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.