October 2018

1. The timing of RRT in Patients with AKI and Sepsis

IDEAL ICU VA Divya

Visual abstract by Dr. Divya Bajpai (@divyaa24)

 

As an anxious first-year nephrology fellow, I had to discuss all the labs with my boss before he leaves department-typically at around 6 in the evening.

“Sir, that bed 2, Gastroenteritis- AKI patient’s serum creatinine is up to 10mg/dl. Now what?”

“Tell me something about the patient whose creatinine you are talking about.”- he would reply coldly.

Results of much awaited IDEAL-ICU trial are out and are largely consistent with the existing evidence that “earlier initiation of RRT doesn’t improve survival and exposes about 40% of patients with AKI to RRT who otherwise have recovered renal function before ever needing it.”

The trial was terminated early for futility after enrolling 488 patients. By then 58% of the patients in the early- strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive RRT. These lines from the paper bother me, “The second limitation is the choice of a delay of only 48 hours, which may not be sufficiently long to allow recovery of renal function in some patients or to detect a difference between early and delayed initiation of RRT. However, we thought that a longer delay would be unethical and unsafe for patients who actually needed renal-replacement therapy.” 

How do you know that delay of 72hrs or 96 hrs necessarily ends up into emergency dialysis and is unsafe? Watchful waiting, in my humble opinion, can continue until an indication develops, irrespective of the timing in hours.

AKI is one of the most common renal emergency and lets’ respect these words of wisdom. “Don’t be in hurry, we are in an emergency” –Anonymous “wise” emergency room physician to his junior colleague.

 

Here is a nice Twitter thread

 

2. Targeted Polymyxin B Hemoperfusion in patients with severe sepsis

Last week a senior surgery colleague was asking me if we can offer extracorporeal therapy to cut down dismally high mortality of perforative peritonitis. She and I were equally hopeful and skeptical respectively about this treatment, and after reviewing the literature we finally settled for the need of a pilot trial if she manages to get funding.

EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled trial of Adults Treated for Endotoxemia and Septic Shock) investigators must be congratulated for a very well conceived and executed RCT addressing this question. In critically ill patients with severe sepsis with high risk of death, this technique did not reduce 28 day mortality (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49). Findings were consistent in patients with more severe sepsis as well. Authors recommend against the use of this strategy.

Blinding by sham hemoperfusion, the inclusion of patients with very severe illness, so, high risk of death, and including endotoxemia >0.60 (indicating high endotoxin activity)  make trial results generalizable to the real world scenarios where such desperate measures are actually used.

Endotoxin was about to become ‘creatinine of intensivists’; thanks to EUPHRATES, it won’t.

3. Antibody-Mediated Rejection of Solid-Organ Allografts

Chronic ABMR is one of those helpless situations in the life of transplant nephrologist where you watch the progressive loss of graft function without much to offer. In spite of significant improvements in the understanding of pathophysiology, (this principally includes new definitions, classifications, revisions that take birth when transplant physicians-pathologist gather at a resort town along Trans-Canada Highway and more sensitive assays of antibody detection which add to the confusion!). Chronic ABMR remains a difficult nut to crack, and if we don’t ‘let go’ beyond a limit, one can potentially add to the number of ‘death with functioning graft’ as a consequence of overtreatment. Here is a NEJM review summarising current standards of treatment and possible future therapies.

Here is a quote from the article- “An improved understanding of the natural history of antibody-mediated rejection has led to a more complex interpretation of the various clinical scenarios encountered in clinical practice, given the heterogeneity, diverse polymorphism, and temporal dependency of the clinical and histologic manifestations of antibody-mediated rejection.”

Yes, ABMR is just as difficult to treat as making sense of these lines!

4. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD)

This 2018 revision of 2011 Cochrane review on phosphate binders concludes this

“Overall, we are not very sure whether specific phosphate binders are beneficial to patients with CKD. There is a possibility that sevelamer may prevent death compared to calcium-based binders, but we don’t know whether this may be caused by an increased risk of calcium-based binders, a lower risk with sevelamer treatment, or the possibility that both may be true. Patients need to know that it is not certain whether phosphate binders help to prevent complications of kidney disease, but sevelamer may be preferred to calcium binders.”

 

What will a man in severe debt feel if asked, “Which credit card you would like to buy? Platinum/ silver/ gold?” A very similar feeling a patient with CKD is likely to get if we (dare to) put the results of this review in context and involve him in shared decision making before choosing to use and then choosing amongst the P binders.

Let me just give you a glimpse of the “very low” quality evidence that suggests a possible advantage of sevelamer over other binders. In an analysis of 248 participants with a median follow up of less than a year showed RR  of death in controls or placebo to be high as compared to sevelamer (RR 2.16). The confidence interval (CI) was 0.2 to 22.8. After what limit a CI become ‘No Confidence Interval’?

 

5.Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease A Randomized Double-Blind Trial

We reviewed renal effects of sacubitril/valsartan and enalapril in participants of PARADIGM-HF trial in our May 2018 blog post.  Sacubitril/ valsartan leads to increase in albuminuria and still preserves eGFR better. While this was not the prespecified analysis, we now have an RCT examining the effects of sacubitril/valsartan on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease.

The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. Participants ≥18 years of age were eligible to participate if they had CKD with either (1) an estimated glomerular filtration rate (eGFR) of ≥45 and <60 mL/min/1.73 m2 and a urine albumin:creatinine ratio (uACR) >20 mg/mmol (177 mg/g), or (2) an eGFR of ≥20 and <45 mL/min/1.73 m2 (regardless of uACR).

At 12 months, there was no difference in the primary endpoint: measured (wow!) GFR (51Cr-EDTA, 99mTcDTPA, or iohexol methods)- 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, ‒0.1 (0.7) mL/min/1.73 m2.

Compared with irbesartan, sacubitril/valsartan further reduces both blood pressure and biomarkers of cardiovascular risk (troponin I and N-terminal pro-B-type natriuretic peptide). Albuminuria was not different in the two groups.

Authors conclude that “sacubitril/ valsartan could be an acceptable treatment to reduce cardiovascular risk in people with chronic kidney disease, a high-risk population with an unmet need”.

Will we have an RCT with hard endpoints? Hard to say given the track record.

 

6. Effect of Increased Daily Water Intake in Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial

In an open-label, controlled trial funded by Danone (which sells bottled water), Hooton et al randomized 140 healthy women with recurrent cystitis (3 episodes in past year) drinking less than 1.5 L in a day to drink, in addition to their usual fluid intake, 1.5 L of water daily (water group) or no additional fluids (control group) for 12 months. The primary outcome measure was the self-reported frequency of cystitis. During the 12-month study period, the mean (SD) number of cystitis episodes was 1.7 (95% CI, 1.5-1.8) in the water group compared with 3.2 (95% CI, 3.0-3.4) in the control group, with a difference in means of 1.5 (95% CI, 1.2-1.8; P < .001)

This low-cost intervention seems to be an effective antimicrobial-sparing strategy in this group of individuals.

7. Are NSAIDs safe in patients with CKD?

Choosing wisely campaign suggests avoiding the use of NSAIDs in patients with hypertension, heart failure, and CKD to which most of us comply. Here is a retrospective cohort NSAID in elderly adults visiting the primary care physician for musculoskeletal complaints. 9.3% of such visits were followed by NSAID prescription, 11% of the physicians chose NSAIDs for these patients. Authors  study in JAMA Int Med evaluating the frequency of identified 35 552 pairs (for each patient exposed to NSAID and they identified (by propensity score matching) a control patient not exposed but the similar likelihood of exposure.

Rates of cardiac complications(288 [0.8%] vs 279 [0.8%]), renal complications(34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]) were similar among cases and control, leading to this rather bold conclusion, “NSAID use in this population is not associated with short term safety concerns”. This should not be overinterpreted to challenge the “choosing wisely recommendations”.

Firstly, as a nephrologist I am  interested in what happens long term rather than within a week. Moreover, we don’t have any information on severity of renal dysfunction of the population (physicians are more likely to use NSAIDs for patients with mild CKD which may well include patients labelled as CKD due to age related GFR decline). Apart from this confounding by indications, several other  limitations of propensity score method like residual confounding, unmeasurable imbalances etc should be taken into account before we put these results into practice.

May 2018

1 Nitrofurantoin beats fosfomycin in the treatment of uncomplicated cystitis

“Among women with uncomplicated UTI, a 5-day course of nitrofurantoin compared with single-dose fosfomycin resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion” concluded the authors of this multinational, open-label RCT that randomised patients to oral nitrofurantoin,100mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). Both of these agents are approved the first choice therapy for this indication, however, uncertainties exist regarding the clinical efficacy of single-dose fosfomycin and this study furthers these concerns.

I have never used nitrofurantoin three times a day and I am not sure how much of this difference is related to the dosing advantage to nitrofurantoin (given TDS  for 7 days vs single dose of fosfomycin). There is also another reason to prefer nitrofurantoin here; we may be able to reserve fosfomycin for MDR Enterococcus/MRSA where its parenteral use may be needed. 

2 Dialysis in elderly: Medicare vs VA

Does it matter who is your predialysis CKD health care provider? Well, yes, if you are an elder with advanced CKD, according to this retrospective cohort study of >11000 patients above the age of 67 years. Patients with incident kidney failure (eGFR <15ml/min) were more likely to be started on dialysis if predialysis care provider was Medicare: 82% vs 53%. RR 1.53 (1.48-1.57). This difference was more pronounced among patients aged 80 years or older and patients with dementia or metastatic cancer, and less pronounced among patients with paralysis (P < .05 for interaction). Mortality was higher among Medicare patients (53% vs 44%).

Making a decision about dialysis or no dialysis in this population is a tough task and we need to face this uncertainty by using shared decision making. Although not an RCT, these results raise an important question about the interaction of incentive structure and utilization of dialysis in this population where homeostenosis can tip the balance towards harm. Possible harms of dialysis initiation in this population have been previously documented as is the differential use of aggressive therapies when patients seek care in the ‘fees for profit’ healthcare systems vs state-sponsored systems.

As editorial accompanying has put it “Given the many unknown factors, the decision on when it is best to initiate dialysis should evoke humility. The goal should be to encourage thoughtful, joint decision making by nephrologists and their patients.”

3 Measuring blood pressure better

Visual abstract by Dr. Divya Bajpai, Assistant Professor, Dept. of Nephrology, Seth G.S.M.C & K.E.M. Hospital

NEJM ABPM

One of the most inaccurate measurements that we make daily in our practice may be the clinic blood pressure and until today, the majority of the decisions regarding diagnosis and treatment of BP are largely based on this value. While it’s intuitive to assume that out of office measurements will perform better, there is limited data on the use of ABPM on clinical outcomes. This Spanish ABPM registry data in NEJM adds significantly to the much-needed evidence base for wider application of ABPM.

In a registry-based, multicenter, national cohort that included 63,910 adults (3808 total and 1295 CV deaths occurred over 4.7 yrs of follow up), they evaluated prognostic significance of four different BP phenotypes: 1) sustained HTN (elevated clinic and elevated 24-hour ambulatory BP), 2) “white-coat” HTN (elevated clinic and normal 24-hour ambulatory BP), 3) masked HTN (normal clinic and elevated 24-hour ambulatory BP), and 4) normotension (normal clinic and normal 24-hour ambulatory BP). 

Masked HTN posed the highest risk of death: HR 2.83; 95% CI, 2.12 to 3.79,  followed by sustained HTN (HR 1.80; 95% CI, 1.41 to 2.31) and white-coat HTN (HR, 1.79; 95% CI, 1.38 to 2.32). Wider use of ABPM is already advocated by NICE and Canadian BP guidelines, other should follow. I have just started realizing the deceptiveness of clinic BP after I started using HBPM and ABPM more often in my practice. 

 

4 Precision in the maintenance dosing of rituximab in vasculitis 

Rituximab is non-inferior for induction of remission in ANCA-associated vasculitis (AAV) and may be superior to azathioprine for maintenance of remission. In MAINRITSAN trial, it was used in a fixed schedule, irrespective of CD19+ B cell count, which expected to reflect the biologic activity of rituximab. Can we individualize rituximab dosing during maintenance treatment?

In an open-label, pragmatic, multicentre RCT, (MAINRITSAN 2) 162 adults with new or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who achieved complete remission (BVAS score 0) with cyclophosphamide, rituximab or methotrexate, were randomized to receive rituximab either in fixed-schedule (control group) or individually-tailored fashion within 1 month after completing induction treatment, if they had received cyclophosphamide or methotrexate, or 4–6 months after the last rituximab infusion, if it had been used to obtain remission.

Tailored-infusion-arm patients always received 500 mg of rituximab at randomization; then ANCA and CD19+ B lymphocytes were assessed every 3 months. Another 500 mg were infused when ANCA status differed from the previous control (ie, reappearance after being negative, indirect immunofluorescence- determined ≥2-dilution–titre increase and/or at least doubled ELISA PR3 or MPO arbitrary units) or CD19+ B cell counts exceeded 0/mm3. The last rituximab infusion could be given at month 18. The control group received 500 mg rituximab infusion on days 0 and 14 post-randomization and at months 6, 12, 18 after the first infusion.

The primary endpoint, the number of relapses at month 28, was not different in the two groups- 14 vs 8 (p=0.22). Notably, relapses did occur in the absence of circulating B cells or when ANCA were negative, questioning the relevance of their monitoring. However, the tailored-infusion group received fewer rituximab infusions [medians (IQR) of 3 (2–4) vs 5 (5–5) administrations]. The safety profile of both the strategies was similar.

Although ANCA evolution and/or circulating CD19+ B cells were not reliable predictors of AAV relapses, combining them achieved fewer infusions in the tailored-infusion arm without significantly more relapses. This is precision medicine indeed!

5 DASH Diets with Mortality in Adults on Hemodialysis: The DIET-HD Study

In the DIET-HD study, the association of DASH and Mediterranean diets and mortality was assessed in 9757 adults on hemodialysis. Dietary intake was ascertained using a standardized questionnaire. Scores were calculated based on this data. Higher scores indicated food intake more consistent with these diets.

During a median follow-up of 2.7 years (18,666 person-years), there were 2087 deaths (26%), of which 829 (40%) were attributable to cardiovascular causes. The distributions of the Mediterranean and DASH diet scores among patients who died from cardiovascular causes were similar to those of patients who survived until the end of the follow-up.

DASH diet in general population is associated with 10%–30% lower risk of cardiovascular disease and mortality. This is not the first time that promising interventions to prevent CVD have failed in dialysis patients (remember statin, ICD, anticoagulation etc). This is not surprising given the major role of non-traditional risk factors here. In addition, any intervention at this point in time may be too late to have a meaningful effect.

The entire analysis was based on self-reported intake of foods. The scales might have underestimated the effect of salt intake, and maybe phosphate intake, in the calculation. And probably we don’t know enough about nutrition in patients on dialysis! Until the time they don’t cross limits of potassium intake during weekends and are not going for low protein fad diets, I prefer to let them enjoy their food preferences.

6 Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure

With increasing use of sacubitril/valsartan (Angiotensin receptor-Neprilysin Inhibitor)in heart failure here, cardio-renal friendship seems to be growing. I am increasingly called for acute kidney injury in a patient with congestive heart failure who is on this combo. I often imagine that this drug should be a part of the sick-day-medication list and I end up holding it temporarily until creatinine returns to the baseline.

Do you monitor albuminuria of patients getting treatment for heart failure if they have baseline albumin excretion of about 8 mg/day? You may do that in an RCT of heart failure though.

An analysis of renal effects of sacubitril/valsartan and enalapril in participants of PARADIGM-HF trial is here. Just to remind you, sacubitril/valsartan reduced the risk of death and hospitalization in this population as per results of PARADIGM-HF. 

Over the study duration, the decrease in eGFR was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m2/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m2/year] vs. -2.04 ml/min/1.73 m2/year [95% CI: -2.21 to -1.88 ml/min/1.73 m2/year]; p < 0.001). In participants in whom The urinary albumin/creatinine ratio (UACR) was available (1872 of the 8399 patients), there was a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001).

That means sacubitril/ valsartan leads to increase in albuminuria and still preserves eGFR better. These were not the prespecified analyses and results are based on surrogates. Heart failure treatment is not the setting and time to bother about albuminuria and bumps in creatinine anyways.

7. Water intake and CKD progression 

Increasing water intake is widely viewed to have health benefits especially so for patients with CKD. This is, in fact, one of the common reasons for asymptomatic mild hyponatremia in my practice. While this notion is supported by observational studies, controlled trials are lacking.

In this multicentre, Canadian RCT of 631 patients with CKD (mean eGFR 43ml), authors randomized patients to receive “coaching to increase water intake” or to maintain the usual water intake. At the end of one year, there was no significant improvement in the primary outcome of rate of eGFR decline:−2.2 mL/min in the hydration group and −1.9 mL/min in the control group (adjusted between-group difference, −0.3 mL/min/1.73 m2 [95% CI, −1.8 to 1.2; P = .74]). Efficacy of the coaching was assessed by self-reported water intake(which however was less than intended in the intervention group), and plasma coeptin level (a degradation product of AVP which is supposed to be negatively correlated to water intake).

Interestingly, 24 hr urinary creatinine excretion was significantly improved in patients in intervention arm: authors hypothesize this to be due to an effect of increased urine flow rate on tubular creatinine secretion. Short follow up, a small difference in water intake between the groups (~800ml), reliance on eGFR, and small sample size (underpowered to detect smaller benefits in eGFR decline) are important limitations to note.  No drop in the serum sodium was noted in the intervention group.

Larger trials with longer follow up duration and better measurements of kidney function are needed (I have this line ready to be put after review of most RCTs in CKD progression!) before we label this simple intervention as ineffective. Until then, everyone can continue to listen to that poorly defined area in the hypothalamus called as thirst center.