Renal outcomes in primary IgA nephropathy patients with segmental glomerular necrosis: a case-control study.

The renal prognosis and treatment of primary IgA nephropathy (IgAN) patients with segmental glomerular necrosis (SGN) remain controversial. Patients with primary IgAN confirmed by renal biopsy were enrolled. Patients with SGN on renal biopsy were selected as the necrosis group, and a propensity score matching method was used to match a control group according to age, gender, weight, height and follow-up time. A total of 825 IgAN patients were enrolled in the present study. Seventy-three (8.8%) patients with SGN were selected as the necrosis group, and 292 patients without SGN were matched as the control group. Compared to the control group, a significantly increased serum fibrinogen level (3.97 g/L vs 3.54 g/L, P=.002) and proportion of patients with macroscopic hematuria (35.6% vs 14.7%, P<.001) was observed in the necrosis group. According to the new IgA pathological classification system, crescent formation was more pronounced in the necrosis group (P=.001). The average estimated glomerular filtration rate was obviously higher in the necrosis group and decreased more slowly during follow-up. However, the time-averaged urine protein-to-creatinine ratio remained low in the necrotic group, whereas it gradually increased in the control group. SGN suggests an active renal inflammatory state, but it was not an independent risk factor for a poor renal outcome in patients treated with immunosuppressive therapy. Furthermore, patients with SGN had a more stable renal function and low urinary protein excretion during follow-up, which may be attributable to aggressive immunotherapy.

Human kidney damage in fatal dengue hemorrhagic fever results of glomeruli injury mainly induced by IL17.

Acute kidney injury is an unusual complication during dengue infection. The objective of this study was to better identify the characteristics of glomerular changes focusing on in situ immune cells and cytokines. An immunohistochemical assay was performed on 20 kidney specimens from fatal human cases of dengue hemorrhagic fever (DHF). It was observed a lymphomononuclear infiltrate, neutrophils and nuclear fragmentation in the glomeruli, hydropic degeneration, nuclear retraction, eosinophilic tubules and intense acute congestion. Sickle erythrocytes were frequent in glomeruli and inflammatory infiltrate. The glomeruli presented endothelial swelling and mesangial proliferation. Lymphocytes CD4+ predominated over CD8+ T cells, B cells and natural killer cells. There were also an expressive number of macrophagic CD68+ cells. S100, Foxp3 and CD123 cells were not identified. Cells expressing IL17 and IL18+ cytokines predominated in the renal tissues, while IL4, IL6, IL10, IL13, TNF-alpha and IFN-gamma were rarely visualized. The high number of cells expressing IL17 and IL18+ could reflect the acute inflammatory response and possibly contribute to the local lesion. CD8+ T cells could play a role in the cytotoxic response. DHF is a multifactorial disease of capillary leakage associated with a "Tsunami of cytokines expression". The large numbers of cells expressing IL17 seems to play a role favoring the increased permeability.

Comparison of Ultrasound Corticomedullary Strain with Doppler Parameters in Assessment of Renal Allograft Interstitial Fibrosis/Tubular Atrophy.

To compare the capability of ultrasound strain and Doppler parameters in the assessment of renal allograft interstitial fibrosis/tubular atrophy (IF/TA), we prospectively measured ultrasound corticomedullary strain (strain) and intra-renal artery Doppler end-diastolic velocity (EDV), peak systolic velocity (PSV) and resistive index (RI) in 45 renal transplant recipients before their kidney biopsies. We used 2-D speckle tracking to estimate strain, the deformation ratio of renal cortex to medulla produced by external compression using the ultrasound transducer. We also measured Doppler EDV, PSV and RI at the renal allograft inter-lobar artery. Using the Banff scoring system for renal allograft IF/TA, 45 patients were divided into the following groups: group 1 with ≤5% (n = 12) cortical IF/TA; group 2 with 6%-25% (n = 12); group 3 with 26%-50% (n = 11); and group 4 with >50% (n = 10). We performed receiver operating characteristic curve analysis to test the accuracy of these ultrasound parameters and duration of transplantation in determining >26% cortical IF/TA. In our results, strain was statistically significant in all paired groups (all p < 0.005) and inversely correlated with the grade of cortical IF/TA (p < 0.001). However, the difference in PSV and EDV was significant only between high-grade (>26%, including 26%-50% and >50%) and low-grade (≤25%, including <5% and 6%-25%) cortical IF/TA (p < 0.001). RI did not significantly differ in any paired group (all p > 0.05). The areas under the receiver operating characteristic curve for strain, EDV, PSV, RI and duration of transplantation in determining >26% cortical IF/TA were 0.99, 0.94, 0.88, 0.52 and 0.92, respectively. Our results suggest that corticomedullary strain seems to be superior to Doppler parameters and duration of transplantation in assessment of renal allograft cortical IF/TA.

Ceftriaxone-induced hemolysis in a child with Lyme arthritis: a case for antimicrobial stewardship.

Guidelines for the treatment of Lyme arthritis were published by the Infectious Diseases Society of America in 2006 and recommended oral doxycycline for initial therapy. We report here the case of a young girl treated with intravenous ceftriaxone who subsequently developed drug-induced autoimmune hemolytic anemia and renal failure. Her severe sequelae highlight the importance of antimicrobial stewardship. We review here the goals of antimicrobial stewardship and several strategies for achieving them. In addition, we briefly discuss the rare adverse drug event experienced by our patient.

ERK pathway mediates P2X7 expression and cell death in renal interstitial fibroblasts exposed to necrotic renal epithelial cells.

We recently reported that necrotic renal proximal epithelial cells (RPTC) stimulate the expression of P2X7 receptor in renal fibroblasts and that P2X7 receptor mediates deleterious epithelial-fibroblast cross talk. The present study was carried out to investigate the signaling mechanism of necrotic RPTC-induced P2X7 expression in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to necrotic RPTC supernatant (RPTC-Sup) induced a time- and dose-dependent phosphorylation of several signaling pathways including extracellular signal-regulated kinases (ERK1/2), p38, c-Jun N-terminal kinases (JNKs), and AKT in NRK-49F. Pharmacological inhibition of ERK1/2, but not p38, JNK, and AKT pathways, blocked RPTC-Sup-induced P2X7 expression and renal interstitial fibroblast death. Knockdown of ERK1/2 or MEK1, a direct upstream activator of ERK1/2, also reduced RPTC-Sup-induced P2X7 expression and cell death of renal fibroblasts. Conversely, overexpression of MEK1 enhanced these responses. Upon necrotic RPTC exposure, phosphorylation of Elk1, a transcriptional factor targeted by ERK1/2, was increased in NRK-49F, and knockdown of Elk1 by siRNA remarkably reduced RPTC-Sup-induced P2X7 expression as well as renal fibroblast death. Furthermore, silencing of MEK1 inhibited Elk1 phosphorylation in response to necrotic RPTC, whereas overexpression of MEK1 increased Elk1 phosphorylation. Taken together, these data reveal that necrotic RPTC induces P2X7 expression in renal fibroblasts through activation of the MEK1-ERK1/2-Elk1 signaling pathway.

Obstetrical associated renal, cortical necrosis: uncommon but not rare!

BACKGROUND: Renal cortical necrosis (RCN) carries high morbidity and mortality in South East Asia. The purpose of this study was to look specifically at the incidence of obstetrical related RCN in renal biopsies and to evaluate its precipitating factors. In addition, prognosis, impact of aetiology and outcomes on discharge were also considered. METHODS: The study was conducted in the Department of Nephrology, Lady Reading Hospital Peshawar, Pakistan. Renal biopsies of 1,670 patients were analysed during the study period of 1998 to 2008. All the patients with obstetrical related RCN were included. Patient records, demographic data, urine output on admission and preceding history of ante-partum haemorrhage (APH), post-partum haemorrhage (PPH), septicaemia, operative interventions and retained product of conception (ROPC) was noted and need for dialysis was considered. RESULTS: Out of 1670 kidney biopsies analysed, 48 turned out to be RCN. Among them 39 patients (81.3%) had diffuse cortical necrosis, 6 patients (12.5%) had patchy cortical necrosis with ATN while 3 patients (6.3%) had predominant ATN with partial patchy cortical necrosis. Out of 48 patients, 25 (52.1%) were oliguric, 18 (37.5%) were anuric while 5 (10.4%) had urine output > 800 ml 24 hr. Operative interventions were found in 29 patients while 19 patients had normal vaginal delivery (NVD). 16 (55.2%) patients with operative intervention had PPH. Thus the association proved to be significant (p = 0.037). CONCLUSION: Overall incidence of RCN was 2.9%. Oliguria/anuria on admission and dialysis dependency are associated with RCN. PPH and history of operative intervention have significant association and are contributing factors to development of RCN.

Pressure-induced renal injury in angiotensin II versus norepinephrine-induced hypertensive rats.

The susceptibility to renal perfusion pressure (RPP)-induced renal injury was investigated in angiotensin II (Ang II)- versus norepinephrine (NE)-infused hypertensive rats. To determine the magnitude of RPP-induced injury, Sprague-Dawley rats fed a 4% salt diet were instrumented with a servocontrolled aortic balloon occluder positioned between the renal arteries to maintain RPP to the left kidney at baseline levels whereas the right kidney was exposed to elevated RPP during a 2-week infusion of Ang II IV (25 ng/kg per minute), NE IV (0.5, 1.0, and 2.0 microg/kg per minute on days 1, 2, and 3 to 14, respectively), or saline IV (sham rats). Over the 14 days of Ang II infusion, RPP averaged 161.5+/-8.0 mm Hg to uncontrolled kidneys and 121.9+/-2.0 mm Hg to servocontrolled kidneys. In NE-infused rats, RPP averaged 156.3+/-3.0 mm Hg to uncontrolled kidneys and 116.9+/-2.0 mm Hg to servocontrolled kidneys. RPP averaged 111.1+/-1.0 mm Hg to kidneys of sham rats. Interlobular arterial injury and juxtamedullary glomerulosclerosis were largely RPP dependent in both models of hypertension. Superficial cortical glomerulosclerosis was greater and RPP dependent in NE- versus Ang II-infused rats, which was primarily independent of RPP. Outer medullary tubular necrosis and interstitial fibrosis were also primarily RPP dependent in both models of hypertension; however, the magnitude of injury was exacerbated in Ang II-infused rats. We conclude that elevated RPP is the dominant cause of renal injury in both NE- and Ang II-induced hypertensive rats and that underlying neurohumoral factors in these models of hypertension alter the pattern and magnitude of RPP-induced renal injury.

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Cardiopulmonary bypass-associated acute kidney injury: a pigment nephropathy?

Acute kidney injury (AKI) is a common and serious postoperative complication following exposure to cardiopulmonary bypass (CPB). Several mechanisms have been proposed by which the kidney can be damaged and interventional studies addressing known targets of renal injury have been undertaken in an attempt to prevent or attenuate CPB-associated AKI. However, no definitive strategy appears to protect a broad heterogeneous population of cardiac surgery patients from CPB-associated AKI. Although the association between hemoglobinuria and the development of AKI was recognized many years ago, this idea has not been sufficiently acknowledged in past and current clinical research in the context of cardiac surgery-related AKI. Hemoglobin-induced renal injury may be a major contributor to CPB-associated AKI. Accordingly, we now describe in detail the mechanisms by which hemoglobinuria may induce renal injury and raise the question as to whether CPB-associated AKI may actually be, in a significant part, a form of pigment nephropathy where hemoglobin is the pigment responsible for renal injury. If CPB-associated AKI is a pigment nephropathy, alkalinization of urine with sodium bicarbonate might protect from: (1) tubular cast formation from met-hemoglobin; (2) proximal tubular cell necrosis by reduced endocytotic hemoglobin uptake, and (3) free iron-mediated radical oxygen species production and related injury. Sodium bicarbonate is safe, simple to administer and inexpensive. If part of AKI after CPB is truly secondary to hemoglobin-induced pigment nephropathy, prophylactic sodium bicarbonate infusion might help attenuate it. A trial of such treatment might be a reasonable future investigation in higher risk patients receiving CPB.

Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells.

Renal ischemia-reperfusion (IR) injury is a major clinical problem without effective therapy. We recently reported that volatile anesthetics protect against renal IR injury, in part, via their anti-inflammatory properties. In this study, we demonstrate the anti-inflammatory and antinecrotic effects of sevoflurane in cultured kidney proximal tubule cells and probed the mechanisms of sevoflurane-induced renal cellular protection. To mimic inflammation, human kidney proximal tubule (HK-2) cells were treated with tumor necrosis factor-alpha (TNF-alpha; 25 ng/ml) in the presence or absence of sevoflurane. In addition, we studied the effects of sevoflurane pretreatment on hydrogen peroxide (H2O2)-induced necrotic cell death in HK-2 or porcine proximal tubule (LLC-PK1) cells. We demonstrate that sevoflurane suppressed proinflammatory effects of TNF-alpha evidenced by attenuated upregulation of proinflammatory cytokine mRNA (TNF-alpha, MCP-1) and ICAM-1 protein and reduced nuclear translocation of the proinflammatory transcription factors NF-kappaB and AP-1. Sevoflurane reduced necrotic cell death induced with H2O2 in HK-2 cells as well as in LLC-PK1 cells. Sevoflurane treatment resulted in phosphorylation of prosurvival kinases, ERK and Akt, and increased de novo HSP-70 protein synthesis without affecting the synthesis of HSP-27 or HSP-32. We conclude that sevoflurane has direct anti-inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury. These mechanisms may, in part, account for volatile anesthetics' protective effects against renal IR injury.

Acute renal failure due to intrinsic renal diseases: review of 1122 cases.

In this study we have analyzed incidence, causes and clinical course of ARF due to primary intrarenal disease other than acute tubular necrosis. Thousand hundred and twenty two cases of ARF of diverse etiology were studied over a period of 16 years; July 1984 to Dec, 1999. Surgical ARF 231 (20.6%) were not included in the present study. Intrinsic renal diseases were responsible for ARF in 891 (79.4%) of cases. The most common intrinsic renal diseases 705 (79.4%) causing ARF were ischemic/toxic acute tubular necrosis, but not included in this study. Acute renal failure was related to acute glomerulonephritis (9.3%), acute interstitial nephritis (7%), and renal cortical necrosis in (4.6%) of cases. Therefore intrinsic renal diseases other than ATN were the causative factor for acute renal failure in 186 (20.8%) patients in our study. Crescentic (51.8%) and endocapillary proliferative glomerulonephritis (34.9%), were the main glomerular diseases responsible for ARF and 75.9% of GN was related to infectious etiology. Fifty three percent of acute interstitial nephritis was drug induced and in 25 (40%) patients it was related to an infectious etiology. Renal cortical necrosis due to HUS was observed in 16 (39%) children and majority (76.47%) of the cases had a diarrhoeal prodrome. Obstetrical complications were the main causes (61%) of cortical necrosis in adults with acute renal failure. Thus, intrinsic renal diseases other than ATN were responsible for ARF in 186 (20.8%) cases. Post-infectious glomerulonephritis, acute interstitial nephritis and renal cortical necrosis (complicating HUS in children and obstetrical complications in adult) are the main causes of acute renal failure in our study. Both acute GN and interstitial nephritis had excellent prognosis, however renal cortical necrosis was associated with a very high mortality.

Necrosis renal cortical aguda / Acute renal cortical necrosis

La necrosis renal cortical aguda (NRCA) es la destrucción parcial o total de todos los elementos de la corteza renal. Se caracteriza por oliguria prolongada y recuperación incompleta de la función renal. Se ha implicado al vasoespasmo y a la liberación de toxinas en los eventos fisiopatológicos que producen esta enfermedad. Las causas más comunes de ARCN son complicaciones del enbarazo, síndrome urémico hemolítico, pancreatitis, sepsis, quemaduras, trauma, mordeduras de serpientes, shock y rechazo de injertos. La mortalidad es muy alta y muchos de los sobrevivientes requieren substitución permanente de la función renal

Infarto renal con hipertensión arterial: informe de un caso pediátrico / Renal infarction with arterial hypertension: report of a pediatric case

El infarto renal puede definirse como la muerte de tejido renal debido a interferencia con su circulación sanguínea. Se presenta el caso de un paciente masculino, de nueve años de edad, con cefalea universal, vómitos de contenido gástrico y una tensión arterial (TA) de 140/100 mmHg. Su renina plasmática periférica fue de 7.4 ng/mL/h (normal hasta 2.5 ng/mL/h). La arteriografía renal indicó infarto parenquimatoso en polo superior de riñón derecho. Actualmente, está controlado con una tensión arterial de 110/70 mmHg, para lo cual recibe 1 mg/kg/día de captopril complementado con dieta hiposódica.

Kidney retrieval from cadaver donors with disseminated intravascular coagulopathy.

Cadaver kidneys from donors with DIC appear to have an increased incidence of delayed function and primary nonfunction. These kidneys may be safely transplanted if cortical necrosis is ruled out. Heparin, antiplatelet therapy, and withholding of cyclosporin A therapy in the early post-transplantation period may improve renal function if there is evidence of glomerular capillary thrombosis.

Necrose cortical bilateral e tuberculose pulmonar: apresentaçäo de um caso e discussäo fisiopatogênica / Bilateral cortical necrosis case and pulmonary tuberculosis: report of a and physiopathological discussion

É apresentado o que se acredita ser o segundo caso da literatura de necrose cortical bilateral (NCB) associado à tuberculose pulmonar, no qual näo foram encontrados fatores que pudessem ser diretamente responsabilizados pela NCB. Os aspectos fisiopatológicos da NCB säo revisados e confrontados com os da necrose tubular aguda (NTA) isquêmica, condiçäo que, ao contrário da NCB, é habitualmente reversível. A possibilidade de que condiçöes mórbidas variadas predisponham a uma resposta vascular anormal que culmine com uma lesäo isquêmica irreversível que inclua o glomérulo é discutida

Inhibition of fibrinolytic system by liquoid (polyanetholesulfonate). A contributing factor in the liquoid-induced renal cortical necrosis.

Liquoid induces microvascular thrombosis and renal cortical necrosis in experimental animals. We hypothesized that thrombosis and renal cortical necrosis may, at least in part, result from the inhibition of the fibrinolytic system by liquoid. Effects of liquoid on plasminogen activation by rat kidney, purified human tissue plasminogen activator (TPA), urokinase, streptokinase, and on the amidolytic activities of TPA, urokinase, and plasmin were studied using chromogenic substrates and clot lysis. Liquoid had a strong inhibitory effect on the fibrinolytic system in vivo and in vitro. The inhibition was most effective at the plasminogen activation level, with activation by streptokinase being most susceptible. The demonstrated stoichiometric binding between liquoid and plasminogen, and to a lesser degree the direct inactivation of plasminogen activators and plasmin, is probably responsible for the reduction of plasminogen activation in circulation and in the kidneys.

Different functional characteristics of residual nephrons in infantile vs adult diffuse cortical necrosis.

In this report we study the functional characteristics of residual nephrons in a 37 year-old woman, 7 months after diffuse bilateral cortical necrosis (CN) of unknown etiology, and in two infants, aged 13 and 15 months, who suffered CN in early infancy after surgical shock and acute dehydration, respectively. In the three cases CN was proven histologically by renal biopsy but undamaged nephrons were only present in the juxtamedullary area in the adult patient whereas in the two infants they were located in the outer part of the cortex. At the time of the study all patients presented a similar degree of renal insufficiency (creatinine clearance: 17-23 ml/min/1.37 m2). The adult patient showed a partly conserved ability to concentrate the urine, a marked free water formation in relation to the degree of distal sodium delivery and an unimpaired capacity to acidify the urine after an acid load. Both infants, by the contrary, were unable to concentrate the urine, had lower free water formation at similar rates of distal sodium delivery and presented a clear incapacity to acidify the urine. These results confirm previous finding indicating the sparing of juxtamedullary nephrons after CN in the adult subject but favor the existence of a surviving population of superficial nephron when CN occurs in early infancy. These differences are probably in relation with associated damage of deep cortex and medulla infancy due to the specific characteristics of blood flow distribution present at that age.