ANP and AKI

Few recent questions in the Acute Kidney Injury in Nephsap 2011 suggest ANP as an option for preventing AKI in certain surgical setting. Early animal data had shown promise. The first study to look at human data was in transplant patients showing negative results. Similar study was done in more transplant patients showing more negative results. What is the data for benefit?

Earlier studies might have been promising but the recent data is discouraging. A NEJM study in 1997 showed that it was beneficial in oliguric patients with ATN and showed a potential promise for a treatment for ATN. Another study showed benefit in post cardiac surgery patients in a randomized trial. Despite the large size of the trial, ANP administration had no effect on 21-day dialysis-free survival, mortality, or change in plasma creatinine concentration. A Cochrane review recently suggested perhaps some benefit. Nineteen studies (11 prevention, 8 treatment; 1,861 participants) were included. There was no difference in mortality between ANP and control in either the low or high dose prevention studies. After major surgery there was a significant reduction in RRT requirement with ANP in the prevention studies, but not in the treatment studies. There was no difference in mortality between ANP and control in either the prevention or treatment studies. There was a reduced need for RRT with low dose ANP in patients undergoing cardiovascular surgery. ANP was not associated with outcome improvement in either radio contrast nephropathy or oliguric AKI. A review in CJASN by the same authors and similar analysis suggests no benefit. Thus, although subset analyses separating low-dose from high-dose ANP trials suggest potential benefits, the preponderance of the literature suggests no benefit of ANP therapy for AKI. The side effects of potential hypotension and harm associated with the use of a vasodilator in high-risk perioperative and ICU patients, and a low value on potential benefit which is supported by relatively low-quality evidence from retrospective subset analyses from negative multicenter trials made KDIGO not recommend this treatment. 

  

KDIGO guidelines on ANP and AKI from 2012 read as follows: “Several natriuretic peptides are in clinical use or in  development for treatment of congestive heart failure, (CHF) or renal dysfunction, and could potentially be useful  to prevent or treat AKI. Atrial natriuretic peptide (ANP) is a 28-amino-acid peptide with diuretic, natriuretic, and vasodilatory activity. ANP is mainly produced in atrial myocytes, and the rate of release from the atrium increases in response to atrial stretch. Early animal studies showed that ANP decreases preglomerular vascular resistance and increases postglomerular vascular resistance, leading to increased GFR. It also inhibits renal tubular sodium reabsorption. Increases in GFR and diuresis have also been confirmed in clinical studies. It could thus be expected that ANP might be useful for treatment of AKI, and several RCTs have been conducted to test this hypothesis.  3.5.3: We suggest not using atrial natriuretic peptide (ANP) to prevent (2C) or treat (2B) AKI."

IN the news: The CANDY Study

The CANcer and DialYsis (CANDY) study, which retrospectively evaluated treatment patterns and clinical outcomes in patients undergoing chronic dialysis who subsequently developed cancer, showed that chemotherapy was omitted or prematurely stopped in many cases or was often not adequately prescribed, and survival was poor in this cohort of patients. This study highlights the challenges facing oncologists who are treating patients with cancer on chronic dialysis.

The number of patients developing cancer on dialysis is increasing. There is lack of data on pharmacokinetics of many chemo agents to be used in CKD and ESRD patients. In this study, over 170 patients in multicenter were evaluated from the time from initiation of dialysis to development of cancer. Most common cancers were genitourinary, followed by hematologic and then others. Close to 30% received anti cancer therapy. Among patients who received anticancer therapy, 72% received at least one drug that required a dosage adjustment, and 82% received at least one drug that needed to be administered after dialysis to avoid elimination. The problems encountered were not enough data on how to administer the chemo and when to in dialysis patients for certain agents. Most data comes from case reports and case studies. The authors concluded that for those drugs that are lacking recommendations, it may be advisable to use another appropriate drug for which clear dosage adjustment recommendations are available (whenever possible). Hence, there is a major need for studies to assess the characteristics of many agents in dialysis patients.

Check out the full paper in Annals of Oncology

Uncomplicated Urinary Tract infections: New guidelines

The infectious disease society of America had new treatment guidelines this year on UTIs.

For acute uncomplicated cystitis( healthy women, ambulatory with no history of anatomical or functional abnormality of urinary tract):
1. The primary goal should be to ameliorate symptoms.
2. New guidelines take into effect not only the efficacy of the drug, but current resistant patterns as well.
3. Nitrofurantoin, TMP-SMX, fosfomycin and pivmecillinam( not in US) are first line agents for cystitis even with resistant patterns with first two and less efficacy with the latter two.
4. Fluroquinolones have now been assigned as second line agents for cystitis but they are the drug of choice for emperic treatment of pyelonephritis.
5. Beta lactams are also second line agents.

Few concerns:
Nitrofurantoin is not as effective in certain cases. TMP-SMX has higher resistant patterns now. Fosfomycin is given as a 3gm sachet in a single dose and has 91% efficacy based on a single trial but less effective than TMP-SMX or fluoroquinolones. Unfortunately, many labs don't test for resistant patterns against this agent. Pivmecillinam is not available in the US.

Complicated UTI is men, women or children with structural, functional abnormalities in urinary tract. Male gender, obstruction, neurogenic bladder, DM, renal failure and transplantation increase the risk.

For a review on these changes, please see NEJM article earlier this year.

IN THE NEWS: SuPAR and FSGS more data revealed

A study done recently looked at suPAR levels in adults and pediatric patients with FSGS of two cohorts - the FSGS CT and PodoNet Cohort.  Compared to controls, they were elevated in 83% and 55% in two respective cohorts. Interestingly, MMF treated was associated with lower levels as compared to cyclosporine. In addition, it appears that the ones that had lower levels had more likely chance of remission. 

Why did one group of cohorts have a higher suPAR relationship compared to other? The mean serum creatinine was significantly higher in patients enrolled in the FSGS CT cohort than the PodoNet cohort and the authors suggest that this might be the reason for the difference. The entire article is an interesting read. 

The take home points are:

1. The circulating suPAR levels were markedly elevated in the majority of patients with primary FSGS in two distinct cohorts including children and adults
2. When evaluated with CRP levels, it was not due to inflammation that the suPAR was elevated. 
3. MMF therapy was associated with a lower serum level of suPAR; 
4. A decline in suPAR levels that was sustained over the course of 26 weeks of treatment was associated with decreased in proteinuria and remission
5. Serum suPAR levels were higher in familial cases including those with a defined podocin mutation.
6. Female patients had higher suPAR levels in both cohorts- unclear why.

Anti suPAR drugs should be great agents if this association continues to hold with FSGS??

Check out the full article in JASN

Free light chain induced Acute Kidney Injury- mechanisms revealed

A recent review of the pathophysiology of light chain damage in the kidney suggests some novel findings.

1. Apoptosis is a feature of experimental monoclonal free light chains( FLC) induced renal injury in animals which might be underlying mechanism in proximal tubulopathy.
2. Cast nephropathy experimental evidence suggests that intraluminal casts formation is the proximate cause of AKI and the most likely first step in the progressive decline of the renal function.
3. When IV infusion of monoclonal FLC was given in rats, elevated proximal tubular pressures were noted and decrease in single nephron GFR with formation of intraluminal protein casts.
4. The FLCs optimal bind via their CDR3 receptor to the Tamm-Horsfall protein in the distal nephron.
5. A inhibitor of the CDR3 part of FLC in rodents inhibited the cast formation.
6. While chemotherapy is the most effective, increasing water intake, avoiding nephrotoxic agents when the FLC burden is high is extremely important.
7. Renal risk from myeloma is very dependent on the circulating monoclonal FLC rather than the M protein.
8. Advent of FLC assays have really helped the diagnosis and management of renal dysfunction seen in patients with paraproteinemias.

Figure reference: the binding site

Clinical Case 64: Answers and Summary

WHICH OF THESE LISTED ARE CAUSES OF ACUTE KIDNEY INJURY AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION?

Contrast dye

  8 (27%)

 

Sepsis

  13 (44%)

 

Tumor lysis syndrome

  12 (41%)

 

Veno occlusive disease

  15 (51%)

 

Thrombotic microangiopathy

  21 (72%)

 

Calcineurin toxicity

  13 (44%)

 

Causes of AKI after HSCT can be divided into two settings:

< 30 days: Sepsis, hypertension, pre renal, nephrotoxic agents, tumor  lysis syndrome( very early), veno occlusive disease(VOD). The nephrotoxic agents usually are: acyclovir, amp B, contrast agents, methotrexate, NSAIDs, allopurinol, ACEI/ARB, CNIs

> 30 days: Thrombotic microangiopathy and CNI toxicity

Costs of Care education initiative? Where do nephrologists stand?

The ABIM is performing a cost of care teaching value project. This will be a multi faceted project to help health care providers get the proper education to help cut costs on medical bills for our patients.
Medical schools don't prepare anyone for this and most medical students are unaware of such training. A medical student survey is being conducted right now to help understand their attitudes on the subject matter. The teaching value project is set to start in Dec 2012 and has had some information on the website. Educators in nephrology should consider joining as well and help pass down the knowledge to the nephrology community. Many medical bills are a result of un necessary consults and testings. Examples of such stories are all over the place. A new york times article had highlighted this point few months ago.
What are some data that we have in nephrology literature?
Pre dialysis nephrology care was associated with fewer hospital days and lower total health care dollars during the year after dialysis initiation in one study of elderly patients. Similar study was found in other CKD patients. An older study looked at the cost of care and length of stay of hospitalized patients under the care of internist vs nephrologists. It found that when under the care of a nephrologists, the cost and length of stay was significantly shorter.
When nephrologists were asked few specific questions regarding costs savings and quality testing about their patients, some interesting findings were noted. A recent survey by medscape on nephrologist compensation report summaries these findings.

1. When asked if the new quality measures and treatment guidelines improve patient care, 43% said no and they will have a negative impact, 27% said no and they will have no change and only 30% said yes.
2. When asked if they would reduce testing to contain costs for their patients: 18% said no because they would still want to practice defensive medicine, 40% felt that the guidelines are not in patient's interests and hence would say no, 13% said yes because it would affect their income and rest said yes as they are good guidelines.
3. Finally, an interesting question was do you discuss costs of treatment with your patients and 34% did regularly, 7% no because they didn't know the cost, 9% didn't feel it was appropriate and 50% only if patient brought it up.