazopanib after failure of a prior TKI. They found that lower circulating levels of IL-10 were observed in responding patients at 8 weeks after treatment . Xu et aZizzari et al. and Montemagno et al. both looked at soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy. Zizzari et al. identified soluble PD-L1 and PD-1 as two of seven soluble immune molecules  as well as CD3 + CD8 + CD137+ and CD3 + CD137 + PD1 + T-cell populations as markers modulated by TKI therapy . MontemaRetrospective studies identified even more unique potential biomarkers that have both predictive and prognostic value when studying the effects of immunologic treatments. Many biomarkers have been studied, the most common of which are CRP and NLR. Many other markers were also studied and can be found in Several retrospective studies have investigated the prognostic value of CRP levels in mRCC patients and their response to TKIs. Takamatsu et al. investigated the prognostic value of baseline CRP level in intermediate-risk mRCC patients treated with first-line VEGFi therapy. They reported that higher baseline CRP levels were associated with inferior OS and PFS outcomes . They thOther studies aimed to show CRP’s efficacy as a predictive marker. Yasuda et al. demonstrated that early response of CRP levels could predict survival in patients with mRCC undergoing TKI treatment. They found that patients who achieved a significant decrease in CRP levels within one month of TKI therapy initiation had improved OS and PFS . KlümperCombination therapy involves the use of multiple drug classes to enhance the efficacy of anti-cancer treatments. This approach potentially reduces drug resistance, while reducing tumor growth, mitotically active and cancer stem cells, and metastatic potential . In RCC,Several studies have provided valuable insights into the clinical activity and molecular correlates of response to immunotherapy in renal cell carcinoma (RCC) patients. McDermott et al. found that atezolizumab–bevacizumab combination therapy showed improved clinical activity and higher overall response rates compared to sunitinib, providing molecular characteristics of each treatment option. The study also identified specific molecular markers associated with response to immunotherapy, such as high tumor mutational burden and PD-L1 expression. These findings provide important information for patient selection and treatment decision making .In a study by Martini et al. the focus was on angiogenic and immune-related biomarkers in patients receiving axitinib/pembrolizumab treatment. The researchers observed that specific angiogenic and immune-related biomarkers, including angiopoietin-2 and vascular endothelial growth factor, were associated with treatment response and outcomes. This highlights the potential of these biomarkers as predictive factors for therapy response and the importance of considering both angiogenesis and immune pathways in RCC treatment strategies .Msaouel et al. conducted a phase 1–2 trial evaluating sitravatinib and nivolumab in clear cell RCC patients who had progressed on antiangiogenic therapy. The results demonstrated promising clinical activity, with a significant proportion of patients experiencing tumor shrinkage and disease control. The study also highlighted the potential of sitravatinib to overcome resistance to antiangiogenic therapy and enhance the efficacy of immunotherapy. These findings suggest that the combination of sitravatinib and nivolumab could be a promising treatment approach for refractory RCC patients .In a study by Kamai et al. the researchers investigated the expression of adenosine 2A receptors (A2AR) in metastatic renal cell carcinoma (RCC) and its impact on treatment response and patient survival. The study revealed that increased expression of A2AR was associated with poorer response to anti-VEGF agents and anti-PD-1/anti-CTLA4 antibodies. Patients with higher A2AR expression levels demonstrated shorter overall survival rates, indicating the potential of A2AR as a prognostic biomarker in metastatic RCC. These findings highlight the significance of A2AR in the immunotherapy response and suggest that targeting A2AR signaling may improve treatment outcomes in RCC patients . The stuGenomic markers are DNA or RNA sequences that are known to cause disease or increase susceptibility to disease. This marker class is the basis of genetic testing, which identifies changes in chromosomes, genes, and proteins , as wellSeveral studies have investigated predictive biomarkers for immunotherapy response in metastatic renal cell carcinoma (mRCC) patients. Incorporvaia et al. and Epaillard et al. specifically studied PD-1 and PD-L1 as genomic biomarkers that may predict response to nivolumab. Incorporvaia et al. identified a “Lymphocyte MicroRNA Signature” as a potential predictive biomarker of immunotherapy response and plasma PD-1/PD-L1 expression levels in mRCC patients, suggesting a role for epigenetic reprogramming in treatment outcomes. They found that patients with higher levels of specific microRNAs had better response rates and improved overall survival . EpaillaMiao et al. and Ross-Macdonald et al. studied other genomic biomarkers that may predict response to nivolumab. Miao et al. explored the genomic correlates of response to immune checkpoint therapies in clear cell RCC and identified specific genomic features associated with treatment response, including mutations in the PBRM1 gene. They observed that patients with PBRM1 mutations had a higher treatment response rate and longer progression-free survival . Ross-MaSeveral genomic markers are being studied as predictive and prognostic potential in immunotherapies. Details regarding these studies can be found in Several studies have investigated the role of biomarkers in predicting treatment response and prognosis in advanced renal cell carcinoma (RCC) patients receiving sunitinib therapy. In a study by Dietz et al. molecular alterations specific to individual patients with metastatic ccRCC were identified, and these alterations were found to be associated with disease progression despite TKI therapy. The results underscore the need for personalized treatment approaches that consider the unique molecular profiles of patients to improve therapeutic outcomes . ExaminiOther studies have looked at the role of biomarkers in predicting treatment response and prognosis in patients receiving sorafenib therapy. Gudkov et al. conducted a study aiming to develop a gene expression-based signature capable of predicting the response to sorafenib in kidney cancer patients. The findings demonstrated that the signature successfully predicted the efficacy of sorafenib treatment, providing valuable insights for personalized therapeutic decision making in renal cell carcinoma (RCC) patients . Crona eBevacizumab was also a commonly explored drug; in a study by Dorff et al. the efficacy of bevacizumab, either alone or in combination with TRC105, was evaluated in patients with refractory metastatic RCC. The results demonstrated the potential clinical benefit of bevacizumab-based therapy in this patient population, suggesting its relevance as a treatment option for refractory metastatic RCC . Bamias Several genomic markers were studied as predictive and prognostic potential in VEGF-TKI therapies. Details regarding these studies can be found in mTOR inhibitors (mTORi) are chemotherapy drugs that deactivate the PI3K/AKT/mTOR signaling pathway, which in turn prevents tumor angiogenesis and downregulates the expression of hypoxia-inducible factors in RCC. Currently, two mTOR inhibitors are approved for use in metastatic RCC: temsirolimus and everolimus. These agents have been successfully used to treat RCC in clinical trials and biomarkers related to mTORi efficacy and prognosis are being studied in several prospective and retrospective studies, and are summarized in Several studies have focused on identifying prognostic and predictive biomarkers for mTOR inhibitors. Palomero et al. conducted a study investigating the role of EVI1, a transcription factor involved in cell proliferation and differentiation, as a prognostic and predictive biomarker in ccRCC. They found that higher EVI1 expression was associated with worse prognosis and resistance to mTORi therapy, indicating its potential as a valuable biomarker for guiding treatment decisions in ccRCC patients .Zeuschner et al. aimed to identify predictive biomarkers for everolimus treatment in second-line metastatic ccRCC. Through their research, they identified thrombospondin-2 and lactate dehydrogenase (LDH) as potential predictive biomarkers associated with treatment response to everolimus. This suggests that assessing the levels of these biomarkers could aid in patient selection for everolimus therapy, allowing for more personalized and effective treatment strategies.In addition, Voss et al. investigated the correlation between PTEN expression and treatment outcome in RCC patients receiving everolimus. They found that PTEN expression, rather than mutation status in TSC1, TSC2, or mTOR, was significantly associated with treatment response to everolimus. This highlights the importance of assessing PTEN expression levels as a potential predictive biomarker for everolimus therapy in RCC .Flaifel et al. conducted an analysis of the randomized clinical trials METEOR and CABOSUN to investigate the relationship between programmed death-ligand 1 (PD-L1) expression and clinical outcomes in mRCC patients treated with cabozantinib, everolimus, and sunitinib. The study aimed to determine whether PD-L1 expression levels could serve as predictive biomarkers for treatment response. The analysis revealed that PD-L1 expression was not significantly associated with clinical outcomes in terms of progression-free survival and overall survival in patients receiving any of the three treatments. These findings suggest that PD-L1 expression may not be a reliable biomarker for predicting response to cabozantinib, everolimus, or sunitinib in mRCC patients .Several other genomic markers were studied as predictive and prognostic potential in mTORi therapies. Details regarding these studies can be found in Both Motzer et al. and McDermott et al. studied gene expression signatures as a biomarker in mRCC by comparing atezolizumab alone or in combination with bevacizumab versus sunitinib. Motzer et al.’s molecular analysis revealed that immune-related gene expression signatures were associated with better outcomes for the combination therapy, while angiogenesis-related signatures showed better outcomes with sunitinib . McDermoSeveral genomic markers were studied as predictive and prognostic potential in combination therapies. Details regarding these studies can be found in Radiomics is an emerging field of study in which advanced imaging strategies provide structural and phenotypic biomarkers related to key disease processes. Radiomics-based biomarkers are being used to deeply analyze pathophysiologic processes and have provided insights to better diagnose, classify, stratify, and prognosticate tumors, and to assess their response to therapy . In recent years, there has been growing interest in identifying radiographic biomarkers that can predict clinical outcomes in mRCC patients receiving immune checkpoint inhibitors (ICIs). Tabei et al. conducted a study to assess the early predictive value of 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with ccRCC who received nivolumab, an immune checkpoint inhibitor. The study aimed to determine whether metabolic response assessed by 18F-FDG PET/CT after two cycles of nivolumab treatment could predict short-term outcomes. The findings revealed that patients treated with nivolumab had significantly longer progression-free survival and overall survival if they showed a metabolic response on 18F-FDG PET/CT. This suggests that early assessment with 18F-FDG PET/CT could serve as a valuable tool for predicting treatment response and patient outcomes in ccRCC patients receiving nivolumab therapy .Drljevic-Nielsen et al. investigated the potential of spectral dual-layer detector CT parameters as imaging biomarkers in patients with metastatic renal cell carcinoma (mRCC) who were treated with TKIs and immunotherapies. Their first study aimed to assess whether early reduction in spectral dual-layer CT parameters could serve as favorable prognostic indicators. They found that early reduction iodine concentration and effective atomic number predicted significantly longer OS and PFS. Their second study continued the focus on CT parameters, corroborating the predictive value of iodine concentration and adding CT parameters, such as virtual monochromatic images at specific energy levels, as a predictive biomarker. These findings suggest that both pretreatment and spectral dual-layer CT parameters have prognostic utility and could potentially aid in risk stratification and treatment decision making in mRCC patients treated with different therapies ,98.Martini et al. conducted a study to evaluate the potential of body composition variables as radiographic biomarkers in this patient population. They found that lower skeletal muscle index and higher visceral adipose tissue area were associated with worse clinical outcomes, including shorter overall survival and progression-free survival. They also found that lower skeletal muscle index was associated with higher levels of systemic inflammation, as indicated by elevated CRP levels. In addition, higher visceral adipose tissue area was linked to greater tumor burden and increased tumor inflammation. These findings suggest that body composition may influence treatment response and prognosis through its impact on systemic inflammation and tumor characteristics .Malone et al. conducted a study to develop a predictive radiomics signature for treatment response to nivolumab in patients with advanced renal cell carcinoma (RCC). Using radiomics analysis, they extracted quantitative imaging features from pre-treatment computed tomography (CT) scans and developed a radiomics signature. The results showed that the radiomics signature was significantly associated with treatment response to nivolumab. This finding suggests that the radiomics signature has the potential to serve as a non-invasive predictive biomarker for treatment response in patients with advanced RCC undergoing nivolumab therapy .Mittlmeier et al. investigated the utility of 18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing TKI or checkpoint inhibitor therapy. The study evaluated the preliminary results of using PSMA-based positron emission tomography/computed tomography (PET/CT) imaging to assess treatment response. The findings indicated that 18F-PSMA-1007 PET/CT showed promising potential in monitoring response to therapy in patients with metastatic RCC. This suggests that PSMA-based PET/CT imaging may serve as a valuable tool for response assessment in RCC patients receiving TKI or checkpoint inhibitor therapy .Zheng et al. compared radiological tumor response assessment based on immune Response Evaluation Criteria in Solid Tumors (iRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in metastatic clear-cell renal cell carcinoma (ccRCC) patients treated with programmed cell death-1 (PD-1) inhibitor therapy. The study aimed to determine the agreement between the two response evaluation criteria and assess their correlation with overall survival. The results showed that iRECIST provided a more accurate response assessment and better prediction of overall survival compared to RECIST 1.1 in metastatic ccRCC patients treated with PD-1 inhibitor therapy. These findings highlight the importance of using iRECIST as a more reliable and clinically relevant tool for response evaluation in this patient population .Park et al. conducted a study to evaluate the use of computed tomography (CT) texture analysis as a predictive tool for clinical outcomes in patients with mRCC treated with immune checkpoint inhibitors (ICIs). They analyzed CT images of mRCC patients and extracted various texture features to assess tumor heterogeneity. The study found that certain CT texture features were significantly associated with treatment response, progression-free survival, and overall survival in patients receiving ICIs. These findings suggest that CT texture analysis could serve as a non-invasive and promising tool for predicting clinical outcomes and guiding treatment decisions in mRCC patients undergoing ICI therapy .Udayakumar et al. conducted a study aimed at deciphering the intratumoral molecular heterogeneity in ccRCC using a radiogenomics platform. They integrated radiomic and genomic data to gain insights into the diverse molecular subtypes within ccRCC tumors. The study demonstrated that the radiogenomics approach could identify distinct molecular subtypes based on imaging features, providing valuable information for personalized treatment strategies. The findings highlight the potential of utilizing radiogenomics to improve the understanding of intratumoral heterogeneity in ccRCC and guide precision medicine approaches .Nakaigawa et al. investigated the predictive value of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) after the first molecular targeted therapy in patients with renal cell carcinoma (RCC). The study aimed to determine whether FDG PET/CT could serve as a prognostic tool to predict patient survival. The results demonstrated that FDG PET/CT findings after the initial targeted therapy were significantly associated with overall survival in RCC patients. This suggests that FDG PET/CT imaging can serve as a valuable non-invasive tool for predicting patient outcomes and guiding treatment decisions in RCC .Drljevic-Nielsen et al. investigated the potential of spectral dual-layer detector CT parameters as imaging biomarkers in patients with mRCC who were treated with TKIs and immunotherapies. Their first study aimed to assess whether early reduction in spectral dual-layer CT parameters could serve as favorable prognostic indicators. The results demonstrated that patients who showed early reduction in CT parameters, such as iodine concentration and effective atomic number, had significantly longer progression-free survival and overall survival. Drljevic-Nielsen et al.’s second study assessed various CT parameters to determine their association with patient outcomes. This study revealed that certain CT parameters, such as iodine concentration and virtual monochromatic images at specific energy levels, were significantly associated with progression-free survival and overall survival in mRCC patients receiving different therapies. These findings suggest that both pretreatment and spectral dual-layer CT parameters have prognostic utility and could potentially aid in risk stratification and treatment decision making in mRCC patients treated with different therapies ,98.In a study by Hall et al. the researchers investigated the prognostic significance of radiological response heterogeneity in mRCC patients treated with VEGF-targeted therapy. The study aimed to determine whether the variation in radiological response within individual patients could predict their overall survival. The findings revealed that higher radiological response heterogeneity was associated with poorer outcomes and shorter survival in mRCC patients. These results highlight the importance of considering the heterogeneity of radiological response as a prognostic factor when evaluating treatment response and predicting patient outcomes in mRCC patients undergoing VEGF-targeted therapy .Go et al. conducted a study aimed at developing a response classifier for VEGFR TKI treatment in mRCC. They analyzed the expression of various biomarkers, including VEGFR and other molecular factors, and developed a response classifier to predict treatment response to VEGFR-TKI therapy. The findings provide insights into the molecular characteristics associated with treatment response, potentially enabling the identification of patients who are more likely to benefit from VEGFR-TKI therapy in mRCC .Mytsyk et al. investigated the usefulness of the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in predicting early therapeutic response in mRCC patients. By analyzing the ADC values before and after systemic treatment, they found that changes in ADC values were correlated with treatment response. These results suggest that DW-MRI, specifically the ADC parameter, can serve as a useful tool for predicting early therapeutic response in mRCC patients, facilitating treatment monitoring and decision making .In another study, Wu et al. aimed to assess the response to anti-angiogenic targeted therapy in pulmonary mRCC using the R2* value as a predictive biomarker. They utilized magnetic resonance imaging (MRI) to measure the R2* value, which reflects the concentration of deoxyhemoglobin and serves as an indicator of tumor angiogenesis and hypoxia. The study demonstrated that the baseline R2* value was associated with treatment response and overall survival in mRCC patients receiving anti-angiogenic therapy. These findings suggest that the R2* value could be a predictive biomarker for assessing treatment response in pulmonary metastatic RCC patients undergoing anti-angiogenic targeted therapy .Mittlmeier et al. investigated the utility of 18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing TKI or checkpoint inhibitor therapy. The study evaluated the preliminary results of using PSMA-based positron emission tomography/computed tomography (PET/CT) imaging to assess treatment response. The findings indicated that 18F-PSMA-1007 PET/CT showed promising potential in monitoring response to therapy in patients with metastatic RCC. This suggests that PSMA-based PET/CT imaging may serve as a valuable tool for response assessment in RCC patients receiving TKI or checkpoint inhibitor therapy .Navani et al. conducted a study to assess the imaging response in patients with mRCC treated with contemporary immuno-oncology combination therapies. The study analyzed radiographic imaging data, including computed tomography (CT) scans, of mRCC patients undergoing combination immunotherapy. They evaluated treatment response based on radiographic assessments such as tumor size reduction, stability, or progression. The results showed that patients who achieved a complete or partial response on imaging had significantly improved progression-free survival compared to those with stable disease or disease progression. This study highlights the importance of radiographic imaging in monitoring treatment response and predicting outcomes in mRCC patients receiving combination immuno-oncology therapies .2, and age ≥ 70 years independently predicted overall survival. SII changes at 3 months also predicted OS [Only one prospective study by De Giorgi et al. studies the role of inflammation and BMI on clinical outcome. They found that a normal BMI combined with inflammation tripled the risk of death, suggesting that these biomarkers are critical prognostic factors for OS in patients with RCC treated with nivolumab. In univariate analysis, markers such as SII, NLR, and PLR were able to predict outcome, and on multivariate analyses, SII ≥ 1375, BMI < 25 kg/micted OS .Other retrospective studies have also investigated the relationship between BMI and treatment outcomes in RCC patients receiving immune-checkpoint inhibition therapy. Labadie et al. conducted a study to evaluate the association between BMI, irAEs, and gene expression signatures with resistance to immune-checkpoint inhibitors and patient outcomes in RCC. They found that higher BMI was significantly associated with poorer response to therapy and reduced overall survival. Additionally, specific gene expression signatures were identified that correlated with resistance to immune-checkpoint inhibition. These findings highlight the potential role of BMI and gene expression profiling as predictive biomarkers for immune-checkpoint inhibition therapy in RCC patients, providing insights into patient stratification and treatment optimization .In a related study, Herrmann et al. explored the prognostic value of BMI and sarcopenia, a condition characterized by muscle loss, in predicting outcomes for RCC patients treated with the immune-checkpoint inhibitor nivolumab. They analyzed the variations in BMI and sarcopenia before and after treatment and assessed their impact on treatment response and overall survival. The study revealed that patients with higher baseline BMI and those who experienced a decrease in BMI during treatment had significantly better outcomes, including improved response rates and prolonged survival. Moreover, the presence of sarcopenia at baseline was associated with worse treatment outcomes. These findings suggest that BMI and sarcopenia can serve as potential prognostic indicators for RCC patients undergoing immune-checkpoint inhibitor therapy, aiding in treatment decision making and patient management .Ueki et al. also conducted a retrospective study to investigate the association between sarcopenia, as determined by the psoas muscle index (PMI), and the response to nivolumab in patients with mRCC. The PMI, which measures the cross-sectional area of the psoas muscle normalized to the patient’s height, is a recognized indicator of muscle mass and overall body composition. The study findings revealed that, patients with a lower PMI, indicating sarcopenia, had a significantly poorer response to nivolumab treatment. These results suggest that sarcopenia, as assessed by the PMI, could serve as a potential biomarker for predicting the response to nivolumab in mRCC patients .Several retrospective studies have also investigated the relationship between body mass and treatment outcomes in renal cell carcinoma (RCC) patients receiving TKI therapy. McKay et al. conducted a study to investigate the effect of weight change during treatment with targeted therapy in patients with mRCC. The researchers assessed the impact of weight loss or gain on treatment outcomes and survival. The study revealed that weight loss during treatment was associated with worse overall survival and progression-free survival in patients with mRCC. On the other hand, weight gain was not significantly associated with survival outcomes. These findings suggest that weight change during targeted therapy may serve as a prognostic factor in mRCC, emphasizing the importance of monitoring and managing weight during treatment . SimilarOthers looked at the predictive and prognostic role of the De Ritis ratio. Janisch et al. conducted a study to assess the predictive value of the De Ritis ratio in mRCC patients treated with TKIs. The De Ritis ratio, calculated as the ratio of aspartate transaminase (AST) to alanine transaminase (ALT), is an indicator of liver function. The researchers found that a higher De Ritis ratio at baseline was associated with poorer survival outcomes in mRCC patients treated with TKIs. This suggests that the De Ritis ratio could serve as a potential predictive biomarker for treatment response and prognosis in mRCC patients receiving TKIs . Kang etZhang et al. investigated the impact of renal impairment on survival outcomes in patients with mRCC treated with TKIs. The study assessed the association between renal impairment, as determined by estimated glomerular filtration rate (eGFR), and overall survival in mRCC patients. The results demonstrated that patients with impaired renal function had significantly worse overall survival compared to those with normal renal function. This highlights the importance of considering renal impairment in the management and treatment of mRCC patients receiving TKIs .Aktepe et al. aimed to evaluate the impact of the albumin-to-globulin ratio (AGR) on survival outcomes of patients with mRCC. The study assessed the association between AGR, calculated as the ratio of albumin to globulin levels, and overall survival in mRCC patients. The findings revealed that a higher AGR was significantly associated with better overall survival in mRCC patients. This suggests that the AGR could serve as a potential prognostic biomarker for survival outcomes in mRCC, providing additional information for risk stratification and treatment decisions .Many studies looked at measures of tumor progression and spread as predictive and prognostic markers in ccRCC. Several other markers are also being studied for predictive and prognostic potential, including race, TKI-induced hypertension, RDW levels, and hemoglobin levels. Details regarding these studies can be found in Roussel et al. and Martini et al. aimed to find mechanisms to predict response to therapy. Roussel et al. conducted a study aimed at understanding the molecular mechanisms underlying the glandular tropism observed in metastatic ccRCC. By investigating the gene expression profiles of ccRCC tumors with glandular tropism, they identified specific molecular signatures associated with this phenotype. These findings have important therapeutic implications as they provide insights into the potential targets for developing novel treatment strategies specifically tailored to ccRCC with glandular tropism . MartiniSeveral studies examined tumor physiology as a biomarker. Shirotake et al. conducted a single institutional study to evaluate early tumor shrinkage as a predictive factor for mRCC in patients undergoing molecular targeted therapy. They found that patients who achieved early tumor shrinkage demonstrated improved progression-free survival and overall survival. Early tumor shrinkage could serve as an early indicator of treatment response, enabling timely modifications in the treatment regimen to optimize outcomes in mRCC patients . KammereIn summary, these studies provide valuable insights into various aspects of mRCC, ranging from molecular underpinnings and therapeutic implications to prognostic factors and predictive biomarkers. The identification of molecular signatures associated with glandular tropism in ccRCC offers potential targets for personalized treatment strategies. Early tumor shrinkage and tumor diameter response serve as predictive factors for treatment response and overall survival, emphasizing the importance of monitoring tumor size changes during therapy. Prognostic factors such as hilar fat infiltration, the ratio of maximum-to-minimum diameter of the primary tumor, and specific clinical parameters contribute to risk stratification and treatment decision making in mRCC patients. These findings contribute to refining treatment approaches, improving patient outcomes, and advancing our understanding of the complex nature of metastatic renal cell carcinoma.There has been a recent focus on the ability to apply artificial intelligence and multi-omics approaches to studying a range of cancers and other clinical conditions. Outside of ccRCC, tumor microarrays followed by image analysis and unsupervised learning with machine learning models has shown the ability to predict bladder cancer chemotherapy response . QuantitThe studies reviewed in this article provide important insights into the prognostic factors, treatment response, and response assessment in mRCC patients undergoing targeted therapies. These studies highlight the significance of various clinical, pathological, and radiological factors in predicting patient outcomes and tailoring treatment strategies. Factors such as C-reactive protein levels, lymphocyte microRNA signature, adenosine 2A receptor expression, EVI1 expression, and radiological response heterogeneity have been identified as potential prognostic markers and predictors of treatment response. Additionally, the use of advanced imaging techniques, such as PSMA-based PET/CT, shows promise in assessing treatment response in mRCC patients. The collective findings underscore the importance of a comprehensive approach to patient evaluation, incorporating multiple factors and innovative tools, to optimize the management of mRCC and improve patient outcomes. Further research and validation of these findings are necessary to refine risk stratification, guide treatment decisions, and ultimately enhance the care of patients with metastatic renal cell carcinoma.While the studies discussed provide valuable insights into prognostic factors, treatment response, and response assessment in mRCC patients, certain limitations should be acknowledged. Firstly, the studies mentioned are based on retrospective analyses or small sample sizes, which may introduce selection bias and limit the generalizability of the findings. Larger prospective studies are needed to validate and further explore the identified prognostic factors and response predictors. Secondly, the studies predominantly focus on specific targeted therapies, such as VEGF-targeted therapy, TKIs, and immune checkpoint inhibitors. The results may not fully represent the entire spectrum of treatment options available for mRCC, including emerging therapies and combination approaches. Therefore, the findings should be interpreted within the context of the specific treatments studied. Additionally, while the studies assess various factors and biomarkers, the complex nature of mRCC and its heterogeneity suggest that multiple factors likely contribute to treatment response and patient outcomes. It is important to consider the interplay between different biomarkers, clinical characteristics, and tumor biology to obtain a comprehensive understanding of prognostic factors in mRCC.Furthermore, the studies primarily rely on retrospective data or imaging modalities for response assessment, which may have inherent limitations. Variability in radiological assessments, lack of standardized criteria, and potential discrepancies between radiological and clinical response could impact the accuracy and reliability of response evaluation. Lastly, the studies reviewed have varying follow-up periods, and long-term outcomes and survival data may not be fully captured. Longer follow-up durations are necessary to assess the durability of treatment response and evaluate overall survival in mRCC patients. Considering these limitations, further research with larger cohorts, prospective designs, longer follow-up periods, and comprehensive evaluation of multiple factors is warranted to enhance our understanding of mRCC prognosis, treatment response, and response assessment.The studies discussed in the previous paragraphs provide valuable insights into prognostic factors, treatment response, and response assessment in mRCC patients. Moving forward, there are several potential directions for future research in this field.Conducting large-scale prospective studies with standardized protocols and longer follow-up periods can provide more robust evidence on prognostic factors, treatment response, and survival outcomes in mRCC patients. These studies can help validate the findings from retrospective analyses and further explore additional factors that may impact patient outcomes.Continued research is needed to identify and validate novel biomarkers that can predict treatment response, prognosis, and therapeutic resistance in mRCC. The integration of genomic, proteomic, and immunological markers may offer a comprehensive approach to understand the underlying mechanisms and develop personalized treatment strategies.Investigating the efficacy and safety of combination therapies, including targeted agents, immunotherapies, and other emerging treatment modalities, is crucial. Studying the synergistic effects of different therapeutic approaches and identifying predictive markers for optimal treatment selection can improve patient outcomes.Exploring novel response assessment techniques, such as functional imaging modalities  and liquid biopsies , may provide more accurate and timely evaluation of treatment response. Developing standardized criteria and guidelines for response assessment in mRCC can enhance comparability and facilitate clinical decision making.Supplementing traditional clinical trials with real-world evidence from diverse patient populations and clinical settings can provide a more comprehensive understanding of treatment outcomes and enable personalized treatment decisions. Large-scale observational studies and data registries can help assess the effectiveness and safety of therapies in real-world clinical practice.Including patient-reported outcomes, quality-of-life assessments, and patient preferences in research studies can provide a holistic perspective on treatment efficacy and impact on patients’ lives. Understanding the patient experience and incorporating patient-centered endpoints can guide treatment decisions and improve the overall care of mRCC patients.By focusing on these future directions, researchers can continue to advance our knowledge of mRCC, refine treatment strategies, and ultimately improve patient outcomes in this challenging disease.


The use of coronary computed tomography angiography (CCTA) in the setting of stable coronary artery disease is highly recommended for low-risk patients. High-risk patients, such as symptomatic subjects with prior revascularization, are suggested to be investigated with noninvasive functional tests or invasive coronary angiography. CCTA is not considered for these patients because of some well-known CCTA artifacts, such as blooming and motion artifacts. However, new technology has allowed us to obtain images with high spatial resolution, overcoming these well-known limitations of CCTA. Furthermore, the introduction of CT-derived fractional flow reserve and stress CT perfusion has made CCTA a comprehensive examination, including anatomical and functional assessments of coronary plaques. Additionally, CCTA allows for plaque characterization, which has become a cornerstone for the optimization of medical therapy, which is not possible with functional tests. Recent evidence has suggested that CCTA could be used with the aim of monitoring revascularization, both after coronary bypass grafts and percutaneous coronary intervention. With this background information, CCTA can also be considered the exam of choice in subjects with a history of revascularization. The availability of a noninvasive anatomic test for patients with previous coronary revascularization and its possible association with functional assessments in a single exam could play a key role in the follow-up management of these subjects, especially considering the rate of false-positive and negative results of noninvasive functional tests. The present review summarizes the main evidence about CCTA and coronary artery bypass grafts, complex percutaneous coronary intervention, and bioresorbable stent implantation. It is well-established that cardiac computed tomography angiography (CCTA) has recently played a key role in the area of ischemic heart disease (IHD). For individuals with a low to moderate pre-test risk of coronary artery disease (CAD), the most recent guidelines for chronic coronary syndrome advocate for using CCTA as the primary anatomical test . RegardiIn recent years, new technological developments have been introduced in the field of CT scanners. Advanced multi-detector CT scanners from newer generations exhibit enhanced spatial and temporal resolution, along with comprehensive heart coverage using wide-detector or dual-source CT. The former offers a coverage area of 16 cm and can capture heart images in a single heartbeat. Dual-source CT can image the heart in about 300 ms. It uses two X-ray tubes and two detectors arranged at 90° angles; this technology allows the reconstruction of images at one quarter of the gantry rotation time, improving temporal resolution. It also shows a good diagnostic image quality in patients with fast heart rates, limiting the use of beta-blockers. Additionally, thinner detectors and faster gantry rotation have also allowed for good image quality in patients with coronary stents and CABG [Photon-counting computed tomography (PCCT) is a recently introduced CT technology. It is based on a new generation of X-ray detectors; they are composed of semiconductor materials that directly convert each X-ray photon into electron-hole pairs. This mechanism enables the counting of photons and their classification into energy levels, avoiding noise at the electronic level. In this way, a substantial spatial resolution improvement can be achieved. Additionally, this technology is related to a decrease in the radiation dose and the amount of contrast media ,14.It must be noted that only 49% of significant CCTA stenoses are associated with abnormal invasive fractional flow reserve, such that current recommendations emphasize that patients with a stenosis of 50% or more are recommended to undergo further investigation with a functional test to guide revascularization. The FFR-CT technique has been developed with the aim of obtaining a noninvasive functional assessment of coronary stenosis. It works on the basis that by considering anatomical coronary features and applying computational flow dynamic algorithms, the coronary reply to adenosine administration can be estimated. A patient-specific three-dimensional 3D) anatomic coronary artery model is obtained, and a physiologic model is then derived based on patient-specific inflow and outflow hemodynamic conditions, with the resting myocardial blood flow proportional to the myocardial mass and the mathematical estimation of microvascular resistance. The decreased hyperemic microvascular resistance to adenosine is also predicted, with no need for adenosine administration. In this way, this analysis can forecast the performance of coronary circulation during conditions of maximum hyperemia [D anatomiAnother technique for functional assessment of coronary stenosis is stress CT perfusion. It takes into account that under resting conditions, the coronary circulation maintains a consistent pressure gradient thanks to an autoregulation mechanism; in the presence of a hyperemic stimulus, this autoregulation is disrupted, resulting in reduced myocardial perfusion when coronary stenosis is present. A rest/stress protocol is recommended, using adenosine as a stressor.Stress CT perfusion images can be obtained using both static and dynamic protocols. The static protocol involves capturing a complete dataset of images throughout the entire cardiac volume during the passage of the contrast medium.The dynamic protocol, on the other hand, involves capturing multiple datasets that correspond to the contrast kinetics within the cardiac chambers, allowing for the derivation of time-attenuation curves.This approach enables the assessment of myocardial blood flow in each individual myocardial segment .A Medline search of full-text articles published in English until October 2023 was performed. Overall, 549 records were identified. The search terms were: ((coronary CTA) OR (cardiac computed tomography) OR (CCTA) OR (CTA) OR (coronary CT)) AND ((left main stent) OR (LM PCI)); ((coronary CTA) OR (cardiac computed tomography) OR (CCTA) OR (CTA) OR (coronary CT)) AND ((bioresorbable scaffold) OR (BRS) OR (bioresorbable stent)); ((coronary CTA) OR (cardiac computed tomography) OR (CCTA) OR (CTA) OR (coronary CT)) AND ((coronary artery bypass graft) OR (CABG)). Only papers published in English-language peer-reviewed journals were selected.After evaluation of the title and abstract, a total of 32 studies were analyzed as full text.The quality of selected papers was tested using MINORS criteria. Unblinded reviewers performed the analysis of the full texts for quality assessment. Discrepancies between reviewers have been solved by consensus. The maximum score obtained was 14, and the minimum was 8. We included in the present review only studies obtaining a score of 10. A total of 10 papers were then considered for this overview.PCI of the left main (LM) improves survival, and in most cases, it is not inferior to surgical revascularization . Intra-sAlthough LM PCI is considered a complex procedure, the assessment of LM stenting by CCTA represents the “best-case scenario” for imagers. Stents implanted in the LM are typically large, and LM runs in an axial plane that corresponds to the scan direction, making it relatively free from motion artifacts. Additionally, it is essential to note that new technologies, such as Photon-Counting CCTA, are currently available in selected centers. These technologies allow for a more detailed assessment of stented segments, providing a better estimation of ISR.Despite these advancements, there is currently a lack of data regarding the use of CCTA in the follow-up of LM stenting from randomized trials. The “Angiographic control vs. ischemia-driven management of Patients undergoing percutaneous revascularization of the Unprotected Left main coronary artery with Second-generation drug-Eluting stents (PULSE) trial” (NCT04144881) is an ongoing prospective, multicenter, randomized trial aiming to determine whether a PAC strategy based on CCTA is superior to ischemia and symptom-driven conservative management approach in reducing major adverse cardiac events (MACE) and target lesion revascularization at 18 months. The results of the PULSE trial could define the role of CCTA in this particular clinical setting.Bioresorbable scaffolds (BRS) were designed to combine the short-term advantages of permanent stents with the long-term benefit of complete reabsorption, facilitating the restoration of vasomotor and endothelial function. This technology helps prevent prolonged inflammation, maintains the integrity of distal bypass grafting sites, and allows unimpeded future vessel imaging. Despite the promising theoretical benefits of BRS, the initial generation of BRS devices exhibited higher rates of stent thrombosis in comparison to other stents . Newer gGraft failure remains a significant concern, with reported occurrence rates ranging from 3% to 10%. Data from the literature underlined that the occlusion of the internal mammary artery within the initial year following surgery has a prevalence of 5.7% in men and 3.4% in women . The sapPresently, the randomized trial by Jones DA et al. investigated the advantages of performing CCTA before ICA in patients with CABG: the study demonstrated that the cohort undergoing CCTA showed reduced procedure time and contrast-induced nephropathy . FurtherRegarding risk assessment, numerous studies have highlighted the value of CCTA for long-term risk stratification through the classification of protected and unprotected coronary territories based on graft patency and obstructive native vessel disease . Lastly,Concerning functional CT modalities such as CT perfusion and CT-based fractional flow reserve (CT-FFR), there is limited data available for CABG patients in published studies, and thus, their additional value remains to be established . In lighThe contentious debate regarding whether anatomical or functional assessment is superior for patients with coronary artery disease has been less frequently explored in individuals with a history of coronary revascularization. The high-risk profile of this type of patient has led to a preference for a functional test in the case of recurrent symptoms. However, in recent years, CCTA has shown advancements in technology that have delivered substantial benefits through enhancements in image quality and reduction of overall radiation exposure so that CCTA represents a promising technique in the assessment of patients previously treated with CABG, complex PCI such as LM PCI, and BRS. The advantages of using CCTA in these settings are several: (a) it is a noninvasive assessment, so it is free from percutaneous angiogram risks; (b) the acquisition is faster than other noninvasive imaging modalities such as stress cardiac magnetic resonance or stress echocardiography; (c) it allows plaque characterization in order to optimize medical therapy; (d) it could be related to a lower amount of unnecessary coronary angiography when compared to symptom-driven strategy; (e) functional assessment can be added to the anatomical one; (f) CCTA can predict PCI results using virtual PCI software, which allows the choice of the best stenting diameter and length to obtain the best final result; (g) stress CTP is able to evaluate myocardial perfusion and to estimate myocardial blood flow. With this background, CCTA is expected to become the exam of choice in the whole spectrum of stable coronary artery disease.


The terms “renal regenerating nodule” and “nodular compensatory hypertrophy” are used in the literature to describe functioning pseudo-tumors (FPT) in the setting of an extensively scarred kidney. FPTs are usually discovered incidentally during routine renal imaging. Differentiating these FPTs from renal neoplasms is critical but can be challenging in the setting of chronic kidney disease (CKD) given the limitations related to using contrast-based imaging.We report a pediatric case series of 5 CKD patients, with history of urinary tract infections, in which tumor-like lesions evolved in scarred kidneys and were incidentally discovered on routine renal imaging. These were diagnosed as FPT by utilizing dimercaptosuccinic acid (DMSA) imaging and showed stable size and appearance upon follow-up with ultrasound and MRI.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 scan showing uptake at the site of the mass can be a useful tool to suggest the diagnosis of FPTs in children with kidney scarring, and that SPECT DMSA scan adds more precision in picking up and accurately localizing FPTs compared to planar DMSA. Urinary tract infections (UTIs) in children can be severe enough to cause renal scarring and chronic kidney disease (CKD). Classically, the mature kidney is considered to have limited cellular regenerative capacity , 2. HoweIn the literature, the terms “renal regeneration nodule” and “nodular compensatory hypertrophy” are used to describe functioning or histologically normal renal masses that develop in the setting of scarred kidneys. For simplicity and to avoid confusing terminology, we elect to call these functioning tumor-like lesions “FPT” throughout the manuscript.The radiologic characterization of these FPT poses a clinical dilemma and a diagnostic challenge. Conducting further clinical investigations to rule out malignancies in these lesions might subject patients to radiation exposure, complications of tissue sampling and possible surgical interventions in addition to the imposed psycho-economic factors such as anxiety and high costs . MoreoveIn this work, we report our experience with five pediatric CKD cases in whom tumor-like lesions were radiologically identified in severely scarred distorted kidneys. The main objective of this work is to highlight the role of DMSA scans with single planar and SPECT images in suggesting the diagnosis FPT and ruling out malignancy. This should facilitate the clinician’s management of these patients. We additionally review the available literature to discuss the possible pathophysiology of developing these FPT in the scarred kidneys.This retrospective case series included all children with established CKD whom incidental finding of tumor-like lesions were discovered upon routine renal imaging. All patients were recruited from Sidra Medicine, the only tertiary children’s hospital in the state of Qatar.(A)). MRI of the abdomen and pelvis was done and showed diffusely abnormal renal parenchyma, multiple scars, irregular outline with undulations and adjacent protrusions of the parenchyma resembling a mass like structure on the left kidney  showed a normotensive thriving young man and no palpable abdominal masses. Urine analysis was negative for leucocyte esterase, nitrites and white blood cells at the time of presentation. Work up revealed creatinine of 122 mcmol/L with estimated glomerular filtration rate (eGFR) of 51 ml/min/1.73m2. Renal US showed bilateral hyper-echogenic kidneys with evidence of scarring . Her course was complicated with frequent UTIs and CKD stage 3. An US done to work up urine leakage around the Metrofenoff site showed an incidental finding of multiple areas of parenchymal irregularities in the right kidney suspicious of renal masses  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 . These cThe presence of multipotent intra-renal progenitor cells , 4–6. ThMature resident renal cells undergoing de-differentiation, migration into the areas of damage, and re-differentiation to replace the neighboring dead cells , 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) . It contFew 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 . AnotherAll 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 , 29. AltThe 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 . Less coA 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 , 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  as a part of the differential diagnosis , 33, howThe 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 .FPTs represent a diagnostic challenge and necessitate further radiologic work-up. Even after conducting US and non-contrast CT, some lesions still remain indeterminate . In one DMSA scan is non-invasive, non-nephrotoxic, readily available technique that usually does not require sedation . It is sNormally, 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 , 14. DMSThree 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. 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 , 15. MRIIn 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.