Galectin-3 and Autophagy in Renal Acute Tubular Necrosis.

Acute kidney injury (AKI) is a public health burden with increasing morbidity and mortality rates and health care costs. Acute tubular necrosis (ATN) is the most common cause of AKI. Cisplatin (CIS) is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies such as lung, breast, ovary, testis, bladder, cervix, and head and neck cancers. Autophagy plays an important role in AKI. Galectin-3 (Gal-3) is significantly increased in renal tubules in AKI; however, its role in autophagy is not well understood. Male C57B6/J and B6.Cg-Lgals3 /J Gal-3 knockout (KO) mice were used to induce AKI using a CIS mouse model of ATN. Renal Gal-3 and autophagy proteins' expression were measured using standard histologic, immunofluorescent, and enzyme-linked immunosorbent assay techniques. The data were presented as the mean ± S.E. Statistically significant differences (p < 0.05) were calculated between experimental groups and corresponding control groups by one-way analysis of variance. There was a significant increase in renal concentrations of Gal-3 in the Gal-3 wild-type CIS-treated mice when compared with sham control mice. There were significantly higher concentrations of renal LC3B, ATG13, Ulk-1, Beclin, ATG5, ATG12, ATG9A, and p-AMPK in the CIS-treated Gal-3 KO mice than in the Gal-3 wild-type CIS-treated mice. Further, there were significantly higher concentrations of mTOR, p- NF-κB, beta-catenin, and p62 in the kidneys of the Gal-3 wild-type CIS-treated mice than in the Gal-3 KO CIS-treated mice. Our findings affirm the connection between Gal-3 and autophagy, revealing its central role as a connector with prosurvival signaling proteins. Gal-3 plays a pivotal role in orchestrating cellular responses by interacting with prosurvival signal pathways and engaging with autophagy proteins. Notably, our observations highlight that the absence of Gal-3 can enhance autophagy in CIS-induced ATN.

Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss.

Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.

Bilateral acute renal cortical necrosis after a dog bite: case report.

BACKGROUND: Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats' normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a "reverse rim sign" in contrast-enhanced computed tomography on hospital admission. CASE PRESENTATION: We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. CONCLUSION: We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis - was visible as "reverse rim sign" on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Systemic complement activation in anti-neutrophil cytoplasmic antibody-associated vasculitis and necrotizing glomerulonephritis.

AIM: Due to the accumulating evidence of complement activation in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), we decided to investigate the possibility of systemic complement activation in patients with Necrotizing Glomerulonephritis secondary to AAV. METHODS: Clinical, laboratory and histological findings, and serum levels of complement components, C3a, C5a and Bb fragment of Factor B and C4d, were estimated in patients with AAV and glomerulonephritis, at time of diagnosis, before any treatment had been applied. All patients were treated with the same immunosuppressive protocol and followed up for total 24 months. Twenty age and sex matched healthy individuals served as controls. RESULTS: Serum levels of all complement components were significantly increased in patients, compared to controls; C5a: 19.9(0.02-48) vs 9.06(2.1-16.3)pg/mL, P = .002, Bb: 7.3(0.02-31.4) vs 0.2(0.02-1.6)pg/mL, P < .0001, C3a: 4.7(0.4-7.2) vs 2.4(1.09-5)pg/mL, P = .05 and C4d: 11.6(0.07-70) vs 0.7(0.07-8.2)pg/mL, P = .001, respectively. There was strong correlation between serum Bb levels and eGFR and FFS2009 score at time of diagnosis (r = -.41, P = .002 and r = .41, P = .003 respectively). Also, serum Bb levels were increased in patients with severe interstitial infiltration (P = .04) and focal necrosis (P = .01) on renal biopsy. Serum Bb levels could also predict renal function outcome during the acute phase of disease, but not at the end of follow up. CONCLUSION: We provided strong evidence of systemic activation of complement alternative pathway in the development and progression of AAV and glomerulonephritis. Serum Bb seem to play a critical role in the induction, also predicting disease activity and outcome, yet activation of classical pathway cannot be excluded.

Renal Morphology in Coronavirus Disease: A Literature Review.

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.

Towards a simplified renal histopathological prognostic score in glomerular nephropathies.

AIMS: An important role of native kidney biopsy evaluation is to predict renal prognosis. We aimed to develop a simplified chronicity score based solely on pathological features that are easily recognisable and can be found in all glomerular nephropathies (GN). In this retrospective study, observational cohort study we included 625 patients with GN diagnosis after native kidney biopsy in a tertiary unit between 1 January 2010 and 31 December 2015. METHODS AND RESULTS: Presence of global glomerulosclerosis (GG), tubular atrophy (TA), interstitial fibrosis (IF) and fibrocellular/fibrous crescents (FC) in any grade was scored with one point; a final score was between 0 and 4 (i.e. 'absent' 0 score, 'moderate' 1-2 score, 'severe' 3-4 score). The primary endpoint was renal replacement therapy (RRT) initiation. Mean baseline estimated glomerular filtration rate (eGFR) was 55.9 ± 29.6 ml/min; during the follow-up (median = 27 months), 78 patients started RRT. The total mean renal survival time was 60.1 (58.0-62.1) months. GG (41%) was the most frequent lesion, followed by IF (25%), TA (18%) and FC (17%). Patients with absent (65.7; 63.6-67.8 months) chronicity had better renal survival than those with moderate (59.1; 56.1-62.2 months) or severe (42.7; 35.6-49.7 months) chronicity. The score was associated with renal survival [hazard ratio (HR) = 1.33; 1.08-1.64)] independently of the classical prognostic factors. Patients with moderate and severe chronicity had a two- and threefold increase in risk of RRT initiation. CONCLUSION: Our score was correlated with renal survival independently of the traditional risk factors, and could improve outcome prediction in patients with GN by reducing the interobserver variability.

COVID-19-associated collapsing glomerulopathy: a report of two cases and literature review.

Nephrotic range proteinuria has been reported during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). However, the pathological mechanisms underlying this manifestation are unknown. In this article, we present two cases of collapsing glomerulopathy (CG) associated with acute tubular necrosis during the course of COVID-19, and review the literature for similar reports. In our two cases, as in the 14 cases reported so far, the patients were of African ancestry. The 14 patients assessed had an APOL1 high-risk genotype. At the end of the reported period, two patients had died and five patients were still requiring dialysis. The 16 cases detailed in the present report strongly argue in favour of a causal link between SARS-CoV-2 infection and the occurrence of CG in patients homozygous for APOL1 high-risk genotype for which the term COVID-associated nephropathy (COVIDAN) can be put forward.

Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis.

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis.

Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA-/- mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA-/- tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA-/- mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.

Acute Thrombotic Microangiopathy and Cortical Necrosis Following Administration of Alemtuzumab: A Case Report.

Alemtuzumab, a humanized monoclonal antibody that targets CD52 antigens on lymphocytes and monocytes, has shown efficacy in preventing relapse in relapsing-remitting multiple sclerosis. Despite known severe (yet rare) renal side effects such as anti-glomerular basement membrane disease and membranous glomerulopathy, to our knowledge, alemtuzumab has never been documented to cause drug-induced thrombotic microangiopathy. We describe a 39-year-old woman with relapsing-remitting multiple sclerosis who developed acute kidney injury requiring renal replacement therapy after 1 dose of alemtuzumab, as well as microangiopathic hemolytic anemia and thrombocytopenia. Pathologic examination of a kidney biopsy specimen demonstrated extensive cortical necrosis and arteriolar fibrin thrombi with nonspecific immunofluorescence staining of immunoglobulin M and C3 and absence of immune deposits on electron microscopy. These findings were consistent with the diagnosis of acute thrombotic microangiopathy. She received dexamethasone and underwent plasmapheresis, which was unsuccessful at removing alemtuzumab. The patient received renal replacement therapy for approximately 7 weeks, followed by slow recovery of kidney function that returned close to her baseline.

HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy.

Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.

Histopathology and Long-Term Outcome of Kidneys Transplanted From Donors With Severe Acute Kidney Injury.

BACKGROUND: Acute kidney injury is a treatable entity although difficult to recognize without diagnostic biopsy. We investigated the potential association between clinically defined deceased donors and acute kidney injury with preimplantation histological findings and recipient outcomes. METHODS: Kidney biopsies from donors were classified using the Acute Kidney Injury Network criteria and assessed for percentage glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular narrowing with the Remuzzi score and for acute tubular necrosis. Differences in incidence rates of delayed graft function (DGF) and cumulative rejection episodes were compared between recipients transplanted with normal and 3 levels of acute kidney injury using the analysis of variance with Bonferroni correction ( P = .0012). RESULTS: Sixteen out of 335 donors showed a severe acute kidney injury level 3 with a median serum creatinine of 458 µmol/L. Fourteen (88%) had 0-3 Remuzzi score and were used for single kidney transplantation and 2 (12%) were used for dual kidney transplantation (score: 4-6). Recipients who received a kidney from a donor with level 3 acute kidney injury had a higher percentage of DGF (47%) without statistical significance ( P = .008). The rate of cumulative rejection (45%) at 2 years was not significantly increased ( P = .09). CONCLUSIONS: Recipients receiving level 3 acute kidney injury kidneys, selected with Remuzzi histopathological score and acute tubular necrosis assessment, had a greater incidence of DGF but a similar long-term cumulative rejection compared to no injury and level 1 and level 2 acute kidney injury donors. The application of the histopathological examination allowed expansion of the kidney donor pool.

Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI.

Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis in vitro, histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils. In vivo, ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.

Gelofusine Ameliorates Colistin-Induced Nephrotoxicity.

Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologically. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

Expression of cleaved caspase-3 in renal tubular cells in Plasmodium falciparum malaria patients.

AIM: In Plasmodium falciparum malaria, the clinical manifestation of acute kidney injury (AKI) is commonly associated with acute tubular necrosis (ATN) in the kidney tissues. Renal tubular cells often exhibit various degrees of cloudy swelling, cell degeneration, and frank necrosis. To study individual cell death, this study evaluates the degree of renal tubular necrosis in association with apoptosis in malarial kidneys. METHODS: Kidney tissues from P. falciparum malaria with AKI (10 cases), and without AKI (10 cases) were evaluated for tubular pathology. Normal kidney tissues from 10 cases served as controls. Tubular necrosis was assessed quantitatively in kidney tissues infected with P. falciparum malaria, based on histopathological evaluation. In addition, the occurrence of apoptosis was investigated using cleaved caspase-3 marker. Correlation between tubular necrosis and apoptosis was analyzed. RESULTS: Tubular necrosis was found to be highest in P. falciparum malaria patients with AKI (36.44% ± 3.21), compared to non-AKI (15.88% ± 1.63) and control groups (2.58% ± 0.39) (all p < 0.001). In the AKI group, the distal tubules showed a significantly higher degree of tubular necrosis than the proximal tubules (p = 0.021) and collecting tubules (p = 0.033). Tubular necrosis was significantly correlated with the level of serum creatinine (r = 0.596, p = 0.006), and the occurrence of apoptosis (r = 0.681, p = 0.001). CONCLUSION: In malarial AKI, the process of apoptosis occurs in ATN.

Renal Cortical Necrosis in Postpartum Hemorrhage: A Case Series.

BACKGROUND: Pregnancy-related renal cortical necrosis may lead to end-stage renal disease. Although this obstetric complication had virtually disappeared in high-income countries, we have noted new cases in France over the past few years, all following postpartum hemorrhage. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We retrospectively identified 18 patients from 5 French nephrology departments who developed renal cortical necrosis following postpartum hemorrhage in 2009 to 2013. OUTCOMES: Obstetric and renal features, therapeutic measures, and kidney disease outcome were studied. RESULTS: All patients had a severe postpartum hemorrhage (mean blood loss, 2.6±1.1 [SD] L). Hemodynamic instability and disseminated intravascular coagulation were reported in 5 and 11 patients, respectively. All developed rapid onset of acute kidney injury and required hemodialysis. Diagnosis of renal cortical necrosis was performed 4 to 33 days following delivery. At 6 months postpartum, 8 patients remained dialysis dependent and none recovered normal kidney function. The length of exposure to tranexamic acid treatment was significantly more prolonged in women whose estimated glomerular filtration rate remained <15mL/min/1.73m(2) (7.1±4.8 vs 2.9±2.4 hours; P=0.03). LIMITATIONS: Retrospective study; small sample size. CONCLUSIONS: In the setting of gravid endothelium, the conjunction of disseminated intravascular coagulation with the life-saving use of procoagulant and antifibrinolytic agents (recently implemented in France in a postpartum hemorrhage treatment algorithm) may give rise to a risk for uncontrolled clotting in the renal cortex and hence irreversible partial or diffuse cortical necrosis.

Postpartum acute kidney injury: a review of 99 cases.

Postpartum acute kidney injury (PPAKI) constitutes an important cause of obstetric AKI. It is associated with high maternal and fetal mortality in developing nations. The aim of this study is to survey the etiology and outcomes of PPAKI in a tertiary care Indian hospital. Ninety-nine patients, without prior comorbidities, treated for PPAKI, between 2005-2014 at M.S. Ramaiah Medical College, were included for analysis in this retrospective, observational study. AKI was analyzed in terms of maximal stage of renal injury attained as per RIFLE criteria. Outcomes included requirement for renal replacement therapy (RRT), maternal and fetal outcomes. PPAKI constituted 60% of all obstetric AKI cases. Median maternal age was 23 years and 52% of patients were primigravidas. Mean serum creatinine was 4.1 mg/dL. Failure (33%) and injury (31%) were the major categories as per RIFLE criteria. Thirty-nine percent of cases required RRT. Sepsis, particularly puerperal sepsis, was the leading causes of PPAKI (75% of cases) and maternal mortality (94% of deaths). Maternal and fetal mortality were 19% and 22% respectively. The incidence of cortical necrosis was 10.3%. Three patients required long-term RRT. In conclusion, consistent with other Indian literature, we report a high incidence of PPAKI. We found incremental mortality on moving from "Risk" to "Failure" category of RIFLE. PPAKI was associated with high maternal and fetal mortality with sepsis being the leading cause. Our study highlights the need for provision of better quality of maternal care and fetal monitoring to decrease mortality associated with PPAKI in developing countries.

Epidermal growth factor attenuates tubular necrosis following mercuric chloride damage by regeneration of indigenous, not bone marrow-derived cells.

To assess effects of epidermal growth factor (EGF) and pegylated granulocyte colony-stimulating factor (P-GCSF; pegfilgrastim) administration on the cellular origin of renal tubular epithelium regenerating after acute kidney injury initiated by mercuric chloride (HgCl2 ). Female mice were irradiated and male whole bone marrow (BM) was transplanted into them. Six weeks later recipient mice were assigned to one of eight groups: control, P-GCSF+, EGF+, P-GCSF+EGF+, HgCl2 , HgCl2 +P-GCSF+, HgCl2 +EGF+ and HgCl2 +P-GCSF+EGF+. Following HgCl2 , injection tubular injury scores increased and serum urea nitrogen levels reached uraemia after 3 days, but EGF-treated groups were resistant to this acute kidney injury. A four-in-one analytical technique for identification of cellular origin, tubular phenotype, basement membrane and S-phase status revealed that BM contributed 1% of proximal tubular epithelium in undamaged kidneys and 3% after HgCl2 damage, with no effects of exogenous EGF or P-GCSF. Only 0.5% proximal tubular cells were seen in S-phase in the undamaged group kidneys; this increased to 7-8% after HgCl2 damage and to 15% after addition of EGF. Most of the regenerating tubular epithelium originated from the indigenous pool. BM contributed up to 6.6% of the proximal tubular cells in S-phase after HgCl2 damage, but only to 3.3% after additional EGF. EGF administration attenuated tubular necrosis following HgCl2 damage, and the major cause of this protective effect was division of indigenous cells, whereas BM-derived cells were less responsive. P-GCSF did not influence damage or regeneration.

The urine sediment as a biomarker of kidney disease.

The modern era of medicine has ushered in new diagnostic technologies to assist the clinician in evaluating patients with kidney disease. The birth of automated urine analysis technology and centralized laboratory testing has unfortunately made examination of urine sediment by physicians a rare event. At the same time, identifying novel urine biomarkers for kidney disease has become a research priority in nephrology, and the search for the "renal troponin" has progressed at a fast pace. Despite this, urine sediment examination remains a time-honored test that provides a wealth of information about the patient's kidney condition and performs favorably as a urinary biomarker. It alerts the clinician to the presence of kidney disease and provides diagnostic information that often identifies the compartment of kidney injury. In addition, sediment findings may guide therapy and assist in prognostication. As such, it is premature to abandon urine sediment examination. It may be more appropriate to combine urine sediment examination with new candidate biomarkers that enter clinical practice to create a "diagnostic panel" that provides clinicians with a useful battery of diagnostic tests. To accomplish this, we as nephrologists must encourage continued training and maintenance of competency in urine sediment examination.