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To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that L-kynurenine, a metabolite of L-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for L-kynurenine in placental health. However, UNx mice failed to show upregulation of L-kynurenine during pregnancy; furthermore, when UNx mice were fed L-kynurenine in drinking water throughout pregnancy, their preeclampsialike state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate L-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia., Introduction Pregnancy is an adaptive state of net sodium and volume expansion for the purpose of increasing perfusion of the placenta and fetus. Blood flow to the uterus can increase [...]

Haemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disease driven by abnormal macrophage activation and regulatory cell dysfunction. HLH can be primary due to genetic mutations or secondary due to infection, malignancy or autoimmune conditions. We describe a woman in her early 30s who developed HLH while being treated for newly diagnosed systemic lupus erythematosus (SLE) complicated by lupus nephritis as well as concomitant cytomegalovirus (CMV) reactivation from a dormant infection. The trigger for this secondary form of HLH may have been either aggressive SLE and/or CMV reactivation. Despite prompt treatment with immunosuppressive therapies for SLE consisting of high-dose corticosteroids, mycophenolate mofetil, tacrolimus, etoposide for HLH and ganciclovir for CMV infection, the patient developed multiorgan failure and passed away. We demonstrate the difficulty in identifying a specific cause for secondary HLH when multiple conditions are present (SLE and CMV) and the fact that, despite aggressive treatment for both conditions, the mortality for HLH remains high. [ABSTRACT FROM AUTHOR]

Nephropathic apolipoprotein L1 (APOL1) risk alleles (G1/G2) have been associated with focal segmental glomerulosclerosis, HIV-associated nephropathy, Systemic lupus erythematosus (SLE)-associated collapsing glomerulopathy and other glomerulonephritides. These alleles confer protection from Trypanosoma brucei infections which are enriched in sub-Saharan African populations. We present a young woman with obesity, hypertension, subnephrotic range proteinuria who was found to have obesity-related glomerulopathy on kidney biopsy while harbouring two high-risk APOL1 alleles (G1/ G2). Given the potential effects on lipid metabolism and their association with obesity, the presence of APOL1 risk alleles may impact cardiovascular health in addition to renal disease in these patients. [ABSTRACT FROM AUTHOR]

Hypoxia is a potent regulator of a multitude of cellular processes, including metabolism and cell survival. The transcriptional response to oxygen deprivation is mainly mediated by hypoxia-inducible factors (HIFs), which are targeted for proteasomal degradation by the von Hippel-Lindau tumor suppressor protein (pVHL) under normoxia. Podocytes, as part of the glomerular filtration barrier, are prone to hypoxic injury during diseases affecting the glomerulus. VHL and HIF1 were functional in mature murine podocytes in vivo and in vitro, with HIFI protein stabilization and target gene transcription under both hypoxia and VHL deficiency. Podocyte-specific Vhlh gene loss, mimicking podocyte hypoxia, in young mice of mixed background led to glomerulomegaly and occasional glomerulosclerosis, despite preserved glomerular development. In parallel, hypoxia effects on podocytes in cell culture included increased susceptibility to apoptosis, associated with nuclear translocation of apoptosis-inducing factor (AIF). Similarly, Vhlh gene inactivation in podocytes in vitro resulted in a significant survival disadvantage, particularly in conjunction with additional proapoptotic stimuli. Evaluation of the global transcriptional response to hypoxia in podocytes by microarray analysis revealed a typical upregulation of HIF target genes as well as the induction of genes relevant for stress response, cell-cell, and cell-extracellular matrix interaction. While the lack of a prominent phenotype in young mice with VHL-deficient podocytes is consistent with the absence of specific glomerular manifestations in human VHL disease, a low-oxygen environment of podocytes may contribute to the progression of glomerular disease by altering cellular metabolism and survival. glomerulosclerosis; hypoxia-inducible factor; von Hippel-Lindau; apoptosis

Though the prevalence of drug induced allergic interstitial nephritis (AIN) appears to be increasing, the diagnostic and treatment strategies still remain vague. We present a 56-year- old man with a history of hypertension, chronic kidney disease stage IIIa, recent exposure to ciprofloxacin who presented with acute kidney injury. Though the suspicion of AIN was high, his urinary sediment was bland, that is, no leucocytes or leucocyte casts. A renal biopsy subsequently showed features of AIN correlating with a resolving phase of inflammation. Given the resolving nature of the pathology, we chose not to complete a course of corticosteroids despite his need for temporary haemodialysis. He was able to fully recover his renal function. In this report, we emphasise the unreliable nature of the urinary sediment in the diagnosis of AIN, the utility of a renal biopsy in helping to guide treatment, and the controversial data in corticosteroid treatment. [ABSTRACT FROM AUTHOR]