1. YEAR IN REVIEW-2011
Nature Reviews

2. 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)

3. 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

4. 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.

5. 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

6. 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, suggesting
drive 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 of
diabetic 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.

7. Membranous Nephropathy:
Summary Albumin as a putative dietary
Bovine 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.

8. Polycystic Kidney Disease in
2011
 The main proteins implicated in PKD—polycystin-
1, polycystin-2 and fibrocystin—and in autosomal
Proteasome inhibition increases polycystin-1 2
dominant polycystic liver disease (glucosidase
subunit β and SEC63) functionally interact.
levels and attenuates cystic disease in
Prkcsh-knockout models, thus offering a
 Transgenic overexpression of polycystin- 1, but
conceptual therapeutic approach to
not polycystin-2, rescues the renal and hepatic
autosomal dominant polycystic liver disease
and 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).

9. Polycystic Kidney Disease in
2011
 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).

10. Polycystic Kidney Disease in
2011
 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).

11. Polycystic Kidney Disease in
2011
 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

12. Polycystic Kidney Disease in
2011
 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.

13. Novel Therapeutics:
1. Tolvaptan.
2. Metformin.
3. PPAR- γ agonists.
4. Circumin
STAT3 Pathway
5. Pyrimethamine
inhibition
Physiological Understanding:
1. Genetic interactions between the various
implicated genes.
2. Macrophage infiltration contributing to the
cyst growth.

14. 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.

15. 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).

16. 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‖.

17. Transplantation in 2011
BENEFIT 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).

18. 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.

19. 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.

20. 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

21. 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.

22. 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 CITs
Advances in transplant biology:
1. APOL1 variants in AA affecting outcomes.
2. Identification of factors in some patients which
permits tolerance and independence from
immunosuppressants.

23. 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.

24. 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).

25. 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).

26. 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

27. 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.