Veterinary Pathology OnlineFirst, published on January 23, 2015 as doi:10.1177/0300985814568358

Guest Editorial Veterinary Pathology 1-4 ª The Author(s) 2014 Reprints and permission: DOI: 10.1177/0300985814568358

Acute Kidney Injury and Chronic Kidney Disease T. M. Khan, MD1, and K. N. M. Khan, DVM, PhD, DABT2 Keywords cat, domestic mammals, species, urinary, tissue

The mammalian kidney is a structurally complex organ. The functional unit of the kidney is the nephron, which plays many important roles in maintaining homeostasis in the body. The major functions include excretion of the waste products of metabolism, regulation of body salt and water balance, maintenance of extracellular fluid volume, maintenance of acidbase balance, and elimination of foreign substances such as drugs and chemicals and their breakdown products. Thus, a thorough understanding of its structure and function, including age-related changes, is important to understand the kidney’s response to different types of insults and potential medical interventional strategies. Generally, renal insult is classified as either acute kidney injury (AKI) or chronic kidney disease (CKD). Acute kidney failure is characterized by a rapid fall in the glomerular filtration rate (GFR), occurring within hours to weeks, along with the retention of nitrogenous waste products as a result of reduced renal perfusion (prerenal azotemia), renal parenchymal damage (acute tubular necrosis, acute interstitial nephritis, and glomerulonephritis), or obstruction of the urinary tract (postrenal azotemia). The most common causes for acute tubular necrosis (ATN) are ischemia and exposure to nephrotoxicants. The kidney is particularly susceptible to nephrotoxicity because of the high blood flow to this organ relative to its mass and the unique property of the renal tubular epithelium in concentrating urine and its constituents, including drugs and chemicals. Age-related structural and functional differences in renal blood flow (RBF) and GFR contribute significantly to susceptibility of the aged population to nephrotoxic response compared with neonates, juveniles, and young adults.5 While the adult kidney receives 20% to 25% of the cardiac output, the human fetal kidney receives only 4%, which increases to 10% by the end of the first postnatal week. Thus, renal function in neonates remains different from that of adults, and GFR and RBF corrected for body size are not comparable to adult values until *1 year of age. GFR gradually increases until adolescence, where it is maintained at adult levels. After age 40 years in humans, there is a progressive decrease in renal function, which is primarily the result of reductions in nephron number. In rats, GFR gradually decreases with age, and by 18 months, the GFR is decreased to approximately twothirds of its rate compared with young adults. In dogs, there

is a gradual increase in GFR in the first 3 weeks of life primarily as a result of continuing maturation of nephrons, but progressive nephron loss in older dogs is associated with reductions in GFR, similar to those in rats. Therefore, potential age-related differences in renal mass and function can contribute to the development of ARF, especially secondary to nephrotoxicity, and should be included in the overall assessment of the renal disease and management strategy. CKD is a multifactorial pathophysiologic process resulting in progressive loss of nephrons in both number and function, frequently culminating in end-stage renal disease (ESRD). The clinical manifestations of ESRD result from irreversible loss of endogenous kidney function, leading to the development of life-threatening uremia. Therefore, it is imperative to diagnose renal disease and its underlying etiology at an early stage so that medical interventions can take place prior to the development of ESRD. Important risk factors for the development of CKD and reduced renal function in humans include age, hypertension, and diabetes. Hypertension in particular is the most common cause and also a consequence of CKD in the elderly, in whom underlying renovascular disease and associated local ischemia further contribute to the pathophysiology of CKD. The progression of CKD is characterized by continuously advancing and irreversible morphologic changes in renal parenchyma, including nephron loss and replacement by a selfperpetuating vicious cycle of fibrosis after the initial renal insult. The common pathological themes of CKD include arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis, suggesting a common pathway in progression of disease. Mechanisms underlying progression of renal pathology are not completely understood, but laboratory investigations suggest potential contributions by systemic and intrarenal

1 Clinical Sciences, Pfizer Global Innovative Pharma, Eastern Point Road, Groton CT, USA 2 Drug Safety R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton CT, USA

Corresponding Author: K. N. M. Khan, DVM, PhD, DABT, Drug Safety R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA. Email: [email protected]

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Veterinary Pathology

hypertension, glomerular hyperfiltration, tubular epithelial hypertrophy and atrophy, interstitial fibrosis, progressive glomerular sclerosis, and arteriosclerosis. Vascular endothelial injury as part of initial tubulointerstitial disease and subsequent vascular dropouts may lead to vicious cycles of tissue hypoxia and ischemia, affecting renal parenchymal repair. The combination of altered tissue oxygenation, renal hemodynamics, and interstitial scarring perpetuates underlying renal damage and progression of CKD. Genetic and pharmacologic manipulations in pathophysiologic models suggest that various cytokines and growth factors play important roles in modulating renal scarring during the progression of CKD. However, these factors and their roles may differ at various stages of injury and may include platelet-derived growth factor, transforming growth factor b, angiotensin II, basic fibroblast growth factor, endothelin, cyclin-dependent kinases (CDKs), peroxisome proliferator–activated receptor g (PPAR-g) and various chemokines. Chronic progressive nephropathy (CPN) is a wellinvestigated renal disease in aging rats characterized by basophilic tubular epithelium with conspicuously thickened basement membranes, tubules filled with proteinaceous casts, glomerulosclerosis, and, in later stages, adenomatous tubular epithelial hyperplasia (Figs. 1–6).3 CPN progresses relentlessly in Sprague-Dawley and F344 strains from a solitary basophilic tubule at around 8 weeks of age to ultimately involving the entire kidney, culminating in ESRD in rats typically over 18 months of age. End-stage CPN is also a risk factor for a marginal increase in the background incidence of renal tubule tumors. A number of factors, such as dietary manipulations, have been shown to significantly modify the expression of CPN. Among these, intervention by restriction of caloric intake is the most effective method for inhibiting the disease process. Reducing protein intake after the rapid growth phase in young rats also significantly reduces the incidence and severity of CPN. Exposure to some drugs (eg, aminoglycoside antibiotics) and chemicals is also associated with early onset or exacerbation of CPN in rodents, and sometimes super-imposition of AKI by nephrotoxicants along with background lesions of CPN can make renal safety assessment of new drug candidates challenging. Consequences of AKI superimposed on CKD are also recognized in human medicine as both share common risk factors.2 AKI can lead to CKD, and patients with CKD are at risk for the development of reductions in renal function consistent with acute renal injury. The mechanisms by which these acute effects may occur include preexisting alterations in renal hemodynamics, susceptibility to antihypertensive agents, and side effects of treatment with drugs such as diuretics and nephrotoxicants. As discussed above, age-related decrements in nephron number and renal function may also place older animals and humans at risk for acute renal injury. Thus, AKI and CKD are being recognized as interconnected syndromes and as risk factors for the development of ESRD and cardiovascular disease. Similar to humans, CKD is commonly reported in aging dogs and cats. For example, almost 50% of cats older than 15 years exhibit morphologic alterations consistent with CKD,

as characterized by varying degrees of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arteriopathy.1 These kidney lesions may be seen in association with neoplasia, pyelonephritis, polycystic kidney disease, and amyloidosis. Drugs, breed, and infections are considered risk factors. Unlike humans, diabetes mellitus is not a major contributor to kidney disease in cats. No microscopically detectable kidney lesions or clinically relevant renal function alterations have been reported in diabetic cats compared with the agematched controls.7 Overall, tubulointerstitial lesions are more common than those affecting glomeruli. The most common glomerular lesion is increased mesangial matrix, with comparable incidence and severity in diabetic and nondiabetic cats. This is in contrast to diabetic humans, who develop severe glomerulopathy with characteristic Kimmelstiel-Wilson nodules due to marked expansion of the mesangial matrix. Staging of CKD is very important to guide the type of treatment, potential response to treatment, and long-term prognosis. Staging by the International Renal Interest Society (IRIS) criteria is initially based on fasting serum creatinine levels followed by refinements to substages based on proteinuria and systemic blood pressure. However, the choice of interventional therapy or risk management strategy by IRIS staging alone can be challenging in the absence of knowledge of the nature and severity of structural damage to the renal parenchyma. In this issue of Veterinary Pathology, McLeland et al6 characterized morphologic alterations in kidneys from cats with CKD representing IRIS stages I to IV, in an attempt to bridge clinical parameters with renal pathology. Their data showed that the prevalence, severity, and nature of histologic changes in the interstitium, tubules, and glomeruli varied significantly among stages. Reversible kidney lesions were present throughout all stages of CKD, while irreversible lesions were more prevalent in later stages. Cortical scarring, tubular epithelial degeneration, and glomerulosclerosis were more common in stages III and IV, while cats with earlier stages had a relatively greater proportion of normal renal parenchyma. While fibrointimal proliferation in renal vessels was seen in CKD cats, there was no correlation with CKD stages. Similarly, vascular lesions were observed in both hypertensive and normotensive cats, questioning the role of vascular lesions in the pathogenesis of feline CKD. Another important observation by McLeland et al6 was the occurrence of focal segmental glomerulosclerosis (FSGS) in cats with higher stages of CKD. FSGS, although infrequently reported in veterinary medicine, is an important form of podocytopathy in humans. It is characterized by proteinuria, segmental thickening of the glomerular tuft and its adhesion to the Bowman’s capsule, and podocytopenia. Podocyte injury is an essential feature of progressive glomerular diseases, including direct damage by infectious agents such as human immunodeficiency virus and drugs such as bisphosphonates, doxorubicin, and immunotherapeutics.4 In preclinical safety studies, monkeys given immunomodulatory biotherapeutics also develop light microscopic and ultrastructural changes consistent with podocytopathy and FSGS. Doxorubicin is a well-

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Khan and Khan


Figures 1–6. Chronic progressive nephropathy (CPN), Sprague-Dawley rats. Figure 1. Cystic and granular surface of the kidney (arrows) in late stage of CPN. Figure 2. The hallmarks of CPN include focal tubular epithelial hyperplasia and thickened basement membrane (arrows). Hematoxylin and eosin (HE). Figure 3. Widespread peritubular (arrows) and glomerular fibrosis (asterisk), interstitial mononuclear cell infiltration, and dilated tubules filled with albumin-rich fluid. HE. Figure 4. Glomerular sclerosis (asterisks), thickening and splitting of basement membranes (arrows) of both Bowman’s capsules and tubules. Periodic acid–Schiff (PAS) reaction. Figure 5. Focal tubular epithelial hyperplasia (arrows). Figure 6. Adenomatous hyperplasia of the renal tubule in the late stage of CPN. HE. (Courtesy of Dr Xiantang Li, Pfizer Worldwide Research & Development, Groton, CT.) Downloaded from at TEXAS A&M UNIV TEXARKANA on August 29, 2015


Veterinary Pathology

known inducer of renal injury in rodents, which mirrors that seen in human CKD due to primary FSGS. Adriamycin induces injury to the glomerular filtration barrier, including podocytes, glomerular endothelial cells, the glycocalyx, and the glomerular basement membrane. On the basis of an evaluation of case histories, McLeland et al6 concluded FSGS in their cats was possibly secondary to progressive loss of renal mass rather than related to specific causes, such as drugs, feline parvovirus, or feline immunodeficiency virus.6 In summary, CKD is a multifactorial pathophysiologic process resulting in the progressive loss of nephron number and function, frequently culminating in ESRD. Thus, a thorough understanding of clinical parameters used in IRIS staging along with histologic assessment of CKD is important to aid in identifying potential causes and medical interventions. The study by McLeland et al6 characterized the incidence and severity of tubular epithelial degeneration, interstitial inflammation, fibrosis, and glomerulosclerosis in feline CKD, which correlated well with an increase in IRIS stages. Together, these data will help refine the therapeutic choice and risk management strategy for ESRD in feline CKD. Author Contribution Conception or design: NK, TK. Data acquisition, analysis, or interpretation: NK, TK. Drafting the manuscript: NK, TK. All authors participated in critically revising the manuscript, gave final approval, and agree to be accountable for all aspects of work to ensure integrity and accuracy.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Chakarabarti S, Syme HM, Brown CA, et al. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Vet Pathol. 2013;50(1):147–155. 2. Chawla L, Eggers PW, Star RA, et al. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371(1):58–66. 3. Hard GC, Khan KNM. A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol Pathol. 2004;32:171–180. 4. Khan KNM, Hard GC, Alden C. Kidney. In Rousseux C, Walig M, Haschek W, eds. Handbook of the Toxicologic Pathology. 3rd ed. New York, NY: Elsevier; 2013:1667–1764. 5. Khan KNM, Hard GC, Radi ZA. Renal toxicity. In: Wilson AGE, ed. New Horizons in Predictive Toxicology. Cambridge, UK: Royal Society of Chemistry; 2012:499–541. 6. McLeland SM, Cianciolo RE, Duncan CG, et al. A comparison of biochemical and histopathologic staging in cats with chronic kidney disease [published online December 16, 2014]. Vet Pathol. 7. Zini E, Benali S, Coppola L, et al. Renal morphology in cats with diabetes mellitus. Vet Pathol. 2014;51(6):1143–1150.

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Acute kidney injury and chronic kidney disease.

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