Wednesday, November 18, 2015

What does SPRINT mean for HTN and CKD?

There has been much fanfare regarding the release of the SPRINT trial in the last several weeks. Finally, evidence that intensive blood pressure reduction is good! But, does this apply to everyone? Is there adverse risk to lowing BP this low? Also, what does this mean for our patients in the CKD clinic?

Let’s take a look at the SPRINT study and try to answer these questions.

What was SPRINT? 
SPRINT was a large randomized controlled trial with over 9,000 non-diabetic patients, funded by the NIH, to study the effect of intensive blood pressure control on cardiovascular health. The trial was terminated early (after a mean follow-up of 3.3 years) due to a significantly lower rate of the primary composite outcome (MI, ACS not resulting in MI, stroke, acute decompensated HF, or death from cardiovascular causes) in the intensive-treatment compared to the standard-treatment group. For more coverage of SPRINT go to NephJC.

The basics of the enrolled population are as follows:
  • All patients were over the age of 50 (mean 68). 36% were female.
  • Patients had elevated cardiac risk based on: a 10 year Framingham risk ≥ 15%, clinical or subclinical CVD, CKD with eGFR 20-60 ml/min/1.73 m2, or being over age 75.
  • 28% of patients (~2,600) had CKD with minimal proteinuria (patients with > 1 g proteinuria or >; 600 mg of albuminuria were excluded). 
  • 28% of patients were over age 75 at enrollment, their mean age was 80.
  • 43-45% of patients were on statins and ~50% were on aspirin.
  • Over 60% of patients started the trial with a SBP of > 145 mmHg.
  • Chlorthalidone was encouraged as the primary thiazide-type diuretic. 
  • The suggested initial triad of medications was a diuretic, CCB (preferably amlodipine), and ACEi or ARB. 
The main results were: 

Intensive Treatment
Standard Treatment
Mean SBP at 1 year
121 mmHg
136 mmHg

Mean # Medications

Primary Outcome (ACS, CVA, CHF, CV death)
1.65 %/year
5.2 % (over 3.3 years)
2.19 %/year
6.8 % (over 3.3 years)
HR 0.75 (0.64-0.89)
RR reduction 25%/year (*driven by CHF and CV death)
NNT 61 (over 3.3 years)
All-Cause Mortality
1.03 %/year
3.3 % (over 3.3 years)
1.40 %/year
4.5 % (over 3.3 years)
HR 0.78 (0.67-0.90)
RR reduction 26%/year
NNT 90 (over 3.3 years)

What about CKD? 
First, SPRINT was not designed to be a CKD progression trial. However, it did include a large group of patients with CKD. In the patients with baseline CKD, intensive blood pressure control had no effect on the composite renal outcome (reduction in eGFR of 50% or more, dialysis or transplantation), nor on the development of incident albuminuria. Indeed, in patients without baseline CKD intensive blood pressure control led to higher rates of developing an eGFR < 60 ml/min/1.73 m2 (patients had to have at least a 30% drop in eGFR). The significance of this is unclear. Importantly, in the pre-specified subgroup analysis, the cardiovascular benefits of intensive blood pressure management were similar in patients with and without CKD. The caveat to all of this discussion was that the trial was not powered to answer this question.

What were the costs of aggressive treatment? 
While overall serious adverse events were not statistically more common (38% vs 37%), there were more episodes of hypotension, syncope, AKI, hyponatremia, and hypokalemia in the intensive group. Interestingly, orthostatic hypotension was actually higher in the standard treatment group and there was no increase in falls with intensive therapy. Patients were seen on a monthly basis by protocol if not at goal. Those in the intensive group had “Milepost Visits” every 6 months where the addition of medication was protocolized for patients with SBP < 120 mmHg (unless compelling contraindications existed). Notably, despite these aggressive measures half the patients were still unable to reach the intensive goal.

What did we know about aggressive BP control prior to SPRINT? 
 Nephrology dogma, codified in guidelines, has long argued for lower BP targets in patients with proteinuric CKD. A meta-analysis from 2011 combined the three key trials on aggressive blood pressure reduction (MDRD, AASK, and REIN-2) with a total of almost 2,300 primarily non-diabetic patients. The results suggested that aggressive blood pressure control (goals ranged approximately 125-130/75-80) on the whole does not improve CKD outcomes however sub-group analyses of proteinuric patients indicate the possibility of a benefit to stricter blood pressure control in terms of CKD progression. This possible benefit was seen in patients with greater than 0.22 g/g of proteinuria in AASK and greater than 1000 mg/d in MDRD. The recent JNC-8 guidelines argued however that this same data represented moderate quality evidence that lower BP targets do not slow CKD progression. For additional discussion of the post-hoc analyses of MDRD and AASK click here (previous review by Graham Abra on RFN). Given this potential equipoise perhaps it is unfortunate that patients with higher proteinuria were excluded from SPRINT.

What do we know then going forward? 
Hypertension is a strong risk factor for CKD. While the exact goal remains unclear, controlling blood pressure to < 140/90 is likely to be beneficial. Importantly, as the nuances of SPRINT are discussed – including additional outcomes such as the effect of intensive control on cognitive function in the elderly – hypertension in general is still very undertreated. Based on a recent CDC report 65% of US adults over the age of 60 have hypertension but only ½ are controlled. While this represents improvement from around 30% at the turn of the Millennium this still means that ½ of the population is not meeting the more conservative goal of 140/90. Increasing the percentage of patients controlled to 140/90 should have a profound and meaningful effect on the incidence of ESRD. SPRINT shows us however that for some of our patients with CKD, aggressive SBP control to < 120 can provide tangible, though not dramatic, improvements in cardiovascular risk.

Post by Robert Rope, Nephrology Fellow, Stanford

Hypertensive emergency during dialysis

We had an interesting discussion yesterday about a young patient with ESRD secondary to diabetic nephropathy who was recently initiated on hemodialysis and reported headaches, chest heaviness and shortness of breath during dialysis sessions associated with a rise in systolic blood pressures to the 200’s. She was being dialyzed for 3.5 hours and was on Clonidine 0.3mg BID, Carvedilol 24mg BID, Norvasc 10mg daily.

 Intradialytic hypertension is defined as an increase in blood pressure after dialysis initiation. It is a common condition affecting up to 15% of patients on hemodialysis. For a thorough review, look at this prior blog.

The pathophysiology is likely multifactorial:

  • volume overload 
  • renin-angiotensin-aldosterone over activation 
  • endothelial dysfunction (rises in the vasoconstrictor endothelin-1) 
  • sympathetic over activation 
  • EPO-related 
  • net sodium gain during dialysis (hyponatremic patients dialyzed with high sodium bath) 
  • electrolyte disturbances (hypokalemia and hypercalcemia) 
  • dialytic removal of antihypertensives: agents that are significantly removed during dialysis include atenolol, metoprolol, lisinopril and enalapril. ARB, labetolol, carvedilol, ramipril, hydralazine, benazepril, clonidine and hydralazine and calcium-channel blockers have little clearance during dialysis (figure above)

Management include:

  • increase time of dialysis with more gentle ultrafiltration
  • attempt to lower dry weight
  • review antihypertensives to favor those not eliminiated on dialysis 
  • consider adding ACEI/ARB
  • if hyponatremia, lower sodium of dialysate

 The patient above had her dialysis time increased to 4.5 hours per session, dialysate sodium was reduced to 135 (predialysis Na was 127) and an ACEI was added to her regimen. This yielded improvement in symptoms over the next few weeks and her dry weight was further lowered about 3 kg.


Monday, November 16, 2015

Attend NephroTalk 2016 to Improve Your Communication Skills

As a nephrology fellow, do you want to take your communication skills to the next level?

Join us in Pittsburgh in February, 2016 for the fourth annual NephroTalk Communication Workshop, a three day course for nephrology fellows modeled on the acclaimed Oncotalk, Intensivetalk, and Geritalk courses ( for more information).

Nephrology fellows in this course will learn advanced communication skills, practicing communication in real time with simulated patients with coaching from expert faculty, in a supportive and safe environment.
Learn how to skillfully handle scenarios such as:
  • Discussing serious news such as worsening kidney function
  • Responding to strong emotion
  • Addressing conflict with patients, families and care team members
  • Eliciting goals of care to assist treatment decision-making
  • Discussing dialysis withdrawal and end of life with patients and families 
Workshop Details 
Date: February 17 to February 19th 2016
Location: Pittsburgh, PA
Course Director: Jane Schell, MD
Additional Faculty: Robert Cohen, MD; Jamie Green, MD; Julie Childers, MD; Robert Arnold, MD
Cost: $500 per participant (includes breakfast and lunch; housing may be available in faculty member’s homes if needed)

For more information: contact Jane Schell or send in this form to Jane.

On a personal note- I would highly recommend this course to anyone. Jane developed this course while we were fellows together at Duke and I can honestly say it is fantastic. I would say completing this course is one of the most effective ways you can improve your clinical practice. -Matt Sparks

Saturday, October 31, 2015

Hypoxya Inducible Factor and Anemia.

Several new therapies to treat anemia in patients with CKD and ESRD have recently been launched that will likely expand the treatment options. For the last few weeks I have been hearing frequently about Hypoxia Inducible Factors (HIFs) and anemia.

First of all, what are HIFs? They are transcriptional activators that function as master regulators of oxygen homeostasis and play an important role in the body’s response to hypoxia. HIF-1 was discovered in 1992 and purified in 1995. In the original research, the authors reported that HIF-1 activates EPO gene transcription in Hep3B cells that are exposed to hypoxic environments. HIF-1 is a heterodimer, consisting of alfa (HIF-1α, HIF-2α and HIF-3α) and a beta subunit which has three isoforms (Arnt1, Arnt2, Arnt3). Under well-oxygenated conditions, HIF-1α is expressed and bound to Von Hippel-Lindau (VHL) protein and is rapidly degraded via hydroxylation at proline residues (PHD2). PHD2 uses oxygen as substrate and its activity is inhibited under hypoxic conditions which causes accumulation of HIF-1α. This process increases vascularization (angiogenesis) in hypoxic states such as ischemia, tumors, immunological responses, homeostasis and anaerobic metabolism. It also has an important role in tumor proliferation as it has been found that the HIF-α levels are increased in certain types of tumors. In chronic kidney disease, the lack of EPO expression causes anemia which typically is treated with recombinant human EPO (rhEPO). This topic has been covered extensibly at the RFN here, here and here.

This month in JASN, a phase II study was published about an investigational drug for the treatment of anemia, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (GSK1278863). In this research, 73 patients with CKD not on dialysis and 83 patients on hemodialysis were enrolled to receive the experimental drug at different doses (0.5 mg, 2 mg and 5 mg) compared to a control group (placebo for patients not on dialysis and patients on hemodialysis receiving recombinant human erythropoietin -rhEPO-) The results were quite surprising: In the nondialysis group, the experimental drug increased the hemoglobin levels at week 4 (average of 1 g/dl). In the hemodialysis patients that were switched from rhEPO to the experimental drug (5 mg), an increase in maintaining a mean hemoglobin concentration was achieved only in the high-dose group, but not in the lower-dose group. These results suggest that this drug may be a good alternative to rhEPO. Theoretically, high EPO concentrations achieved during rhEPO treatment, contribute to the cardiovascular effects in patients with CKD.

Although this study was short, it brings to light the importance of finding good alternatives to treat anemia in patients with CKD and on hemodialysis. Given the reported adverse events with rhEPO treatment and the promising results of this trial, a phase III trial, a larger population study and longer duration is required to test the safety and efficacy of this drug. Keep your fingers crossed.

Figure from: The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. V H Haase. Kidney International (2006) 69, 1302–1307

Tuesday, October 27, 2015

Blogger Night at ASN Kidney Week

Everyone is invited to the 2015 blogger night (I believe it is the 5th annual) at BarleyMash on the corner of 5th and Market on Thursday November 5th from 7-11pm. The event is hosted by NephJC and Satellite Healthcare. That means free appetizers and refreshments. Would be great to see many RFN fans show up and support online nephrology. See you all in San Diego. 

Thursday, October 15, 2015

Kidney regeneration. The stride continues…

The past two weeks have been exciting for the field of regenerative medicine in nephrology. Two papers demonstrated the feasibility of developing kidney cells from human pluripotent stem cells. One from the USA by Dr Joseph Bonventre’s group at the Renal Division of the Brigham and Women’s Hospital (Morizane, Lam et al. Nat Biotechnol 2015) and one from Australia by Dr Melissa Little’s Group at University of Melbourne (Takasato et al. Nature 2015).
The major breakthrough of these publications is that they were able to generate with a high efficiency mature nephrons (with podocytes, proximal tubules, loops of Henle and distal tubules) starting from nephron progenitor cells!

Albert Lam, one of the co-authors of the Nat Biotechnol paper, stated that: “We established a differentiation protocol that would mimic the stages of nephron formation as closely as possible. Our approach in recapitulating the steps of kidney development resulted in a highly efficient protocol for generating kidney organoids. The ability to do this using induced pluripotent stem (iPS) cells, which are derived from skin or blood cells of patients, allows the creation of kidney tissue without ethical concerns and allows the tissue to be “personalized”, that is, generated from a particular patient. If in the future the tissue is re-implanted back into the patient, the immune response may then be very limited since the tissue will be recognized as self.” This achievement has an enormous potential impact on a variety of clinical and translational applications, including kidney tissue bioengineering to replace lost kidney tissue, renal assist devices to treat acute and chronic kidney injury, drug toxicity screening, screening for novel therapeutic agents, and human kidney disease modeling.

Albert kindly shared with me that I shouldn’t be anxious yet about my job as a transplant nephrologist since more years are needed to develop a full organ incorporating the blood supply and urinary collecting system. I selfishly hope so…

Figure above: Nephron 3D structure 28 days after protocol initiation demonstrating the presence of markers of distal tubules (CDH1), podocytes (PODXL) and proximal tubules (LTL)

Tuesday, September 29, 2015

Alemtuzumab for refractory rejection: what is the data?

For severe or refractory rejections, thymoglobulin/ATG is commonly employed in combination with steroids and B-cell targeted therapies when indicated. However, alemtuzumab could be more effective then thymoglobulin since it depletes not only T cells but also memory B cells, NK cells and some DCs (Figure demonstrating expression of CD52 on different immune cells; Rao et al. PLOS One 2012).

 Despite the absence of randomized trials, one small study reported the use of alemtuzumab for steroid-resistant cellular rejection (van den Hoogen et al. AJT 2013). They compared adult patients with steroid-resistant renal allograft rejection that were treated with either alemtuzumab (15-30 mg s.c. on 2 subsequent days; n = 11) or rabbit ATG (2.5-4.0 mg/kg bodyweight i.v. for 10-14 days; n = 20). Although not statistically significant, 27% of alemtuzumab-treated patients experienced treatment failure compared to 40% in ATG group (p = 0.70). Incidence of infection was similar, while ATG had more significant infusion-related reactions. Few other case reports of success in treating refractory/severe rejections in kidney transplants (case report 1 and 2) and lung transplants (n=22, Reams et al. AJT 2007) are referenced here.

 One of the advantages of alemtuzumab is that it can be given subcutaneously with only one or two doses and it is cheaper than ATG. We had few patients with plasma-cell rich rejections or refractory cellular rejections, in which we stained for CD52 and it was diffusely positive. We decided to administer Alemtuzumab. Due to the heterogeneity of the group, it is difficult to conclude at this time how effective it was though few patients had great responses.

 In sum, alemtuzumab should be considered as an alternative therapy for severe/refractory rejection. Whether staining CD52 on biopsies would help guide us in selecting alemtuzumab in place of thymoglobulin still requires further investigation.

Infections and intravenous iron

An interesting study appeared in my email this morning examining the association between the use of iv iron and outcomes in hemodialysis patients with systemic infections. Current guidelines from all of the major societies suggest that if patients are admitted with bacterial infections in particular, iv iron should be stopped. There are both basic and clinical data supporting this recommendation although it should be said that the evidence is weaker than one would imagine.

The biologic plausibility argument rests on the fact that high iron concentrations have two negative effects in the context of infection. First, iron appears to impair the function of both neutrophils and T-cells. Patients on dialysis with iron overload have been shown to have reduced neutrophil function and phagocytosis. Similarly, impaired PMN function has been seen when neutrophils from healthy controls are incubated with ferric compounds. However, it should be pointed out that iron is vital for normal neutrophil function and individuals with iron deficiency also have impaired function. Clearly there is a sweet spot for neutrophil function but we are uncertain what it might be.

The evidence for a clinical effect for iron infusions on increasing infection frequency and severity is based on two separate strands (well summarized here). First, multiple observational studies have shown that high ferritin levels (particularly when >1000) are associated with an increased frequency of bacterial infections. There are clear limitations here. First, this finding is not consistent across all studies (4 of 14 studies did not find this association). Second, ferritin is an acute phase reactant itself and is not necessarily always elevated due to iron overload. Third, most of these studies were done in the pre-ESA era where much of this iron overload may have been due to transfusions. Finally, all of these studies were observational. As such, it is impossible to say if the risk of infection may not have been due to other factors which also lead to a higher iron requirement/ferritin levels.

The second strand of evidence is observational studies showing that higher doses or frequency of iron infusions are associated with a higher risk of future infection. Again, all of these studies are observational and so the same criticism as above applies. Similarly, there is a lack of consistent results across all studies although it should be said that the largest studies with the most patients did find an effect. However, in the most recent large study of ~120,000 medicare patients, while there was an increase in the risk of infection with higher doses of iron, the HR for infection for high vs. low dose was only 1.05. None of these studies examined the effect of ongoing iron administration on the severity of infection in dialysis patients. One could say that they are an argument against using iron in dialysis patients (which is not realistic) rather than arguments for stopping during an infection.

Today's email is thus especially welcome. This is a study published in CJASN which examines the relationship between ongoing iron use and severity of infection in Medicare patients. In total, 22,820 individual who had received iv iron in the 14 days prior to admission with a bacterial infection were included. 10% of these patients also received the iron while they were inpatients or shortly afterwards and were included as the cases. The controls were individuals who did not receive iron (i.e the iron was stopped per guidelines). The receipt of iv iron was not associated with increased short or long term mortality, LOS or likelihood of readmission in the next 30 days.

What is the explanation for this finding? One important question is why those 10% of patients did not stop iv iron after admission despite the clear consensus suggesting that it should be done? Looking at the table of demographic and clinical characteristics, there was nothing sticking out that suggested a reason for this difference and there may have been unmeasured characteristics that explained the difference. The outcomes were hard (as they would have to be given the source of the data) but may miss some subtle differences in outcomes related to the infection itself. That said, mortality and readmission are probably the most important outcomes. Finally, again this study was observational and needs to be interpreted as such.

All that said, this is an excellent addition to the literature which raises many more questions that it answers. These are important questions - too much of what we do in nephrology is based on consensus rather than clinical trials. Perhaps this might stimulate someone to do the necessary trial to answer this question once and for all.

Gearoid McMahon

Monday, September 21, 2015

KDPI score and donor urinary biomarkers: poor predictors of graft outcome

KDPI (kidney donor profile index) is a numerical measure that combines ten variables about a donor, including clinical parameters and demographics, to express the quality of the donor kidneys relative to other donors.  It has been reported by UNOS in attempt to classify the quality spectrum of cadaveric kidneys in order to use it for better matching with recipients’ characteristics (previously reviewed by Andrew here). 

One of the major limitations of the KDPI score is its poor predictive power with a C-statistics of 0.6 (0.5 would be the flip of a coin) (Reese et al. JASN 2015). The score relies heavily on age (diverse renal function within same age group is common), donor terminal creatinine (may reflect acute kidney injury), and it does not take into account HLA matching or other immunological risk factors. Therefore, KDPI score is not a good predictor of graft outcome.

In attempt to improve this prediction, Reese et al. (JASN 2015) conducted a nice prospective study in deceased kidney donors and respective recipients to assess associations between urinary biomarkers (NGAL, KIM1, IL18, L-FABP) in deceased-donor urine with three outcomes: donor AKI, recipient delayed graft function and recipient's graft function at 6 months post-transplant. Although donor urinary injury biomarkers was strongly associated with donor AKI, biomarkers provided limited value in predicting delayed graft function or early allograft function after transplant. The search for better predictive tools continues...

Figure above from Kidney Transplant iBook

Monday, August 24, 2015

Eculizumab dosing in aHUS patients undergoing kidney transplantation

Hemolytic uremic syndrome is a thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia and renal impairment. Most cases (90%) are secondary to infections, such as E. Coli (serotypes O157:H7, O103:H2). For a more comprehensive review about aHUS, check this paper. The rest of the cases are classified as atypical uremic syndrome (aHUS), which is typically associated with a poor prognosis. There is a previous post about Eculizumab and renal transplantation on the RFN.

The majority of the patients with aHUS are affected during childhood and teenage years to the point of developing kidney failure. When kidneys are severely involved the best treatment option is kidney transplantation. These patients are at high risk for recurrence of the disease after transplantation and a high percentage of these patients lose their kidney allografts. In patients with mutations in Factor H and Factor I, recurrence occurs in about 70-80% of the cases. Other less common mutations associated with recurrence, are C3 and FB. Furthermore, it has been reported that mutations in the MCP (membrane associated regulator, CD46) gene are less likely to be associated with recurrence, because the mutation affects the endothelial cells and renal transplantation would restore normal endothelial MCP function in the kidney. 

Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria and aHUS. It is also used in ABO-incompatible living donor kidney transplantation and antibody mediated rejection. This monoclonal antibody binds the complement protein C5, blocking its cleavage into C5a and C5b, hence preventing the formation of MAC. The authors of this paper concluded that eculizumab was effective in patients with aHUS and native kidneys. I found approximately 15 adult cases reported in the literature that received prophylactic eculizumab to prevent post-transplant aHUS suggesting that this approach is effective. However there are no standardized protocols for administration of the drug preoperatively. In these cases, patients received a dose of eculizumab 1,200 mg IV 24 hours prior to transplantation, and after transplantation 900 mg IV weekly for 4 weeks started on post-operative day 1, and then 1,200 mg IV bi-weekly afterwards. This is based on the manufacturer’s recommendations. There are also pediatric cases and the majority of them have had successful transplantation without recurrence of aHUS. All of these case reports, have used different pre-emptive protocols. In one case , the patient was started on eculizumab 7 months prior, receiving 600 mg as the initial dose, followed by 300 mg every two weeks thereafter. In another case, eculizumab was given 2 hours prior to kidney transplantation and in other case, it was given 6 hours prior.

The University of Iowa has developed a protocol aimed for the pediatric population. Additionally, an aHUS longitudinal study is currently underway by the Molecular Otolaryngology and Renal Research Laboratories lead by Dr. Richard Smith, that will follow up biomarkers to assess what happens to patients with aHUS over time. This data-gathering is mostly because eculizumab has changed the survival curve and it is important to know the long-term outcomes.

Unfortunately, there is no data in regards to treatment withdrawal, but it is clear that single doses of eculizumab are ineffective and discontinuing the medication is associated with risk of recurrence in the first 3 months, hence treatment should be life-long. In regards to maintenance therapy, it has been reported that although tacrolimus and cyclosporine are associated with TMA (data is conflicting), tacrolimus is the first choice due to lower rates of TMA. Additionally, plasma exchange was also reported to be effective in some patients prior to the introduction of eculizumab as reported by Zuber et al. Furthermore, liver- kidney transplantation could be a potential cure for aHUS as the authors concluded in this paper. Also, it’s important to point out that patients require meningococcal vaccination prior to eculizumab administration

Zuber et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012 Nov;8(11);543-57

Eculizumab is expensive. I checked different sources for costs; a 300-mg vial costs around $7,500; consider the fact that this drug needs to be given life-long on a bi-weekly or monthly basis. Some sources consider it the most expensive drug in the world. Finally, eculizumab has protected rights until 2017 and until then, biosimilars would have the potential to reduce treatment costs. In conclusion, given the rarity of this disease it would be difficult to have a large randomized control trial, but given the available evidence, it appears to be effective in preventing the recurrence of the disease after transplantation.
(A warm thank you to Dr. Smith, Dr. Haririan and Dr. Thomas for their support and guidance)

Sunday, August 16, 2015

What is the expected kidney function of a patient after donating a kidney?

A 31 year-old healthy male donated his kidney to his mother who had IgA nephropathy. Prior to donation, his creatinine was 1.08 mg/dl. One year after donation, his creatinine is 1.59 mg/dL. He was seeing in clinic and he is concerned about his high creatinine.
  What is the expected kidney function after donation? Kidney donation results in a 50% reduction in the kidney mass. However, there is an immediate hemodynamic compensation that increases the glomerular filtration rate in the remaining kidney. Studies have shown that there is a highly predictable increase in GFR of 20-40% within days resulting in a post-donation GFR of 60- 70% of baseline (reviewed by Mueller, Luyckx. JASN 2012). Subsequently, the remaining kidney undergoes some hypertrophy that will further compensate for the loss kidney.

 The most detailed paper describing the changes of renal function after kidney donation is from Rook et al. (AJT 2006), who evaluated 125 consecutive donors with iothalamate GFR clearance pre- and post-donation (around 2 months post-surgery). The average increase in creatinine was 35%. Older patients and those with greater BMI had a greater rise in creatinine. Another study reported the renal function of kidney donors 12 years post-transplant (Ibrahim et al. NEJM 2009). They noticed a drop ~24% in GFR at 12 years when compared to pre-donation. Reduced GFR was associated with aging, higher BMI and female sex. Longer time since donation is associated with the development of hypertension (~50%) and proteinuria (~35%) (Saran et al. NDT 1997).

  Our patient had a 51% increase in creatinine, which one may consider higher than expected. However, one must consider that creatinine is not a perfect marker of kidney function since it is significantly affected my muscle mass. This patient was muscular. When a creatinine clearance was calculated using CKD-EPI, his pre-donation eGFR was 95 ml/min and post-donation 63 ml/min – an expected drop in kidney function. A 24-hour urine collection confirmed this measurement. An iothalamate test would more reliably quantify his renal function but this test is not frequently performed. Equally important, his blood pressure has been well controlled and he does not have evidence of proteinuria.

 In summary, it is critical to monitor kidney donors with serum creatinine/eGFR (CKD-EPI), proteinuria and blood pressure levels. A drop in GFR ~35% is expected. More accurate GFR assessment may be considered with iothalamate in selected cases (e.g., older patients, patients with high or low BMI). After kidney donation, counseling patients about kidney risk factors is critical.

Wednesday, August 5, 2015

Midwest Transplant Symposium

Washington University at St Louis will be holding the inaugural Midwest Transplant Symposium on October 16th and 17th 2015.

This course is designed to be an in-depth review and update in kidney and pancreas transplant.
8.5 AMA PRA Category 1 Credits are available for this course.
Fellows and residents registration fee is $45 (plus $100 if CME credits are required).
For more information

Monday, August 3, 2015

OncoNephrology Conference 2015

One day symposium on OncoNephrology: Cancer, Chemotherapy and the Kidney

Where: Hofstra NSLIJ School of Medicine

When Sept 26th, 2015 from 7:30AM to 4PM 

The conference will highlight and review the latest happenings in OncoNephrology

This CME is free for all trainees including fellows

Talks and Speakers highlighted;
  • AKI in Cancer Patients; Joseph Bonventre, Harvard Medical School
  • Chemotherapy Toxicities: Mark Perazella, Yale University 
  • Targeted Therapy and the Kidney: Kenar Jhaveri, Hofstra University 
  • Hypercalcemia of Malignancy: Naveed Masani, Winthrop University 
  • Anemia, CKD, ESKD and cancer: Steven Fishbane, Hofstra University 
  • Renal Cancer, an update: Thomas Bradley, Hofstra University, NSLIJ Cancer Institute
  • Paraneoplastic GN; Hitesh H Shah, Hofstra University 
  • TMA: Bradley Dixon, Cincinnati Children Hospital 
  • Post Kidney Transplant Cancers: Vinay Nair, Mt Sinai Medical Center 
  • Paraproteinemias, an update: Gerald Appel, Columbia University Medical Center 
  • Cases with the Onconephropathologist: Glen Markowitz, Columbia Medical Center 
Course directors: Kenar Jhaveri, Steven Fishbane and Thomas Bradley (Division of Nephrology and Hematology/Oncology at Hofstra NSLIJ School of Medicine)

Planning committee: Kenar Jhaveri, Steven Fishbane and Thomas Bradley, Hitesh H Shah, Pravin Singhal, Jyotsana Thakkar and Rimda Wanchoo (all from Division of Nephrology, Hofstra NSLIJ School of Medicine)

To Register: go here
Email for any questions re the conference.

This conference is endorsed by ISN, ASN, C-KIN and NKF

Sunday, August 2, 2015

Keep cool and carry on...

Delayed graft function (DGF) after kidney transplant is associated with long-term allograft dysfunction. Niemann et al. (NEJM 2015;373:405) reported that therapeutic hypothermia reduced DGF (defined here as the requirement of dialysis in the recipient within 7 days after renal transplantation).

Study group enrolled 370 kidney donors after neurological determination of death (DNDDs), randomized to either normothermia (36.5 to 37.5 deg., n= 280) vs. mild hypothermia (34-35 deg. either by allowing to spontaneously reach the temperature, or by passive-cooling devices or forced-air systems, n=286). Incidence of DGF was significantly lower in hypothermia group (28.2% vs 39.2%, p=0.008), and study was terminated early.  

Therapeutic hypothermia (targeted temperature management) is an established intervention for outside-hospital cardiac arrest to protect neurological function.
In transplant field, in contrast, current organ procurement protocol (e.g. one from NATCO) has a stipulation that normal body temperature should be maintained in donors, frequently requiring active warming with warm blankets.
 What is the protective mechanism?  Authors discussed possible contribution of ischemia-reperfusion injury. Is this procedure applicable to other organs? Many questions arise and there is a nice open forum with NEJM group to discuss these (til August 7th EDT).

Naoka Murakami, MD PhD

Tuesday, July 14, 2015

Nephrotoxicity of Dietary Supplements and Alternative Medicine

A few weeks ago, one of our pharmacists gave a comprehensive presentation about the potential nephrotoxicity of a variety of commonly used herbal, alternative and dietary supplements. He has a particular interest in this as he deals largely with our transplant patients. There are many potential interactions between these compounds and immunosuppressant medications. He agreed to allow me put it up in full here. It is a really useful guide that I know I'll be referring to often in the future.

Posted by Steven Gabardi

Monday, June 29, 2015

Recurrence of Kappa monoclonal gammopathy after kidney transplantation

Monoclonal gammopathies generally arise from the development of an abnormal clone of B-cell lineage. The monoclonal protein can be intact immunoglogulin (often associated with free light chain), free light chain (FLC) in isolation, or more rarely immunoglobulin heavy chain, either in isolation or with associated free light chain. Monoclonal light chains have the ability to self-aggregate and form tissue deposits either in the form of beta-pleated fibrils (amyloid) or not (non-amyloid deposits).

Monoclonal gammopathies may lead to kidney injury through a variety of mechanisms, depending on the biochemical properties of the light chain and/or immunoglobulin. These include: cast nephropathy (usually kappa); monoclonal immunoglobulin deposition disease; crystal-storing tubulopathy; amyloidosis (usually lambda), cryoglobulinemia or MPGN (membranoproliferative glomerulonephritis).

Monoclonal gammopathies can frequently recur after transplant (Sethi et al. CJASN 2010). In a cohort of transplant recipients in our center, Dr Batal had reported 8 cases of IgG/Kappa MPGN, of which 3 failed post-transplant while 2 were still functioning; 3 were lost on follow up (Batal et al. AJKD 2014).

Recently, a 65 year-old Female with CKD secondary to MPGN/IgG Kappa monoclonal gammopathy underwent a living-unrelated kidney transplant. Creatinine came down to nadir of 1.2mg/dl three days after transplant and then started to rise up to 2.5mg/dl. An emergent kidney biopsy was performed which revealed aggressive MPGN (view picture above). Immunofluorescence staining was negative for IgG, kappa or lambda. However, when the biopsy sample was treated with pronase and restained, suddenly diffuse Kappa staining was uncovered, confirming recurrence of her primary disease. Pronase digestion has a denaturing effect on cell membranes, which may unveil sequestered antigenic sites. This was previously shown to be useful in other forms of monoclonal gammopathies such as in crystal-storing tubulopathy. Electron microscopy may also help in identifying the deposits and triggering additional tests to elucidate the composition of those. Unfortunately, prognosis of early recurrence is not good and requires aggressive treatment against the possible source of light chain (abnormal plasma cells) and removal of light chains from the circulation through plasmapheresis.

Tuesday, June 23, 2015

Point of Care Evidence-Based Nephrology Diagnosis

The use of evidence-based diagnosis is what we are taught that we should all do but in practice, this is quite difficult. EBM diagnoses rely on likelihood ratios but it is impossible to remember the diagnostic accuracy of the thousands of tests out there.

This is why I developed a simple tool to help with the scientific diagnosis of common nephrological problems, as well as diseases spanning most specialties. It is a database of more than 700 likelihood ratios of tests (history, physical exam, radiology, etc.). The likelihood ratios are completely free for all to access and are available on my website and on an app I developed for the iphone/ipad called DxLogic. Android users are not left out as the website is mobile-friendly.

The following examples will demonstrate how you to can use this resource to approach some common clinical nephrology situations in a probabilistic and rational manner. The screenshots found below are from the iOS application.

Example #1

You are consulted for a 50yr old man admitted with pneumonia who has developed AKI in hospital. He was started on ceftriaxone 10 days ago and, after examining the patient and a chart review, you wonder about acute interstitial nephritis secondary to antibiotics. You remember being told that urinary EOS are a great test for this disease. But does this test actually increase or decrease the possibility of this diagnosis? From the screenshot below, we see that the presence of EOS in the urine actually has no diagnostic value for AIN. You save the lab time and money by not ordering the test.

Example #2

A 30 year old woman presents to your clinic with symptoms and signs consistent with nephrotic syndrome. She also has a questionable malar rash and a family history of lupus.  You wonder if she could have lupus nephropathy. Using the resource we find that her probability of having lupus nephropathy before any tests are ordered is 14%,

You order an ANA titer and this comes back negative. Plugging this into that app we find that her probability of having lupus nephropathy on renal biopsy is now 3% - a low, but not an insignificant percentage. 

I hope this article has made you aware of the important role that likelihood ratios can play in nephrological practice. Please give my app/website a try and feel free to contact me with any comments or suggestions.

Contact information:
Michael Garfinkle
University of Calgary
Twitter –  @joyofmed 

Sunday, June 21, 2015

Renal Effects of Anti-Cancer Medications

With the proliferation of new therapies for cancer including novel targeted therapies, it is difficult to keep up with the potential renal problems related to these medications. Thankfully, Nature Reviews Nephrology have published a comprehensive review of the nephrotoxic effects of targeted anticancer therapies that could serve as a reference for practicing nephrologists. As is pointed out in the review, this is a rapidly evolving field and novel toxicities are being recognized with real world use that may not have been seen in the initial trials..

Of particular interest was the fact that many of these agents cause severe electrolyte abnormalities. For example, approximately 17% of individuals receiving cetuximab (an EGFR inhibitor used in the treatment of some lung cancers) develop hypomagnesemia. It turns out that TRPM6, a DCT  magnesium channel, it regulated by EGF which is highly expressed in that area of the nephron and cetuximab therapy leads to inhibition of Mg reabsorption and subsequent hypomagnesemia (along with hypocalcemia and hypokalemia).

The figure below shows a list of the commonest adverse effects of chemotherapeutic agents. Click on the picture for a larger image:

Tuesday, June 9, 2015

EVOLVEing past Cinacalcet

One of the regular criticisms of nephrology is the lack of good quality randomized controlled trials. This is particularly the case in the world of renal bone disease where we target surrogate endpoints without necessarily knowing for certain what the effect this has on the most important outcome - patient survival. The EVOLVE trial was once such trial which examined the role of cinacalcet in preventing all-cause and cardiovascular mortality. The results of this trial were somewhat ambiguous in that the overall results were negative but this could have been affected by the slightly older age of the treatment group (after adjustment for age, there was a benefit to cinacalcet). There was, however, a wonderful rebuttal to this particular argument in a letter to the editor published later in the NEJM by Giovanni Tripepi.

Overall, the number needed to treat to prevent a single death was 500 and this is balanced by a 62% drop-out rate in the treatment group. There was also a lower rate of parathyroidectomy in the treatment group.

Last month NDT published and ERA-EDTA position statement on the use of calcimimetics in patients on dialysis. Based on a meta-analysis (which was largely derived from the EVOLVE trial), they made the definitive statement that cinacalcet should not be used in patients on dialysis to reduce cardiovascular or all-cause mortality. Further, they pointed out that although the original trials showed that PTH could be successfully lowered using these drugs and that this could reduce the rate of parathyroidectomies, there is no evidence that this has any benefits either beyond the prevention of surgery. They called for a randomized trial of parathyroidectomy vs. cinacalcet for the treatment of intractable hyperparathyroidism with hard endpoints. I second that call.

Monday, June 8, 2015

Osteoporosis treatment in patients with renal failure: the gray zone...

Chronic kidney disease (CKD) patients develop significant changes in bone mineral density (BMD) and bone structure, which together with an increased risk for falls, put them at high risk for fracture. This can be due, in part, to renal osteodystrophy, since bone loss and reduced bone quality may be present in both low- (osteomalacia and adynamic bone disease) and high-turnover bone disease (osteitis fibrosa and mixed uremic osteodystrophy). In addition, some patients may have underlying traditional risk factors for bone loss, such as early menopause or smoking. The heterogeneity of bone loss in patients with CKD complicates its management, requiring frequently a combination of interventions. Performing a bone biopsy is the gold-standard to characterize potential etiologies though not frequently available in most centers. 

 One of the major challenges of treatment of osteoporosis in patients with eGFR below 30 mL/minute is the limited available data. Bisphosphonates are usually not advocated in this population since most agents have renal clearance and patients were frequently excluded from clinical trials. Post-hoc analyses of studies in postmenopausal women with grades 4 and 5 CKD and a definite diagnosis of osteoporosis revealed efficacy and short-term safety of bisphosphonates, denosumab, and raloxifene in addition to calcium and vitamin D supplementation. Bisphosphonates demonstrated increase in BMD, and reduction in vertebral fracture incidence regardless of degree of renal dysfunction. To date, anti-osteoporotic agents have not been recommended in CKD stage 5D due to lack of data on security and on its beneficial impact against fracture. Though some small studies have reported an amelioration of BMD with these drugs in hemodialysis patients. 

Patients with severe renal impairment are at higher risk for hypercalcemia due to calcium and vitamin D supplements, or for hypocalcemia if taking denosumab therapy. Therefore, serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D should be monitored at least every four months. Furthermore, renal function should be routinely measured in patients taking bisphosphonates. Markers of bone turnover, including but not limited to C terminal telopeptide (CTX), N terminal telopeptide (NTX), and pyridinolines (PYR) are metabolized and/or excreted renally, and will accumulate in renal dysfunction. Therefore, they should not be used to monitor response to therapy in patients with eGFR below 30 mL/minute. Despite neither predicting fracture risk nor the type of renal osteodysthrophy, bone densitometry of the hip and spine may be performed to monitor for changes in BMD. In complex patients, a bone biopsy should be considered prior to initiating osteoporosis treatment. 

• For patients with low BMD (T-score below 2.5) associated with fragility fracture and grades 4 or 5 CKD, pharmacologic therapy might be considered after excluding all other CKD-related low BMD diagnoses. 
• Adjusted dose of oral bisphophonates are typically recommended based on clinical experience and existing data. 
• Intravenous (IV) bisphosphonates should be used as a last resort only in patients who cannot tolerate previous therapies and are at high risk for multiple fractures. 
• Nephrotoxicity is a significant potential problem with IV bisphosphonates (Zoledronic acid). It is dependent on both dose and infusion rates. 
 • The patterns of nephrotoxicity from IV bisphosphonates include acute tubular necrosis and collapsing focal segmental glomerulosclerosis. 
 • Strict adherence to guidelines for monitoring renal function prior to each dose and temporarily withholding therapy in the setting of renal insufficiency, may help prevent nephrotoxicity from these agents. Denosumab can be an interesting alternative since it is not renally excreted. Further studies are required in patients with CKD. 
• Medications that increase bone formation, such as teriparatide and anti-sclerostin monoclonal antibodies (romosozumab and blosozumab) seem to be promising alternatives for treating osteoporosis in CKD patients with low-turnover bone disease.

Sandra El Hajj, PharmD
Steven Gabardi, PharmD, BCPS, FCCP
Fellype Barreto, MD, PhD
Leonardo Riella, MD, PhD

Additional References: