Effect of Allopurinol on CKD and CVD: Journal Club

Effect of Allopurinol on CKD and CVD

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Reverse epidemiology in ESRD: Digoxin

Conventional risk factors of cardiovascular disease and mortality in the general population such as obesity, hypercholesterolemia, and hypertension appear to be paradoxically protective and are associated with increased survival among dialysis patients (Kalantar-Zadeh et al, Kidney Int. 2003). Also, it was reported recently that there is paradoxical increase in the risk of stroke among dialysis patients receiving warfarin therapy for atrial fibrillation (Chan et al, JASN Oct 2009). Now there is an addition to the list of reverse epidemiology in ESRD. In the current issue of JASN, Chan and colleagues report increased mortality with digoxin use in ESRD patients (Chan et al, JASN, June 2010). In this study, authors compared 4549 dialysis patients on digoxin with 116,315 dialysis patients who were not on digoxin. This is a retrospective study. However, authors did propensity score analysis to match patients with similar comorbidities in both groups. It was found that digoxin use was associated with 28% increased risk of death. This was most pronounced in patients with lower predialysis serum potassium of less than 4.3 mEq/L. It is likely that hypokalemia, which frequently occurs immediately post dialysis in our ESRD patients, enhances the toxicity of digoxin. In conclusion, we all apply same principles of medicine learnt from general population to our dialysis patients. It seems we have to re-examine everything in our ESRD population.

Survey on innovative teaching tools

Dr. Jhaveri of Nephron Power and Online Transplant Center is conducting a survey on innovative teaching tools. Please see the link - http://www.surveymonkey.com/s/vrnjjx3

Billing and Coding Seminars

Renal Physicians Association (RPA) has excellent series of presentations on billing, coding and documentation. These are very helpful for all practicing nephrologists especially for those going to practice in the community.

SNP of Caveolin-1 gene is associated with renal allograft function

Caveolin-1 is the primary structural component of caveolae which are cell membrane invaginations on endothelial cells, adipocytes, fibroblasts and pneumocytes etc. It is anti-fibrotic and is shown to be reduced in conditions such as scleroderma and idiopathic pulmonary fibrosis. In a recently published JAMA paper (Moore et al, JAMA, April 2010), it was shown that donor single nucleotide polymorphism in gene encoding for Caveolin-1 was associated with long term renal transplant outcomes. Authors investigated this SNP in 785 white kidney transplant donors and their respective recipients with median follow up of 81 months post transplantation. It was found that donor genotype AA, compared to AC and CC genotypes, was associated with increased risk of allograft failure (Hazard ratio of about 2). The findings were confirmed in another independent cohort within UK. This is an interesting study that may not alter our clinical practice at present but will atleaset open new avenues in renal fibosis research if the findings are replicable in other studies.

Renal outcomes after preeclampsia

Recently, I had to look up this topic after one of my patients posed this question. In the largest study that I could find on this topic (Vikse et al, NEJM, Aug 2008), outcomes data on 570,433 women from national registries of Norway were reviewed. The relative risk of ESRD among women with history of preeclampsia was 3.2 to 6.7 compared to women without history of preeclampsia, with risk being higher in women who had preeclampsia in more than one pregnancy or if preeclampsia resulted in low birth weight or preterm infant. This translates into an absolute risk of less than 1% after a mean time of 17 years after first pregnancy. The main limitation of this study is that it is based on administrative database and is not a prospective study. There is a systematic review and metanalysis on this topic in the current issue of AJKD (McDonald et al, AJKD, June 2010). In this review, data from 7 cohort studies involving 273 patients with preeclampsia and 333 patients with uncomplicated pregnancies were analyzed. It was found that, after a mean of 7.1 years postpartum, 31% of women with history of preeclampsia had microalbuminuria compared to 7% of controls.

MICA antibodies

Please refer to the Online Transplant Center for my post on MICA antibodies.

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

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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.

Multiplicative risk of CKD and albuminuria

A metanalysis to assess the independent and combined association of low eGFR and albuminuria with mortality is just published in Lancet (CKD Prognosis Consortium, Lancet, May 2010). In this well-conducted study, data from about 1.2 million participants from 21 eligible studies were analyzed. Median follow up was about 8 years. It was found that mortality was lowest with eGFR between 105 and 75 ml/min, and rose exponentially as eGFR decreased with statistical significance for eGFR below 60 ml/min. In regards to albuminuria, the risk was linear with significance starting at albumin/creatinine ratio of 10 mg/g (which is well below the microalbuminuric range of 30-300) or more. Risk was multiplicative when both eGFR and albuminuria were plotted together. Authors propose to use both these measures for risk assessment and CKD staging.

Normoalbuminuric Diabetic Nephropathy

Recently, one of my colleagues gave an interesting talk on diabetic nephropathy without proteinuria. Traditionally, we are taught that diabetic nephropathy progresses along 5 stages: 1.Hyperfilitration, 2.Normoalubminuria, 3.Microalbuminuria, 4.Macroalbuminuria and 5.ESRD. GFR declines as patients progress from one stage to the next stage. However, according to a nice review article on diabetic nephropathy, (Jerums et al, Nature Rev Nephrol 2009), about 10-25% of patients follow 'normoalubminuric pathway' in which GFR continues to decline without worsening proteinuria. All studies excepting one quoted on this subject in the paper suffer from lack of renal biopsy to exclude other causes of low GFR such as nephrosclerosis. Caromori et al (Diabetes 2003, 52(4):1036-40) biopsied 105 type 1 diabetic patients without albuminuria and compared patients with low GFR with those with normal GFR. It was found that patients with low GFR had advanced diabetic glomerular lesions despite absence of albuminuria. These data indicate that a proportion of diabetic patients suffer decline in GFR with progressive glomerular lesions in the absence of worsening albuminuria. We have to keep this in mind in evaluation of diabetic patients in our CKD clinic.

Politics of drug coverage for transplantation

Currently, Medicare covers 80% cost of immunosuppressive medications up to 3 years after transplantation in those patients who are Medicare eligible because of ESRD. American Society of Transplantation (AST) and transplant community have been advocating for extending coverage beyond 3 years. However, despite showing evidence for long term benefit of incurring short term expense to extend coverage, this has not become a reality yet. Just published cJASN article by David Cohen and Barbara Murphy (immediate past president of AST) outlines the politics behind the exclusion of transplant drug coverage provision in the recent Affordable Health Care for Americans Act and how powerful lobby of mighty dialysis industry trumped the long overdue coverage for transplant recipients.

Emerging role of FGF 23 in CKD-MBD

Just released article (Evenepoel et al, cJASN 2010) provides additional support for a new paradigm for the pathogenesis of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). In the old traditional paradigm of CKD-MBD, loss of functioning kidney mass in CKD causes low active vitamin D level which leads to increased PTH production either directly or indirectly via diminished GI calcium absorption. However, in our CKD practice, we often see hyperparathyroidism without low active vitamin D or hypocalcemia. According to new phosphate-centric paradigm, CKD causes a decrease in renal phosphate excretion which leads to increased Fibroblast Growth Factor 23 (FGF-23) from bone osteocytes. FGF-23 act on kidney to inhibit phosphate reabsorption and also suppress production of active vitamin D to lower GI absorption of phosphorous. FGF-23 overproduction due to mutations in FGF gene was originally described in Autosomal Dominant Hypophosphatemic Rickets (ADHR consortium, Nature Genetics 2000). Recently, there has been explosion of literature on FGF-23 in CKD including its potential role in increased mortality (Gutierrez et al, NEJM 2008), left ventricular hypertrophy (Gutierrez et al, Circulation 2009) and progression of CKD (Fliser et al, JASN 2007). However, causal relationship between excess FGF-23 and adverse outcomes, and the potential mechanisms remain to be proven.

Controversy over eponym 'Wegener's granulomatosis'

The eponym "Wegener's granulomatosis" was derived after Friedrich Wegener (1907-1990), the german pathologist who initially described the condition. In a recent JASN review article on ANCA disease (Falk and Jennette, JASN 2010), alleged Nazi connections of Wegener are brought to the attention of nephrology community. Although no definitive evidence was found regarding his involvement in Nazi crimes, he was reportedly an early member of Nazi party. The authors proposed to medical community studying vasculitis to agree on an alternative name for Wegener's granulamatosis. In 2007, American College of Chest Physicians (ACCP) did an eloborate review of available data (Rosen MJ, Chest 2007) and finally decided to rescind their Master Clinician Award given to Wegener in 1989.

Growing evidence for treating metabolic acidosis to slow CKD progression

There are two published trials in the last few months that showed the benefit of treating metabolic acidosis in slowing progression of CKD. In a trial of 134 patients with stage IV CKD and serum bicarbonate of 16-20(de Brito-Ashurst et al JASN 2009), patients were randomly assigned to standard care plus oral sodium bicarbonate or standard care only for 2 years. Compared with the control group, decline in GFR was slower with bicarbonate supplementation (5.93 vs. 1.88 ml/min, P < 0.0001). Fewer patients supplemented with bicarbonate developed ESRD (6.5 versus 33%, P < 0.001). Also, nutritional parameters improved significantly with bicarbonate supplementation. In another study that is just published (Phisitkul et al, KI 2010), out of 59 patients with hypertensive CKD and metabolic acidosis on standard care including ACEi, 30 patients were prescribed sodium citrate and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 2 years. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower in the treatment group. Although patient groups are similar, the major limitation is that it is not a randomized study. Thus, alkali supplementation seems to be an inexpensive addition to the limited arsenal we have to retard CKD progression. Please see the graphic at the top from editors of KI showing the likely pathway of acidosis exacerbating renal injury.

TNF alpha inhibitors and the Kidney

Recently I came across a patient with Crohn's disease on Certolizumab with renal issues now. Certolizumab is a TNF-alpha inhibitor. So I did some literature search on adverse effects of TNF--alpha inhibitors esp. on kindey. There are many TNF-alpha inhibitors in market at present - Infliximab(Remicade), Etanercept(Enbrel), Adalimumab(Humira), Certolizumab(Cimzia) and Golimumab(Simponi). These agents are now more frequently prescribed for patients with Crohn's disease, Rheumatoid arthritis, Psoriatic arthritis, Ankylsoing spondylitis. There is increasing evidence that a minority of patients treated with TNF-alpha inhibitors develop new autoimmune diseases like vasculitis, lupus, interstitial lung disease, uveitis etc (Ramos-Casals et al, Medicine(Baltimore) 2007). Most of these conditions resolved with discontinuation of the TNF-alpha inhibitor. There is also a published series of 5 Glomerulonephritis cases reported with these agents (Stokes et al, NDT 2005). 2 out of these 5 cases were lupus nephritis, 2 were pauci-immune GN and 1 membranous GN with immune complex renal vasculitis. Mean duration of TNF-alpha inhibitor exposure in these patients was 6 months and there was clinical/laboratory improvement in most cases with drug withdrawal.

Hydronephrosis in Pregnancy

I just came across a 24 year old asymptomatic woman with no prior renal issues presenting with acute renal failure at 32 weeks of gestation. Work up was pretty much negative excepting for bilateral hydronephrosis and hydroureters proximally on renal ultrasound. Although hydronephrosis is usually physiologic in pregnancy, we proceeded with ureteral stenting as no other cause of her renal failure is evident. Her urine output improved and renal failure resolved. So I did some literature review on this topic. Here is what I found: Upto 90% of pregnant women show some dilation of the renal pelvis and proximal ureters by the thrid trimester of pregnancy. 2 Reasons: hormonal (progesteron) effect on ureters leading to reduced peristalsis and mechanical effects of enlarging gravid uterus on ureters. The development of hydronephrosis is considered physiologic as it is usually asymptomatic and does not lead to renal failure. Occasionally, you may across a rare patient like our patient with renal failure. The last published case report on this topic that I could find in any nephrology journal is almost 15 years before (Jena et al, AJKD 1996). In this report, authors reported that there were only 18 published case reports of reversible obstructive uropathy linked to the gravid uterus thus far. The risk factors for renal failure are twin gestation, polyhydramnios and solitary kidney but our patient has none of these.

Are you aware of CKD-EPI equation?

The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), a research group established by National Institute of Diabetes, Digestive and Kidney Diseases, proposed a new equation last year for GFR estimation. In a study published in Annals (Levey et al, Annals of Internal Medicine 2009), authors developed a new equation using a large database of 8254 participants pooled from 10 studies and further validated this equation in 3896 other participants pooled from 16 studies. Essentially, it used the same variables as MDRD equation - serum creatinine, age, sex, race - but with different intercepts for these. Authors showed that CKD-EPI equation is more accurate than MDRD equation, especially at higher GFRs. Please see image above. Major limitations of the study are that the study participants were from pooled studies and there were only few participants older than 70 or of non-african american minorities. Here is the online calculator for this new equation (QxMD.com).

FDA advisory panel recommends approval of Belatacept

Belatacept is a costimulation blocker that acts by binding to CD80 and CD86 on antigen presenting cells. Phase II (Vincenti et al NEJM 2005) and Phase III (BENEFIT Study Vincenti et al AJT 2010) trials showed that Belatacept patients (as compared to those receiving Cyclosporine) have comparable graft/patient survival, superior renal function with less fibrosis and better cardiovascular risk profile (lower risk of diabetes, hypertension and hyperlipidemia) at 12 months. Other advantage with Belatacept is that it is given as IV infusion every few weeks and so no issues with compliance as compared to BID PO Cyclosporine. However, the downsides are higher rate of acute cellular rejection (ACR) and posttransplant lymphoproliferative disease (PTLD). ACR is likely result of dual blockade of CTLA-4 dependent immunoregulatory pathway. PTLD mainly occured in EBV-negative recipients recieving EBV-positive kidneys. The other caveat is that there is no data on outcomes beyond 12 months follow-up.

ASCEND trial terminated prematurely

Endothelin antagonist Avosentan showed promising results in reduction of proteinuria and prevention of progressive renal disease in animal studies. Please see images above that showed improvement in renal histology after administration of endothelin antagonist in animal studies. ASCEND trial (Mann et al, JASN 2010) is a multicenter, multinational, double-blind, placebo-controlled trial of 1392 patients that evaluated addition of Avosentan to ACEi/ARB in diabetic nephropathy. Trial was terminated prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events (esp.CHF) with avosentan. During this short follow-up, no difference was detected in the frequency of time to doubling of serum creatinine, ESRD or death between groups. However, Avosentan significantly reduced proteinuria by about 50%.

New transplant medicine on the horizon

Recent focus in transplant pharmacology has been T cell co-stimulation. Here is a nice graphic from Nature Reviews in Immunology on interaction between T cell and Antigen Presenting Cell(APC). As you can see in the picture, both CD28 and CTLA-4 on T cells interact with same receptor CD80/CD86(B7-1/B7-2) on antigen presenting cells. While CD28 is co-stimulatory, CTLA-4 is required for immune regulation and inhibition. While Belatacept blocks CD80/86, thus interfering with both CD28 and CTLA-4 pathways, a newly identifiied true CD28 antagonist was shown to be preserve CTLA-4 dependent immune regulation and improve allograft survival in primates (Poirier et al, Science Translational Medicine 2010).

Confirmation of adverse outcomes with proteinuria

In a recently published study (Hemmelgarn et al, JAMA 2010), the adverse outcomes of proteinuria were confirmed by studying almost a million patients. In this mammoth study of 920928 adults in Canada, it was demonstrated that prognosis associated with a given level of eGFR varies substantially based on the presence and severity of proteinuria. In fact, patients with heavy proteinuria but without overtly abnormal eGFR appeared to have worse clinical outcomes than those with moderately reduced eGFR but without proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. Authors proposed that future revisions of the classification system for CKD should incorporate information on proteinuria. The main limitation of this study is that it is an observational study.

Welcome to Nephrology World

It is with great pleasure that I created this blog. Dr.Nathan Hellman of Renal Fellow Network is an inspiration for me to create this blog. The main intention of this blog is to share knowledge among various renal communities around the world. The renal pathology that we see in US and the rest of the world is diverse. So it is rewarding for everyone to discuss interesting cases and new literature.