Acute Interstitial Nephritis and Acute Tubular Injury Due to a Transdermal Loxoprofen Patch.

A transdermal patch formulation of a non-steroidal anti-inflammatory drug (NSAID) used by a 44-year-old man resulted in acute interstitial nephritis and acute tubular injury. This patient also had a history of mild kidney dysfunction and osteoporosis. The NSAID patch had been prescribed after a traffic accident. He was also receiving a vitamin D analog and taking over-the-counter calcium supplements. Two months later, renal dysfunction and hypercalcemia were discovered. A renal biopsy showed acute interstitial nephritis and acute tubular injury. Once these agents were withdrawn, the renal function recovered. This is the first reported occurrence of biopsy-proven acute interstitial nephritis attributable to NSAID patch usage.

Oxalate nephropathy associated with chronic pancreatitis.

BACKGROUND AND OBJECTIVES: Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis-associated AON followed in four French renal units. RESULTS: Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. CONCLUSION: AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented.

Azelnidipine exerts renoprotective effects by improvement of renal microcirculation in angiotensin II infusion rats.

BACKGROUND: Hypoxia-induced tubulointerstitial injury caused by loss of peritubular capillary (PTC) blood flow may be associated with progressive renal disease. Therefore, the maintenance of blood flow in PTCs may protect against loss of renal function. A long-acting calcium channel blocker, azelnidipine, has been shown to be useful in the treatment of progressive renal disease. However, its mechanism of action remains unclear. The aim of the present study was to elucidate whether azelnidipine maintains PTC blood flow and to compare it to nifedipine in its ability to improve tubulointerstitial injury caused by angiotensin II (AII) infusion in rats. METHODS: PTC blood flow was initially monitored using a pencil-lens interval microscope before and after intravenous AII (30 ng/kg/min) infusion with or without azelnidipine (10 microg/kg/min). Next, Wistar rats were treated with chronic infusion of AII (500 ng/kg/min) via an osmotic minipump with or without azelnidipine (3 mg/kg/day, orally) or nifedipine (60 mg/kg/day, orally) for 14 days, and tubulointerstitial damage (PTC loss, interstitial fibrosis, tubular atrophy) was examined. RESULTS: PTC blood flow was reduced after AII infusion but improved after a bolus injection of azelnidipine. Tubulointerstitial damage observed in chronically AII-treated kidneys was associated with hypoxic conditions, as indicated by the measurement of hypoxia biomarkers (intracellular hypoxyprobe-1 adducts). These tubulointerstitial injuries in AII-infused rats were more effectively reduced by azelnidipine than by nifedipine. The area showing hypoxic conditions in the kidney was also more reduced with azelnidipine than nifedipine treatment. CONCLUSIONS: Azelnidipine may increase PTC blood flow and improve renal hypoxia and tubulointerstitial injury induced by AII infusion.

[Effect of kurarinone on renal tubular epithelial cell-mesenchyma trans-differentiation in rats with renal interstitial fibrosis].

OBJECTIVE: To study the effect of Kurarinone on renal tubular epithelial cell-mesenchyma (ECM) trans-differentiation in rats with renal interstitial fibrosis and to explore its possible mechanisms. METHODS: The rat model of renal interstitial fibrosis was established by unilateral ureteral obstruction (UUO). Sprague-Dawley male rats were randomly divided into 3 groups, the sham-operated group, the UUO group and the Kurarinone treated group (KTG). Rats in the KTG were intraperitoneally injected with Kurarinone 100 mg/kg daily after modeling. Five rats of each group were killed respectively at day 7, 14 and 21 after UUO. The serum levels of blood urea nitrogen (BUN), serum creatinine (SCr), total protein (TP) and albumin (ALB), 24-h urinary protein excretion in rats were measured. Pathological changes of renal tissue were observed by PAS and Masson stain. The expression of transforming growth factor beta1 (TGF-beta1), Smad3, alpha-smooth muscle actin (alpha-SMA) and collagen I (Col I) in kidney were determined with immunohistochemistry. And the expressions of TGF-beta1 and alpha-SMA mRNA in renal tissue were determined using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The expression of TGF-beta1, Smad3, alpha-SMA and Col I in the KTG was significantly decreased as compared with that in the UUO group respectively, and the degree of tubular damage and renal interstitial fibrosis was also ameliorated more obviously in the KTG. The TGF-beta1 and alpha-SMA mRNA expressions in KTG were significantly lower than those in the UUO group determined at the corresponding time points (P < 0.05). CONCLUSION: Kurarinone could down-regulate the expression of TGF-beta1 and Col I, inhibit EC-M trans-differentiation, suppress the activation and proliferation of myofibroblast. The probable pathway may be by way of down-regulating Smad3 expression to interfere its induction on intercellular signal transduction and consequently ameliorate renal interstitial fibrosis.

Acute tubulointerstitial nephritis following ingestion of Chlorella tablets.

Here, we report on a boy with acute tubulointerstitial nephritis (ATIN), who developed it following ingestion of Chlorella tablets as a food supplement. He was incidentally detected to have glucosuria, proteinuria, and leukocyturia during school mass screening. He had had a history of ingestion of Chlorella tablets for 3 months. Laboratory studies showed anemia, increased levels of creatinine, decreased glomerular filtration rate (GFR), hypokalemia, hypo-uricemia, hypophosphatemia, hypergammaglobulinemia, proteinuria, leukocyturia, and glucosuria. ATIN was diagnosed by renal biopsy. The patient's renal function improved after initiation of corticosteroid therapy and discontinuation of Chlorella for 6 months. Chlorella may be a causative allergen inducing tubulointerstitial injury in kidney.

Role of peritubular capillary loss and hypoxia in progressive tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy.

BACKGROUND/AIMS: To investigate the effects of peritubular capillary (PTC) loss and hypoxia on the progression of tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy (AAN). METHODS: Female Wistar rats received Caulis aristolochiae manshuriensis (CAM) decoction by gavage for 8 weeks, and were sacrificed at 8, 12 and 16 weeks, respectively, after administration. Blood urea nitrogen (BUN), serum creatinine (Scr) and urinary protein were monitored prior to sacrifice. PTC loss and tubulointerstitial hypoxia were assessed by CD34 immunostaining and hypoxia-inducible factor-alpha subunit 1 (HIF-1alpha) expression, respectively. Myofibroblasts were assessed by alpha-smooth muscle actin (alpha-SMA) expression. The expression of angiogenic factor was assessed by vascular endothelial growth factor (VEGF). RESULTS: AAN rats differed from controls by increased BUN, Scr and 24-hour urinary protein excretion rates. There was a progressive loss of PTCs in the AAN model, which was associated with the decreased expression of VEGF. A significant increase in nuclear localization of HIF-1alpha was seen 16 weeks after treatment with CAM decoction in the context of severe tubulointerstitial damage. Multifocal tubulointerstitial fibrosis was seen in AAN rats at weeks 12 and 16, predominantly in the area of the outer stripe and outer medulla. No significant pathologic changes were found in control rats. CONCLUSION: Following the reduction of PTCs density and up-regulation of HIF-1alpha, the tubulointerstitial fibrosis area increased. Ischemia and hypoxia are the important causes of severe tubulointerstitial fibrosis in AAN rats.

Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis.

BACKGROUND: Tubulointerstitial nephritis (TIN) is characterized by progressive inflammatory infiltrate of the renal interstitium, induction of cortical tubular inducible nitric oxide synthase (iNOS) and reductions in glomerular filtration rate (GFR). These studies were designed to examine the changes in glomerular hemodynamics 7 and 21 days after induction of TIN and to evaluate the effect of acute iNOS blockade on glomerular function in the early stages of this model. METHODS: TIN was induced by immunizing Brown Norway rats with renal tubular antigen in complete Freund's adjuvant (RTA/CFA). Control rats were immunized with CFA alone. Micropuncture and morphologic studies were performed 7 and 21 days after immunization. RESULTS: Histology revealed minimal peritubular and interstitial inflammation in the RTA/CFA group one week after immunization while extensive interstitial inflammation with few preserved superficial nephron was observed three weeks after RTA/CFA immunization. Micropuncture studies on day 7 in the RTA/CFA group revealed a significant reduction in single nephron GFR due to a profound reduction in nephron plasma flow and in the ultrafiltration coefficient. Studies performed on day 21 revealed that single nephron GFR (SNGFR), nephron plasma flow (SNPF) and the ultrafiltration coefficient had returned to the normal baseline value despite the severe reduction in GFR. To assess the role of increased nitric oxide production secondary to iNOS induction on the glomerular hemodynamic changes observed in the early stages of the disease, the iNOS blocker (l-N(6)-iminoethyl lysine, L-NIL) was administered IV (1 mg/h) in RTA/CFA rats and CFA rats. L-NIL had no effect in CFA rats but produced significant increases in GFR, SNGFR and SNPF in RTA/CFA rats. CONCLUSIONS: These results demonstrate that TIN is associated with a progressive reduction in GFR, which is likely the result of functional vasoconstriction and decreases in the ultrafiltration coefficient in the early stages of the disease and on a significant reduction in the number of functioning nephron in the later stages. Induction of iNOS with increased NO production actively participates in the functional changes observed in the early stages of the disease most likely by inhibiting normal endothelial NOS activity.

[Effect of coenzyme Q10 in patients with kidney diseases]. / Ucinok koenzýmu Q10 u pacientov s ochoreniami obliciek.

BACKGROUND: Coenzyme Q10 belongs to important antioxidants and it has a key role in the synthesis of adenosinetriphosphate. Its beneficial effect was proved in several diseases, e.g. in mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial cardiomyopathy. MATERIAL AND METHODS: All 15 patients of the studied group (5 with tubulopathy and 10 with chronic tubulointersticial nephritis) received antioxidative therapy for three months (E vitamin, C vitamin, riboflavin) and for the last two months coenzyme Q10 was added. Renal functions, spectrum of lipids, parameters of lipid peroxidation (malondialdehyde), levels of alpha-tocopherol, beta-carotene, coenzyme Q10. RESULTS: Before the substitutive antioxidative treatment, coenzyme Q10 levels reached in blood 0.11 +/- 0.03 mumol/l and 0.15 +/- 0.04 mumol/l in plasma. These values were well below the reference range (rr) is 0.4 +/- 1.0 mumol/l). After the substitution coenzyme Q10 levels significantly increased (p < 0.001) to the values of 1.66 +/- 0.16 mumol/l in blood and to 1.78 +/- 0.27 mumol/l in plasma. Plasma levels of beta-carotene increased from the markedly subnormal values 0.25 +/- 0.07 mumol/l (rr > 0.8 mumol/l) to 0.56 +/- 0.02 mumol/l (no statistical difference). Plasma levels of alpha-tocopherol remained within the reference range 32.15 +/- 4.73 mumol/l (rr 15-30 mumol/l) and they increased up to the plasma level of 44.83 +/- 5.82 mumol/l during the period of testing. Malondialdehyde levels did not significantly change within the testing period. No changes in renal functions and parameters of lipid metabolism were described. Patients well tolerated the treatment and no adverse effects were seen during the period of observation. CONCLUSIONS: Our results ascertained that levels of antioxidant CoQ10 were lower in patients with nephropathy who underwent conservative treatment with peroral substation. Such deficit can be amended by CoQ10 administration, which could be therefore taken as complementary treatment of nephrology.

[The effect of the preparation Wobe-Mugos E on the functional and biochemical status of the kidneys in the polyuric stage of sublimate-induced nephropathy]. / Vplyv preparatu Wobe-Mugos E na funktsional'nyi ta biokhimichnyi stan nyrok u poliurychnu stadiiu sulemovoï nefropatiï.

The protective effect of Wobe-Mugos appliance on the kidney function and biochemical state in polyuric stage of sublimate nephropathia at the moment of tubulointerstitial component formation was revealed in experiments on 40 white male rats. It appeared in the increase of hydrogenous ion excretion, titred acids, renal tissue fibrinolytic and proteolytic activity. The succinatdehydrogenase activation in renal cortex matter pointed out on the improvement of energy balance.

[Interstitial nephropathies of toxic or drug origin. New causes, new prospects]. / Néphropathies interstitielles d'origine médicamenteuse ou toxique. De nouvelles causes, de nouvelles perspectives.

PHENOTYPING INTERSTITIAL INFILTRATIONS: Recent progress has led to the distinction between type I and type II fibroblasts in the renal interstitium. The cellular phenotype of pathological infiltrations can be identified with monoclonal antibodies. DRUG-INDUCED INTERSTITIAL NEPHROPATHIES: Extrarenal manifestations (skin eruptions, fever, joint pain) often suggests the diagnosis but may be absent, in which case renal histology is required. CAUSAL DRUGS: Among the different causal agents, nonsteroid anti-inflammatory drugs cause abnormal leakage from glomerular capillaries favoring the development of a nephrotic syndrome associated with renal failure and major cell infiltration into the interstitial tissue. CHRONIC DISEASE: Chronic interstitial nephropathy is nearly asymptomatic and may only be discovered at an advanced stage. Briefly, there are three categories which result from long-term administration of 5-aminosalicylate, use of Chinese herbal medicines to lose weight, and chronic intoxication with ochratoxin (a mycotoxin). COMPLEX PHYSIOPATHOLOGY: Immunological mechanisms are involved although it is not always easy to distinguish between manifestations of humoral and cellular reactions. Both could be implicated as indicated in recent experimental animal models which throw more light on the pathological process in humans. RENAL PROGNOSIS: Different strategies can be used to halt or limit the development of fibrosis and thus improve prognosis of toxic interstitial nephropathies: counteract cellular immunity reactions, inhibit fibroblast proliferation and activation, reduce synthesis and stimulate degradation of the extracellular matrix, and inhibit collagen formation.

Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis.

T lymphocytes are exquisitely sensitive to the antiproliferative effects of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with either inhibitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase-PCR demonstrated that L-NAME-treated animals displayed significantly augmented levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data suggest that the L-NIL-treated animals had a skewing of their immune response toward a Th1-like response. We conclude that in autoimmune interstitial nephritis, generation of nitric oxide through the iNOS pathway has host-protective effects, and suggest that this may be broadly applicable to T cell-mediated pathologies.

Natural history of aminoglycoside nephrotoxicity in the dog.

The natural history of aminoglycoside nephrotoxicity is not well described. This study investigated in the dog renal functional and electrolyte abnormalities during and for 20 days following a 10-day course of low-dose gentamicin (7 mg/kg/day), high-dose gentamicin (30 mg/kg/day), and netilmicin (30 mg/kg/day). Renal histology was examined at the end of the study. Renal functional abnormalities occurred only in animals receiving high-dose gentamicin. A fall in maximal urinary osmolality (1579 +/- 347 mOsm/kg/H2O to 450 +/- 118, p less than 0.05) was followed by renal glycosuria and a fall in GFR (66.9 +/- 11.9 ml/min to 21.3 +/- 8.6, p less than 0.05). These three functional indices had recovered by day 30 in the survivors. Plasma potassium fell in animals receiving high-dose gentamicin (3.8 +/- 0.02 mEq/L to 3.3 +/- 0.4, p less than 0.05) and reached the lowest values (2.7 and 2.9 mEq/L) just prior to death in two animals dying in uremia. Netilmicin also caused a significant fall in plasma potassium (4.3 +/- 0.1 mEq/L to 3.9 +/- 0.1, p less than 0.05). Hypocalcemia (10.0 +/- 1.3 mg/dl to 7.8 +/- 1.4, p less than 0.05) but not hypomagnesemia developed following high-dose gentamicin. Peak serum aminoglycoside levels after high-dose gentamicin and netilmicin were comparable, but trough levels rose only in high-dose gentamicin animals and paralleled the fall in GFR. Light microscopy of the kidney 3 weeks after high-dose gentamicin demonstrated no proximal tubular necrosis but extensive focal tubulointerstitial nephritis, especially in the juxtamedullary cortex. Similar but less extensive derangements were noted in animals receiving low-dose gentamicin, despite the absence of functional abnormalities. Minor histological abnormalities were noted in animals receiving netilmicin. To summarize: 1) major renal functional and electrolyte abnormalities developed only following high-dose gentamicin and included impaired urinary concentration, glycosuria, reduced GFR, hypokalemia, and hypocalcemia (except for a fall in plasma potassium, similar doses of netilmicin were not nephrotoxic); (2) tubulointerstitial nephritis, particularly in the juxtamedullary cortex, occurred with low-dose gentamicin as well as high-dose gentamicin and may be a factor in delayed or incomplete recovery from gentamicin nephrotoxicity; (3) in this model, netilmicin at comparable doses was substantially less nephrotoxic than gentamicin; (4) renal postassium wasting may be a heretofore unrecognized consequence of aminoglycoside administration.