Loss of gluc/SEC 63 expression reduces pc-1 and to a lesser extent pc2 expression, blockes pc-1 translocation to primary cilia, worsens cystic disease in heterogenouspkd ½ +/- mice.
Year in review 2011-Nature reviews
YEAR IN REVIEW-2011 Nature Reviews
Glomerular disease in 2011 Previous studies have hypothesized that BSA can induce MN and exposure to BSA is common in the diet and that antibody-BSA immune complexes can cause MN. 11/50 patients with iMN, but only 2/172 controls, harbored high-titer serum antibody that recognized epitopes in BSA not present in human albumin. 7/11 patients with MN, but no controls, also had higher than normal serum levels of BSA, and in four of these patients the cationic BSA colocalized with the BSA-specific antibody in their subepithelial immune complex deposits. Debiec, Ronco et al. N. Engl. J. Med. 364 , 2101–2110 (2011)
Glomerular disease in 2011 This was a landmark study that demonstrated that exogenous circulating antigens derived from diet becomes a ―planted antigen‖ to induce MN. This study raise the possibility that other dietary antigens may also cause sMN. Peripheral tolerance is present to protect the kidney structures from the filtered antigens but this tolerance fails if the antigen is retained at the GFB as in the case of the cationic BSA. The challenge in discovery of other antigens lies in the search for the best candidates and in mapping them to the diet andetotherEngl. J. Med. 364 , Debiec, Ronco al. N. environmental
Glomerular disease in 2011 Plasminogen activator and PAR are a part of the innate immune mediator of tissue remodeling during inflammation. Wei, Reiser et al. made some interesting observations: LPS produced by commensal bacteria in the gut, caused proteinuria in mice by inducing systemic release of suPAR, which crossed the GFB & activated podocyte β3 integrin in both native uPAR +/+ kidneys & transplanted uPAR –/– kidneys. Nat. Med. 17, 952–960 (2011). Experimentally sustained secretion of suPAR from sites outside the kidney induced FSGS.
Glomerular disease in 2011 serum suPAR level was significantly elevated in• this study with primary FSGS (highest in recurrent patients also provides suggestive evidence FSGS after Tx). that FSGS may be an outcome of otherwise ‗clinically silent‘ inflammation from glomerular In patients in whom FSGS recurred, lesions showed activated podocyte β3 integrin, & environmental pathogens. suPAR removed from serum by Nat. Med. 17, 952–960 (2011). plasmapheresis correlated with remission of recurrent FSGS.• this hypothesis could lead to prophylactic strategies that manipulate the microbiome to lessen exposure and secondary damage to as This was a breakthrough in the study of FSGS podocytes from these PAMPs. circulating factor it identified a long-sought-after that is causative of recurrent FSGS. This also provides a potential therapeutic target for treating a disease in which current therapies
Glomerular disease in 2011 Gene expression studies in microdissected human kidneys of patients with diabetic nephropathy showed a marked up regulation of• podocyte gene–environment interactions can target genes of the mTOR pathway, suggestingdrive the progression of diabetic nephropathy. to that over activation of this pathway in response the dysregulated nutrient environment of diabetes• mTOR pathways can be a potential contributes to the development of diabetic nephropathy.therapeutic target to abrogate the progression ofdiabetic nephropathy. mice haploinsufficient for mTORC1 in podocytes had had experimental diabetic nephropathy induced with streptozotocin. Intriguingly, the mice showed significant ameliorationClin.diabetic , 2197– Godel, Huber et. Al. J. 2209 (2011) of Invest. 121 nephropathy.
Membranous Nephropathy:Summary Albumin as a putative dietaryBovine Serum antigen. FSGS (recurrent): Soluble urokinase-type PAR induced by LPS Diabetic Nephropathy:Overactivation of podocyte mTOR pathways in response to the dysregulated nutrient environment.
Polycystic Kidney Disease in2011 The main proteins implicated in PKD—polycystin- 1, polycystin-2 and fibrocystin—and in autosomalProteasome inhibition increases polycystin-1 2 dominant polycystic liver disease (glucosidase subunit β and SEC63) functionally interact.levels and attenuates cystic disease inPrkcsh-knockout models, thus offering a Transgenic overexpression of polycystin- 1, butconceptual therapeutic approach to not polycystin-2, rescues the renal and hepaticautosomal dominant polycystic liver diseaseand possiblyof tissue-selective Prkcsh-knockout or phenotype ADPKD. Sec63-knockout mice and the renal phenotype of Pkhd1del 4/del 4 mice. Fedeles et al. Nat. Genet. 43, 639–647 (2011).
Polycystic Kidney Disease in2011 The vasopressin V2 receptor antagonist, tolvaptan, inhibits cystogenesis in vitro. Low concentrations inhibited vasopressin-induced cAMP production, cell proliferation, Cl secretion & cyst growth in Reif et al. Am. J. Physiol. Renal Physiol. 301 , collagen matrices. F1005–F1013 (2011). Tolvaptan also reduced the volume of polycystic kidneys after 1 week of treatment (3.1%), and slowed the growth of polycystic kidneys in a 3- Higashihara et al. CJASN. 6, 2499–2507 year, open-label study of patients with PKD (1.7% (2011). vs 5.8% in historical controls).
Polycystic Kidney Disease in2011 Metformin stimulates the energy-sensing molecule AMP-activated protein kinase (AMPK), inhibits the activities of AMPK-dependent CFTR & mTOR in Madin–Darby canine kidney renal epithelial cells, & attenuates cAMP-dependent growth of these cysts in collagen matrices & of cysts in metanephric organ explants, & cystogenesis in constitutive & inducible Pkd1-knockout mice. Sci. USA 108 , 2462–2467 Takiar et al. Proc. Natl Acad. (2011). PPAR-γ agonist pioglitazone inhibits renal and hepatic cystogenesis in PCK rats by possibly complementary mechanisms through the inactivation of MAPK3 & mTOR, & inhibition of Am. J. Physiol. Renal Physiol. 300 , F465–F474 (2011).
Polycystic Kidney Disease in2011 Karihaloo et al. hypothesized that macrophage infiltration contributes to the proliferation of cyst- lining cells and PKD progression. Macrophages undergo a transition from classically activated, pro inflammatory cells to alternatively activated cells that promote epithelial cell proliferation. They found high concentrations of macrophage chemoattractant molecules and macrophages in pkd1-knockout mice. Macrophage depletion by intra-peritoneal liposomal clodronate administrationAm. Soc.Nephrol. 22, 1809–1814 J. inhibits epithelial cell
Polycystic Kidney Disease in2011 Three studies have shown marked upregulation of the signal transducer and transcription activator (STAT)3 in patients with ADPKD and in rodent PKD models. Proc. Natl Acad. Sci. USA 108 , 7985– 7990 (2011). Takakura et al. showed that Pyrimethamine, an inhibitor of STAT3 was found to supress epithelial cell proliferation & inhibit cystogenesis in pkd1 knockout mice. Hum. Mol. Genet. 20, 4143–4154 (2011). Leonhard et al. found that curcumin, a compound with anti-inflammatory and antiproliferative properties, reduced STAT3 activation, attenuated cell proliferation and cystogenesis andJ.delayed renal failure in, F1193–F1202 (20 Am. Physiol. Renal Physiol. 300 an inducible Pkd1 -knockout model.
Novel Therapeutics:1. Tolvaptan.2. Metformin.3. PPAR- γ agonists.4. Circumin STAT3 Pathway5. Pyrimethamine inhibitionPhysiological Understanding:1. Genetic interactions between the various implicated genes.2. Macrophage infiltration contributing to the cyst growth.
AKI in 2011 The source of urinary NGAL seems to be nearly exclusively from the renal tubule and does not seem to be released during pre-renal azotemia in healthy animals. Paragas et al. Nat. Med. 17, 216–222 (2 Plasma NGAL has been known to hasten the diagnosis of AKI. Srisawat and colleagues showed that its level also helps predict which patients with severe acute kidney injury (AKI) will Kidney Int. 80, 545–552 (2011). recover renal function.
AKI in 2011 Urine output remains an important ‗biomarker‘ of AKI, and predicts death even in the absence of a rise in serum creatinine level. The consecutive hours of oliguria was more sensitive than average oliguria over fixed periods of time in this study. It validated the use of u.o. in the AKIN definition of AKI. Macedo et al. Kidney Int. 80, 760–767 (2011). Micro RNAs are a new class of AKI biomarkers that may prove to be important new tools in the diagnosis and treatment of AKI. Elevated levels of miR-210, also found to be involved in6, 1540–1546 Lorenzen et al. CJASN molecular response to stress, predicted mortality. (2011).
1. Further support to using NGAL as a diagnostic and prognostic biomarker that may shape the current practice.2. Search of newer biomarkers like mRNAs.3. Further support to the age-old ―urine output estimation‖.
Transplantation in 2011BENEFIT trial (Phase III results): 686 de novo kidney transplant were randomly assigned to more-intensive or less-intensive belatacept regimens or to ciclosporin. All patients received basiliximab induction therapy, MMF and corticosteroids. Equivalent rates of graft and patient survival were noted despite an increased frequency and severity of early rejection episodes and increased frequency of PTLD associated with Vincenti et al. Am. J. Transplant. 10, 535–546 belatacept. (2010).
Transplantation in 2011 Graft survival was equivalent across all regimens. At year 3 post-transplantation, the mean eGFR was 21 ml/min/1.73 m2 higher in the belatacept groups than in the ciclosporin group. More importantly, from month 3 through to month 36, the slope of eGFR in the belatacept groups averaged 1.1 ml/min/1.73 m2/year versus – 2.0 ml/min/1.73 m2/year with ciclosporin. Neither a significant increase in acute rejection episodes nor new cases of PTLD after 18 months post-transplantation http://dx.doi.org/10.1111/j.1600– Am. J. Transplant. were observed.
Transplantation in 2011 Desensitization protocols are used for transplantation in sensitized patients but there was a lack of control groups in many studies. Montgomery et al. showed in 211 sensitized patients treated with a desensitization regimen (low dose IVIG + PP) had better survival than patients on dialysis or sensitized patients who undergo compatible transplantation. J. Med. 365 , 318–326 (2011). N. Engl. This study however did not give the actual graft survival or AMR rates and the outcome in deceased donor sensitized transplantation remains to be seen.
Transplantation in 2011 Recent studies suggest an association between variants of the apolipoprotein L1 gene ( APOL1 ) and nondiabetic nephropathy among African Americans. Friedman et al. JASN 22, 2098–2105 (2011). In a single-center study, kidneys from AA deceased donors with two APOL1 risk variants were more likely to fail than kidneys from individuals with one Reeves-Daniel et al. Am. J. Transplant. 11, 1025– 1030 (2011). or no APOL1 risk variants. This points to a biological influence rather than race underlying transplantation outcomes. The application of these associations to improve
Transplantation in 2011 Increased cold ischemia times of extended criteria donor kidneys are associated with delayed graft function, but do not affect graft survival. Am. J. Transplant. 11, 2657–2664 (2011). This study is limited by its retrospective nature and is prone to selection bias, it provides some impetus to reconsider discard of ECD kidneys with higher CITs and optimize ECD utilization and acceptance.
Therapeutic advances:1. Advent of a new, possibly safer alternate to CNIs in the form of Belatacept.2. Better trials supporting better outcomes with desensitization protocols.3. Absence of difference in graft outcome with longer CITsAdvances in transplant biology:1. APOL1 variants in AA affecting outcomes.2. Identification of factors in some patients which permits tolerance and independence from immunosuppressants.
Dialysis in 2011 Inflammation is present in majority of patients in HD .Both factors related to the dialysis procedure (such as dialysis catheters and quality of dialysate) and factors unrelated to the dialysis procedure per se (such as infectious complications and volume overload). Catalytic hypothesis: Inflammation was shown to amplify the risk of death and CV events associated with high asymmetric dimethylarginine (ADMA) levels as shown in a study on 225 HD Tripepi et al. CJASN. 7, 1714–1721 (2011). patients followed for 13 yrs.
Dialysis in 2011 Hung et al. demonstrated in 22 patients that 4 weeks of treatment with a recombinant human IL- 1 receptor antagonist (anakinra) significantly reduced mean CRP level (by 53%) and mean IL- 6 level (by 40%), while mean prealbumin level increased by 23%. Moreover, the anti-cytokine treatment was well tolerated and safe. It is the first study showing that targeted anti- cytokine treatment decreases inflammation parameters in this patient group and22, 437–442 J. Am.Soc. Nephrol. long term studies are needed to study its impact. (2011).
Dialysis in 2011 The SHARP study is the largest randomized study ever conducted in nephrology and included 9,270 patients randomized to receive either 20 mg simvastatin plus 10 mg ezetimibe daily or placebo. Statin Rx was associated with beneficial effects on major atherosclerotic events in the entire chronic kidney disease population; the effect is less pronounced in the subpopulation of dialysis Lancet 377 , 2181–2192 patients. (2011).
Dialysis in 2011 Winkelmayer et al., in a study based on 2.5 million observations of hemodialysis patients, showed that the prevalence of atrial fibrillation had increased threefold from 1992 (3.5%) to 2006 (10.7%). They also showed that mortality was twice as high among hemodialysis patients with AF compared to those without. J. Am. Soc. Nephrol. 22, 349–357 (2011). In another report, warfarin seemed to increase the risk if hemorrhagic stroke without lowering the risk of ischemic stroke. Thus it was concluded that unless an adequately powered RCT was done, it is not advisable toCJASN. http://dx.doi.org/10.2215/CJN.04550511. prescribe warfarin in HD patients
1. Inflammatory markers and detection of atrial fibrillation should be included in the assessment of patients on hemodialysis.2. Statins have a modest but significant benefit on preventing cardiac events.3. Warfarin treatment should not advocated in HD patients till a large RCT shows anything new.