Acute tubular injury is an important component in type I acute antibody-mediated rejection.

BACKGROUND: "Acute tubular necrosis (ATN)-like" changes in type I acute antibody- mediated rejection (AAMR) have been proposed since 2005, but the presence of "ATN-like" injury in AAMR has not well been established. The aim of this study was to confirm the presence of acute tubular injury in type I AAMR, using the specific proximal tubular injury marker, kidney injury molecule-1 (KIM-1). DESIGN: The study included 3 groups of cases, namely, a negative control group (normal nontransplantation renal parenchyma as group 1, n = 11), a positive control group (transplant ATN with negative C4d staining as group 2, n = 12), and study cases (type 1 AAMR as group 3, n = 19). Biopsy specimens from all groups were stained immunohistochemically for KIM-1 (monoclonal antibody) and KIM-1 staining intensity in proximal tubules was graded from 0.5 to 3+. Clinical indices were also correlated and analyzed. RESULTS: Group 1 demonstrated significantly lower serum creatinine levels (1.02 ± 0.10 mg/dL) when compared with both group 2 and group 3. Both groups 2 and 3 showed similar serum creatinine levels (4.02 ± 0.59 mg/dL in group 2 and 3.24 ± 0.34 mg/dL in group 3). The negative control group demonstrated negative proximal tubule staining for KIM-1, whereas both groups 2 and 3 showed positive KIM-1 staining in proximal tubules (intensity ranging from 1+ to 3+ in group 2 and from 0.5 to 3+ in group 3). CONCLUSION: Our results, using KIM-1 immunohistochemistry, demonstrated that acute tubular injury is an important component of type I AAMR.

Glomerulitis during acute cellular rejection may be a surrogate marker of vasculitis in renal allografts--better index for diagnosis of vasculitis.

BACKGROUND: The Banff criteria (from 2005 to 2009) use "T cell-mediated rejection" to indicate acute cellular rejection. Vasculitis in smaller arteries is an important diagnostic criterion for moderate and severe T cell-mediated rejection. The renal allograft endothelium is a significant target of inflammatory response-mediated tissue damage. Medium-size arteries (arcuate arteries) are mostly absent in routine allograft biopsies, so identification of vasculitis relies on its identification in small arteries (arterioles to interlobar arteries). Although inflammation in terminal vessels such as the glomerular capillaries has been previously recognized, their role in grading the rejection process is not well characterized. We therefore evaluated the expression of CD3-positive T lymphocytes and CD68-positive macrophages in glomeruli, small arteries, and arcuate arteries of nephrectomy specimens obtained from transplant and renal tumor patients. METHODS: The study group included 21 renal explant subjects with nonreversible moderate to severe T cell-mediated rejection (IIa to III) and/or severe chronic changes. The control group comprised 17 individuals with nephrectomy for renal tumors. In each case, a large renal section from cortex to medulla was stained for CD3 and CD68 by immunohistochemical method. CD3-positive T lymphocytes and CD68-positive macrophages per balanced high-power field were counted in glomeruli, interlobar arteries, and arcuate arteries. RESULTS: In control kidney sections, neither CD3-positive T lymphocytes nor CD68-positive macrophages were noted in glomeruli, interlobar arteries, or arcuate arteries. In the study group, 15/21 showed diffuse C4d positivity. Also in the study group, positive CD3 and CD68 counts in glomeruli were significantly correlated to both interlobar and arcuate artery counts by linear regression analysis. CONCLUSION: We conclude that in renal allograft biopsies, T lymphocytes and macrophages in the glomeruli not only represent a separate entity, "transplant glomerulitis," but also may be a surrogate marker of vasculitis present in larger vascular beds. Comparable amounts of T cells and macrophages imply that "acute cellular rejection" may be a better terminology to reflect the true inflammatory status.

Contrast-induced acute kidney injury in renal transplant recipients after cardiac catheterization.

Renal transplant (RTX) recipients remain at high-risk for acute kidney injury (AKI) despite having improved renal function and quality of life after transplantation. We sought to identify the incidence and risk factors for contrast-induced AKI in RTX recipients after cardiac catheterization at our institute as identified by electronic records. After excluding patients on dialysis at time of procedure due to failed transplant and who did not have post-exposure creatinine values within 3 days, we reviewed 77 procedures on 57 patients. We studied one case per patient (the most recent procedure). Among the 57 patients, 42 were male, 42 were Caucasian and mean age was 58.2 +/- 10.1 years. Mean serum creatinine 24 h pre-procedure was 1.7 +/- 0.8 mg/dl. Contrast-induced AKI, defined as rise in serum creatinine of 25% or 0.5 mg/dl within 3 days post-catheterization, occurred in 9 procedures (15.8%). One procedure was complicated by AKI requiring dialysis. AKI occurred more frequently with use of low-osmolar contrast (ioxaglate or iohexol) in comparison with iso-osmolar contrast (iodixanol) (9/36 vs. 0/21, p = 0.019). Patients who received prophylactic N-acetylcysteine had lower incidence of AKI than those who did not (4/41 vs. 5/16, p = 0.046). Exact logistic regression analysis revealed odds ratio of developing AKI with use of low-osmolar vs. iso-osmolar contrast to be 7.747 (1.101 - yen); p = 0.0381). Contrast-induced AKI was common in RTX recipients after cardiac catheterization. Iso-osmolar contrast was associated with a lower risk of contrast-induced AKI in comparison with low-osmolar contrast.

The effect of weight loss after bariatric surgery on albuminuria.

BACKGROUND: Bariatric surgery achieves long-term weight loss in obese adults with improvement of diabetes and hypertension. Little is known about the effect of this weight loss on renal parameters. METHODS: We performed a retrospective study of 94 obese adults who had Roux-en-Y gastric bypass surgery with a mean 12-month follow-up. Baseline (preoperative) mean age was 49 years, 76% were female, 37 had blood pressure (BP) >or= 140/90 mmHg and 32 had Type 2 diabetes. 73 patients had normoalbuminuria (urine albumin creatinine ratio (ACR) <30 mg/g) while 21 had microalbuminuria (ACR 30<300 mg/g). RESULTS: At follow-up (postoperative), we observed a decrease in mean body weight (133.6 to 97.9 kg, p<0.0001), mean hemoglobin A1c (6.3 to 5.6%, p<0.0001) and mean systolic blood pressure (132.7 to 114.0 mmHg, p<0.0001). There was a significant reduction in ACR (median with interquartile range) from 9.5 (5-28) to 5.5 (3-10) mg/g, p < 0.0001. Fewer patients had microalbuminuria (22.2 to 6.2%, p=0.004) after surgery. Subgroup analysis revealed that significant decrease in ACR was present in the 32 patients with diabetes (16.5 (5-67) to 6.0 (4-11) mg/g, p=0.001) and in the 37 patients with metabolic syndrome (8.0 (5-16) to 6.0 (3-13) mg/g, p=0.012), while 25 patients with obesity alone had a lower ACR (6.5 (4-13) to 4.5 (3-8) mg/g, p=0.270). Multiple linear regression analysis showed change in hemoglobin A1c (p=0.011) and baseline level of ACR (p<0.0001) to be significantly associated with change in ACR. CONCLUSION: We conclude that obese adults have a reduction in albuminuria after surgical weight loss, most importantly in patients with diabetes or metabolic syndrome.

Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality.

PURPOSE: This study set out to define the incidence, predictors, and mortality related to acute renal failure (ARF) and acute renal failure requiring dialysis (ARFD) after coronary intervention. PATIENTS AND METHODS: Derivation-validation set methods were used in 1,826 consecutive patients undergoing coronary intervention with evaluation of baseline creatinine clearance (CrCl), diabetic status, contrast exposure, postprocedure creatinine, ARF, ARFD, in-hospital mortality, and long-term survival (derivation set). Multiple logistic regression was used to derive the prior probability of ARFD in a second set of 1,869 consecutive patients (validation set). RESULTS: The incidence of ARF and ARFD was 144.6/1,000 and 7.7/1,000 cases respectively. The cutoff dose of contrast below which there was no ARFD was 100 mL. No patient with a CrCl > 47 mL/min developed ARFD. These thresholds were confirmed in the validation set. Multivariate analysis found CrCl [odds ratio (OR) = 0.83, 95% confidence interval (CI) 0.77 to 0.89, P <0.00001], diabetes (OR = 5.47, 95% CI 1.40 to 21.32, P = 0.01), and contrast dose (OR = 1.008, 95% CI 1.002 to 1.013, P = 0.01) to be independent predictors of ARFD. Patients in the validation set who underwent dialysis had a predicted prior probability of ARFD of between 0.07 and 0.73. The in-hospital mortality for those who developed ARFD was 35.7% and the 2-year survival was 18.8%. CONCLUSION: The occurrence of ARFD after coronary intervention is rare (<1%) but is associated with high in-hospital mortality and poor long-term survival. Individual patient risk can be estimated from calculated CrCl, diabetic status, and expected contrast dose prior to a proposed coronary intervention.

Hypertension after renal transplantation.

Hypertension is a frequent complication after organ transplantation in both children and adults and is a significant risk factor for the development of cardiovascular disease and graft dysfunction. There are multiple mechanisms responsible for the development of posttransplant hypertension. In the precyclosporine era, chronic rejection was the most common cause. The introduction of cyclosporine A has increased the prevalence of hypertension in solid organ transplant recipients. Cyclosporine increases renal vascular resistance by causing vasoconstriction of the afferent arteriole. From a pathophysiologic point of view, a calcium channel blocker should be used as the initial therapy in patients with cyclosporine-associated hypertension. Hypertension needs to be treated aggressively in all transplant recipients in an attempt to minimize allograft and cardiovascular damage.

The impact of nonidentical ABO cadaveric renal transplantation on waiting times and graft survival.

Blood type O recipients of cadaveric renal transplants have longer pretransplant waiting periods than blood type A, B, and AB recipients. To evaluate reasons for and consequences of this discrepancy, we studied both the frequency of various donor and recipient blood type combinations and their outcomes. Among 37,659 cadaveric renal transplants performed during 1983 through 1989, there were 2,625 transplants (7%) received by patients of compatible but nonidentical blood types. Of 18,575 type O donor organs, 16,784 were received by type O patients for a recipient to donor ratio of 0.9. The corresponding ratios were greater than 1.0 for all other blood types (1.02 for blood type A, 1.14 for type B, and 2.18 for type AB). This causes blood type O patients to have a lower access to transplantation and to have significantly longer waiting times than patients of all other blood types. This inequality of access diminished significantly (P less than 0.001) over the years, but did not resolve by 1989. Analysis of relative risk for first graft loss by multiple regression (Cox) showed that transplantation across compatible blood types had a 9.1% higher risk (P less than 0.1) than that of transplantation among identical blood types. Cadaveric renal transplantation within identical blood types optimizes access to transplantation and avoids further aggravating past disadvantages for blood type O recipients.

Obesity and renal transplantation.

In this study, we examined the influence of pre-existing obesity (weight more than 120 per cent of ideal body weight) on outcome after renal transplantation. Among 263 cyclosporine-treated recipients of renal allografts, 223 (85 per cent) were nonobese and 40 (15 per cent) were obese prior to transplantation. Obese and nonobese recipients were similar with regard to age, sex, renal diagnosis, history of prior transplant, donor source, pretransplant blood pressure, pretransplant antihypertensive agents, diabetic recipients with insulin requirements more than 40 units per day and pretransplant serum cholesterol. Duration of hospitalization was similar (26 +/- 25 versus 25 +/- 14 days; p = NS). There was a significantly higher incidence of wound infections in obese recipients (17.5 versus 6.3 per cent; p = 0.036); other complications occurred with similar incidence. Preoperative per cent of ideal body weight correlated with post-transplant weight gain during the first post-transplant year (p = 0.00002). After one year, obese recipients had gained 14.2 +/- 2.2 kilograms compared with 8.9 +/- 0.6 kilograms for nonobese patients (p = 0.002). Mean doses of prednisone, azathioprine and cyclosporine were similar at three, six and 12 months post-transplant. There were no differences in blood cyclosporine, serum cholesterol or blood glucose levels at any time. Blood pressure measurements were similar throughout the first post-transplant year. There was no difference in the incidence or number of rejection episodes. Actuarial patient survival rate for nonobese patients was 93 per cent at three years. For obese patients, three year actuarial patient survival rate was 90.5 per cent (p = NS). Actuarial graft survival rate among nonobese patients was 71.8 per cent at three years. For obese patients, three year actuarial graft survival rate was 64.5 per cent (p = NS). In conclusion, obese patients with end stage renal disease are good candidates for renal transplantation. Obesity does not seem to constitute a major risk factor, the most notable adverse outcomes being an increased incidence of wound infection and continued weight gain through the first post-transplant year.

Short-term changes in renal function, blood pressure, and electrolyte levels in patients receiving cyclosporine for dermatologic disorders.

We compared the changes in renal function, blood pressure (BP), and concentrations of serum potassium, magnesium, and urate (uric acid) in two groups of patients not given transplants. Group 1, comprising 21 psoriatic patients, was treated with 14 mg/kg per day of oral cyclosporine for 4 weeks in a prospective, placebo-controlled study; group 2, comprising 28 patients with diverse cutaneous diseases, was given 6 mg/kg per day of oral cyclosporine for 1 to 3 months in a prospective, open-labeled study. Renal function (determined by serum urea nitrogen [SUN] and creatinine levels and urinalysis), BP, serum electrolyte levels (potassium and magnesium), and urate level were measured weekly for the first 4 weeks in both groups, and then, after 2 and 3 months of therapy, in group 2 only. During the first 4 weeks in group 1 patients, there were significant increases in values of SUN, creatinine, BP, potassium, and urate, and a significant decrease in the serum magnesium value. When data for the two groups were combined, the changes from pretherapy values in each of the above measures (except systolic BP) during the first 4 weeks correlated significantly with cyclosporine trough levels. In group 2, the changes that occurred in the first 4 weeks in the SUN value, SUN/creatinine ratio, and BP were magnified over the subsequent 8 weeks of treatment. In the combined group for the first 4 weeks of therapy, duration of therapy, independent of cyclosporine trough levels, correlated with changes in SUN, creatinine, and urate levels, but not with changes in the potassium or magnesium level or in BP. We conclude that the cyclosporine blood level was a better discriminant than cyclosporine dosage in the analysis of renal dysfunction and hypertension in these patients.

Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial.

BACKGROUND: Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects. METHODS: In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding. RESULTS: The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P less than 0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivity reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin. CONCLUSIONS: Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined.

Effects of cyclosporine on renal function in psoriasis patients.

Several prospective studies have documented the effectiveness of oral cyclosporine in the treatment of psoriasis. Despite this, the use of cyclosporine has been limited because of concern about the possibility of drug-induced renal dysfunction. We review the effects of cyclosporine on renal function.

Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis.

Cyclosporine is known to be effective in the treatment of psoriasis. In this study, we have used oral cyclosporine (6 mg/kg per day) given for 5 to 30 weeks to 24 patients for the treatment of 12 different dermatoses. Patients with the following diseases demonstrated a marked response or total clearing: 1 patient each with pyoderma gangrenosum, pityriasis lichenoides chronica, and psoriasis of the acrodermatitis continua of Hallopeau type. Moderate to marked response occurred in both patients with epidermolysis bullosa acquisita and the patient with hidradenitis suppurativa. Minimal to moderate responses were obtained in both patients with granuloma annulare, 1 of 2 with acrodermatitis continua of Hallopeau, both patients with Darier's disease, and 1 of 6 patients with vitiligo. Little or no response was noted in both patients with sarcoidosis, all 3 patients with pityriasis rubra pilaris, 5 of 6 patients with vitiligo, 1 patient with pemphigus foliaceous, and 1 with pemphigus vulgaris. Clinical side effects were mild and transient and included dysesthesia, fatigue, hypertrichosis, nausea, and flushing. The most frequent clinically significant abnormalities were hypertension and renal dysfunction, with all factors normalizing within 1 month of discontinuation of cyclosporine therapy.

Cyclosporine in dermatology.

Cyclosporine is a potent immunosuppressive agent with no appreciable effect on the bone marrow and a selective inhibitory effect on helper T cells. Oral cyclosporine was first used to prevent organ rejection but also has been reported to be effective in other disorders. In cutaneous diseases that respond to oral cyclosporine helper T cells appear to be involved in their pathogenesis. This article reviews the cutaneous diseases that have been treated with cyclosporine and its pharmacology and side effects. Two significant adverse side effects are renal dysfunction and hypertension, both of which are reversible when short-term low-dose (less than 5 mg/kg per day) oral cyclosporine is discontinued. Lymphoma is unlikely in an otherwise healthy patient who has received low-dose oral cyclosporine for limited periods. The use of oral cyclosporine in any patient should be carefully considered in terms of the risk/benefit ratio and needs to be carried out under close medical supervision. In view of the limited experience with cyclosporine in dermatology, whenever possible its use should be confined to formal clinical studies with established protocols and guidelines. Further controlled studies need to be performed to evaluate the efficacy of low-dose cyclosporine in many dermatoses and its side-effect profile, particularly over the long term.

Cyclosporine-induced hyperuricemia and gout.

To evaluate the frequency and the pathogenesis of hyperuricemia and gout during cyclosporine therapy, we studied renal-transplant recipients who were treated with either cyclosporine and prednisone (n = 129) or azathioprine and prednisone (n = 168). Among the patients with stable allograft function and serum creatinine concentrations below 265 mumol per liter, hyperuricemia was more common in the cyclosporine group than in the azathioprine group (84 percent vs. 30 percent; P = 0.0001). Gout developed in nine patients (7 percent) in the cyclosporine group, but no episodes occurred in the azathioprine group. Serum urate levels became elevated in 90 percent of the patients in the cyclosporine group who were treated with diuretics, as compared with 60 percent of those not treated with diuretics (P = 0.001); in the azathioprine group, the corresponding values were 47 percent and 15 percent (P = 0.0001). Serum urate levels did not correlate with trough blood cyclosporine levels in a selected subgroup (n = 40) of patients from the cyclosporine group, who were studied from 4 to 96 weeks after transplantation. Detailed studies of urate metabolism in six cyclosporine-treated patients revealed normal turnover rates for urate and decreases in creatinine and urate clearance, as compared with seven control subjects. We conclude that hyperuricemia is a common complication of cyclosporine therapy and is caused by decreased renal urate clearance. Gouty arthritis is the cause of considerable morbidity among renal-transplant recipients who receive cyclosporine.

Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine.

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapy of dermatologic disease with cyclosporin A.

Cyclosporin A is a potent immunosuppressive drug with almost a decade of clinical use. Due to its lack of bone marrow toxicity, it has assumed a leading role in organ transplant surgery. Likewise, it has shown remarkable efficacy in psoriasis and has shown potential usefulness in other dermatologic diseases, most of which are thought to have an autoimmune T-cell-mediated pathogenesis. There are many other inflammatory skin conditions in which T lymphocytes represent a majority of the cellular infiltrates, and theoretically such disorders may be responsive to CsA. Diseases such as lichen planus, allergic contact dermatitis, photoallergy, and vitiligo are potential areas of further study. The potential use of topical and intralesional CsA also warrants further clinical evaluation. There are reports of topical CsA showing effectiveness for alopecia areata and nickel contact sensitivity. Griffiths et al. treated six psoriatic patients with 2% CsA ointment twice daily for 4 weeks. The response to placebo or CsA at the end of the study was similar in all patients. Notably, there was no measured systemic absorption and no change in blood pressure or renal function. We had similar unimpressive results in several patients treated with a 10% solution of CsA; minimal to no response was seen. Of great benefit would be an effective topical preparation without systemic absorption or toxicity. Future studies will need to carefully evaluate the vehicle used and the strength of topical CsA employed. The role of CsA in dermatologic disease still needs much investigation, both at the clinical and basic science levels. The studies to date show dramatic and exciting results. Indeed, CsA may well represent a major advance in the understanding and treatment of psoriasis. However, the decision to use CsA for nonfatal diseases such as psoriasis will require a careful balance between efficacy and toxicity. If long-term side effects can be avoided or kept within reasonably safe, acceptable limits, CsA holds great promise for the treatment of psoriasis. It may at times be used as an acute intervention, with a relatively large, initial dose for a short period of time to quickly clear severe psoriasis. This could be followed by either a reduction to a lower and safer maintenance dose or a program of other treatments. Cyclosporin A may also prove useful alone in very low doses or in combination therapy, as with UVB or PUVA. Optimal dosing protocols are currently under investigation.