Acute kidney injury associated with smoking synthetic cannabinoid.

CONTEXT AND OBJECTIVES: Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation. MATERIALS AND METHODS: Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May-October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13-40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse. RESULTS: Patients were males aged 15-27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6-17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone). DISCUSSION AND CONCLUSION: Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.

Enteric oxalate nephropathy in the renal allograft: an underrecognized complication of bariatric surgery.

Enteric hyperoxalosis is a recognized complication of bariatric surgery, with consequent oxalate nephropathy leading to chronic kidney disease and occasionally end-stage renal failure. In patients with prior gastrointestinal bypass surgery, renal allografts are also at risk of oxalate nephropathy. Further, transplant recipients may be exposed to additional causes of hyperoxalosis. We report two cases of renal allograft oxalate nephropathy in patients with remote histories of bariatric surgery. Conservative management led to improvement of graft function in one patient, while the other patient returned to dialysis. Interpretation of serologic, urine and biopsy studies is complicated by oxalate accumulation in chronic renal failure, and heightened excretion in the early posttransplant period. A high index of suspicion and careful clinicopathologic correlation on the part of transplant nephrologists and renal pathologists are required to recognize and treat allograft oxalate nephropathy. As the incidence of obesity and pretransplant bariatric surgery increases in the transplant population, allograft oxalate nephropathy is likely to be an increasing cause of allograft dysfunction.

Acute kidney injury with cryoglobulinemic peritubular neutrophilic capillaritis.

BACKGROUND: Neutrophil predominant capillaritis and interstitial inflammation is an uncommon renal biopsy finding, with a broad differential diagnosis. CASE: A 77-year-old woman presented with a complicated history including vasculitis, cryoglobulinemia, malaise, and systemic symptoms, which progressed to acute kidney injury. Renal biopsy demonstrated prominent neutrophilic capillaritis with interstitial inflammation, and fibrinoid deposits in medullary capillaries and interstitium. Glomeruli showed membranoproliferative glomerulonephritis, but no crescents or necrosis. DISCUSSION: We interpret the capillary and interstitial changes as evidence of cryoglobulin-associated vasculitis, and discuss the differential diagnosis of this uncommon histologic pattern of renal pathology, including other vasculitides, infection, ischemia-infarction, collagen vascular disease, and antibody-mediated allograft rejection, among others.

Maturation of cytokine receptors in preparation for birth.

The elucidation of the tissue-specific profile of expression of the prolactin (PRL) and growth hormone (GH) receptors during embryonic and fetal development in a range of species has provided a new impetus for the delineation of the specific roles of the hormone ligands for these receptors in development. During late gestation, there is a requirement to shift from a phase of predominant cellular proliferation, where placental nutrient supply is a dominant influence on organ and body growth, to one of functional differentiation, which is required for independent homoeostasis after birth. In this review we discuss the interactions between the pre-partum increases in cortisol and thyroid hormones and the synthesis, secretion and actions of fetal PRL and GH. We also review the changes that occur in the tissue-specific expression of the PRL and GH receptors before birth which may play an important role in precocial species in the successful transition of the fetus to extra-uterine life.

Membranous nephropathy associated with chronic immune thrombocytopenic purpura in childhood.

Membranous nephropathy has been associated with many autoimmune diseases. We describe a child with membranous nephropathy associated with chronic immune thrombocytopenic purpura (ITP) and Coombs'-positive hemolytic anemia. After 3 years of ITP, the patient developed nephrotic syndrome during a flare of ITP. A biopsy specimen showed membranous nephropathy. Treatment with corticosteroids led to improvement of the thrombocytopenia and resolution of the proteinuria. Two years later, the patient again developed thrombocytopenia and proteinuria. Both conditions resolved after treatment with corticosteroids. This case suggests that ITP can cause membranous nephropathy.

The regulation of prolactin receptor messenger ribonucleic acid levels in the sheep liver before birth: relative roles of the fetal hypothalamus, cortisol, and the external photoperiod.

We have investigated the separate actions of hypothalamo-pituitary disconnection (HPD), with or without cortisol administration, and changes in the external photoperiod on the regulation of the levels of messenger RNA (mRNA) encoding long (PRLR1) and short (PRLR2) forms of PRL receptor in the liver of the fetal lamb. In pregnant Merino ewes (n = 20), the hypothalamus and pituitary were surgically disconnected in 13 fetuses (HPD group), and fetal vascular catheters were implanted in the HPD group and in an additional 7 fetuses (intact + saline group) between 104-120 days gestation (d). Fetal sheep in the HPD group were infused with either cortisol (3.5 mg/4.8 ml saline/24 h; HPD + F; n = 5) or saline for 5 days between 134-141 d, and saline was also infused in the intact group within the same gestational age range. A second group of pregnant ewes (n = 12) was kept in a 12-h light, 12-h dark cycle from 70 d until implantation of fetal vascular catheters between 106-120 d, after which ewes were allocated to either a long photoperiod (16 h of light, 8 h of darkness; LL group; n = 6) or a short photoperiod (8 h of light, 16 h of darkness; SL group; n = 6) regimen. Circulating cortisol concentrations were higher (P < 0.05) in the intact fetal sheep (18.7 +/- 3.8 nmol/liter) than in the HPD + saline group (1.5 +/- 0.6 nmol/liter), and were further increased (P < 0.05) in the HPD + cortisol group (97.4 +/- 23.7 nmol/liter). Fetal PRL concentrations were lower (P < 0.05) in the HPD + saline (10.6 +/- 4.3 ng/ml) and HPD + cortisol (5.6 +/- 2 ng/ml) groups compared with those in the intact group (38.9 +/- 6.8 ng/ml). The levels of hepatic PRLR mRNA were higher (P < 0.05) in the intact (PRLR1, 27.4 +/- 6.1; PRLR2, 17.7 +/- 2.5) and HPD + cortisol (PRLR1, 23.4 +/- 0.4; PRLR2, 15.3 +/- 3.0) groups than in the HPD + saline group (PRLR1, 10.6 +/- 1.8; PRLR2, 8.9 +/- 1.8) at 140/141 d. The mean plasma PRL concentration in the LL group (70 +/- 9 ng/ml) was higher (P < 0.05) than that in the SL group (34 +/- 15 ng/ml), whereas the levels of hepatic PRLR1 mRNA (LL group, 4.6 +/- 0.9; SL group, 4.3 +/- 0.8) and PRLR2 mRNA (LL group, 3.4 +/- 0.4; SL group, 3.0 +/- 0.5) at 140-141 d were not different. These data indicate that cortisol acts directly or indirectly to maintain hepatic PRLR mRNA levels in the sheep fetus during late pregnancy. In contrast, changes in the external photoperiod and circulating PRL concentrations in the sheep fetus do not directly alter PRLR expression in the fetal liver. These studies provide further insight into the role that the PRL axis may play in the transduction of signals about the external environment to the fetus as it prepares for the transition to extrauterine life.

Immune complex disease associated with Epstein-Barr virus infectious mononucleosis.

We describe a patient with immune complex-mediated glomerulonephritis and leukocytoclastic vasculitis associated with Epstein-Barr virus (EBV) infectious mononucleosis. The patient required hemodialysis and has residual hypertension. This case implicates acute EBV infection as a cause of immune complex-mediated glomerulonephritis.

Photoperiodic history and hypothalamic control of prolactin secretion before birth.

We investigated whether the fetal lamb can construct a photoperiodic history in utero. We measured the fetal PRL response to a 12-h photoperiod in intact fetal sheep and in fetal sheep after hypothalamo-pituitary disconnection (HPD), following exposure of the ewe to either a long (16 h L) or short (8 h L) photoperiod for 50 days in early pregnancy. Ewes were maintained on either a long light (LL, n = 20) or a short light (SL, n = 19) regimen from 57 days gestation until fetal HPD (pre-LL, n = 7; pre-SL, n = 7) or sham surgery (pre-LL, n = 13; pre-SL, n = 12) was performed at 99-113 days gestation. All ewes were housed in a 12-h photoperiod from surgery until 140 days gestation. In HPD fetal sheep previously exposed to SL, fetal PRL concentrations were significantly higher (P < 0.05) after 20 days in the 12-h L regimen than previously (0-5 days, 3.2 +/- 0.6 ng/ml; 21-25 days, 5.6 +/- 1.4 ng/ml). In the HPD fetal sheep previously exposed to LL, however, fetal PRL concentrations significantly decreased (P < 0.05) after 5 days exposure to the 12-h L regimen (6.7 +/- 2.9 ng/ml) and remained low throughout the remaining study period (31-35 days, 1.7 +/- 0.5 ng/ml). In contrast, in the sham group there was no effect of photoperiodic history on the gestational age profile of fetal PRL, and PRL concentrations increased significantly (F = 22.4, P < 0.001) in fetal sheep previously exposed to either SL or LL. Fetal PRL concentrations were significantly higher (P < 0.05) after 121 days gestation in the 12-h L regimen in all sham fetal sheep (<110 days, pre-SL 6.4 +/- 0.3 ng/ml, pre-LL 12.0 +/- 3.3 ng/ml; 121-125 days, pre-SL 20.0 +/- 3.9 ng/ml, pre-LL 25.9 +/- 4.4 ng/ml). TRH (50 microg) was administered i.v. to all fetal sheep at 130-134 days gestation. There was a significant fetal PRL response to TRH in both the HPD (F = 20.9, P < 0.001) and sham (F = 31.3, P < 0.001) groups. There was no difference, however, in the PRL response to TRH in fetal sheep previously exposed to SL or LL in either the HPD or sham groups. The maximum percentage changes in PRL occurred at +10 min after TRH administration in the HPD (pre-SL, 421 +/- 75%; pre-LL, 555 +/- 76%) and sham groups (pre-SL, 394 +/- 68%; pre-LL, 369 +/- 59%). In summary, therefore, we have demonstrated that there is an effect of photoperiodic history on the PRL response to an intermediate photoperiod in utero in HPD fetal sheep. It appears, however, that the effect of photoperiodic history on PRL secretion in intact fetal sheep is either masked or suppressed by the stimulatory effect of factors associated with an increase in gestational age acting at the fetal hypothalamus.

Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506.

Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunophilin, also inhibits calcineurin. We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK, does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.), RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood flow and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drugs is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand may be related to inhibition of calcineurin.

Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.

Cyclosporine (CsA) administration and nitric oxide (NO) blockade promote similar chronic renal hemodynamic alterations in rats. We evaluated various clinical CsA doses under conditions of NO blockade using L-NAME (N-nitro L-arginine methyl ester). Groups of Sprague-Dawley rats kept on a normal salt (+NaCl) or low-salt (-NaCl) diet were given CsA 7.5 mg/kg, 2.5 mg/kg, or vehicle (VH) for 21 days. CsA or VH treatment was preceded by one week of L-NAME and continued for three weeks. Inulin clearance, CsA blood level, and weekly blood pressure change were assessed at 28 days. Marked CsA dose dependent reductions in GFR in -NaCl animals (P < 0.01 versus VH + L-NAME) and +NaCl animals (P < 0.05 versus VH + L-NAME, +NaCl) as well as blood pressure elevations (P < 0.01 versus VH + L-NAME at 28 days) occurred in groups concurrently treated with CsA and L-NAME. In addition, Impaired renal function and morphologic lesions in rats (CsA 2.5 mg/kg) receiving L-NAME or CsA alone demonstrated CsA blood levels within the therapeutic range of human renal transplant patients. VH groups treated with L-NAME alone produced blood pressure elevations but were spared of renal functional or morphological alterations. Primary renal morphologic lesions in CsA treated animals included proximal tubule collapse and vacuolization and, less frequently, interstitial edema and vacuolization of interstitial cells. Unique to rats treated simultaneously with CsA and L-NAME were vascular abnormalities consisting of endothelial and arteriolar medial hyperplasia and occasional acute medial necrosis. In conclusion, acute CsA nephrotoxicity can be enhanced by simultaneous NO blockade, suggesting NO has a protective effect in CsA-induced nephropathy. These results can be achieved with a drug exposure profile that correlates with clinical therapy.

Evolution of metabolic and renal changes in the ZDF/Drt-fa rat model of type II diabetes.

Studies of the pathophysiology of renal disease in non-insulin-dependent diabetes mellitus (NIDDM) have been hindered by the lack of an appropriate experimental model. We examined the natural history of metabolic and renal changes in the partially inbred Zucker Diabetic Fatty Rat (ZDF/Drt-fa), a model that closely mimics the metabolic abnormalities of NIDDM. Lean nondiabetic littermates served as controls. Body weights in the obese rats were higher initially, but thereafter stabilized at values similar to those in lean controls. Blood glucose levels rose to overtly hyperglycemic levels in the obese group, stabilizing in the 300 to 400 mg/dL range. Serum insulin, cholesterol, and triglyceride levels were all elevated in the obese group, though insulin levels declined later in life. Values for systolic blood pressure rose slightly with age in both groups, but remained within the normal range, and did not differ between groups. Urinary albumin excretion values were higher in the obese group at all time points, and rose progressively throughout the study. Morphologic examination revealed the presence of severe hydronephrosis in almost all animals, affecting lean as well as obese rats. In some cases, complications were found, including tubular dilation, necrotizing granulomas, inflammatory changes, and pyelonephritis, some of which were fungal. Accordingly, the ZDF/Drt-fa rat appears to be an excellent model of the metabolic changes that characterize NIDDM. Unfortunately, the utility of this model for study of diabetic renal disease is compromised by the ubiquitous presence of other, nondiabetic renal lesions.

Functional and structural characteristics of experimental FK 506 nephrotoxicity.

1. FK 506 (Tacrolimus, Prograf) is a novel immunosuppressant which is effective in solid organ transplantation and autoimmune diseases. The lack of a suitable animal model has hindered the study of the nephrotoxicity of the drug which has emerged as a common adverse effect in clinical trials. We report both acute and chronic nephrotoxicity with tacrolimus (FK) in which renal structure and function are worsened by sodium depletion. 2. Pair fed male Sprague-Dawley rats were given FK (3 or 6 mg/kg, p.o.) or vehicle for 7, 21 and 42 days on low salt or normal diet. The FK whole blood trough levels achieved (3-10 ng/mL) were similar to those observed in FK treated transplant patients. 3. In salt depleted animals treated for 7 days, FK (6 mg/kg) decreased renal blood flow and glomerular filtration rate (1.8 +/- 0.1 and 0.2 +/- 0.1 mL/min per 100 g vs 2.9 +/- 0.2 and 1.1 +/- 0.1 mL/min per 100 g in the vehicle group, P < 0.01). 4. After 21 days of treatment of FK on low salt diet but not normal salt, FK induced focal collapse and vacuolization in proximal tubules and discrete or confluent zones of tubulointerstitial oedema and mononuclear cell infiltration. 5. After 42 days in salt depleted rats, there was significant tubulointerstitial scarring that was associated with an increased plasma renin activity (PRA) (64 +/- 10 vs 30 +/- 4 ng AI/mL per h in the vehicle group, P < 0.05). Animals given normal salt diets did not develop significant histological lesions even up to 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of prolactin to different photoperiods after surgical disconnection of the hypothalamus and pituitary in sheep fetuses.

The aim of this study was to determine the impact of surgical disconnection of the fetal hypothalamus and pituitary on the fetal prolactin response to different photoperiods. Disconnection of the hypothalamus (HPD) or a sham operation was carried out at around day 110 of gestation (term = 145 +/- 3 days). Before surgery, pregnant ewes were maintained under a photoperiod of 12 h light:12 h dark. After surgery, ewes carrying HPD fetuses (n = 10) or intact fetuses (n = 13) were exposed to either a long day (16 h light:8 h dark) or a short day (8 h light:16 h dark) regimen until day 143 of gestation. Thyrotrophin-releasing hormone (50 micrograms) was administered intrafetally at days 130-135 of gestation and chlorpromazine (a dopaminergic antagonist) was administered to all sheep fetuses at days 141-142 of gestation. Mean fetal prolactin concentrations were significantly higher in the long day group (HPD: 37.3 +/- 11.3 ng ml-1; intact: 71.0 +/- 16.2 ng ml-1) than in the short day group (HPD: 9.0 +/- 4.8 ng ml-1; intact: 34.2 +/- 16.0 ng ml-1). In the intact group, fetal prolactin concentrations increased significantly between day 6 and day 30 of exposure to either photoperiod. However, in the HPD group, fetal prolactin increased with increasing exposure to the long day photoperiod and decreased with increasing exposure to the short day photoperiod.(ABSTRACT TRUNCATED AT 250 WORDS)

Melatonin and the development of circadian and seasonal rhythmicity.

We have investigated whether the maternal melatonin rhythm provides the fetus with either a circadian or seasonal 'signal' during development. Our findings provide evidence that melatonin can generate and entrain the early evening peak in the daily rhythm of fetal breathing movements. In contrast, daily variations in maternal and fetal prolactin concentrations are present in pinealectomized ewes, are altered by changes in the time of onset of darkness, but are unaltered by changes in the phase of the daily melatonin rhythm. The mechanisms that generate and control the daily prolactin rhythm before and after birth are therefore unknown. It is clear from a number of studies that the duration of the nocturnal melatonin signal provides the adult and fetal sheep with photoperiodic information. We investigated whether there are differences in the fetal plasma concentrations of prolactin in ewes held in long and short photoperiods after surgical disconnection of the fetal hypothalamus and pituitary and demonstrated that there was a fetal prolactin response to the external photoperiod in sheep fetuses in which the hypothalamo-pituitary axis was either intact or surgically disconnected. We have suggested that one potential extrahypothalamic site of action of maternal melatonin is at the pars tuberalis of the fetal pituitary. It appears therefore that there are a number of different mechanisms for the neuroendocrine transmission of information about the time of day and duration of the external photoperiod to the sheep fetus throughout late gestation.

Evidence for hypothalamic control of the diurnal rhythms in prolactin and melatonin in the fetal sheep during late gestation.

We have investigated the effect of surgical disconnection of the fetal hypothalamus and pituitary (HPD) on generation of the daily rhythm in fetal plasma melatonin and PRL concentrations under long and short photoperiods. Fetal HPD or a sham operation was carried out at around 110 days gestation. Ewes carrying either HPD fetal sheep (n = 10) or intact fetal sheep (n = 12) were exposed to a long light (LL; 16 h of light and 8 h of darkness) or a short light (SL; 8 h of light and 16 h of darkness) regimen for the remainder of gestation. All ewes were subjected to a 24-h blood-sampling experiment (13 samples collected between 0900-0900 h the following day) between 135-140 days gestation, and fetal and maternal plasma melatonin and PRL concentrations were measured using specific RIAs. The hormonal data were analyzed using multifactorial analysis of variance and cosinor analysis. There was an increase in maternal melatonin concentrations during the dark phase in each lighting regimen in ewes carrying HPD or intact fetal sheep. In the SL regimen, there was also a significant increase in fetal melatonin concentrations during the dark phase in the HPD and intact groups. Under LL conditions, however, fetal melatonin concentrations were only consistently increased during the dark phase in the intact, not the HPD, group. The 24-h mean fetal plasma concentrations of PRL were significantly higher (P < 0.001) in both intact and HPD fetuses in the LL (intact, 111.0 +/- 22.0 pg/ml; HPD, 37.6 +/- 7.3 pg/ml) than in the SL regimen (intact, 37.8 +/- 18.4 pg/ml; HPD, 6.7 +/- 4.3 pg/ml). There was also a significant interaction (P < 0.001) between the effects of fetal surgical treatment and time of day on fetal PRL concentrations. In the intact group, fetal PRL concentrations were significantly higher (P < 0.05) at 1300 and 1700 h than between 0300-0700 h in both lighting conditions. Cosinor analysis also identified a significant rhythm in 8 of the 12 fetal PRL profiles in the intact group. In contrast, in the HPD group, there was no significant effect of time of day on fetal PRL in either the LL or SL regimen, and cosinor analysis only identified a significant rhythm in 2 of the 10 fetal PRL profiles in this group. We have, therefore, demonstrated that in the fetal sheep, HPD resulted in abolition of the diurnal melatonin rhythm under LL conditions and in the loss of the diurnal PRL rhythm under LL and SL conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Altered renal vascular responses in the aging rat kidney.

Age-related renal functional changes may relate to alterations in the responsiveness to vasoconstrictors and vasodilators. Blood pressure and renal responses to angiotensin II (ANG II), endothelin-1 (ET), NG-nitro-L-arginine methyl ester (L-NAME), and to the ANG II receptor antagonist losartan were compared in young (3-mo-old) and older (15-mo-old) male rats. Baseline mean arterial pressure (MAP) values were slightly lower in the older rats, and glomerular filtration rate (GFR) and renal plasma flow (RPF) were higher. ANG II and ET induced comparable pressor responses in both groups but produced greater GFR and RPF reductions in the older rats. In contrast, the MAP, GFR, and RPF responses to L-NAME were exaggerated in aging rats. Losartan induced modest MAP reductions in both groups, and comparable renal vasodilatory responses. Thus the aging kidney exhibits exaggerated responses to systemic vasoconstrictor stimuli, whereas responsiveness to ANG II blockade is preserved but not enhanced. Whether or not this balance is further impaired later in the aging process remains to be determined.

Necrotizing medullary lesions in patients with ANCA associated renal disease.

One hundred and five renal specimens from patients with antineutrophil cytoplasmic antibody and antiglomerular basement membrane antibody-associated diseases were reviewed for necrotizing lesions involving the renal medulla. Necrotizing medullary lesions were identified in eight of 56 cases in which medullary tissue was present. All eight were in patients with antineutrophil cytoplasmic antibody (ANCA) associated disease (seven, C-ANCA; one P-ANCA). Four types of medullary lesions were identified; necrotizing capillaritis (seven cases), necrotizing arteriolitis (two cases), pathergic granulomas (three cases) and papillary tip necrosis (one case). Both medullary arteriolitis and medullary peritubular capillaritis developed without corresponding cortical arteriolitis or cortical peritubular capillaritis. Although necrotizing glomerulonephritis was present in seven of eight patients, its activity did not parallel the severity of the medullary lesions. We conclude that several forms of necrotizing medullary vascular lesions may develop in ANCA-associated disease and that there is discordance between state of activity and types of vessel affected between cortical and medullary vascular compartments.

Enhancement of FK506 nephrotoxicity by sodium depletion in an experimental rat model.

FK506 can show efficacy in transplant rejection even after other immunosuppressive drugs have been ineffective. However, the lack of a suitable animal model has hindered the study of FK nephrotoxicity, which has been noted as a common adverse effect in human trials. In this paper, we report a model of chronic FK nephrotoxicity in which renal structure and function are worsened by sodium depletion. Pair-fed male Sprague-Dawley rats were given FK (6 mg/kg p.o.) or vehicle for 21 days on a low-salt or normal diet. There was no significant difference in body weight between FK and vehicle groups. The FK whole-blood trough levels (3-10 ng/ml) in rats are similar to those in FK treated transplant patients. In sodium-depleted rats, FK clearly decreased GFR (0.09 +/- 0.03 ml/min/100 g vs. 0.94 +/- 0.06 ml/min/100 g in the vehicle group, P < 0.01), urinary osmolarity (UOsm, P < 0.01) and plasma magnesium (P < 0.01) and increased plasma creatinine (Pcr, P < 0.01), fractional excretion of magnesium (P < 0.01), urine volume (P < 0.01), plasma renin activity (PRA, P < 0.05), and alanine aminopeptidase (AAP, P < 0.05) as compared with those in the vehicle group. Salt depletion significantly potentiated these functional changes as compared with those in the normal salt group (GFR, UOsm, Pcr, PRA, and AAP of the low salt group vs. those of the normal salt group, P < 0.05 by ANOVA). In the sodium-depleted rats, the main lesion in the rat kidneys was focal collapse and vacuolization in proximal tubules, but there was also significant interstitial fibrosis. In contrast, no injury was observed in the sodium-replete rat kidneys. In conclusion, an experimental model of FK nephrotoxicity in sodium-depleted rats has been developed that is characterized by reduced GFR and structural damage to the proximal tubule accompanied by interstitial fibrosis. Sodium depletion appears to potentiate these changes at blood levels similar to those achieved in patients receiving FK.

Nephrotoxicity of immunosuppressive drugs.

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity.

Hypomagnesaemia with magnesuria are common findings in cyclosporin-(CsA)-treated patients and have been proposed as both a cause and a consequence of nephrotoxicity. To investigate the role of Mg depletion in the pathogenesis of acute CsA nephrotoxicity, rats kept on a low-salt diet were maintained on plain water (Mg(-)group) or water supplemented with 2% MgCl2 (Mg(+)group) and randomly assigned to treatment with CsA 15 mg/kg (CsA) or vehicle (VH) s.c. for 7 days. Water and food ingestion in VH animals was adjusted to the intake of CsA animals. CsAMg(-) group showed a significant plasma magnesium (PMg) reduction as compared to baseline (1.13 versus 1.53 mg/dl, P < 0.001) or VH values (versus 1.60 mg/dl, P < 0.001) and a significantly greater posttreatment fractional excretion of magnesium (FeMg) as compared to VH (9.4 versus 5.4%, P < 0.01). Magnesium supplementation increased PMg (2.11 versus 1.57 mg/dl P < 0.001) and FeMg (13.6 versus 6.2%, P < 0.001) but did not prevent a reduction in GFR with CsA treatment. Alanine aminopeptidase (AAP) excretion at 7 days was significantly greater than baseline (130 versus 44 IU/gCr, P < 0.05) or VH (36 IU/gCr, P < 0.05) values only in the CsAMg(-) rats. No differences were observed in intraerythrocyte Mg, blood pressure, and urinary excretion of N-acetyl-beta-D-glucosaminidase among groups. Renal histology was similar in CsA rats independent of magnesium supplementation: mild vacuolization and tubular collapse in proximal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)