Ed Gane, M.D., F.R.A.C.P.

• Associate Professor
• Faculty of Medicine
• University of Auckland
• Consultant Hepatologist
• Liver Unit
• Auckland City Hospital
• Auckland, New Zealand

However medications on nclex rn purchase online topamax, it appears that neither condition represents a higher risk if renal function is normal symptoms at 4 weeks pregnant discount topamax uk. Whether dosage and route of administration are independent risk factors is a matter of debate medications not to take during pregnancy topamax 200 mg low price. Some studies found a significant correlation between the volume of administered contrast media and the degree of nephrotoxicity medications elavil side effects 200 mg topamax, particularly in patients with underlying renal disease such as diabetes mellitus and in the setting of reduced renal function symptoms vaginal yeast infection 100 mg topamax order amex. Dose may not be a significant risk factor in patients with normal renal function, but dosage as an independent risk factor has not been investigated in most published studies. An equation, to determine maximum acceptable Chapter 26 Ischemic and Toxic Acute Tubular Injury and Other Ischemic Renal Injuries 1175 contrast dose, 5-mL contrast volume × body wgt (kg)/baseline sCr (mg/dL), has been developed (157). Several recent studies confirm that exceeding this threshold increases the risk for contrast-induced nephropathy (158,159), at least in percutaneous coronary intervention studies. Following the introduction of nonionic (low-osmolality) contrast media, some studies suggested that such media are less nephrotoxic than the conventional ionic (highosmolality) contrast media. However, several prospective clinical studies comparing the nephrotoxic effect of low- and high-osmolality contrast media did not find differences in the incidence of nephrotoxicity (152). In contrast, patients with preexisting renal impairment receiving ionic contrast material were 3. Thus, it appears that the considerably cheaper conventional ionic contrast media can be safely used in patients with normal renal function, but ionic contrast media should be used with caution in those with preexisting renal insufficiency. However, in those receiving high contrast volume (163) or in diabetic patients (164), there may be a lower risk with the iso-osmotic agent. With appropriate supportive therapy, the majority of patients recover, but the mortality rate in some cohorts approaches 15% (166). Renal infarction is a rare complication; patients present with flank pain, fever, leukocytosis, elevated lactate dehydrogenase, and hematuria. Risk factors include preexisting renal impairment, particularly if it is caused by compromise of the afferent arteriolar blood supply, such as renal artery stenosis. These agents may also produce interstitial nephritis and are discussed in detail in Chapter 25. Botanical/herbal preparations are inconsistent in composition and effect and, in general, are poorly regulated (173). Adulteration of herbal preparations by dichromate may underlie toxicity in some cases. Fanconi syndrome has been described with Chinese herbs containing aristocholic acids or adulterated with cadmium (169). Urinary excretion of 2-microglobulin and other low molecular weight proteins is increased, and proximal tubular enzymuria has been described with aristocholate exposure (173­175). Cases caused by Takaout roumia (paraphenylenediamine) are often associated with rhabdomyolysis (176). Pathology of Acute Renal Failure/Acute Tubular Injury Gross Pathology At a gross level, as a result of extensive interstitial edema, the kidneys become enlarged and swollen. On cut section, the tissue bulges above the cut surface and has a flabby consistency. The outer medulla may appear as a deep red band, in contrast to the more pale cortex and papillary tip, the result of congestion of the vasa recta. Autopsy kidneys, even if optimally harvested and processed, often have major preservation artifacts, especially in tubules. Also, premortem ischemia induces tubular injury that is difficult to discern from a previous in vivo insult. Biopsy with rapid processing provides the best histologic preparation, although it has inherent sampling errors. Reactive changes in the proximal tubule extend from the tubular takeoff to involve these epithelial cells, which have marked increase in cytoplasm compared to normal quiescent cells. Morphologic changes of cellular injury are usually more subtle in the ischemic type, with more obvious cytopathologic changes in the toxic form. In the ischemic form, tubular damage is patchy, affecting relatively short lengths of the straight segments of the proximal tubule and focal areas of the ascending limbs of the loop of Henle. In the toxic form, the tubular epithelial damage is more extensive along segments of the proximal tubule; the degree of involvement of the segments varies with the specific toxin. In addition to differences in localization along nephron segments, different degrees of damage are visible between cortical and juxtamedullary nephrons. In the ischemic form, the S3 segments are most severely affected, along with focal areas of the ascending limbs of the loop of Henle. The cortical nephrons show more extensive damage than the juxtamedullary nephrons. Whereas mercury shows some predilection for the S3 segment, other heavy metals and organic toxins often show more extensive involvement of all nephron segments, also with a greater predilection for cortical nephrons. Injured cells have detached, leaving areas of tubular basement membrane covered by a thin layer of cytoplasm from adjacent cells (arrowheads). There are also interstitial edema and inflammatory cells largely marginating in capillaries. It is the relative prominence of these distal changes that gave rise to the term lower nephron nephrosis. The denuded basement membrane sections are covered by proliferating adjacent viable epithelial cells. There is some evidence that transdifferentiated tubular cells may contribute to fibrogenesis in later stages (182). As the lesion progresses after the initial injury, evidence of tubular regeneration can be seen. These results indicate that regeneration of injured tubule cells through proliferation of surviving tubule cells is the predominant mechanism of repair after ischemic injury (183). There may be a mild interstitial inflammatory infiltrate with small numbers of lymphocytes, macrophages, and neutrophils or, occasionally, eosinophils. The cellular infiltrate tends to be clustered around necrotic and ruptured segments of tubules or where Tamm-Horsfall protein has been extruded, forming small granulomas. Injured cells have detached from sites in proximal nephron and aggregate into casts, often around a protein core. It is possible to detect the nuclear and cytoplasmic condensation of cells undergoing apoptosis by light microscopy. Apoptotic bodies, representing membranebound nuclear fragments, may also be detected in adjacent tubular cells, which have engulfed these cell remnants. The cellular lesions are most prominent in the S3 segment of the proximal tubule and tend to be more uniform in character. Apical blebbing may be the only finding in milder forms, whereas the more severe cases also show focal necrosis with rupture of the tubular basement membrane. The cell has separated from the basement membrane but is still adherent to the adjacent epithelial cell through the cell-to-cell junctions. Lymphocytes are predominant in the first 24 to 48 hours, followed later by immature cells of the myeloid series and eventually by nucleated red cells and red cell precursors. The countercurrent nature of blood flow in the vasa recta would result in dilution of cellular elements as blood flows toward the hairpin turn, resulting in a concentration of cellular elements at the proximal end of the vasa recta vasculature in the outer medulla. There is also some evidence that up-regulation of adhesion molecules on ischemic endothelium leads to accumulation of leukocytes in the microvasculature, which may contribute to stasis and lack of reflow in ischemia-reperfusion injury (see section "The Inflammatory Response in Ischemic Injury"). Other potential injury markers in tissues are described below in the section on "Pathophysiology. However, a range of morphologic changes may be seen in the renal tubules as the result of toxic injury. The extent and severity of the changes will vary depending on the agent, the dose, and the timing of the morphologic assessment. Intracellular inclusions are occasionally seen in renal tubular cells exposed to drugs. Giant mitochondria, appearing as bright eosinophilic inclusions, have been described after the administration of relatively high doses of CsA to humans. Calcification of tubular cells has been described in cases of severe toxicity caused by amphotericin or bacitracin (205). Extensive coagulative necrosis of tubular cells has been seen in cases of poisoning by heavy metals such as mercuric chloride, rarely seen today, or in cases of poisoning due to chemicals such as diethylene glycol (206). It is clear that both necrosis and apoptosis occur in toxic nephropathies in experimental models as well as in clinical tubular injury (208,209). In vitro studies have documented apoptosis in cell culture on exposure to nephrotoxins. Our understanding of the role of apoptosis in the pathogenesis of toxic renal injury has evolved over the past decade. Taurine is one of the organic osmolytes, which have important antiapoptotic properties in the kidney (214). The antiapoptotic function of organic osmolytes in kidney cells is mediated through suppression of efflux of proapoptotic molecules, such as cytochrome c, from the mitochondria. Tubular casts, which may include cells and cell debris, are frequently seen with toxic tubular injury. In addition, tubular crystalline deposits are found in cases of renal toxicity produced by nephrotoxins. Anesthetic agents, including methoxyflurane and halothane, and antiretroviral agents such as indinavir may produce tubular crystalline deposits. Mechanical obstruction may also result from deposition of intratubular crystals in patients treated with sulfonamides or acyclovir. In addition, radiocontrast agents are uricosuric and oxaluric, and casts and birefringent crystals have been identified following administration of these agents. Uric acid lithiasis with tubular obstruction has been reported with phenylbutazone (215). Finally, pigmented casts may result from hemolysis in rare cases of fulminant drug reactions and with the rhabdomyolysis caused by cocaine. Vessels Vessels usually show no remarkable features unless there is intercurrent disease. However, newer studies in experimental models have refocused attention on injury to the microvasculature, which may have been underappreciated in clinical specimens. Certainly, vascular congestion in the outer medulla with margination has been noted. Electron Microscopy Electron microscopy of injured tubules reveals loss of brush border microvilli and basolateral infoldings in the proximal tubules. Cells may show rarefaction of the cytoplasm, with intracellular vacuoles and swollen organelles. Degenerative changes in mitochondria, including swelling and loss of cristae, loss of endoplasmic reticulum, or alterations in lysosomes, are often visible. Within the cells, membranebound structures consisting of concentrically arranged whorls of membrane may form, especially with exposure to aminoglycosides; however, these so-called myeloid bodies do not necessarily indicate toxicity. In general, we limit our discussion to those drugs for which toxicity has been well documented in humans by disappearance of toxic effects when the drug is withdrawn, recurrence of symptoms after readministration of the drug, or both. A range of chemotherapeutic agents and other toxins may produce direct injury to the renal tubular epithelium. The focus in this discussion is on primary toxic tubular injury, recognizing that secondary injury to the renal tubule may also occur with other types of toxic renal injury, including tubulointerstitial nephritis, hemodynamic changes, and vascular disease. Antibiotics There have been many reports of renal damage associated with antibiotic therapy. Some drugs are more nephrotoxic and can promote acute renal injury even with brief exposure. One such example is the aminoglycosides (especially neomycin), which are classic nephrotoxins. However, in many cases, there is an association, but the causative role of the antibiotic in the etiology of tubular injury cannot be firmly established. First, the infection for which the drug is being used may damage the kidney directly or indirectly. Second, infections are frequently treated with several agents, making it difficult to implicate a particular drug. Finally, the paucity of renal biopsy studies makes it difficult to define the pathologic changes produced by individual drugs and the pathogenetic mechanisms involved in producing renal injury. In other cases, there may be tubular dilation and tubular cell injury without detectable crystals in the urine or kidney (218); crystals, of course, might be missed if relatively few collecting ducts are sampled. Proximal tubular injury has been described, Pathology of Specific Nephrotoxins As a preface to this discussion, it should be recognized that it is often difficult to establish a pathogenetic link between a pathologic lesion and a particular drug or toxin. Several factors contribute to this uncertainty, including concurrent factors that may produce renal injury, such as administration of other potentially nephrotoxic drugs, lack of or inadequacy of morphologic data in reported cases, and the fact that some drugs may have multiple effects. On electron microscopy, alterations in mitochondria have been observed, with swelling and dysmorphic changes. Changes include variable mitochondrial size, with some small and rounded and others swollen with irregular contours, clumping, loss and disorientation of cristae, and focal marked reduction of mitochondria (61). Patchy interstitial inflammation has been described without crystals (222), and, occasionally, granulomas have been described. Renal tubular cell apoptosis has been detected in renal biopsy of a patient with irreversible cidofovir toxicity (223), and fibrosis and tubular atrophy have been described with tenofovir (61), with persistent renal dysfunction. Accumulation of high concentrations within lysosomes and release to the cell cytoplasm promotes phospholipid membrane rupture, oxidative stress, and mitochondrial injury. Tubulointerstitial inflammation with tubular necrosis also has been reported (225). Zager (226) has shown experimentally that gentamicin in a dose that does not by itself cause renal failure will trigger severe renal failure when combined with 1 hour of moderate renal hypoperfusion, which also does not produce renal failure on its own. In those studies, there was tubular necrosis in the S3 proximal tubule segment, a pattern of injury characteristic of renal ischemia rather than gentamicin toxicity; this suggests that in some instances, gentamicin may worsen ischemic injury rather than causing injury to the S1 and S2 segments, which is more typical of toxic doses of gentamicin (226). There are few descriptions of renal pathologic lesions in patients receiving kanamycin or tobramycin. In one patient with oliguria who received 21 g of kanamycin over a 2-week period (227), a renal biopsy was done 25 days after the onset of oliguria (21 days after diuresis) and was reported to show some flattening of tubular epithelial cells.

Bone infection would be accompanied by fever and systemic symptoms such as weakness symptoms vs signs safe 100 mg topamax. Mycobacterium tuberculosis rickets osteoporosis gout calcium treatment uterine cancer purchase 200 mg topamax amex, phosphate osteoblasts synovial myasthenia gravis gout calcium Chapter 17: Diseases and Disorders of the Integumentary System Answers to Cases for Critical Thinking 1 symptoms stroke purchase topamax 100 mg fast delivery. Impetigo is the diagnosis; Staphylococcus aureus or Streptococcus pyogenes are potential causes medications 377 topamax 100 mg on-line. Possible causes of the rash include tinea cruris medicine quiz discount topamax 100 mg on line, candidiasis, pediculosis, and scabies. Basal cell carcinoma or squamous cell carcinoma are possible diagnoses; treatment includes a visual examination and biopsy. Hormones, overproduction of sebum, bacteria, lack of or uneven exfoliation of skin cells. Treatment may include topical antibiotics and antibacterials, retinoid, oral antibiotics, oral contraceptives, and isotretinoin. Prevention of acne includes not overcleansing the skin, not using harsh scrubs, avoiding products with high concentrations of alcohol, and keeping the hands away from the face. False A-40 L Appendix C Interactive Exercises with herpetic lesions, or contact with skin that is shedding the virus. False Appendix D Prevention Plus Suggested Answers Chapter 1: Introduction to Disease Four Modifiable Risk Factors for Chronic Disease 1. Four modifiable risk factors for chronic disease are lack of physical activity, poor nutrition, tobacco use, and excessive alcohol consumption. Moderate alcohol consumption is defined as two drinks a day for men, one for women. The immune response takes from 10 days to 2 weeks to reach its peak because after initial exposure to the antigen, lymphocytes need to become activated, reproduce, and develop. You should get a vaccine appropriate for your destination at least 2 weeks before your trip. Many people in the United States are vaccinated against childhood illnesses such as measles, pertussis, and chickenpox. While in the United States, your relative should take the same precautions that you do to protect from infectious diseases. Chapter 4: Cancer Chapter 2: Immunity and Disease Epinephrine Treatment for Life-Threatening Allergic Reactions 1. Epineprhine is a prescription medication because it could be dangerous if injected when not suffering from a life-threatening allergic reaction. Injection of epinephrine into the thigh muscle offers the fastest systemic absorption. When suffering life-threatening anaphylaxis the speed at which epinephrine is absorbed is critical. If not absorbed quickly, the patient could die before adequate levels of epinephrine are achieved. A-41 A-42 í Appendix D Prevention Plus Suggested Answers Chapter 6: Diseases and Disorders of the Cardiovascular System Risk Factors for Coronary Heart Disease 1. Modifiable risk factors for coronary heart disease include diet, exercise, and smoking. While genetics may predispose a person for disease, that person can reduce risk by eliminating behavioral and environmental factors. Chapter 9: Diseases and Disorders of the Gastrointestinal System Bacteria, Coolers, and Food Poisoning 1. At cold temperatures the chemical reactions of metabolism slow down too much to sustain life. However, the cold temperature does not damage the bacterial cell, its molecules, or metabolic machinery, so when temperatures increase, bacteria can grow again. At extreme temperatures like those used for cooking food, heat destroys bacterial cells, their molecules, and metabolic machinery. Iron is required for the synthesis of hemoglobin, so vegetarians are at risk for developing irondeficiency anemia. Meat contains heme iron, which is more easily absorbed than nonheme iron found in plants. To obtain iron and B12, they need to eat a variety of fruits, beans, and vegetables. Beans also provide protein as do foods such as eggs, peanut butter, Greek yogurt, cottage cheese, and soy milk. Therefore the benefits of screening for colorectal cancer outweigh the risks after approximately age 50. Young people should be screened if they have a family history of colon cancer, familial polyposis, or if they exhibit signs and symptoms that suggest colon cancer. Workers in the food service industry must use sanitary procedures when handling food, including the simple task of washing their hands. Health care workers receive vaccination against hepatitis B, and blood is screened for contamination by hepatitis B and C. Chapter 8: Diseases and Disorders of the Respiratory System Appropriate Antiobiotic Use 1. Antibiotics affect bacteria, not viruses, so they are not an appropriate treatment for a viral infection. The influenza virus causes flu, so an antibiotic should not be taken to treat flu. Chapter 10: Diseases and Disorders of the Urinary System Chronic Kidney Disease 1. The thick and rigid arteries that develop with atherosclerosis reduce blood flow and filtration, thereby contributing to kidney disease. Appendix D Prevention Plus Suggested Answers í A-43 Chapter 11: Diseases and Disorders of the Reproductive System Self-Screening for Breast Cancer 1. A self-exam may detect something you think may be abnormal that should be checked in a clinical breast exam. A clinical breast exam is performed by a health care professional who is trained to recognize many different types of abnormalities and warning signs. This in-office exam will most likely be completed by your family physician or gynecologist at your annual visit. In addition to motorcycle riding, bicycling, skateboarding, rock climbing, snowboarding, and rollerblading all require head and neck protection. Repeated exposure to loud noises can destroy hair cells in the inner ear, leading to hearing loss. A tuning fork test can determine if there is a conduction problem due to an ear ossicle problem. Chapter 15: Mental Illness and Cognitive Disorders Exercise and Mental Disorders 1. Chapter 13: Diseases and Disorders of the Nervous System Head and Neck Injuries Are Preventable 1. Help convince a motorcycle rider to wear a helmet by explaining that motorcycle accidents are a leading cause of traumatic brain injury. Chapter 16: Diseases and Disorders of the Musculoskeletal System Bones, Joints, and Muscles Benefit from Exercise 1. Moderate exercise strengthens bones, joints, and muscles, maintaining flexibility. A person with arthritis will benefit from moderate low impact exercise such as walking, swimming, or bicycling. In the bronchi, smooth muscle is arranged in a spiral fashion internal to the cartilaginous plates. The muscle coat becomes more complete distally as the cartilaginous plates become more fragmentary. The cilia beat with a whip-like action, and waves of contraction pass in an organised fashion from cell to cell so that material trapped in the sticky mucus layer above the cilia is moved upwards and out of the lung. Larger bronchi also have acinar mucus-secreting glands in the submucosa, which are hypertrophied in chronic bronchitis. There is a potential space between the alveolar cells and the capillary basement membrane, which is only apparent in disease states, when it may contain fluid, fibrous tissue or a cellular infiltrate. This results in narrowing of the lumen, which increases the shearing force from the moving air on the mucus lying on the tracheal walls. The trachea divides into the right and left main bronchi at the level of the sternal angle (angle of Louis). The left main bronchus is longer than the right and leaves the trachea at a more abrupt angle. The right main bronchus is more directly in line with the trachea, so that inhaled material tends to enter the right lung more readily than the left. Bronchi are airways with cartilage in their walls, and there are about 10 divisions of bronchi beyond the tracheal bifurcation. Smaller airways without cartilage in their Lung perfusion the lungs receive a blood supply from both the pulmonary and the systemic circulations. The pulmonary artery arises from the right ventricle and divides into left and right pulmonary arteries, which further divide into branches accompanying the bronchial tree. The pulmonary capillary network Respiratory Medicine Lecture Notes, Ninth Edition. The pulmonary venules drain laterally to the periphery of lung lobules and then pass centrally into the interlobular and intersegmental septa, ultimately joining together to form the four main pulmonary veins, which empty into the left atrium. Several small bronchial arteries usually arise from the descending aorta and travel in the outer layers of the bronchi and bronchioles, supplying the tissues of the airways down to the level of the respiratory bronchiole. Pneumocytes and endothelial cells rest upon thin continuous basement membranes, which are not shown. The pulmonary circulation normally offers a much lower resistance and operates at a lower perfusion pressure than the systemic circulation. The pulmonary capillaries may be compressed as they pass through the alveolar walls if alveolar pressure rises above capillary pressure. To inspire, the strong muscular sheet contracts, stiffens and tends to push Inspiration Physiology the core business of the lungs is to bring oxygen into the body and to take carbon dioxide out. The movement of air in and out of the lungs (between the outside world and the alveoli). The exchange of oxygen and carbon dioxide between the airspace of the alveoli and the blood. This process continues throughout life, largely unconsciously, coordinated by a centre in the brain stem. These forces include the inherent elastic property of the lungs and the resistance to airflow through the bronchi (airway resistance). Diagram of the ribcage, abdominal cavity and diaphragm showing the position at the end of resting expiration (a). The diaphragm meets a variable degree of resistance to downward discursion, which forces the lower ribs to move up and outward to accommodate its new position. This can sometimes be observed radiographically in the context of a complete pneumothorax (see Chapter 16). Breathing at close to this lung volume (normal tidal breathing) is therefore relatively efficient and minimises work. It is rather like gently stretching and relaxing a spring from its neutral, tension-free position. Breathing then is rather like stretching and relaxing a spring that is already under a considerable degree of tension. The work of breathing is therefore increased, a factor that contributes to the sensation of breathlessness. Test this yourself: take a good breath in and try to breathe normally at this high lung volume for a minute. The natural tendencies for the chest wall to spring outwards and the lung to contract down present opposing forces, which generate a negative pressure within the pleural space. Clearly, at higher lung volumes, the lung is at greater stretch and a more negative pleural pressure is required to hold it in position. There is variable resistance to this downward pressure by the abdomen, which means that in order to accommodate the new shape of the diaphragm, the lower ribs (to which it is attached) also move upwards and outwards. In such circumstances, there is an involuntary limitation to the downward excursion of the diaphragm and, as the potential for upward movement of the ribs is limited, the capacity for full inspiration is diminished. This inability to fully inflate the lungs is an example of a restrictive ventilatory defect (see Chapter 3). Electromyographic studies, however, have demonstrated that these muscles are active even in quiet breathing, although less obviously so. They therefore transfer the effects of actions on the upper or lower ribs to the whole rib cage. They also brace the chest wall, resisting the bulging or in-drawing effect of changes in pleural pressure during breathing. This bracing effect can be overcome to some extent by the exaggerated pressure changes seen during periods of more extreme respiratory effort, and in slim individuals intercostal recession may be observed as a sign of respiratory distress. Whilst inspiration is the result of active muscular effort, quiet expiration is a more passive process. The inspiratory muscles steadily release their contraction and the elastic recoil of the lungs brings the tidal breathing cycle back to its start point. Forced expiration, however ­ either volitional or as in coughing, for example ­ requires muscular effort. Airway resistance In addition to overcoming the elastic properties of the lungs and the chest wall, during active breathing the muscles of respiration also have to overcome the frictional forces opposing flow up and down the airways. Left to its own devices, a lung would tend to shrink to little more Site of maximal resistance It is generally understood that resistance to flow in a tube increases sharply as luminal radius (r) decreases (with laminar flow, resistance is inversely proportional to r4). In both subjects A and B, we see that lung compliance ­ the change in lung volume per unit change in intrapleural pressure (or slope of the curve) is reduced at higher lung volumes.

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In patients with both 1- and 5-year protocol biopsies medicine woman dr quinn buy generic topamax online, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts treatment integrity topamax 100 mg buy lowest price. These results in the recent era of transplantation demonstrate fewer medications held for dialysis buy discount topamax 100 mg online, less severe gas treatment topamax 200 mg purchase without prescription, and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported (735) medicine of the people generic 200 mg topamax with mastercard. In a large European multicenter study with 551 protocol biopsies from crossmatch-negative patients, 4. C4d was associated with retransplants and inflammation in peritubular and glomerular capillaries, similar to the C4d associations in indication biopsies. However, C4d had no immediate impact on allograft survival during the time of observation (approximately 1 year). Further follow-up and correlations with circulating antibody will be needed to interpret the clinical significance of "incidental" C4d deposition. In one instance, endarteritis was present in a protocol biopsy, and the patient developed clinically evident rejection 3 days later (736). We have seen only three cases in which endarteritis was present in a biopsy with no clinical evidence of rejection at the time of biopsy or later. The findings are significantly different in protocol biopsies from presensitized patients undergoing transplantation after desensitization. A total of 54% of patients had variation of C4d score between 3 months and 1 year posttransplant. Cumulative (3 months + 1 year) C4d scores correlated with long-term renal function worsening. Intratubular calcium oxalate crystals were found in 52% of biopsies in the first 3 months and were associated with prior acute tubular injury, graft dysfunction, and decreased 10-year graft survival (50% vs. Tubular calcification with high parathormone levels predicted inferior graft function 1 year after transplantation (740). Surrogate Endpoints Protocol biopsies have also been used to predict outcome, with the potential benefit of shortening the follow-up time needed to evaluate efficacy in drug trials (742,743). Candidates for an early surrogate marker of long-term graft survival rely on protocol biopsies at a time relatively close to transplant, that is, 3 to 6 months. One example of this approach is the finding that patients who had early withdrawal of steroids had increased interstitial fibrosis at 12 months (745). In an analysis from the Mayo Clinic, two groups of kidney transplant recipients were compared: In the first (n = 245), tacrolimus levels were significantly higher than in the second (n = 330). The recipient and donor demographics were not statistically different between the two groups. It should be emphasized that the outcome of a graft is not predetermined by early events alone, but is also influenced by subsequent events that are not always predictable, such as noncompliance, drug toxicity, infections, and recurrent or de novo diseases (743). Routine biopsies at late intervals (1 to 5 years) are recommended in investigative therapeutic trials, since the pathologic lesions may be silent, and the risk of protocol biopsies is minimal (73,747). Using microarrays and pathogenesis-based transcript sets on protocol biopsies taken 6 weeks posttransplantation confirmed quantitative differences and qualitative similarities between subclinical and clinical rejection episodes. Furthermore, several genes with transporter and metabolic functions showed decreased expression in the progressors in the 3-month biopsies. Similar findings are described from microarray analysis of sequential protocol biopsies taken at 1, 3, and 12 months posttransplantation (751). Changes in gene expression predated histologic damage, suggesting a possible adjunct role in early diagnostic testing. Transcripts associated with the immune response peaked at 1 month, while fibrotic expression at 3 months, injury and remodeling, and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Injury-repair and remodeling genes were expressed before interstitial fibrosis was observed by histology. Long-lasting apoptosis of graft-infiltrating T cells occurred, which may have contributed to the limitation of the immune response. Foxp3+ cells have also been detected in accepted grafts in humans and mice (20,322,327). On the other hand, Foxp3+ cells have also been observed in human grafts with acute cellular rejection. Thus, the significance of Foxp3+ cells is still not fully determined; it is possible that high numbers of such Treg cells are beneficial, in view of their known regulatory functions. Accommodation Accommodation, Acceptance, and Tolerance Acute rejection episodes become less frequent with time, for largely unknown reasons. Graft acceptance probably involves events in the graft and changes in the immune response. It has been hypothesized that events in the graft are critical to the development of tolerance. Not all infiltrates in the graft lead to graft injury, and some may actually promote acceptance. Individual patients can have biopsies that meet the histologic criteria for rejection, yet remain stable for 6 months even without increased immunosuppression (752). Grafts in animals that are developing tolerance typically have graft infiltrates, which has been termed the "acceptance reaction" (753). In certain class I disparate murine and pig renal allografts, the intense infiltrate spontaneously disappears and is followed by indefinite graft survival (754,755). For example, grafts from recipients with donor-reactive alloantibodies are considered to show complete accommodation if they show no pathologic changes, such as interstitial fibrosis, glomerulopathy, or arteriopathy. At a cellular level, accommodation may occur via multiple mechanisms, including internalization, down-regulation, inactivation, or inhibition of the target antigen. Endothelial Repopulation One of the proposed mechanisms for accommodation is the replacement of donor endothelium by recipient cells. This has been documented in human organ allografts, but recipient endothelial repopulation is neither common nor predictable. In human renal allografts, 8% had detectable, focal recipient endothelium, as judged by the development of Barr bodies in male to female kidney transplants (762). The Barr body technique is limited, because not all sections are in the right plane and the interpretation is difficult. These data suggest that endothelium damaged by vascular rejection is repaired by circulating cells from the recipient. Biopsy taken 18 months after transplantation, with over a year off all immunosuppression. While this can be done predictably in rodents, it has been achieved only sporadically in patients (768,769). In patients, the term "operational tolerance" is preferred, because proof of tolerance by rechallenge with donor and third-party grafts cannot be done. A great need is an assay that will predict a state of operational tolerance, to guide immunosuppressive reduction. The most promising at the time of writing is induction of mixed chimerism, using bone marrow cells from the kidney donor and nonmyeloablative treatment that spares the recipient marrow (770­773). Stable, fully chimeric recipients of bone marrow transplants have successfully been transplanted years later with kidneys from the same donor without immunosuppression (774) or the converse (769). Stem cell transplant combined with a kidney transplant from the same donor has also reported to be successful in short-term pilot studies (21). Mixed chimerism protocols are being refined in nonhuman primates, with the expectation that a combination of costimulatory blockade and other measures might make this approach work, even after an organ has been transplanted under conventional immunosuppression (776). Recently, two large consortia from Europe and North America reported independently a B-cell signature in peripheral blood as specific for operational tolerance. In a collaborative study in the United States, tolerant subjects showed increased expression of multiple B-cell differentiation genes, and a set of just three of these genes distinguished tolerant from nontolerant recipients. Thus, noninvasive testing for this signature may allow in the future more tailored immunosuppression in the individual patients avoiding the side effects of over-immunosuppression in some and inappropriate withdraw of immunosuppression in others. However, none of these studies were designed to predict who could safely go off immunosuppression. This highlights the delicate balance between over- and under-immunosuppression in transplant patients. While the initial pathogenesis is usually acute ischemic injury, numerous other causes may contribute such as drug toxicity and rejection. Therefore, if allograft function remains poor posttransplantation, a diagnostic biopsy is indicated to render a specific diagnosis. The changes associated with ice storage include endothelial swelling and vacuolization with obliteration and collapse of glomerular capillary lumens (791). In addition, intraglomerular fibrin thrombi, for example, in the setting of a disseminated intravascular coagulopathy in the donor, may contribute to delayed function; however, they did not predict poor outcome (114), presumably due to rapid lysis by the normal host fibrinolytic system. Ischemic tubular injury is commonly associated with nonisometric tubular cell vacuolization. Changes can be most prominent in the vasa recta of the outer medulla and increase over the first days postgrafting. Also, the cumulative 1-year incidence of biopsy-proven clinical and subclinical rejection was not different between the groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. Arteries, arterioles, and glomeruli typically only show minor "nonspecific" abnormalities (788). Proliferation in proximal tubular epithelium is higher in transplanted kidneys (8. Intratubular cellular debris and scattered neutrophils may be found that resembles acute pyelonephritis. In cases of pyelonephritis, however, the neutrophil casts are typically densely packed, and neutrophils are additionally found in the adjacent interstitium. Whether a molecular marker profile in patients suffering from ischemic injury can help as an adjunct prognostic tool to histology remains to be shown. New treatment strategies for ischemia-reperfusion injury include antioxidants as well as anti-inflammatory drugs (785). Cyclosporine (cyclosporine A, CsA, Neoral) increased 1-year deceased donor kidney graft survival from less than 60% to more than 80% during the decade of its clinical introduction in the 1980s (799). The peptide was relegated to obscurity as a mediocre antifungal agent until the screening system of Jacques Borel documented its potent immunosuppressive activity in 1976 (801). Clinical trials were soon reported by Calne, Powles, and colleagues in kidney and bone marrow transplant recipients (802,803). The results confirmed the promising animal studies; however, high doses of CsA (20 mg/kg/d) caused profound oliguric renal failure (803,804). Over the years, CsA drug preparations, as well as dosing and monitoring protocols, have undergone significant adaptations (805). It was introduced into clinical transplantation in the early 1990s as an alternative to CsA. Tacrolimus does not share any structural similarities with CsA, but it has similar therapeutic mechanisms and toxicity. Tacrolimus is favored by many because it seems to reduce the incidence of acute rejection episodes, and it has a lower incidence of hirsutism and gingival hyperplasia (806­808). Both CsA and tacrolimus have the same nephrotoxic side effects with indistinguishable histologic lesions primarily involving tubules, arterioles, and glomeruli (739,808,809). Under modern therapeutic regimens, classical signs of toxicity have dramatically decreased. Nephrotoxicity also occurs in native kidneys of patients treated with CsA or tacrolimus, such as recipients of heart or bone marrows or patients with autoimmune diseases (810). We will modify his terms to "calcineurin inhibitor­induced" arteriolopathy and glomerulopathy, since they also apply to tacrolimus. Functional toxicity is typically not associated with any characteristic morphologic changes and is fully reversible (815). Often, allograft biopsies display a normal architecture, and the diagnosis of "functional toxicity" is made by exclusion. Mild forms are without great clinical significance; they are fully or partially reversible on dose reduction. Tubules and the interstitial compartment also show pathologic lesions, but these are of only limited diagnostic use. Note the "string of pearl"-like arrangement of hyaline nodules along the adventitial aspect in some arterioles (arrowheads in A); figure (B) shows an example with very severe transmural and circumferential hyaline accumulations. In contrast, ordinary hypertension-induced arteriolosclerosis (C) typically demonstrates subendothelial hyaline deposits (asterisk) surrounded by (sometimes atrophic) medial smooth muscle cells. The patient clinically presented on day 11 after transplantation with new onset anuria and anemia. The graft biopsy shows fibrin thrombi in glomerular capillaries and arterioles at the glomerular vascular poles. Renal function in the patient remained stable with a serum creatinine level of 1 mg/dL 7 months postgrafting. Peripheral glomerular capillary walls show segmental duplication (arrowheads in A, B, and C) without conspicuous cell interposition that is only occasionally seen (short arrow in A). Superimposed on the toxic glomerulopathy is segmental tuft sclerosis (C) interpreted to be a secondary phenomenon. Although typically the entire cytoplasm of an affected tubular cell is densely packed with equal size vacuoles, they can be less abundant in the early phase of toxic injury. Under current therapeutic dose regimens, cytoplasmic vacuolization most often involves only scattered proximal tubules with predominance of the straight portion (818); the convoluted portion and parietal epithelial cells lining the Bowman space are only infrequently affected. Tubular epithelial cells with isometric vacuolization suggestive of toxic tubulopathy can occasionally also be found in urine cytology specimens (819,820). Giant mitochondria, typically one per cell, are heterogeneously distributed in tubules and are characteristically absent in epithelial cells with isometric toxic vacuolization. Dystrophic microcalcifications (often not bigger than a tubular cell) can occasionally be found scattered throughout the nephron. Interstitium In acute toxicity, the interstitium is often normal and lacks inflammation or edema. If marked mononuclear inflammatory cells, tubulitis, and marked peritubular capillaritis are found, a concurrent acute rejection episode has to be considered.

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