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Scared to the Marrow: Pitfalls and Pearls in Renal Imaging

      Medical science can only flourish when it is conducted in alignment with society's interests. We value the health of our patients and want to ensure the safety of our diagnostic procedures. Often the quality and value of these procedures are increased with intravascular contrast. Common contrast materials include iodinated contrast (useful in too many X-ray-enhanced examinations to list) and gadolinium-based contrast for nuclear magnetic resonance imaging.
      Until recently, patients with either acute or CKD were excluded from most contrast-enhanced studies despite imaging modality. This issue of Advances in Chronic Kidney Disease addresses a number of clinically relevant topics (Fig 1). It represents a collaborative work among nephrologists, radiologists, pharmacologists, clinicians, basic scientists, and physician-scientists.
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      Figure 1Diagrammatic representation of the content of this renal imaging issue of Advances in Chronic Kidney Disease. See text for details. Abbreviations: CIN, contrast-induced nephropathy; HCS, high content screening; MRI, magnetic resonance imaging; PET, positron-emission tomography.

      Functional Magnetic Resonance Imaging

      The mission of this issue is to share science that relates to the early identification of kidney disease. Jeff L. Zhang provides a useful review that highlights the ability of gadolinium enhancement to provide renal functional information simultaneously with diagnostic imaging. He also details newer magnetic resonance-based techniques that evaluate renal perfusion and tissue oxygenation. These studies may prove useful as an adjunct to conventional imaging during evaluation of renal masses or obstruction. Furthermore, arterial spin labeling, blood oxygen level-dependent “functional” magnetic resonance imaging, or diffusion-weighted imaging represent promising alternatives to contrast-enhanced imaging.

      Contrast-Induced Nephropathy

      Contrast-induced nephropathy (CIN) has been one of medicine's hobgoblins. The nephrologists of my generation were indoctrinated that CIN was an objectively identifiable entity that could be prevented with elixirs of N-acetylcysteine (NAC) concomitantly with saline or bicarbonate. Prospectively, it has been difficult do demonstrate that any pharmacologic intervention (short of those that are protective for most types of acute kidney disease) affects acute kidney injury.
      • Gomes V.O.
      • Poli de Figueredo C.E.
      • Caramori P.
      • et al.
      N-acetylcysteine does not prevent contrast induced nephropathy after cardiac catheterisation with an ionic low osmolality contrast medium: a multicentre clinical trial.
      Moreover, diagnostic criteria for CIN lack specificity and the incidence varies.
      Section 4: contrast-induced AKI.
      Guidelines are split. The Kidney Disease Improving Global Outcomes Clinical Practice Guidelines recommend oral NAC (with intravenous crystalloids) prior to iodinated contrast for high-risk individuals.
      Section 4: contrast-induced AKI.
      The quality of evidence was ranked “very low” and low grade (“we suggest”). Conversely, the joint American College of Cardiology/American Heart Association guidelines do not recommend NAC. Disparate guidelines echo dissonant science. Catherine Do concisely summarizes how CIN is perceived at present. Lyndon Luk, Johnathan Steinman, and Jeffrey H. Newhouse make a strong case for the overestimation of risk attributed to “intravenous” iodinated contrast.

      Gadolinium

      CIN became such a threat that before 2006, it was common to recommend gadolinium-enhanced nuclear magnetic resonance imaging. Annually, nearly 20 million persons undergo magnetic resonance imaging, many using gadolinium-based contrast. Six million doses of magnetic resonance imaging contrast are administered annually.
      • Idee J.M.
      • Port M.
      • Raynal I.
      • et al.
      Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review.
      Before 2005, magnetic resonance imaging contrast materials were ranked among the safest substances in clinical use. Now every gadolinium-containing contrast agent carries a Food and Drug Administration “black-box” warning detailing the risk for inducing systemic fibrosis.
      Gadolinium is not a physiological element, and we have no idea what threshold triggers pathologic consequences. Miguel Ramalho and colleagues provide a timely overview of 2 newly described lanthanide disorders, gadolinium storage condition, and gadolinium deposition disease. John Prybylski contends that different chemical properties of 2 brands of gadolinium-based contrast have different propensities to liberate the gadolinium ion.
      Current fears focused on CIN, nephrogenic systemic fibrosis, and gadolinium deposition disease affect clinical reasoning. The product of probability and potential damage is at play irrespective of whether clinicians choose iodinated- or gadolinium-based contrast. CIN overall has a low probability of inducing acute kidney injury or harm, and gadolinium-induced disease is even lower. Yet the gravity of potential, serious adverse reactions, which may be catastrophic for gadolinium, is so great that clinicians and patients are forced to struggle with difficult choices. Patients who may benefit from contrast-enhanced imaging risk a delay in diagnosis. Without detailed knowledge of the mechanics of gadolinium-induced disease, there is an undefined set of patients who will eventually fall prey to a ghastly, painful, and incurable disease.
      Bone marrow-derived fibroblasts home to specific sites of fibrosis, such as skin, and may mediate gadolinium-induced fibrosis.
      • Wagner B.
      • Tan C.
      • Barnes J.L.
      • et al.
      Nephrogenic systemic fibrosis: evidence for bone marrow-derived fibrocytes in skin, liver, and heart lesions using a 5/6 nephrectomy rodent model.
      The process hinges on the monocyte chemoattractant protein 1 and its target C–C chemokine receptor 2.
      • Drel V.R.
      • Tan C.
      • Barnes J.L.
      • Gorin Y.
      • Lee D.Y.
      • Wagner B.
      Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis.
      Yanlin Wang has focused on a similar phenomenon of myeloid-derived fibroblasts in renal fibrosis. His work details the roles of the cytokine C-X-C motif ligand 16 (CXCL16) and the C-X-C receptor 6 in many experimental models of fibrosis. Because the degree of fibrosis of the interstitial compartment determines overall renal prognosis, the better that this compartment can be assessed in all forms of CKD, the greater its prognostic value. Dr Wang summarizes a few of these promising techniques.
      Physiological renal clearance is dependent on the capillary integrity inside Bowman's capsule maintained by endothelial, mesangial, and glomerular visceral epithelial cells. Often, it is the latter—the podocyte—that is the central target in many forms of kidney disease. Jochen Reiser and colleagues detail a new method of imaging cultured podocytes using high-content screening microscopy. This technique—capable of testing a variety of compounds and measuring the effect on podocyte phenotypes—has the potential to usher personalized medicine to the field.

      Positron Emission Tomography

      Given the potential for nephrogenic systemic fibrosis induction from gadolinium exposure and the evolving controversy involving iodinated contrast, a practical, an alternative imaging solution may be positron emission tomography. Namrata Krishnan and Mark A. Perazella provide an overview of the expanse of renal maladies that necessitate various radiologic procedures. They explore the potential application of 2-deoxy-2-[18F]fluoroglucose-enhanced (positron emission tomography) methods for acute tubulointerstitial nephritis, retroperitoneal fibrosis, and differentiating malignancies, in patients afflicted by cystic disease of the liver or kidneys.
      In summary, multiple opinions are voiced in this renal imaging issue pertinent to the practice of clinical nephrology. It is safe to state that there are many patients with acute or chronic kidney disease who find themselves in circumstances where either a contrast-enhanced radiologic examination or nuclear magnetic resonance image would provide useful diagnostic information. Instead, diagnoses are often delayed, a form of passive harm to our patients.

      Acknowledgment

      B.W. is funded by a Veterans Administration Merit Award (I01 BX001958) and the National Institutes of Health through grant R01 DK-102085 .

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