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L. Lester, M.B.A., M.D.

Professor, Medical College of Georgia at Augusta University

This can be seen as granular, bumpy deposits by immunofluorescence within the basement membranes of the glomeruli. Linear fluorescence, on the other hand, is seen in primary antiglomerular basement membrane disease, in which antibodies are directed against the 372 Pathology glomerular basement membrane itself. Plasma cell interstitial nephritis is seen in immunologic rejection of transplanted kidneys. The presence of red blood cell casts in the urine nearly always indicates that there has been glomerular injury but is not specific for any given cause. Thickening of the glomerular basement membrane caused by subepithelial immune deposits is seen in membranous glomerulonephritis. While the morphology of membranous glomerulonephritis is different from that of nephritis caused by circulating antigen-antibody complexes (immune complexes), there are similarities in the pathogenesis in that both disorders may be a consequence of or exist in association with infections such as hepatitis B, syphilis, or malaria. Other causes of membranous glomerulonephritis include reactions to penicillamine and gold, and certain malignancies such as malignant melanoma. This peculiar entity presents clinically as insidious nephrotic syndrome, characteristically occurring in younger children but also seen in adults (rarely), with hypoalbuminemia, edema, hyperlipidemia, massive selective proteinuria, and lipiduria (lipoid nephrosis). These polyanions normally block the filtration of the small but negatively charged albumin molecules. These patients have no tendency to develop chronic renal failure, and they respond to steroid therapy. The glomeruli are known for their rather normal appearance on light microscopy-at worst, there is mild and focal sclerosis. The podocytes may revert to normal (with steroid immunosuppressive therapy), or the foot process attenuation may persist to some extent, in which case the proteinuria also persists. In the late stages of the disease, the process may become diffuse, affecting most or all glomeruli. Initially, the process is also segmental, involving some but not all of the lobules within an individual glomerular tuft. Electron microscopy shows increased mesangial matrix and dense granular mesangial deposits. Immunofluorescence typically shows granular mesangial fluorescence for IgM and C3. The process is much less responsive to steroids and is much more prone to progress to chronic renal failure. These diseases have similar names and findings, which makes them easily confused with each other. This finding can be documented by the presence of protein in a dipstick examination of the urine. This illness typically occurs 1 to 3 weeks after a group A -hemolytic streptococcal infection of the pharynx or skin, such as impetigo or scarlet fever. Patients develop hematuria, red cell casts, 374 Pathology mild periorbital edema, and increased blood pressure. Electron microscopy reveals the mesangial deposits and large, hump-shaped subepithelial deposits in peripheral capillary loops that are characteristic. Immunofluorescence shows granular deposits containing IgG, C3, and often fibrin in glomerular capillary walls and mesangium. Children with poststreptococcal glomerulonephritis usually recover, and therapy is supportive only. In both types there is mesangial proliferation accompanied by thickening of the glomerular basement membranes, and a special finding that often supports the diagnosis of membranoproliferative glomerulonephritis is the presence of actual splitting of the glomerular basement membranes. The hematuria may become recurrent, with proteinuria that may approach nephrotic syndrome proportions. A small percentage of patients may progress to renal failure over a period of years. There are focal interruptions of the glomerular basement membrane as well, along with deposits of fibrin, as seen with electron microscopy. The pathogenesis of this same lesion in diabetes mellitus and renal vein thrombosis is unknown. Electron-dense deposits are classically seen in a subendothelial position on the glomerular basement membrane but may be subepithelial as well in some cases. This can be quite variable, however, and certain causes may be associated with damage to specific portions of the kidney. Both ischemia and heavy metals primarily damage the epithelial cells of the proximal straight tubules, while aminoglycosides primarily affect the proximal convoluted tubule.

These polyols result in disturbed processing of normal intermediary metabolites leading to complications of diabetes. Excessive oxygen free radicals In hyperglycaemia, there is increased production of reactive oxygen free radicals from mitochondrial oxidative phosphorylation which may damage various target cells in diabetes. Both types of diabetes mellitus may develop complications which are broadly divided into 2 major groups: I. Clinically, the condition is characterised by anorexia, nausea, vomitings, deep and fast breathing, mental confusion and coma. Thrombotic and bleeding complications are frequent due to high viscosity of blood. It may result from excessive administration of insulin, missing a meal, or due to stress. Atherosclerosis Diabetes mellitus of both type 1 and type 2 accelerates the development of atherosclerosis. Consequently, atherosclerotic lesions appear earlier than in the general population, are more extensive, and are more often associated with complicated plaques such as ulceration, calcification and thrombosis. The possible ill-effects of accelerated atherosclerosis in diabetes are early onset of coronary artery disease, silent myocardial infarction, cerebral stroke and gangrene of the toes and feet. Gangrene of the lower extremities is 100 times more common in diabetics than in non-diabetics. Diabetic microangiopathy Microangiopathy of diabetes is characterised by basement membrane thickening of small blood vessels and capillaries of different organs and tissues such as the skin, skeletal muscle, eye and kidney. Diabetic nephropathy Renal involvement is a common complication and a leading cause of death in diabetes. Four types of lesions are described in diabetic nephropathy: i) Diabetic glomerulosclerosis which includes diffuse and nodular lesions of glomerulosclerosis. Diabetic neuropathy Diabetic neuropathy may affect all parts of the nervous system but symmetric peripheral neuropathy is most characteristic. There are 2 types of lesions involving retinal vessels: background and proliferative. Infections Diabetics have enhanced susceptibility to various infections such as tuberculosis, pneumonias, pyelonephritis, otitis, carbuncles and diabetic ulcers. This could be due to various factors such as impaired leucocyte functions, reduced cellular immunity, poor blood supply due to vascular involvement and hyperglycaemia per se. In symptomatic cases, the diagnosis is not a problem and can be confirmed by finding glucosuria and a random plasma glucose concentration above 200 mg/dl. The severity of clinical symptoms of polyuria and polydipsia is directly related to the degree of hyperglycaemia. In asymptomatic cases, when there is persistently elevated fasting plasma glucose level, diagnosis again poses no difficulty. More sensitive and glucose specific test is dipstick method based on enzyme-coated paper strip which turns purple when dipped in urine containing glucose. Renal glucosuria: After diabetes, the next most common cause of glucosuria is the reduced renal threshold for glucose. Renal glucosuria is a benign condition unrelated to diabetes and runs in families and may occur temporarily in pregnancy without symptoms of diabetes. Alimentary (lag storage) glucosuria: A rapid and transitory rise in blood glucose level above the normal renal threshold may occur in some individuals after a meal. A characteristic feature is that unusually high blood glucose level returns to normal 2 hours after meal. Ketonuria Tests for ketone bodies in the urine are required for assessing the severity of diabetes and not for diagnosis of diabetes. Whole blood or plasma may be used but whole blood values are 15% lower than plasma values. A grossly elevated single determination of plasma glucose may be sufficient to make the diagnosis of diabetes. A fasting plasma glucose value above 126 mg/dl (>7 mmol/L) is certainly indicative of diabetes. Blood and urine specimen are collected at half-hourly intervals for at least 2 hours.

IgG antibodies against platelets is the pathophysiology of idiopathic thrombocytopenic purpura, which is characterized by thrombocytopenia leading to mucosal or skin bleeding, purpura or petechiae, and epistaxis. In children it has an acute onset after a viral infection, whereas in adults it has a gradual onset and often follows a viral infection or the administration of a new drug (eg, sulfa drugs). The patient is experiencing a metabolic acidosis, but there is also a simultaneous respiratory alkalosis. If the patient were experiencing metabolic acidosis with respiratory compensation, given the bicarbonate level of 7 mEq/L, we would expect to see a partial pressure of carbon dioxide of 16. This patient is acidotic, and her bicarbonate level is low, so we know this is a metabolic acidosis, not a respiratory acidosis or metabolic alkalosis. The patient is experiencing a respiratory alkalosis, but there is also a simultaneous metabolic acidosis. Sarcoidosis is characterized by immune-mediated noncaseating granulomas and also produces restrictive lung pathology. Asthma is a characteristic obstructive respiratory disease caused by airway hyperreactivity. Emphysema is an obstructive respiratory disease caused by alveolar destruction and airway collapse, whereas Goodpasture syndrome produces a restrictive lung disease. Kartagener syndrome leads to bronchiectasis, a disease with obstructive pathology due to immotile cilia and impaired mucociliary clearance of particles from the lung. Renal prostaglandins are produced in response to increased sympathetic activity and act to preferentially vasodilate afferent arterioles. Other appropriate medications that could be administered under these conditions would be neuroleptic agents (to control the agitation and psychotic symptoms) and diazepam (to control possible seizures). Atropine is a muscarinic antagonist that would be appropriate therapy for overdose of an acetylcholinesterase inhibitor. A patient presenting with acetylcholinesterase inhibitor overdose would have miotic pupils and bradycardia. The clinical features of acute benzodiazepine intoxication include slurred speech, lack of coordination, unsteady gait, and impaired attention or memory. Naloxone is an opioidreceptor antagonist that would be appropriate therapy for an opiate overdose such as with heroin or morphine. A patient who presents with opioid overdose would appear sleepy, lethargic, or comatose, depending on the degree of overdose. Blood pressure and heart rate are typically decreased, and respiration would be depressed. Physostigmine is an acetylcholinesterase inhibitor that might be used for an antimuscarinic drug overdose, such as with atropine, scopolamine, or Jimson weed. The hyperthermia seen with an antimuscarinic overdose is accompanied by hot and dry skin (due to blockade of cholinergic receptors present on sweat glands); however, stimulant overdose is associated with profuse sweating. This child most likely has retinoblastoma, a rapidly progressive neoplastic growth in the retina. Retinoblastoma may present in one eye, as in this patient, or bilaterally, as in approximately 30% of cases. The clinical vignette does not allude to any family history, in which case the retinoblastoma is called sporadic, in contrast with the familial form, which is associated with a family history. A second hit to any retinoblast will result in cancer, making it more likely that multiple tumors will occur. This is a rare event, therefore tumors are typically solitary and more often occur later in life. Note that monoclonal antibodies may be triggering, depleting, or blocking, and therefore it is absolutely necessary to characterize which of these effector functions they elicit, as those three scenarios would have three very different therapeutic applications. It is characterized by pink or flesh-colored pearly papules found in sun-exposed areas; the papules are locally invasive but usually nonmetastatic. Areas of palisading nuclei, or small fusiform cells with little cytoplasm and hyperchromic dense nuclei, are characteristic of the disease.

These changes are predominantly the result of altered plasma protein or tissue binding or of volume expansion secondary to reduced renal sodium and water excretion. The plasma concentration of the principal binding protein for several basic drug compounds, 1-acid glycoprotein, is increased in kidney transplant patients and in hemodialysis patients. The increase in unbound fraction, to values as high as 20% to 25% from the normal of 10%, results in increased hepatic clearance and decreased total concentrations. Therefore the maintenance of therapeutic unbound concentrations of 1 to 2 mcg/mL provides the best target for individualizing phenytoin therapy in patients with reduced kidney function, and the optimal approach to management relies on the measurement of unbound phenytoin serum concentrations. The absolute amount of digoxin bound to the tissue digoxin receptor is reduced, and the resultant serum digoxin concentration observed after the administration of any dose is greater than expected. Monitoring of unbound drug concentrations is suggested for drugs that have a narrow therapeutic range, those that are highly protein bound (>80%), and those with marked variability in the bound fraction. Alterations in the function of and interactions between metabolic enzymes and transporters can significantly affect the pharmacokinetic disposition and, correspondingly, patient exposure to drugs that are cleared via nonrenal pathways. Similarly, functional expression of several intestinal and hepatic transporters is altered in experimental models of kidney disease. These studies must be interpreted with caution, however, because concurrent drug intake, age, smoking status, and alcohol use were often not taken into consideration. For these reasons, prediction of the effect of reduced kidney function on the metabolism and/ or transport of a particular drug is difficult, and a general quantitative strategy to adjust dosage regimens for drugs that undergo extensive nonrenal clearance has not yet been proposed. However, some qualitative insight may be gained if one knows which enzymes or transporters are involved in the clearance of the drug of interest and how those proteins are affected by a reduction in kidney function. And the P-gp transport system in the kidney is involved in the secretion of cationic and hydrophobic drugs. The importance of an alteration in kidney function on drug elimination usually depends on two variables: (1) the fraction of drug normally eliminated by the kidney unchanged and (2) the degree of kidney functional impairment. There are a few drugs for which a metabolite is the primary active entity; in that situation, a key variable is the degree of renal clearance of the metabolite. However, urine is difficult to collect accurately in most clinical settings, and the interference of many commonly used medications with creatinine measurement limits the utility of this approach. Second, when presented with various kidney function estimates that potentially translate into different drug dosing regimens, clinicians should choose the regimen that optimizes the risk-benefit ratio given the patientspecific clinical scenario. For drugs with a narrow therapeutic range, typically more conservative kidney function estimates and corresponding doses should be used, particularly if therapeutic drug monitoring is not readily available. Third, when estimating equations are not expected to provide accurate measures of kidney function. All of these methods are extremely poor predictors of kidney function in individuals with liver disease, and their use is not recommended for such patients. Most dosage adjustment references have proposed the use of a fixed dose or interval for patients with a broad range of kidney function. Each of these categories encompasses a broad range of kidney function, and the calculated drug regimen may not be optimal for all patients within that range. The principal means to achieve this goal is to decrease the dose or prolong the dosing interval. If the dose is reduced and the dosing interval is unchanged, the desired average steady-state concentration will be near normal; however, the peak will be lower and the trough higher. Alternatively, if the dosing interval is increased and the dose remains unchanged, the peak, trough, and average concentrations will be similar to those in the patients with normal kidney function. This interval adjustment method is often preferred, because it is likely to yield significant cost savings as the result of less frequent drug administration. Whenever feasible, plasma drug concentration monitoring for certain drugs such as aminoglycosides and vancomycin is highly recommended. Dosing recommendations are available for many agents, especially those with a wide therapeutic index. However, for those drugs with a narrow therapeutic index, individualization of the drug therapy regimen is highly recommended based on prospective serum concentration monitoring. Although many new hemodialyzers have been introduced in the past 15 years and the average delivered dose of hemodialysis has increased, the effect of hemodialysis on the disposition of a drug is rarely reevaluated after its initial introduction to the market.