The Role of the Gut for Potassium Homeostasis in CKD

Recently the FDA approved one of the newer exchange resins (Lokelma, ZS-9) for the treatment of hyperkalemia. (Veltassa, Patiromer), a calcium based cation exchange resin, was recently developed and approved since 2015 for the treatment of hyperkalemia. These two new drugs, which each have large randomized placebo controlled trials confirming their effectiveness, now seem bound to replace the ancient but much experienced Kayexalate (Sodium Polystyrene Sulfonate; SPS) for the management of hyperkalemia. However, they are not approved in Canada and their cost makes them less enticing options in a publicly funded health care system. Also, what about safety concerns? SPS has been used since the 1950s, however it took decades for case reports to come out possibly linking fatal colon necrosis to Kayexalate use. This association remains hotly debated. A systematic review in 2013 found a total of 58 cases of biopsy confirmed bowel injury that were “possibly” related to SPS use based on the WHO causality criteria. Interestingly, these cases were not limited to patients using SPS with sorbitol, nor to the post-operative population as was once thought to be the major risk factors for adverse GI events from SPS. On the other hand, a retrospective single-centre review over a 10 year period found only 3 cases of colon necrosis among 2,194 patients having received SPS. When they compared this incidence of colon necrosis to control patients having not received SPS, they found a non-significant RR of 2.10 (0.66-6.64; P=0.2). Many nephrologists will argue that SPS has a long standing proven track record and that colon necrosis is such a rare side effect that it is unlikely to be related. While no one knows if this is truly the case, the uncertainty surrounding this issue is one of the major reasons that led to the development of the newer exchange resins: ZS-9 and patiromer.

Before praising and widely accepting these newer, expensive products, would it not be wise to use the same caution we would for SPS? It can take years for such a rare adverse event as colon necrosis to manifest itself, how do we know we won’t be facing this GI safety issue 5 to 10 years from now?

Perhaps we could look for other ways of trying to enhance GI elimination of potassium.

--> BK-channel in colon enterocyte (Source: Sandle et al. QJM. 2010 Feb;103(2):85-9)    
The colonic enterocyte has an ability to excrete potassium in stool. This may be an important physiologic property in patients with advanced CKD who lose the ability to renally excrete potassium. In fact, patients with ESKD are known to have a greater excretion of potassium in their stool compared to individuals with normal kidney function. An important transporter involved in this process is the BK-channel located on the apical side of the colonic enterocyte within the colon crypts (see Figure). This channel is responsible for actively secreting potassium in the GI lumen. Aldosterone stimulates this channel, enhancing K secretion in the stool, similar to its effect in the kidneys. In fact, a study in the 1970s of patients suffering from acute cholera showed that within 12 hours of receiving a single dose of 100mg of spironolactone, there was a significant decrease in stool loss of potassium and an increase in stool loss of sodium. This likely is a major reason explaining why anuric patients with ESKD may still have from hyperkalemia if given RAAS blockade. The BK channel will also be stimulated by various diarrheal states such as Ogilvie’s syndrome, villous adenoma and certain laxatives such as bisacodyl. Bisacodyl is a stimulant laxative which enhances peristalsis through parasympathetic nerve activation, but also stimulates cAMP production within the colon enterocyte. This cAMP is thought to enhance K excretion via the BK-channel. A study performed in 2005 used immunohistologic analysis of colonic enterocytes in patients with ESKD and showed that BK-channels are upregulated in these patients compared to controls with normal kidney function. The upregulation of BK-channels probably represent an adaptation to chronic potassium load in order to maintain homeostasis. Interestingly, a small study in 2003 tested the effect of Bisacodyl on potassium in patients with ESKD. Eight controls normal kidney function and 13 patients with ESKD were given Bisacodyl 5-10mg PO titrated to achieve 2 soft bowel movements per day and these were compared to 5 ESKD patients given lactulose 10ml PO titrated also to 2 soft bowel movements per day. After 2 weeks of treatment, they found that the ESKD patients with Bisacodyl had a significant decrease in potassium from 5.9 to 5.4mmol/L whereas the controls given Bisacodyl and the ESKD patients given lactulose had no change in potassium values after 2 weeks of therapy. This suggests that Bisacodyl increases potassium excretion in the stool in patients with ESKD through a mechanism not simply related to its laxative effect, but likely through stimulation of the BK-channel of the colonic enterocyte. It is unfortunate that no further studies have looked into this therapeutic option for maintaining potassium homeostasis in patients with advanced CKD. Unfortunately, we don’t know if Bisacodyl would work as well in the non-dialysis population since we could expect these patients may not have as upregulated BK channels as in ESKD who are faced with more chronically elevated potassium loads. However, this would be an interesting study to pursue since Bisacodyl would be a cheap and safe way of controlling potassium in patients with advanced CKD by enhancing the body’s natural adaptation to potassium handling.

David Massicotte-Azarniouch
Nephrology Fellow
University of Ottawa

The evidence behind the use of plasmapheresis in glomerular diseases

Therapeutic plasma exchange (PLEX) is a type of therapy where a patient’s plasma volume is removed over a period of a few hours, through a process of centrifugation of blood with subsequent separation of its constituents, and replaced by different types of colloid fluids, most commonly Albumin or Fresh Frozen Plasma (FFP). Its most frequent use in nephrology is for certain glomerulopathies such as ANCA-associated vasculitis, anti-GBM disease, recurrence of idiopathic FSGS post-transplant and atypical HUS. The data with regards to PLEX use for these indications is mostly historical and based on mechanistic concepts which led to multiple observational studies and reports claiming efficacy. There are very few randomized trials directly comparing PLEX to other therapies and a review of the data (see table summary of KDIGO recommendations) has really brought me a new perspective on what justifies our use of PLEX for renal disease.

Table: KDIGO recommendations on PLEX use for glomerular disease

	KDIGO recommendation	Grade
Anti-GBM disease	We recommend initiating immunosuppression with cyclophosphamide and corticosteroids plus plasmapheresis in all patients with anti-GBM GN except those who are dialysis-dependent at presentation and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage	1B
	Start treatment for anti-GBM GN without delay once the diagnosis is confirmed. If the diagnosis is highly suspected, it would be appropriate to begin high-dose corticosteroids and plasmapheresis while waiting for confirmation	Not graded
ANCA-associated vasculitis	We recommend the addition of plasmapheresis for patients requiring dialysis or with rapidly increasing SCr	1C
	We suggest the addition of plasmapheresis for patients with diffuse pulmonary hemorrhage	2C
	We suggest the addition of plasmapheresis for patients with overlap syndrome of ANCA vasculitis and anti-GBM GN, according to proposed criteria and regimen for anti-GBM GN	2D
Post-transplant FSGS	We suggest plasma exchange if a biopsy shows minimal change disease or FSGS in those with primary FSGS as their primary kidney disease	2D
Atypical HUS	Not mentioned in KDIGO guidelines

Adapted from: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9:S1; and Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney international. 2010 Feb 2;77(4):299-311.

Anti-GBM disease

Anti-GBM disease has always been regarded as a sine qua non indication for PLEX.  I still remember my first teachings on anti-GBM disease in medical school which were were it causes lung hemorrhage, it causes acute kidney injury and it is treated with plasmapheresis. When reviewing the literature, I was surprised to find only a single randomized trial on the use of PLEX in anti-GBM disease. This a study published in 1985 in Medicine by Johnson et al where they randomized 17 (yes, only 17!) patients with biopsy and serology proven anti-GBM disease to either Prednisone + PO Cyclophosphamide (N=9) vs PLEX + Prednisone + PO Cyclophosphamide (N=8). Patients at baseline were not equally matched as the patients in the conventional group had higher serum creatinine (SCr) at start of therapy and had more severe disease on biopsy. Indeed, 5/8 biopsies available had >70% gloms with crescents in the conventional group vs only 1/7 in the PLEX group had > 50% gloms with crescents. They did find that more patients were dialysis dependent at the end of the study in the conventional group (6/9) vs the PLEX group (2/8). Four patients in the PLEX group had improvement in their renal function vs only 1 in the conventional group. These patients who had improvement were the ones with lower SCr at presentation. Eight patients had pulmonary hemorrhage (4 in each group) and all these episodes were treated with IV Methylprednisone pulse and responded promptly. There were only 3 deaths in all, 1 in conventional and 2 in PLEX group. Anti-GBM titers became undetectable much more quickly with PLEX, after about 2 months. Overall, it is somewhat surprising that what we consider such a strong indication for PLEX is supported by only 1 randomized trial showing improved renal survival with PLEX, where the groups were unevenly matched. What is also important to consider with anti-GBM disease is the possible futility of treatment in patients with most severe disease. A review of anti-GBM disease in the UK from 1980-1984 by Savage et al looked at outcomes for 108 patients. There were 69 patients who were dialysis dependant on presentation. At 8 weeks, none were off dialysis (51 on dialysis and 18 dead). Out of 12 who presented with a SCr>600umol/L, only 1 had improvement in renal function (other 11 either on dialysis or dead). Another British study published in 2001 in the Annals of Medicine by Levy et al retrospectively looked at all anti-GBM disease treated at the Hammersmith hospital in since 1975. They had 71 patients, 39 of which were dialysis-dependant on presentation. Only 2 were off dialysis at 1 year follow-up. When looking at outcomes based on biopsies, they found that 23% of patients with >50% crescents survived off dialysis and that 3 patients survived off dialysis despite >70% crescents. However, no patients with 100% crescents recovered renal function. Together, these results certainly seem to suggest that patients with severe anti-GBM disease presenting dialysis dependent have very little chance of recovery and may not benefit at all from immunosuppressive therapy and PLEX. While a trial of treatment may still be indicated, I believe a rapid re-assessment of the patient’s condition and need for continued immunosuppressive therapy is indicated given the high infectious risks with treatment. Patients with 100% crescents on an adequate biopsy are very unlikely to get any benefit and should probably just be managed conservatively.

ANCA-associated vasculitisAnother frequent indication for PLEX in glomerular disease is ANCA-associated vasculitis and thankfully there is a bit more data to guide us here. The best data comes from the MEPEX trial by Jayne et al published in JASN in 2007 where 137 patients with biopsy/serology proven ANCA vasculitis and SCr > 500umol/L were randomized to either PLEX (7 exchanges in 14 days) or IV methylprednisolone (1g IV daily x 3), both in combination with oral Cyclophosphamide and Prednisone. Patients with severe lung hemorrhage requiring mechanical ventilation were excluded. Just over 2/3 of patients were dialysis-dependent on presentation. They found that treatment with PLEX had a better renal recovery (alive and off dialysis and SCr<500umol/L) at 3 months than IV steroids (70% vs 49% respectively, P=0.02). The HR for ESRD at 12 months for PLEX vs IV steroids was 0.47 (0.24-0.91, P=0.03). Survival however was not significantly different (19 deaths in PLEX group vs 16 in IV steroids group) and most deaths were due to infections (19), lung hemorrhage (6) or cardiovascular disease (4) and very few due to vasculitis. A sub-study of the MEPEX trial by Van Wingaarden et al found that for patients requiring dialysis on presentation and with severe tubular atrophy on biopsy, the point at which patients would get more benefit for renal survival from treatment over risk of death from treatment was when they had 18% or more normal glomeruli for IV steroids group as opposed to only 2% normal glomeruli for PLEX. This suggests that patients with most severe disease are more likely to reap renal benefit from treatment when they are given PLEX. In 2013, Walsh et al published the long term follow-up data from the MEPEX trial and found that the short term benefit seen in MEPEX was lost. Indeed, for patients treated with PLEX there was no significant improvement in the composite of ESRD or death (HR 0.81, 0.53-1.23; P=0.32) nor in the outcome of ESRD (0.64, 0.40-1.05; P=0.08). At final follow-up, half the patients died and 2/3 were either dead or on dialysis, reaffirming the poor prognosis of severe ANCA vasculitis. A meta-analysis of all randomized trials looking at PLEX for ANCA vasculitis by Walsh et al in 2011 found PLEX to be associated with a 20% risk reduction in the composite of ESRD-death (HR 0.80, 0.65-0.99) and a 36% reduction in ESRD (HR 0.64, 0.47-0.88) but no effect on death (RR 1.0, 0.71-1.42). The authors did warn though that overall most trials were small, none of them individually found a significant result for the composite of ESRD-death and they had notable methodological flaws such as randomization concealment was only performed in 4/9 trials and the methods of concealment weren’t described in any. Hopefully, the PEXIVAS study which is now nearing completion and should be presented at the upcoming ASN Kidney Week 2017 (hopefully as a late-breaking trial) will help clarify the role for PLEX in ANCA vasculitis. For now, it would seem that PLEX is indicated for patients presenting with severe renal failure due to ANCA-vasculitis as it improves renal survival, without a mortality benefit though.

Post-transplant FSGS

It is sad to say that there are unfortunately no other prospective trials studying the role of PLEX for glomerular disease. While the use of PLEX for recurring idiopathic FSGS post-transplant is recommended (the rationale being the removal of some as of yet unidentified pathogenic plasma permeability factor), the data is purely observational. A review of 77 case-reports and case-series, totalling 423 patients with recurrence of FSGS post renal transplant, published in BMC Nephrology in 2016 showed that overall 71% of patients achieved complete or partial remission. Factors most associated with response were male sex and starting treatment within 2 weeks of recurrence. However, the lack of control group prevents us from establishing a clear benefit from PLEX itself. Also, the treatment regimens were extremely varied and it is unclear exactly how much PLEX, for how long should it be given and which replacement fluid to use. Finally, the frequent use of PLEX in these patients who are already on immune-suppressing drugs may predispose to even more infections given the removal of Immunoglobulins by PLEX.

Atypical HUS

Similar to FSGS, the use of PLEX for atypical HUS is based purely on observational data (case reports and case series). The rationale behind its use for this indication certainly makes sense by removing defective complement factors and replacing properly functioning complement factors to halt the overactivity of the alternative pathway. Patients diagnosed with TMA are often started on PLEX promptly while awaiting results of diagnostic testing (Shiga toxin E. Coli cultures, ADAMSTS13 level and complement pathway factor levels and mutations). If diagnostic tests suggest an alternative complement pathway disease, it will be maintained until Eculizumab is available. Unfortunately, while most observational studies suggest an initial response around 60% to PLEX, this is mostly a hematologic response and patients will often become dialysis dependent.

Conclusion

Overall the evidence to support the use of PLEX for the treatment of glomerular diseases is not great. While anti-GBM disease and lung hemorrhage are considered some of the strongest indications for PLEX, this is not firmly supported by good prospective data. The best evidence is for its use is in severe ANCA-vasculitis and with the upcoming PEXIVAS study results hopefully this will further help us in our decision making. I think it is great that such a large study such as PEXIVAS (over 700 patients) for such a rare disease has been able to come to completion and this highlights the importance of proper collaboration to conduct prospective studies in GN. Hopefully this will inspire us to continue to strive for well-designed studies to guide us in the treatment of our patients.

David Massicotte-Azarniouch

Nephrology Fellow, University of Ottawa