Wednesday, January 29, 2014

IMAGINE trial for Transplant Immunosuppression: Dream RCT in Nephrology

I thought I would throw in my two cents on the Dream RCT in Nephrology poll being co-ordinated at UKidney. My choice focuses on transplant immunosuppression and you can see the entry by Joel Topf on PB Fluids here.

There is no standardization of immunosuppression post kidney transplant and before I’m attacked on the blogosphere, I do think that’s a good thing. Each transplant operation is unique with differing immunological risks based on donor & recipient factors. A non-sensitized, white, living donor transplant recipient should be managed different to a deceased-donor, African American, re-transplant. However, there are almost as many different protocols as there are transplant centers and new immunosuppressive agents are becoming available for clinical use. Therefore the transplant community is far from certain which exact agents should be employed for different risk groups. My pick for dream RCT in Nephrology is admittedly a tricky one. If I could have 2 or 3 dream RCTs that would certainly make things easier for me.

Before I start I would like to justify why I feel we need this. The ELITE-Symphony study was a landmark RCT in kidney transplant immunosuppression. Briefly, a regimen of low dose tacrolimus together with MMF, steroids and induction with daclizumab was more beneficial regarding eGFR, allograft survival and acute rejection (AR) at 1 year. Comparison regimens were low dose cyclosporine, low dose sirolimus (both instead of tacrolimus above) plus an additional arm without induction but with standard dose cyclosporine, MMF & steroids. Note that the patients were overall low risk: predominantly white, 35% living donors, mean PRA 20%. This trial solidified the current standard of care for most patients as low dose, triple immunosuppression based around tacrolimus. However since then we have a new kid on the block in belatacept, follow up in SYMPHONY was only 1 year and the issue of induction therapy is not resolved.

Belatacept is a T-cell co-stimulatory blocker and has demonstrated efficacy as a maintenance agent for both standard and expanded criteria donor kidneys. The belatacept studies (BENEFIT & BENEFIT-EXT) used cyclosporine as the comparator and both demonstrated an improvement in eGFR at 3 years despite more early AR.

Let us consider these 2 points which will simplify my imaginary trials:
1. Firstly, no mTOR inhibitors. They’re out! Why do we keep trying to find a mainstream role for mTOR inhibitors in renal transplantation?. I will admit that they have a (limited) role in renal transplantation, mostly when malignancy is an issue or in certain cases of calcineurin inhibitor toxicity (when no proteinuria and preserved GFR). In the ELITE-Symphony study, they had the worst allograft survival & the most adverse events with almost half of patients withdrawing from the sirolimus group. They will never be the cornerstone of immunosuppression post-transplant, especially early post transplant, so they will not be considered.

2. Why is cyclosporine always the control group for new immunosuppressive drugs post transplant? The FDA has traditional mandated that the control arm be a cyclosporine based regimen, despite this not being the standard of care anymore. Tacrolimus is now the leading agent used for >85% of patients as per the SRTR Report 2011 (versus about 4% for cyclosporine). Therefore, cyclosporine is also out. Transplant centers will be more willing to participate as their patients in the control arm will be getting current standard of care.

Immunuosuppression MAnagement for Graft survival IN the current Era (IMAGINE) will be a multi-center randomized controlled trial comparing 2 immunosuppression regimes in general real-world kidney transplant recipients (living & deceased donors, calculated PRA <50%, re-transplants with cPRA <30%). The trial will have a 2x2 factorial design based on 2 induction and 2 subsequent maintenance arms.
1. Induction arm: Basiliximab (daclizumab no longer available) versus rATG. There is an argument for including Alemtuzumab here but this trial is already getting messy so we’ll leave that for IMAGINE-2.
2. Maintenance arm: tacrolimus V belatacept, both with MMF (1g BID)/steroids. It is an open-label design given that belatacept is administered IV and therapeutic drug monitoring is needed with tacrolimus. Maintenance trough levels will be 4-7ng/ml. Note that actual achieved levels in SYMPHONY were close to 7ng/ml despite target being 3-7ng/ml.

Induction: I have included an induction arm as I feel this is another area which needs clarity. For highly sensitized patients there is more consensus that lymphocyte-depleting agents are the way to go (with rATG being more favourable to ATGAM & OKT3). For general low-to-moderate risk recipients, the optimal induction agent is less clear. There is evidence that again rATG is more efficacious but with infection risk and logistical reasons perhaps being important, basiliximab use is common (approximately 1/3 of transplants in 2011).
The sister trial Immunuosuppression MAnagement for Graft survival IN A RiskY population (IMAGINARY) will include highly sensitized recipients with cPRA>50% and re-transplants with prior graft loss due to AR or cPRA >30%. This study will use rATG as induction.
Outcomes: Primary outcome is allograft & patient survival (hard outcomes) at 5 years. Secondary outcome are eGFR and early AR (a relatively soft outcome in my opinion post transplant). Most trials report one year follow-ups which has less relevance for an organ you hope to last >10 years.

Therefore notable features of these trials include hard endpoints, longer follow-up, comparison to the current standard of care and induction arms. That’s my trial design which will form the template for further imaginary studies of newer immunosuppressive agents currently in development. I apologize for the protracted post but these issues couldn’t be dealt with any more briefly! I realize that my dream RCTs may leave me open to criticism but the point of this exercise is to provoke discussion and challenge us to think about what we do and why we do it. And yes, I came up with the trial acronyms before I even wrote the post!

Tuesday, January 28, 2014

Treatment of secondary amyloid

Recently I've been dealing with an unfortunate individual with a long history of RA who has developed nephrotic range proteinuria after being stable for many years. Despite the deteriorating renal function, NSAIDs have been continued because without them the patient has no quality of life. Biologics were tried in the past with very severe adverse effects and so we are reduced to treating this much the same as it was treated many years ago. Recently, a review in Nature Reviews Nephrology summarized the most up-to-date thinking on the treatment of systemic amyloid. Similar to my patient, about 50% of patients with AA amyloid have nephrotic syndrome and ~10% have ESRD at diagnosis. More than 40% of patients with AA amyloid eventually progress to ESRD.

For AA amyloid, the primary goal of treatment is to suppress the underlying inflammatory disease and hence prevent further amyloid production.

1. Colchicine: Colchicine has been shown to be effective in the treatment of Familial Mediterranean Fever in particular. It is used as a prophylactic agent to prevent the development of renal amyloid and, in higher doses, can be used to treat nephrotic syndrome although care must be used in patients with decreased renal function. There is less evidence for its effectiveness in rheumatoid diseases.

2. DMSO: This has been shown in small studies to be effective in treating secondary amyloid and in murine studies. However, in one study, there was no effect in patients who had already developed significant renal dysfunction.

3. Cytotoxic Therapy: Cyclophosphamide has been shown to have some effect in AA amyloid in small cases series and retrospective studies. There are no RCTs available. One recent study compared cyclophosphamide with etanercept and found that there was a far higher response rate with etanercept. However, this was a small study and was not an RCT so it is difficult to fully draw conclusions. Methotrexate, chlorambucil and axathioprine have also been shown to have some effect.

4. Anticytokine Therapy: This is currently probably the gold standard of treatment. Anti-TNF treatments has been shown to be effective in preventing the development of AA amyloid and even reversing established disease. More recently, in a small retrospective study, toclizumab, a new IL-6 antagonist was shown to be more effective than TNF antagonists in the treatment of AA amyloid. Other anti-cytokine therapies are being tested for their effectiveness in treating secondary amyloid and this is a field that is advancing rapidly.

Sunday, January 26, 2014

Warfarin for Atrial Fibrillation in Dialysis Patients: Where’s the data?

ESRD patients have an increased incidence of atrial fibrillation (AF) and a higher risk of stroke compared to patients with normal renal function. However they also have an increased bleeding tendency due in part to uremia and the associated platelet dysfunction. Anticoagulation with warfarin for AF is widespread in the general population, where the sense of risk and benefit are better understood. Like many other conditions, ESRD patients are routinely excluded from clinical trials in AF and therefore we lack hard data on how to manage our ESRD patients with AF. We must rely on observational data, which is often contradictory. Firstly, increased INR variability has been demonstrated in dialysis patients treated with warfarin and they spend much time outside of target INR range. Some registry data supports warfarin use with a suggestion of improved survival in dialysis patients with AF while other studies demonstrate an increased risk of stroke with warfarin [here, here, here]. Overall, the majority of studies do not support a protective effect for warfarin in ESRD patients with AF.

A current study from Canada in Circulation weighs in on the issue. The authors conducted a retrospective cohort study of patients > 65 years admitted with a diagnosis of AF from 1998 to 2007. There were 1,626 dialysis patients (46% received warfarin) and >200,000 non-dialysis patients. In a multivariate analysis, warfarin use in the dialysis patients was associated with similar risk of non-hemorrhagic stroke but a significantly higher risk of bleeding (defined as intra-cerebral, intra-ocular, GI, unspecified hemorrhage & hematuria; HR 1.44). The non-dialysis patients did see a lower incidence of ischemic stroke with warfarin use.

Our ESRD patients comprise a unique cohort with labile, often high blood pressure, repetitive AV access puncture, proven variability in INR and usually anticoagulation use during dialysis. They are certainly high risk for bleeding. Moreover, warfarin use is associated with accelerated vascular calcification in CKD patients and calciphylaxis, an admittedly uncommon but devastating condition. Unfortunately we suffer from a lack of alternatives to warfarin. Accumulation of low-molecular weight heparin in ESRD precludes its use and there is no experience with newer agents such as direct thrombin and Factor Xa inhibitors.
Many authors, including those at UpToDate, recommend warfarin use with AF and an eGFR<15mls/min. They are equivocal when CHADS2=0, but this is rare in a dialysis patient. Remember CHADS2 includes congestive heart failure, hypertension, age ≥75, diabetes and previous stroke/TIA. Despite older age being part of the CHADS2 score suggesting treatment efficacy, age >75 has been associated with a particularly high risk of bleeding in dialysis patients treated with warfarin. Also, CKD is part of the HAS-BLEED score which predicts high risk of hemorrhagic complications to warfarin when the score is ≥3. Many dialysis patients would fall into this category based on hypertension, older age and concomitant meds (85% in the current study in Circulation). I often feel uncomfortable using warfarin in ESRD and certainly feel it should be an individualized patient choice. With the current evidence (or lack of it) to guide us and the significant potential for harm, withholding warfarin for many of our older dialysis patients would not seem unreasonable.

Thursday, January 23, 2014

Screening for CKD - The new ACP guidelines - Part 3

Recommendation 3: The ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II-receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation)

This is the recommendation that I have most of a problem with. The most recent KDIGO guideline on the management of blood pressure in CKD is 85 pages long and although this degree of detail is not necessary for a guideline for general practioners, there is a substantial amount of nuance that has been missed and, in fact, I believe that this recommendation is potentially harmful.

It is clear from many RCTs going back to the 1980s that ACE/ARB therapy is indicated for the treatment of hypertension in all individuals with UACR>300mg/g. Similarly, ACE/ARB are also indicated for all diabetic patients who have a UACR>30mg/g. However, there is no clear evidence that ACE/ARB are preferred in non-diabetic patients with a UACR between 30 and 300 mg/g. The current KDIGO guidelines grade the evidence for the use of ACE/ARB in that setting as 2D (the lowest quality evidence) although there are suggestions from trials that there may be benefit.

However, for non-diabetic patients without albuminuria, there is no evidence that ACE/ARB reduce CVD or mortality relative to other antihypertensives. In fact, there is evidence that ACE/ARB are associated with more complications in non-proteinuric patients (AKI, hyperkalemia etc.) In the TRANSCEND trial the investigators studied the use of telmisartan in patients who could not tolerate ACE inhibitors. Of note, none of the patients had macroalbuminuria although all were high risk individuals. A pre-specified secondary analysis of this study examined renal outcomes and found no significant difference in the treatment group vs. placebo. However, when these patients were separated into those with and without albuminuria, there was a trend towards a benefit in those with albuminuria. In patients without albuminuria, there was an interaction for the main renal outcome (p=0.01) in the direction of harm (HR 2.35, CI 1.33-4.15). This result is not altogether surprising. In my (admittedly anecdotal) experience, the use of ACE/ARB in patients with non-proteinuric kidney disease is hazardous. These patients, usually elderly, are prone to hypotensive episodes and are exquisitely sensitive to volume depletion. the majority have vascular renal disease, even if they do not have clinically significant renal artery stenosis.

It appears that the authors of the recommendation did not take albuminuria into account when formulating this guideline. I would alter it to state that ACE/ARB should be first line therapy in patients with CKD and albuminuria but that they should be used with caution in patients with no albuminuria, particularly in the elderly and those with vascular renal disease. Score this a 0.

Recommendation 4: The ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoproteinn in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate quality evidence)

This is a pretty uncontroversial statement. Although the benefits of statins in patients with ESRD are no clear-cut, two recent meta-analyses have clearly demonstrated that statins reduce CV mortality in patients with early stage CKD. Score 1.

Overall, I would score these guidelines 2.5/4. Reading around this has certainly highlighted to me the lack of good RCTs to guide therapies that we treat as routine and suggests many avenues for future research although it is difficult at this stage to see who would pay for these studies as they would need to be extremely large and hence, very expensive.

Monday, January 20, 2014

Screening for CKD - The new ACP guidelines - Part 2

Recommendation 2: The ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker. (Grade: weak recommendation, low quality evidence)

This is an interesting recommendation and from a nephrologist's perspective, at first glance, it appears inappropriate but it should be remembered that these guidelines are not aimed at nephrologists but at primary care doctors and internists who are not dealing with patients who have frank nephrotic syndrome. This is similar in a way to the new guidelines for managing LDL cholesterol - there is no longer a specific target and regular monitoring of LDL is recommended only to demonstrate an appropriate response to therapy and compliance with treatment.

What is the evidence for UACR monitoring in patients with CKD. First of all, all patients with macroalbuminuria and all diabetics with microalbuminuria should unequivocally be on RAAS blockade unless there are contraindications. However, there are no trials demonstrating that targeting a specific level of proteinuria or that regularly monitoring proteinuria improves outcomes. With the recent demise of double RAAS blockade, it could be argued that once an individual is maximized on a single drug, regular checks of UACR are not going to alter therapy anyway.

That said, I do feel that there is value in rechecking UACR levels in patients on therapy. The ONTARGET Study showed very nicely that response to therapy was an excellent predictor of long term outcomes. A greater than twofold increase in albuminuria from baseline to 2 years despite therapy was associated with a 50% increase risk of mortality and a 40% increased risk of ESRD or doubling of creatinine. In contrast, a twofold decrease in UACR was associated with a 15% decrease in mortality and a 25% decrease in renal outcomes. Thus, periodic measurement of the UACR, despite its faults, provides important prognostic information.

The UACR is a surrogate marker and as a result it is suboptimal but if we learned anything from the Bardoxolone saga, it was that we should not ignore increasing albuminuria as a signal of adverse outcomes. As I said, this guideline was aimed at PCPs and it can certainly be argued that checking the UACR at every visit will not be enormously beneficial in that setting, particularly in patients with minimal albuminuria and early stage CKD. However, I don't think nephrologists will stop checking the UACR anytime soon, or stop seeing its value. However, I would agree that we do not know for certain what to do with an increasing UACR in a patient on maximal ACE/ARB therapy or what level we should be targeting. I would score this one 0.5/1 (total so far, 1.5/2)

Friday, January 17, 2014

Screening for CKD - The new ACP guidelines - Part 1

A few days ago, I was asked to present the new ACP guidelines for screening for CKD stages 1-3 to a group of non-nephrologists. These guidelines were published online last October in Annals of Internal Medicine and provoked a furious response from some nephrology groups including the ASN. The ASN's statement in particular took issue with the first recommendation and suggested that population screening of adults for CKD was justified. I'm going to present the 4 recommendations, briefly review the evidence and give a score for each recommendation based on what I believe. I know I'm sticking my neck out but I welcome any comments.

1. The ACP recommends against screening for CKD in asymptomatic adults without risk factors for CKD. (Grade: weak recommendation, low quality evidence).

In the response to this the ASN said "If detected early in its progression, kidney disease can be slowed and the transition to dialysis delayed. This evidence based fact is why regular screening and early intervention by a nephrologist is so important to stemming the epidemic of kidney disease in the US and why the ASN strongly recommends it". The problem with this response is that there is no evidence from trials that it is true. Remember that it is stages 1-3 CKD that we are talking about and that about 50% of individuals identified through screening will have stages 1-2. The risk of progression to ESRD in this population is very small. Note that the recommendation only refers to adults without risk factors. There is no suggestion that individuals with risk factors (diabetes, hypertension etc.) should not be screened.

The PREVEND study screened 41,000 adults in the Netherlands for albuminuria. After 9 years follow-up, 45 individuals required RRT. Screening only those who had risk factors (a history of hypertension, diabetes or CVD) identified 87% of those who eventually required dialysis. Of the 26,000 individuals without risk factors who were screened, only 5% had albuminuria and just 6 eventually required dialysis. Of those 6, only 2 had albuminuria at the time of screening. More recently, a cost-effectiveness study sponsored by the CDC found that the cost per QALY of screening was $155,000 for adults without risk factors compared with $21,000 for those with diabetes and $55,000 for those with hypertension when using CKD progression/ESRD as the outcome. It should be said that a subgroup analysis of the PREVEND study did find that there was marginal benefit to screening for microalbuminuria to prevent CVD with ACEi treatment. The benefit was substantially higher if only those with risk factors or individuals over the age of 60 were included. Another recent study examined the cost-effectiveness of albuminuria screening in African Americans and found that the cost-effectiveness was far higher in this population. However, they made a number of assumptions including that ACE therapy would be as effective in non-diabetics and non-hypertensives as in patients with these conditions and that ACE therapy would have the same effect on CKD progression as it does in non-African Americans.

It should be noted that the ACP is not the only group that recommends against population screening for CKD. The US Preventative Services Task Force also recommend against screening while the most recent KDIGO guidelines recommend screening for albuminuria and decreased GFR only in individuals with risk factors. Even KDIGO has an issue with the frequency of screening and recommendations range from yearly to every 3 years depending on the presence of co-morbid conditions.

Overall, after reviewing the (extremely poor) evidence, I would tend to agree with the ACP on this one. However, given the high prevalence of CKD in older populations, I would perhaps include individuals over the age of 65 in the group of those who should be screened along with patients with diabetes, hypertension and a family history of CKD. Score one for the ACP.

After writing this, I realize that I can't deal with all of the recommendations in one post so I'm going to split it up and post on the remaining recommendations over the weekend.

Saturday, January 11, 2014

Not so symple: End of the road for renal denervation procedures?

Since the advent of minimally invasive renal denervation procedures about a decade ago, the nephrology community had been eagerly awaiting conclusion of the SYMPLICITY 3 trial. As many of you might already know, Medtronic, the device’s company issued a press release on January 9th about the procedure failing to meet the primary efficacy endpoint. To a lot of us, this result has been surprising, and disappointing to a certain extent.

1952 paper from Mayo: Renal denervation/sympathectomy is not a new concept and has been around for almost a century. 

To understand the context, let’s review the background of renal denervation’s role in treatment of resistant hypertension briefly. Per NHANES data from the period 2003-2008, the prevalence of resistant hypertension is 8.9 ± 0.6% of the US hypertensive population, and continues to increase.  I am guessing the prevalence could theoretically be a little lower if the new, more relaxed, hypertension treatment goals of JNC 8 are considered. This was discussed by Matt earlier

Renal denervation is supposed to work on the premise that the sympathetic nervous system is hyperstimulated in patients with treatment resistant high blood pressure, and the kidneys modulate that to a large extent. Afferent signaling from the kidneys increases central sympathetic drive, while efferent signals to the kidneys increase renin release and sodium retention, while reducing renal blood flow. Hence, if you could cut off this two way traffic between the kidneys and the sympathetic nervous system, you should be able to bring the blood pressure down. Here is a picture that explains this. And below is a video of how the procedure is performed: 

Renal sympathetic afferent and efferent fibers run circumferentialy in the wall of the renal artery, and ablation reduces both pathways  

We have seen a succession of studies done to validate this hypothesis. Earlier, Matt had talked about the SYMPLICITY-1 trial, which was a non-randomized pilot study. Then we had SYMPLICITY-2 trial in 2010 which was a larger randomized study with 106 patients. This was conducted in Europe, Australia, and New Zealand. This showed significant reduction in office based blood pressures at 6 months, with no serious side effects. And so, with much fanfare and hype, the SYMPLICITY-3 trial was initiated in August 2011. While the study has not been published, the authors chose to communicate the procedure’s lack of efficacy (in meeting the primary end point) via a press release. There was no mention about the status of secondary end points (which included ambulatory BP changes) in the statement.

Why did the trial fail to meet the primary efficacy end point, in spite of the prior data that looked promising? It appears to be the best designed trial till date to study this issue. SYMPLICITY-3 was bigger (535 patients) and better designed (control patients underwent a sham procedure) than its predecessors. I wonder if that itself could have been the reason for us seeing the lack of any benefit. That in fact, the prior trials were outliers given smaller size of the studies, or lack of randomization. Or, could it have something to do with anatomical and functional regrowth of sympathetic nerves that can happen after they are ablated (as can happen post transplant)?  Let us know your thoughts about what you think could have been the reasons!  

Something that I have always wondered about (and which has nothing to do with this press release) is the safety and efficacy of this procedure in CKD patients. It is plausible that if you are tinkering with the renin angiotensin system, you could adversely affect renal function. Just like you could be leery of giving ACE inhibitors to an advanced CKD-4 patient with hypertension, would you consider not doing this procedure as well? Could we see hyperkalemia develop? In the absence of adequate data, I would say that I don’t know, but we did see a study that tried to answer this question. However, it was a small study (15 patients, and even those didn’t complete follow up), and a short follow up period.   
So is this development the beginning of the end of renal denervation procedure? Maybe; or maybe not. Medtronic has already suspended further enrollment in other renal denervation trials in the US (SYMPLICITY-4), Japan, and India. However, the device will still remain available for “discretionary use” by physicians (good luck convincing insurance companies to pay for a procedure that is about as good as sham!). But, we still have other potential indications under the sun which could be a breath of life for the device/procedure. These include heart failure, metabolic syndrome, and obstructive sleep apnea.   
Finally, we also have another device that works on the principle of baroreceptor activation that is being actively studied for treatment of resistant hypertension.

Wednesday, January 8, 2014

An atypical form of renal failure: granulomatous interstitial nephritis

A 42-year-old man developed AKI during his recent hospitalization due to presumed sepsis. He was started on vancomycin and levofloxacin as empirical therapy. When renal was consulted 7 days after admission, creatinine level had peaked at 4.39 mg/dl and WBC 33K with eosinophilia. Urinalysis was associated with 2+ proteinuria and 2+ leukocyte esterase with some granular casts, though no cellular casts were visualized. On examination, he had generalized erythematous rash associated with diffuse body edema.

The initial diagnosis by the team was thought to be ATN associated with sepsis, though the presence of rash and eosinophilia raised the concern for superimposed drug-induced acute interstitial nephritis (AIN).

A renal biopsy was performed and the histopathologic findings revealed an AIN with granulomatous features (figure on the top left - Courtesy of Dr Rennke/Dr Bijol).

AIN is a common finding in kidney biopsies of patients with acute renal failure in the hospital. However, granulomatous interstitial nephritis (GIN) occurs in only about 1% of biopsies. GIN is a histologic form of interstitial nephritis characterized by the presence of necrotizing or non-necrotizing granulomas in renal biopsy. Its pathogenesis is not well defined. Some immunologic mechanisms were proposed as culprits such as T-cell-mediated delayed hypersensitivity, anti-tubular basement membrane antibodies and autoimmune antibody response.

Potential etiologies include:

 - Drug-induced processes [[most common]] (Antibiotics, NSAIDs, Diuretics (thiazide), Allopurinol, Anticonvulsant (lamotrigine), Omeprazole, Bisphosphonate, All-trans retinoic acid, Heroin abuse)
- Infections (xanthogranulomatous pyelonephritis, tuberculosis and other mycobacterial infections; Histoplasmosis and other fungal infections; adenovirus)
- Systemic inflammatory conditions (Sarcoidosis, Wegener granulomatosis, TINU, Crohn’s disease)

In about 15% of cases, an exact etiology for GIN is not found.

Further work-up on the case above did not reveal any systemic inflammatory process or infections, though a high suspicion for antibiotic-induced GIN was raised. In particular, there has been case reports of levofloxacin-associated GIN.

The treatment of GIN depend on the underlying associated factor. For example, in drug-induced processes, the removal the offending agent will play a central role in the treatment; while in infection-related cases, the underlying infection must be controlled.

In the case presented, antibiotics were changed and an empirical trial of steroids was administered. Patient’s creatinine slowly trended down in the subsequent weeks but plateau at 1.5 mg/dl. Though there has been no randomized trials, most GIN cases deserve a trial of steroids once infectious etiologies are excluded, in particular based on the intense inflammation observed on the biopsies.

Anthony Gueratto Klepp
Eduardo Kaiser Ururahy Nunes Fonseca
Leonardo V. Riella

Monday, January 6, 2014

BK nephropathy: Diagnosis and Management Update

The BK polyomavirus is a small, non-enveloped DNA virus, which is an ongoing concern for the transplant population as it primarily causes clinical disease in immunocompromised hosts, leading to BK-associated nephropathy (BKN) and graft loss.

Primary infection of BK virus is thought to occur early in childhood, commonly presenting as a viral respiratory infection. After that, BK virus remains latent in renal epithelial and lymphoid cells, where it can get re-activated in immunocompromised population.

Risk Factors include: 1- Degree of immunosuppression 2- Donor determinants (deceased donation, HLA-mismatches). 3- Recipient determinants (older age, male). 4- Re-transplantation due to BK virus graft loss

A definitive diagnosis of BKN requires analysis of tissue from renal biopsy (figure with positive staining for SV-40; courtesy of Dr Rennke). However, the diagnosis may be missed on biopsy since definitive lesions are focal in nature. Therefore, at least two biopsy cores should be taken and medulla ideally should be included in the sample. The suspicion of the diagnosis is supported by quantitative PCR for BK virus on urine and/or plasma.

Prevention of BKN is the cornerstone of routine screening. The two most commonly used ways of BK virus screening are blood and urine for viral DNA monitoring, monthly for the first 3-6 months, then every 3 months until the end of the first post-transplant year, and wherever there is an unexplained rise in the serum creatinine.

Based on retrospective studies, fluoroquinolones may have a role in the prevention, but are not effective for treatment. The mainstay of therapy is reduction in immunosuppressive medications, especially mycophenolic acid, followed by calcineurin inhibitors. If reducing immunosuppressive therapy is not effective, clinicians may try using adjunct medications with potentially antiviral action, even though the efficacy of the agents in vivo has not been demonstrated. These agents include: Intravenous immune globulin (IVIG), Leflunomide, and Cidofovir. None of them have been approved by the FDA for the treatment of BKN.

Kidney retransplantation after BKN yields satisfactory results and prior BK infection should not be a contraindication for re-transplantation. Note that extensive phase of aggressive immunosuppressive therapy post retransplant should be avoided, and close monitoring/screening for BK viral load is advisable.

Antiviral adjuvant agents for the treatment of BK associated nephropathy.

Major side effects
0.2-2.0 g/Kg IV
Renal dysfunction,  thrombosis
$$$$ (~$10-22K/dose)
Leflunomide# (Arava®)
LD*: 100 mg x 5 days
MD^: 20-60 mg daily
Peripheral neuropathy, bone marrow suppression, hepatitis
$$$ (~$2000/month)
Cidofovir (Vestide®)
0.25-1 mg/Kg every 1-3 weeks without probenecid
$$ (~$800/vial)

 *LD: Loading dose ^MD: Maintenance dose #Target blood levels: 40-100 ng/mL 

It is quite clear that prospective, multicenter, randomized clinical trials are needed to define the best strategy for immunosuppression reduction and also to investigate more antiviral agents based on the poor outcome of grafts after development of BK nephropathy.

 Brianne Ritchie, PharmD, MBA
 Sandra El Hajj, PharmD
Steven Gabardi, PharmD

Sunday, January 5, 2014

Does octreotide hold promise for treatment of polycystic kidney disease?

One of the most frustrating things in clinical nephrology is to give a diagnosis of polycystic kidney disease (PKD) to a young patient, and follow that up by saying that they could progress to end stage renal disease requiring dialysis, and “there is not much I can offer to change that”.

Autosomal dominant PKD is the most prevalent monogenic disorder, and the average rate of GFR decline could be as much as 4.4 to 5.9 ml/min. Recently, the well-publicized TEMPO trial has shown a potential clinical application for tolvaptan in stemming the progression of PKD by slowing the growth of the total kidney volume and eGFR decline over a 3-year period.

Another agent that is being studied for a few years for a potential role in inhibiting cyst growth in PKD is octreotide, a long acting somatostatin analogue. This is an agent we in the nephrology universe have been using for some time for the treatment of hepatorenal syndrome. A randomized placebo controlled trial had first reported in 2005 that a 6-month treatment with somatostatin could slow cyst growth. Although we know that decline in kidney function in PKD follows cyst growth, the study stopped short of saying that slowing the cyst growth in this case would translate in to clinically meaningful renoprotection. A similar effect on liver volume has been reported as well.

A few months ago, we saw the results of the ALADIN trial published in the Lancet. This study had a longer follow-up period than the previous studies, and indicated a significantly lower kidney volume in patients treated with octreotide at 1-year follow-up, but not at 3-years.

Given the data we have so far, it appears that octreotide could have a potential role in the treatment of PKD. For some reason, it appears that octreotide slows growth in kidney volume over one year, but the effects become insignificant over the long term. Obviously, more comprehensive studies looking at long-term hard outcome data are needed. Another interesting thing would be to compare the data for octreotide vs. tolvaptan. Although both these agents have shown promise so far (in addition to other contenders like mTOR inhibitors), a major concern is cost. All other things being equal, octreotide could me a cheaper alternative than tolvaptan for what essentially could be a lifelong treatment. At my time of writing this, a ten-day course of 15 mg tolvaptan pills was priced at $3440.00, while a 100 mcg octreotide injection was priced at $11.93!

I can’t wait for the day when we will be able to offer our patients something more definitive for treatment of PKD, rather than the current bandaid regimen of ACE inhibitors, increased water intake, hand-holding, etc.

Posted by Veeraish Chauhan

Friday, January 3, 2014

Are bioengineered kidneys becoming reality?

The lack of transplantable kidneys is an unavoidable problem for those of us who practice Nephrology. Whilst government policies and extended criteria for donor organs have a role to play in solving this problem, it has always seemed to me that science is going to have to serve us up a definitive solution.

Although many of us appreciate that induced pluripotent stem cells (iPSCs) will likely form part of the answer to this question, it is more difficult to visualise how iPSCs could be used to reconstitute a complex multi-cell organ such as the kidney. Additionally, since the emergence of 3D printing we have had media friendly stories of printed kidneys without much information about what will be used as the 'ink' in the printer.  

A paper in this month's Cell Stem Cell may hint at the future. Firstly, the authors worked out the developmental origins of the metanephric mesenchyme (MM), the embryonic tissue that generates most elements of a functioning kidney (see diagram). The group then used this information to derive MM from PSCs and found that this derived MM successfully reconstituted glomeruli and proximal and distal tubules in vitro. Furthermore, when these generated nephrons were transplanted beneath the renal capsule of mice they showed new vascularisation suggesting they may be functional.

So, is the answer to our transplantation problem to use these authors' protocol to derive lots of MM which can then be 3D printed around a small core of functioning renal tissue to make a working organ? Well, a number of issues remain. Firstly, as can be seen from the diagram, the collecting duct is derived from the separate ureteric bud. Therefore, it is not included in this model and successful combination of these structures would likely be needed to make a truly functional nephron. Perhaps most glaring is that the Cell Stem Cell paper makes no assessment of the excretory function of these derived nephrons.

In conclusion this is probably only "a good start" but I think it represents significantly more progress than any number of eye catching 3D printer stories.

Thursday, January 2, 2014

Contrast-Induced Nephropathy (CIN): An Update from the Cardiology Literature

Happy new year to all! I’ve been thinking about how much Nephrology content there is in non-renal journals and how much we miss by just reading the usual renal periodicals each month. You cannot be expected to read every Cardiology/Endocrinology/Rheumatology journal every month so I thought I would bring you what I’ve noticed in the non-Nephrology literature recently. Today I’m focusing on CIN. If the post proves popular, we may run a regular literature watch from non-Nephrology journals on RFN.

Since, N-acetylcysteine (NAC) has fallen out of favor, all we have in our armamentarium for CIN prevention is IV volume expansion. There were 3 recent publications in the Journal of the American College of Cardiology which you may have missed regarding novel therapies for CIN prevention. Firstly, the PRATO-ACS study which was a RCT of rosuvastatin in >500 consecutive statin-naïve patients presenting with a NSTEMI who proceed to cardiac catheterization. Greater then 50% of patients were diabetic and mean eGFR was 82mls/min. The incidence of CIN was significantly lower in the rosuvastatin group (6.7 vs 15.1%) as were other renal, cardiac events and mortality. In the same issue, a study of 3000 diabetic CKD (Stage 2 or 3) patients randomized patients to either rosuvastatin or placebo 5 days before intra-arterial contrast. The rosuvastatin group had a significantly lower incidence of CIN compared to controls (2.3% vs 3.9%). Statins are postulated to improve CIN by their anti-inflammatory and positive endothelial effects. These large scale prospective RCTs support a meta-analysis from 2012 suggesting a benefit in statin use for CIN.

A meta-analysis of trials using ascorbic acid for the prevention of CIN was also recently published in J Am Coll Card. Over 1500 patient were included from 9 RCTs and it was demonstrated that receiving ascorbic acid (mix of oral and IV) had 33% less risk of CIN compared to the control group. Six of the 9 studies had significantly p values themselves. The postulated mechaism of action of ascorbic acid is similar to the theory behind NAC, antioxidant free-radical scavenger i.e who knows?

Verdict: The 2 statin trials are good sized prospective studies in high risk populations (ACS & diabetic CKD) receiving intra-arterial contrast and do support short term statins in this circumstance. Knowledge gaps exist for lower risk patients and those already on statins (a lot of patients these days) as well as dose, duration and the benfit of other statins. The Vitamin C meta-analysis looks interesting but given the study heterogeneity and the NAC story, I remain skeptical until well powered RCTs are performed.