ISBP Annual Conference 2010

Dr. Gura from UCLA forwarded a brochure regarding upcoming annual meeting of International Society of Blood Purification (ISBP) on September 24-26, 2010 in Marina del Rey, California. I have not attended this conference before but heard that it is a good one. If you are interested, please refer to brochure for details.

Vitamin D attenuates renal fibrosis

In addition to pleiotropic beneficial effects of vitamin D on musculoskeletal system, immune system, cancer prevention, mortality, cardiovascular and mental health, there is increasing evidence in the recent years for its role in attenuating renal fibrosis in various animal models. An article by Zhang and colleagues in the current issue of JASN (Zhang et al JASN, June 2010) is the latest in the series. In this study, Vitamin D Receptor (mediator of action of active vitamin D) knock out mice developed more severe renal damage, compared to wild type mice, following unilateral ureteral obstruction. There was significant induction of fibrogenic and inflammatory mediators like fibronectin, collagen I, TGF-b, MCP-1 etc. Administration of Losartan eliminated the difference in fibrosis between VDR knockout and wild type mice. There are also handful of human studies that showed antiproteinuric effect of active vitamin D. The trial with largest number of patients was published in 2005 (Agarwal et al, Kidney Int. 2005). In this study, 220 stage 3 and 4 CKD patients with secondary hyperparathyroidism were randomized to oral paricalcitrol or placebo. There was reduction of proteinuria independent of use of RAAS blockers. Do these data support a role for active vitamin D in attenuating progression of CKD? May be.

Urine NGAL in AKI: Journal Club

Urine NGAL Moderately predicts Acute Kidney Injury in critically ill adults

Journal Club Presentation

View more presentations from Anand Reddy.

Intragraft gene expression can predict graft loss

In an article just published in 'Journal of Clinical Investigation' (Einecke et al, JCI: June 2010), intragraft molecular signature was found to predict late graft loss. Authors perfomed microarrays to analyze gene expression in 105 'for-cause' biopsies taken 1 to 31 years after kidney transplantation. Based on this, authors derived a molecular risk score (comprising of 30 genes related to tissue injury, epithelial dedifferentiation, matrix remodelling and TGF-beta) that was associated with future graft failure. This molecular risk score was superior to classical features associated with progression to renal failure (histological findings, proteinuria and low eGFR at the time of biospy) in predicting incipient graft loss. The main limitation of this study is that it was not a prospective study. However, the important point here is that intragraft gene expression studies will likely help us in prognosticating, identifying pathogenic mechanisms, initiate specific therapy if available (personalized therapy rather than one-size-fits-all approach) and develop potential new therapies.

The kidney in sickle cell disease

Today, one of my colleagues presented an interesting case of sickle cell disease with microscopic hematuria, nephrotic range proteinuria and elevated serum creatinine. The renal manifestations of sickle cell disease are myriad. There is a nice review article published last year on this topic (Scheinman, Nature Reviews Nephrology 2009). Common renal manifestations of sickle cell disease include:
- Painless microscopic or gross hematuria as a result of RBC sickling in vasa recta in relatively hypoxic renal medulla. More severe ischemia due to vaso-occlusive phenomena in vasa recta can lead to renal papillary necrosis.
- Tubular function defects like hypoesthenuria/impaired concentrating ability (because of involvement of juxtamedually nephron collecting ducts), incomplete distal RTA with hyperkalemia (because of voltage defect), supranormal proximal tubular function in initial stages causing increased sodium & phosphrous reabsorption and increased creatinine/uric acid secretion (?? because of prostaglandins)
- Sickle cell glomerulopathy with nephrosis more common than nephritis. Most common pathological diagnosis is FSGS predominantly involving juxta medually nephrons that are perfused by vasa recta. Medullary fibrosis is prominent.
Other key points:
- Lower incidence of hypertension
- More prone to acute renal failure (In addition to usual causes, keep in mind the renal vein thrombosis and urinary tract obstruction from blood clots)
- Renal medullary carcinoma: rare but exclusive to sickle cell patients
- For ESRD, transplant outcomes are not as good as for other ESRD patients

Genetic Kidney Diseases

There is an excellent review article on genetic kidney diseases published in Lancet last month (Hildebrandt Lancet April 2010). It has the comprehensive list of prominent single gene kidney disorders and polygenic risk alleles of common disorders.

Few general points to recap what we learned before:
- Diseases caused by recessive genes usually manifest early (prenatal, childhood or adolescence) and have complete penetrance. Ex: Congenital nephrotic syndrome, Nephronophthisis, Bartter's, Cystinuria etc.
- Diseases caused by dominant genes typically manifest late (adulthood), have variable expression and incomplete penetrance. Ex: ADPKD, Liddle's, Gordon's etc.
- In polygenic diseases, genotype-phenotype correlation is weak and usually only a relative risk can be assigned to a genetic change. Ex: MYH-9, ELMO1 etc.
A nice article indeed!

Size does matter for renal transplant outcomes

In an interesting study from France (Giral et al, JASN express May 20, 2010), effects of nephron underdosing on long term allograft function were studied. The novel marker used in the study was ratio of the weight of kidney before implantation (Kw) to the weight of recipient (Rw) i.e Kw/Rw. In a multicenter cohort of 1189 transplant recipients with mean follow up of 6.2 years, those with Kw/Rw < 2.3 g/kg had worse long term graft survival, more GFR decline, more proteinuria, more hypertension and more glomerulosclerosis than those with Kw/Rw > 2.3 g/kg. Low nephron mass (relative to recipient weight) with resultant chronic functional overload likely forms basis for the study findings. The main caveat of the study is absence of data on outcomes with transplantation of kidneys from pediatric donors. In an earlier study, outcomes of adults who undergo transplantation with pediatric kidneys were comparable to those from older donors (Zhang et al, cJASN, 2009). It would be interesting to see if current study findiings replicate in other studies.