By N. Benito. University of Texas Health Science Center at Houston.

Renal com plications are frequent order nicotinell 35mg mastercard, and IM M UNODEFICIENCY VIRUS INFECTION these rates are expected to increase as patients with H IV live longer generic nicotinell 52.5 mg on line. M any renal diseases are incidental and are the consequences of opportunistic infections 35mg nicotinell with mastercard, neoplasm s, or the treatm ent of these Acid-base and electrolyte disturbances infections and tum ors. The renal diseases include a variety of acid- Acute renal failure base and electrolyte disturbances, acute renal failure having various causes, specific H IV-associated nephropathies, and renal infections Human immunodeficiency virus–associated nephropathies and tum ors. Renal infections and tumors FIGURE 7-17 PATHOGENESIS OF HYPONATREM IA IN PATIENTS H yponatrem ia pathogenesis in AIDS. Single and m ixed acid-base W ITH ACQUIRED IM M UNODEFICIENCY SYNDROM E disturbances, as well as all types of electrolyte disorders, can be observed in patients with AIDS. These disturbances and disorders develop spontaneously in patients with com plications of AIDS or Hypovolemia follow pharm acologic interventions and usually are not associated Tubular dysfunction with structural lesions in the kidneys unless renal failure also is present. Hyponatremia is the most prevalent electrolyte abnormality, Mineralocorticoid deficiency occurring in 36% to 56% of patients hospitalized with AIDS Syndrome of inappropriate antidiuretic hormone [118–122]. In euvolem ic patients, hyponatrem ia is com patible with nonosm olar inappropriate secretion of antidiuretic horm one [120,121,126]. H yponatrem ia in patients with hypervolem ia is dilutional in origin as a result of excessive free water intake in a context of renal insufficiency [122]. H ypernatrem ia m ay be TREAT ACQUIRED IMMUNODEFICIENCY SYNDROME the result of drug-induced diabetes insipidus. H yperkalem ia can occur in 16% to 24% of patients with AIDS, even in the absence of renal insufficiency. H ypokalem ia is associated with tubular Hypernatremia: foscarnet, rifampin, amphotericin B nephrotoxicity. H ypocalcem ia m ay result from urinary losses of Hyperkalemia: pentamidine, ketoconazole, trimethoprim magnesium and hypomagnesemia (pentamidine and amphotericin B) Hypokalemia: rifampin, didanosine, amphotericin B, foscarnet or from drug-induced pancreatitis (pentam idine, didanosine, and Hypomagnesemia: pentamidine, amphotericin B foscarnet). Hypercalcemia occurs in association with granulomatous Hypocalcemia: foscarnet, pentamidine, didanosine disorders, dissem inated cytom egalovirus infection, lym phom a, Hypercalcemia: foscarnet hum an T-cell leukem ia (H TLV) related to H TLV-I infection or Hypouricemia: rifampin foscarnet adm inistration. H ypouricem ia was described in 22% of Hyperuricemia: didanosine, pyranzinamide, ethambutol patients as a result of an intrinsic tubular defect in urate transport Tubular acidosis: amphotericin B, trimethoprim, cidofovir, rifampin, foscarnet unrelated to drug therapy. In contrast, hyperuricem ia usually is the result of drug interference with purine metabolism (didanosine) or tubular urate secretion (pyrazinam ide and etham butol). In the absence of clinical m anifestations that readily explain acid-base FIGURE 7-18 or electrolyte disturbances, a careful review of the pharm acopeia Drugs causing electrolyte com plications. A num ber of drugs used used to treat patients with H IV infection is m andated. Extensive in the treatm ent of patients with AIDS can induce acid-base or reviews of the com plications associated with drugs are available electrolyte abnorm alities from direct renal toxicity (didanosine, [127,128]. The clinical presentation, laboratory findings, and course of acute tubular necrosis do not differ in patients with AIDS and those in other clinical settings. Prerenal azotemia, acute tubular necrosis Prevention includes correction of fluid and electrolyte abnormalities and dosage adjustments of Allergic interstitial nephritis potentially nephrotic drugs. Identification and withdrawal of the offending agents usually result Obstructive nephropathy in recovery of renal function. Dialysis m ay be needed before renal function im proves. Less Rhabdomyolysis, myoglobinuric acute renal failure frequent causes of acute renal failure include allergic acute interstitial nephritis; complicating Thrombotic thrombocytopenic purpura, hemolytic treatm ents with trim ethoprim and sulfam ethoxazole, rifam pin, or acyclovir; and acute uremic syndrome obstructive nephropathy, resulting from the intrarenal precipitation of crystals of sulfadiazine, Rapidly progressive glomerulonephritis acyclovir, urate, or protease inhibitors [134,139–146]. O bstructive uropathy without hydronephrosis also may develop in patients with lymphoma as a result of lymphomatous ureteropelvic infiltration or retroperitoneal fibrosis [147–149]. Rhabdomyolysis with myoglo- binuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute FIGURE 7-19 renal failure associated with intravascular coagulation related to thrombotic thrombocytopenic Causes of acute renal failure. Acute renal purpura (TTP) or hemolytic uremic syndrome (HUS) have been reported (vide infra). Rare failure is related to complications of AIDS, its causes of acute renal failure include disseminated microsporidian infection or histoplasmosis treatment, or the use of diagnostic agents in [151,152]. A clinical presentation of acute renal failure also can be seen in patients with acute about 20% of patients [129,130]. Acute tubu- immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephritis, or fulminant lar necrosis occurs with a prevalence of 8% to HIV-associated glomerulosclerosis. An example of nonoliguric acute tubular 7 7 necrosis associated with administration of large doses of intravenous 6 6 acyclovir is illustrated, which was readily reversible on decreasing 5 5 the dose of acyclovir from 2. Patients infected with 4 4 HIV can exhibit a broad spectrum of conditions that may affect the 3 3 kidneys. Renal biopsy is useful for diagnostic and prognostic purpos- 2 2 es when the cause of acute renal failure is not clinically evident. In a 1 1 recent study of 60 patients with acute renal failure, a percutaneous 0 0 renal biopsy yielded a pathologic diagnosis in 13% that was not 1 2 3 4 5 6 7 8 expected clinically [154].

This type of analysis intrinsic noise in the time series signal cheap 17.5mg nicotinell fast delivery. The standard devia- assumes that the BOLD response behaves in a manner that tion of the signal is on the order of 1% order nicotinell 17.5mg amex. The second source can be completelydescribed bylinear systems analysis order nicotinell 17.5 mg line, of variabilityis that of the hemodynamic response. Regardless, observed hemody- tioned, this ranges from 450 to 1,250 ms, depending on namic response to anyneuronal activation can be predicted whether one is observing the rising phase of the signal or 26: Spatial, Temporal, and Interpretive Limits of Functional MRI 347 A B FIGURE 26. Demonstration of several of the limits of functional magnetic resonance imagingtemporal resolution. Echo-planar imag- ing was performed at3Tbyusing a Bruker Biospec 3T/60 equipped with a local head gradient coil. A time course series of axial images (matrix size 96 96, field of view 20 cm, echo time 40 ms, repetition time 500 ms, flip angle 80 degrees) through the motor cortex was obtained. Bilateral finger tapping was performed for 2 s, followed by 18 s of rest. These figures demonstrate that the upper temporal resolution is determined by the variability of the signal change in time and space. A: Time course of the signal elicited by tapping fingers for 2 s. The standard deviation at each point is in the range of 1% to 2%. The standard deviation of the hemodynamic change, in time, is in the range of 450 to 650 ms. B: Map of the dot product (a measure of the activation-induced signal change magni- tude) and the relative latencies or delays of the reference function (the plot in A was used as the reference function) at which the corre- lation coefficient was maximized. The spatial distribution of hemo- dynamicdelayshasastandarddeviation ofabout900ms. Thelongest delays approximately match the regions that show the highest dot product and the area where veins are shown as dark lines in the T2*- weighted anatomic image. The third source of variabilityis the la- maybe almost fullydiluted back to resting state oxygena- tencyspread over space. Again, work is ongoing to characterize this correlation analysis and allowed to shift 2 s. The spread in As previouslydiscussed, the magnitude of the fMRI signal latencies is more than 4 s. Making a com- latency; the regions showing the longest latency roughly plete and direct correlation between neuronal activityand correspond to the regions that show the largest signal fMRI signal change magnitude in a single experiment will changes. Although these largest signal changes are likely remain impossible until all the variables can be characterized downstream draining veins, it is important to note that this on a voxel-related basis. Because of these primarilyphysio- approximate correlation between latencyand magnitude is logic variables, the magnitude of BOLD signal changes on extremelyweak. Manyverysmall signal changes show very brain activation maps typically ranges from 1% to 5% [at, long latencies. It is also interesting to note that the inverse, say, 1. This implies that manydownstream vessels years, considerable progress has been made in characterizing 348 Neuropsychopharmacology: The Fifth Generation of Progress the magnitude of the fMRI signal changes with underlying would be present in the voxel. The same could applyif the time constant of the neuronal area corresponding to specific, well-characterized oxidative metabolic rate were slightlyslower than that of tasks. Second, inferred neuronal modulation was carried out flow and volume changes. Evidence for an increased oxida- by systematically varying some aspect of the task. Clear cor- tive metabolic rate after 2 min of activation is given by relations between BOLD signal change magnitude and vis- Frahm et al. This parametric seconds longer than the flow increase time constant—as experimental design represented a significant advance in the would be required to be applicable onlyto relativelyhigh- manner in which fMRI experiments were performed, en- amplitude single-event responses. These hemodynamics, abling more precise inferences, not about the BOLD signal which mayalso differ on a voxel-related basis, remain to be change with task modulation. Recently, several more intriguing studies have emerged SCANNER-RELATED ISSUES correlating measured neuronal firing rate with well-known stimuli in animals (51) and humans (52,53) and demon- A complete discussion of all scanner-related issues and po- strating a remarkablyhigh correlation between BOLD sig- tential solutions is beyond the scope of this chapter. Most practitioners of functional MRI typically undergo a Linearity painful, frustrating, and prolonged period of learning about Related to the topic of signal change magnitude is that of all scanner-related limitations and issues. This learn- that it behaves as a linear system (54,55). This greater than ing process also applies to understanding the physiology of expected BOLD signal change is generallyspecific to stimu- the signal, but typically the greatest anguish arises in the lus durations below 3 s. Reasons for nonlinearities in the context of MRI pulse sequences and hardware. In this section, an attempt is made to walk ple boxcar function.

The different versions of the guideline are shown in Table 2 17.5mg nicotinell with amex. Future guideline updates will consider evidence published after this cut-off date 17.5mg nicotinell overnight delivery. Two years after publication of the guideline cheap 17.5 mg nicotinell free shipping, NICE will ask a National Collaborating Centre to determine whether the evidence base has progressed significantly to alter the guideline recommendations and warrant an early update. If not, the guideline will be considered for update approximately four years after publication. The recommendations cited here are a guide and may not be appropriate for use in all situations. The decision to adopt any of the recommendations cited here must be made by the practitioner in light of individual patient circumstances, the wishes of the patient, clinical expertise and resources. The NCC-CC disclaims any responsibility for damages arising out of the use or non-use of these guidelines and the literature used in support of these guidelines. For quantification and monitoring of proteinuria, PCR can be used as an alternative. ACR is the recommended method for people with diabetes. Offer ACEI/ARBs to non-diabetic people with CKD and hypertension and ACR ≥30 mg/mmol (approximately equivalent to PCR ≥50 mg/mmol, or urinary protein of ≥0. Stage 3 CKD should be split into two subcategories defined by: q GFR 45–59 ml/min/1. People with CKD should usually be referred for specialist assessment if any of the following apply: q stage 4 and 5 CKD (with or without diabetes) q heavy proteinuria (ACR ≥70 mg/mmol, approximately equivalent to PCR ≥100 mg/mmol, or urinary protein excretion ≥1 g/24 h) unless known to be due to diabetes and already appropriately treated q proteinuria (ACR ≥30 mg/mmol, approximately equivalent to PCR ≥50 mg/mmol, or urinary protein excretion ≥0. Offer people testing for CKD if they have any of the following risk factors: q diabetes (types 1 and 2) q hypertension q cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease and cerebral vascular disease) q structural renal tract disease, renal calculi or prostatic hypertrophy q multisystem diseases with potential kidney involvement, e. Take the following steps to identify progressive CKD: q obtain a minimum of three glomerular filtration rate (GFR) estimations over a period of not less than 90 days q in people with a new finding of reduced eGFR, repeat the estimated glomerular filtration rate (eGFR) within 2 weeks to exclude causes of acute deterioration of GFR, e. In people with CKD, aim to keep the systolic blood pressure below 140 mmHg (target range 120–139 mmHg) and the diastolic blood pressure below 90 mmHg. SLE • Family history of stage 5 CKD or hereditary kidney disease • Opportunistic haematuria or proteinuria in the absence of a urological cause • If none of these are present, do not use age, gender or ethnicity as risk markers Identify and delay progression (see section 6) Identify those at risk of progression (presence of cardiovascular disease; proteinuria; hypertension; diabetes; smoking; Black or Asian ethnicity; chronic use of NSAIDS; urinary outflow tract obstruction) Exclude causes of acute deterioration in GFR by repeating eGFR within 14 days Assess rate of progression by repeating eGFR measurement three times over a period of not less than 90 days and then annually Use ACEI/ARB therapy in people: • with diabetes and ACR >2. This algorithm should be used as an aide memoire in primary care to trigger various investigations and interventions relevant for people in different stages of CKD. Stages of CKD are shown from left to right and activities appear as horizontal bands, some of which are more relevant to early or late disease, as indicated by their positioning and by the graded shading. BP = blood pressure; NSAID = non-steroidal anti-inflammatory drug; PTH = parathyroid hormone. SLE Abnormal Protein in Blood in • opportunistic haematuria or proteinuria eGFR urine urine If none of the above, do not use age, gender or ethnicity as risk markers. Exclude • Measure eGFR infection or • Send urine for ACR (or PCR) urological cause • Monitor GFR in people prescribed drugs known to be nephrotoxic such as calcineurin inhibitors and If ACR is 30–70 or PCR is 50–100, confirm If eGFR <60, repeat within lithium. Blood results eGFR ≥60 eGFR ≥60 eGFR 30–59 eGFR <30 No risk factors for Risk factors for CKD Confirmed by a Confirmed by a CKD repeat test within repeat test within 14 days 14 days ACR <30/PCR <50 Repeat eGFR in No further action* 12 months ACR 30–69 or PCR 50–99 Follow recommendations in this guideline on the Confirmed on early morning sample management and monitoring of CKD + no haematuria ACR 30–69 or PCR 50–99 Confirmed on early morning sample + haematuria Consider referral for specialist opinion ACR ≥70 or PCR ≥100 *See pages 33 and 147 for management of isolated invisible haematuria. Albumin:creatinine ratio (ACR) and protein:creatinine ratio (PCR) are expressed as mg/mmol. Albumin:creatinine ratio (ACR) is expressed as mg/mmol. Knowledge of GFR is essential for the diagnosis and management of CKD and is a translatable concept. The gold standard methods of estimating GFR require measurement of an ideal filtration marker. These markers should be freely filtered by the glomerulus, should not be bound to plasma proteins, must be excreted unchanged and not be subject to either tubular secretion or absorption. Commonly used markers include inulin, 51Cr-EDTA, 125I-iothalamate and iohexol. At the other end of the accuracy scale lies measurement of serum creatinine, which is a universally available endogenous test of kidney function. Although easy and cheap to measure, creatinine is subject to non-renal and analytical influences which make it insufficiently sensitive to detect moderate CKD on its own. Measurement of 24-hour urinary creatinine clearance improves the accuracy but is also subject to the same non-renal and analytical influences compounded by inaccuracies in urine collection, to say nothing of the inconvenience associated with 24-hour urine collections. An alternative and more accurate endogenous marker is cystatin C, a 13 kDa cationic protein produced by all nucleated cells. Serum cystatin C levels are chiefly determined by GFR. Potential limitations of cystatin C as a marker of GFR include lack of assay standardisation, the requirement for a dedicated analytical system, and increased costs relative to serum creatinine (approximately £3/assay compared to <£0.