- Does cyclophosphamide still play a role in glomerular diseases? [Review]
- ARAutoimmun Rev 2018 Aug 11
- Cyclophosphamide is a prodrug that is converted to inactive carboxy-cyclophosphamide, acrolein and phosphoramide mustard, an agent that adds alkyl groups to oxygen and nitrogen atoms of guanine, one ...
Cyclophosphamide is a prodrug that is converted to inactive carboxy-cyclophosphamide, acrolein and phosphoramide mustard, an agent that adds alkyl groups to oxygen and nitrogen atoms of guanine, one of the four nitrogen bases that form the DNA nucleotides, causing DNA cross-links and introducing DNA breaks. These cytotoxic and mutagenic effects mainly occur in proliferating cells. Repair mechanisms may prevent DNA damage in quiescent cells, but they may be insufficient to contrast the side effects of cyclophosphamide if high doses of the drug are used. Most adverse events are dose- and age-dependent. Phosphoramide mustard can cause bone marrow toxicity, gonadal toxicity, and may favor the development of leukemia, bladder cancer and other types of malignancy. Acrolein can produce hemorrhagic cystitis and even bladder fibrosis when given for prolonged periods. A number of precautional measures should be taken to prevent these untoward events. In particular, long-term administration and high doses of cyclophosphamide should be avoided whenever possible. Today the indications to cyclophosphamide in glomerular diseases are more restricted than in the past, but the drug is still used as a steroid-sparing agent in steroid-sensitive minimal change disease and focal segmental glomerulosclerosis. In membranous nephropathy, cyclophosphamide, alternated or associated with corticosteroids, proved to be beneficial in obtaining remission of nephrotic syndrome and preserving renal function. Cyclophosphamide is considered as a first-line treatment for rapidly progressive glomerulonephritis and the hectic phases of lupus nephritis. In conclusion, cyclophosphamide is a cheap drug that may be useful in a number of glomerular diseases but it may lead to severe side effects. A close monitoring of blood count and clinical conditions, as well as low cumulative doses of cyclophosphamide are strongly recommended when using the drug in patients with renal diseases.
- Multiple Myeloma in a Patient with Focal Segmental Glomerulosclerosis: A Case Report. [Journal Article]
- AJAm J Case Rep 2018 Aug 13; 19:946-950
- CONCLUSIONS: There is an association between FSGS and MM through an unclear mechanism.
- JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis. [Journal Article]
- KIKidney Int 2018 Aug 06
- Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Sinc...
Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT 1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.
- Case of human immunodeficiency virus infection presenting as a tip variant of focal segmental glomerulosclerosis: A case report and review of the literature. [Journal Article]
- WJWorld J Nephrol 2018 Aug 07; 7(4):90-95
- The incidence of the collapsing variant of focal segmental glomerulosclerosis (FSGS) as a human immunodeficiency virus (HIV)-associated nephropathy has reduced since the introduction of antiretrovira...
The incidence of the collapsing variant of focal segmental glomerulosclerosis (FSGS) as a human immunodeficiency virus (HIV)-associated nephropathy has reduced since the introduction of antiretroviral therapy (ART). However, the incidence of other variants of FSGS, except for the collapsing variant, is increasing, and its therapeutic strategies remain uncertain. A 60-year-old HIV infected man in remission with ART was admitted for progressive renal insufficiency and nephrotic-ranged proteinuria. Renal biopsy revealed a tip variant of FSGS and his clinical manifestations resolved with corticosteroid therapy. HIV infected patients might develop non-collapsing FSGS, including tip variant of FSGS and corticosteroid therapy might be effective for them. A renal biopsy might be essential to determine the renal histology and to decide on corticosteroid therapy.
- Genetics, Genomics, and Precision Medicine in End-Stage Kidney Disease. [Review]
- SNSemin Nephrol 2018; 38(4):317-324
- Recent advances in genetics of renal disease have deepened our understanding of progressive kidney disease. Here, we review genetic variants that are of particular importance to progressive glomerula...
Recent advances in genetics of renal disease have deepened our understanding of progressive kidney disease. Here, we review genetic variants that are of particular importance to progressive glomerular disease that result in end-stage kidney disease (ESKD). Some of the most striking findings relate to APOL1 genetic variants, seen exclusively in individuals of sub-Saharan African descent, that create a predisposition to particular renal disorders, including focal segmental glomerulosclerosis and arterionephrosclerosis. We also review the genetics of cardiovascular disease in ESKD and note that little work has been published on the genetics of other ESKD complications, including anemia, bone disease, and infections. Deeper understanding of the genetics of ESKD and its complications may lead to new therapies that are tailored to an individual patient's genetic profile or are discovered based on genetic approaches that identify novel pathways of renal cell injury and repair.
- Takayasu arteritis with an initial presentation of chronic monoarthritis mimicking oligoarticular juvenile idiopathic arthritis. [Journal Article]
- PRPediatr Rep 2018 May 24; 10(2):7648
- Patients with Takayasu arteritis (TA) generally present with non-specific symptoms that, if unrecognized and untreated, may develop vessel stenosis and/or aneurysm. There is limited data regarding ch...
Patients with Takayasu arteritis (TA) generally present with non-specific symptoms that, if unrecognized and untreated, may develop vessel stenosis and/or aneurysm. There is limited data regarding chronic monoarthritis as the initial presentation in children with TA. We report a 6-yearold girl diagnosed and treated as oligoarticular juvenile idiopathic arthritis (JIA). She later developed stroke with malignant hypertension and was definitively diagnosed with TA. She additionally developed proteinuria secondary to focal segmental glomerulosclerosis. This is the report of a patient with chronic monoarthritis mimicking oligoarticular JIA which chronic monoarthritis was the presentation of TA. Since JIA is a diagnosis of exclusion, any atypical features of oligoarticular JIA should illuminate the possibility of an alternative diagnosis. Our literature review focused on musculoskeletal presentations of children with TA.
- Children with Steroid-Resistant Nephrotic Syndrome: A Single -Center Experience. [Journal Article]
- MSMater Sociomed 2018; 30(2):84-88
- CONCLUSIONS: With current treatments, some children will ultimately achieve a sustained remission with one of the second line or third line of the proposed drugs. Patients with refractory NS will go to progression towards ESRD. The rapid development of molecular genetics will give a new contribution to the pathogenesis and treatment of this disease.
- An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome. [Journal Article]
- AJAm J Hum Genet 2018 Aug 02; 103(2):232-244
- Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the...
Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map these signals, eQTLBMA to discover GLOM- or TI-specific eQTLs, and single-cell RNA-seq data of control kidney tissue to identify the cell type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IgAN) GWAS to perform a transcriptome-wide association study (TWAS). We discovered 894 GLOM eQTLs and 1,767 TI eQTLs at FDR < 0.05. 14% and 19% of GLOM and TI eQTLs, respectively, had >1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM specific and TI specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IgAN TWAS identified significant GLOM and TI genes, primarily at the HLA region. In this study, we discovered GLOM and TI eQTLs, identified those that were tissue specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are available for browsing and download via our eQTL browser, "nephQTL."
- Donor's APOL1 Risk Genotype and "Second Hits" Associated With De Novo Collapsing Glomerulopathy in Deceased Donor Kidney Transplant Recipients: A Report of 5 Cases. [Journal Article]
- AJAm J Kidney Dis 2018 Jul 25
- The presence of 2 APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease in individuals of African descent. Alt...
The presence of 2 APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease in individuals of African descent. Although recipient APOL1 genotype is not associated with allograft survival, kidneys from deceased African American donors with 2 APOL1 risk variants demonstrate shorter graft survival. We present a series of cases of presumed de novo collapsing FSGS in 5 transplanted kidneys from 3 deceased donors later identified as carrying 2 APOL1 risk alleles, including 2 recipients from the same donor whose kidneys were transplanted in 2 different institutions. Four of these recipients had viremia in the period preceding the diagnosis of collapsing FSGS. Cytomegalovirus and BK virus infection were present in 3 and 1 of our 5 cases, respectively, around the time that collapsing FSGS occurred. We discuss viral infections, including active cytomegalovirus infection, as possible "second hits" that may lead to glomerular injury and allograft failure in these recipients. Further studies to identify additional second hits are necessary to better understand the pathologic mechanisms of donor APOL1-associated kidney disease in the recipient.
New Search Next
- A familial case of Galloway-Mowat syndrome due to a novel TP53RK mutation: a case report. [Journal Article]
- BMBMC Med Genet 2018 Jul 27; 19(1):131
- CONCLUSIONS: We report on a familial case of GAMOS with three affected siblings carrying a novel homozygous TP53RK mutation. To our knowledge, this is only the second report on GAMOS in association with a TP53RK mutation.