July 2018

1 Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU)

BICAR ICU

(Visual abstract by Divya Bajpai @divyaa24 )

While the threshold for starting treatment may differ, most of us use sodium bicarbonate in acidemic patients in ICU, especially in the setting of acute kidney injury. This is one of those practices where very little evidence exists to guide decisions (in fact nearly equal basic science data exists for and against bicarbonate use).

Much-needed evidence addressing this dilemma now comes from this multicentre, open-label RCT of 389 adult patients who were admitted within 48 h to the ICU with severe acidemia (pH ≤7⋅20, PaCO2 ≤45 mm Hg, and bicarbonate concentration ≤20 mmol/L) and with a SOFA score of ≥4 OR an arterial lactate concentration of ≥2 mmol/L randomized to receive either no sodium bicarbonate (control group) or 4⋅2% of iv sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7⋅30. The primary outcome -a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7- was not different in the two arms: 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate –5⋅5%, 95% CI –15⋅2 to 4⋅2; p=0⋅24) without significant effect of the treatment group (crude OR 0⋅775, 95% CI 0⋅505–1⋅190; p=0⋅24).

In the pre-specified subgroup involving 182 (47% ) patients with AKI-AKIN stage 2 or 3, therapy offered some benefit: the primary outcome occurred in 74 (82%) of 90 patients in the control group and 64 (70%) of 92 patients in the bicarbonate group (absolute difference estimate –12⋅3%, 95% CI –26⋅0 to –0⋅1; p=0·0462)

More patients in control group underwent renal-replacement therapy during their ICU stay (52% vs 35%, absolute difference estimate –16⋅7 days, 95% CI –26⋅4 to –7⋅0; p=0⋅0009; figure 3); and when indicated, renal replacement therapy was started earlier in the control group than in the bicarbonate group (7 hours vs 19 hours). Hyperkalemia and acidosis were the main reasons for RRT in the control group and Serum creatinine and serum blood urea nitrogen were the main reasons to start renal-replacement therapy in the bicarbonate group.

Do these findings change my practice? Not really; IV bicarbonate in lactic acidosis is unlikely to offer any survival advantage where the primary treatment is the treatment of the underlying cause. But in presence of renal insufficiency, bicarbonate therapy may be useful in postponing dialysis and at least is not associated with significant harm. In this sense, the study findings support what we do. See an excellent post on PulmCrit blog here.

 

2 Canagliflozin and renal outcomes in type 2 diabetes

canvas (1)

(Visual abstract by Divya Bajpai @divyaa24 )

Results of CANVAS program were published last year. We discussed the paper here. The trials concluded that patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation.

The results of a prespecified exploratory analysis of the effects of canagliflozin on a range of renal outcomes were published last month in the Lancet. CANVAS program included two comparable studies- CANVAS and CANVAS-R. Participants in CANVAS were randomized to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomized to receive canagliflozin at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. People with type 2 diabetes and an HbA1c of 7·0–10·5% who were aged at least 30 years and had a history of a symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were included in the study.

The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient- years in the placebo group; hazard ratio 0·53, 95% CI 0·33–0·84). After an initial drop in the eGFR, Canagliflozin preserved the eGFR better. New onset albuminuria (micro/macroalbuminuria) occurred less frequently in the canagliflozin group.

Rates of acute kidney injury and hyperkalemia did not differ in the two groups. The heightened risk of amputation and fractures in canagliflozin group was similar in participants with eGFR above and below 60 mL/min per 1·73 m².

Considering very few clinically relevant renal events, these results are hypothesis generating at the best and as authors admit, aren’t enough for the drug to get formally approved for renoprotection in diabetes. The number needed to treat (NNT) for the primary composite outcome in this trial was 771! If we think 40% reduction in MDRD eGFR is a clinically relevant outcome, 296.2 patients would have to receive canagliflozin (instead of control treatment) for one additional patient to NOT have 40% reduction in MDRD eGFR. For surrogate like albuminuria though, the NNT was 36.9.

 

3 Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients

Gabapentin and pregabalin are often prescribed for neuropathic pain in patients on hemodialysis. KDIGO suggests the use of gabapentin for pruritus and restless leg syndrome. Not surprisingly, many of these patients do not tolerate these medications dependent on renal clearance for their elimination.

From the US Renal Data System, Ishida et al identified 140,899 Medicare-covered adults receiving hemodialysis and investigated the association between gabapentin and pregabalin, and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture.

19% and 4% of patients received gabapentin and pregabalin, respectively. Not unexpectedly, gabapentin was associated with 50%, 55%, and 38% higher hazards of altered mental status, fall, and fracture, respectively, in the highest dose category (>300 mg/day), but even lower dosing was associated with a higher hazard of altered mental status (31%–41%) and fall (26%–30%). Pregabalin was associated with up to 51% and 68% higher hazards of altered mental status and fall, respectively.

Finding the safer doses of these drugs or the safer alternatives to improve the quality of life of these patients is the need of the hour.

 

4 Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome (RITURNS)

Vitamin R is rocking again!

In an RCT from Kolkata, Basu et al randomized 176 children aged 3 to 16 years with the corticosteroid-dependent nephrotic syndrome to receive either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375mg/m2). Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95%CI, 1.93-14.07). Among the patients who experienced relapse, the median time to the first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Rituximab group had lower cumulative corticosteroid dose (25.8 ±27.8 vs 86.3 ± 58.0 mg/kg) and better catch-up growth.

Mild to moderate infections were twice as common in the tacrolimus group.

Authors conclude that in children with the corticosteroid-dependent nephrotic syndrome, rituximab is more effective than tacrolimus in maintaining disease remission.

A significant number of children with this disease suffer morbidity and mortality that can be associated with immunosuppression and until long-term safety data become available, we need to involve patient families in shared decision making before resorting to the vitamin R.

 

Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones

TAMSULOSIN VA

(Visual abstarct by Aakash Shingada @aakashshingada)

Meltzer et al randomized 512 adults presenting to the emergency department with symptomatic ureteric stones <9 mm in diameter on CT to receive either Tamsulosin or placebo. The primary outcome was the passage of a ureteral stone within 28 days after randomization, as determined by the participant’s visualization or physical capture of the stone. At the end of the 28-day treatment period, the urinary stone passage rate of 49.6% among participants assigned to Tamsulosin did not differ significantly from the placebo passage rate of 47.3%(relative risk, 1.05; 95.8%CI,0.87-1.27;P = .60)

In a large study done in China, tamsulosin arm had a higher stone expulsion rate compared to the placebo (86% vs 79%; p<0.001) for distal ureteral stones of size 4-7 mm. In the subgroup analysis, stones larger than 5 mm had higher odds of expulsion.

It is possible that Tamsulosin does not facilitate expulsion of small stones or the stones in the upper ureter. In the case of larger stones, will this study change the current practice?

 

Belimumab in kidney transplantation

While T-cell mediated rejections are largely treatable, antibody-mediated rejections pose a significant threat to the renal allografts. B cells also have a regulatory role and thus could play both a positive and negative role. Strategies targeting B cells with preservation of their regulatory functions would be a boon to transplantation.

B lymphocyte stimulator (BLyS) is a cytokine that promotes B cell proliferation. High serum concentrations of BLyS are associated with the development of de-novo donor specific antibodies.

We know belimumab as an FDA-approved therapy for non-severe auto-antibody positive SLE. Belimumab is a monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human BLyS to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity.

In a double-blind, randomised, placebo-controlled phase 2 trial sponsored by GSK (manufacturer of belimumab), 28 kidney transplant recipients were randomly assigned to receive iv belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions, in addition to the standard immunosuppression (Basiliximab, tacrolimus, MMF, prednisolone).

Belimumab effectively removed circulating free BLyS. However, the co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. There was no major safety concern observed. There was a nonsignificant trend towards reduction in naive B cells and kidney specific IgG, with significant reductions in activated memory B cells and circulating plasmablasts. In authors’ words, ‘the reduction in activated memory B cells and preformed IgG indicates the drug’s potential in sensitized kidney transplant recipients.’

In larger studies, it will be interesting to see the long-term safety and efficacy of belimumab.

 

7) Analysis of Luminex-based algorithms to define unacceptable HLA antibodies in CDC-crossmatch negative kidney transplant recipients

With the solid phase assays for identifying anti-HLA antibodies, we now can hope to improve transplant outcomes by avoiding transplantation if anti-HLA antibodies are present. However, this approach will result in a smaller donor pool available for a growing waiting list. CDC cross match may be negative even when anti-HLA antibodies are present. However, relevance of a positive single antigen bead assay in presence of negative CDC cross match is less clear.

In a study from Germany, transplant-day sera of CDC cross-match negative kidney transplant patients were screened retrospectively for the presence of anti-HLA class I and class II IgG antibodies using solid-phase microsphere-based assay. If pretransplant sera revealed the presence of anti-HLA IgG antibodies, the corresponding HLA were classified as unacceptable HLA-antigen mismatches.

Among the 211 patients studied, 115 (54.5%) had anti-HLA-specific IgG antibodies retrospectively detected by the Luminex assay using day of transplant sera. 67/211 patients (31.8%) had donor-specific anti-HLA-antibodies. Among the 67 DSA-positive patients, 16 (23.9%) experienced AMR during a median follow up of 4.9 years, majority occurring within the first year.

Of these 16 patients with AMR, 11 could be identified if the threshold of positive DSA test was kept at MFI value 3000 SAB assay [according to the German Society of Immunogenetics (DGI) consensus, algorithm I]. Authors also tested two more algorithms.

  • Algorithm II (ME algorithms): all antibodies against HLA A, B or DR with MFI above 5000 or antibodies against HLA DQ with MFI above 10,000.
  • Algorithm III (MFI_10,000): all anti-HLA antibodies with MFI above 10.000.

Algorithms (I) and (II) had comparable efficacy but were superior to (III) in identifying at-risk patients.

To calculate the extent of the Eurotransplant donor pool that would be excluded during organ allocation due to the presence of this kind of unacceptable antigen match due to donor specific antibody, the virtual panel-reactive antibody (vPRA) level was calculated. Median vPRA was between 69.2 and 79.1%, translating into a potential prolongation of waiting time between 1.5 and 1.8 years, respectively.

Donor specific antibodies in absence of CDC cross match positivity reflect a high immunologic risk. At the expense of a better match, this will shrink the donor pool and prolong waiting time.

In order to minimize this impact, we need to understand how to identify those who had DSAs but did not develop rejection.

 

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June 2018

1 Early Postoperative Acetaminophen Exposure and AKI in Children after Cardiac Surgery

In a primary cohort of 666 children and a validation cohort comprising of 333 children who underwent cardiac surgery with cardiopulmonary bypass, the incidence of AKI was higher among those with no acetaminophen exposure than among those with acetaminophen exposure, according to the result of this retrospective observational study.  This is thought to be due to reduced oxidation of free hemoglobin by preventing the oxidation of iron from Fe3+ to Fe4+  by acetaminophen. Exposure to this agent was protective against postoperative AKI (odds ratio, 0.86 [95%CI, 0.82-0.90] per each additional 10mg/kg). About 50% of the children in the primary cohort had AKI (defined as an increase by ≥0.3mg/dL from baseline or at least 1.5-fold more than the baseline).

Apart from not getting exposed to acetaminophen, controls had a lot of other reasons to develop AKI (younger age, lower weight, longer duration on CPB, higher nephrotoxin exposure to mention a few). Given all the limitations of the retrospective study, this finding is hypothesis generating at best. A similar but smaller study in patients with sepsis failed to show such a protective effect.

2 Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women

 Most uncomplicated UTIs are self-limiting, but they are almost always treated with antibiotics. In a randomized, controlled, double-blind non-inferiority trial, Vik et al randomized 383 non-pregnant women presenting with symptoms of uncomplicated UTI to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. By day 4, 38.7% of the patients in the ibuprofen group ‘felt cured’ versus 73.6% in the pivmecillinam group. After 4 weeks’ follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group. The number needed to harm here was 26!

More than half of the patients initially treated with ibuprofen got well without taking antibiotics. Who are these patients? If we could identify these less severe cases who don’t progress to pyelonephritis, we may avoid antibiotic exposure to these people. Until then, it is prudent to continue prescribing antibiotics for uncomplicated UTIs.

3 Oral Antibiotic Exposure and Kidney Stone Disease

Disruption of the gut and urinary microbiota is associated with nephrolithiasis. Effect of antibiotics on the microbiome is well established. To examine if antibiotic exposure is associated with nephrolithiasis, Tasian et al conducted a population-based, nested case-control study with 25,981 patients with nephrolithiasis and 259,797 controls observed for a median of 5.4 years. Sulfas, cephalosporins, fluoroquinolones, nitrofurantoin/ methenamine, and broad-spectrum penicillins were associated with an increased odds of nephrolithiasis diagnosis 3–12 months after antibiotic prescription. The highest magnitude of risk was estimated for exposure to these antibiotics at younger ages and for antibiotic exposure 3–6months before diagnosis (compared to more distant antibiotic use).

Oral antibiotics often prescribed for various indications, may be contributing to the increasing prevalence and earlier age at onset of nephrolithiasis.

Change in the overall diversity of the gut microbiome, selection of multidrug-resistant bacteria in the urinary microbiome that promotes the stone formation and direct antibiotic crystallization in the kidney could underly these findings. However, it is very difficult to ignore a major confounding factor here- UTIs. Both the antibiotics as well and stones are associated with UTIs. Although the sensitivity analysis excluding the previous UTIs showed similar findings, I think it will be very difficult to remove this confounding factor. (For example, nitrofurantoin prescriptions must have been given for UTI). But these findings are hypothesis-generating and a more detailed analysis, particularly in children, should be able to clarify these doubts.

4 The Drug-Intoxication Epidemic and Solid-Organ Transplantation

The opioid crisis has led to a dramatic increase in the number of drug overdose deaths in the United States, with an increase in the number of donors who died from drug overdose.

In a study published in NEJM from the United States, Mehta et al noted a large increase in the proportion of organ donors who died from drug intoxication — from 59 (1.2%) in the year 2000 to 1029 (13.7%) in the year 2016. This shift accounted for much of the increase in organ transplantation activity. In contrast, in Europe, there was no significant change over time in the frequency of drug intoxication as the cause of donor death (≤1% in any year). The survival among recipients of allografts from donors who died from drug intoxication was similar to survival among recipients from donors who died from other causes.

If the much of the increase in the donor pool was because of deaths from drug intoxication, there is an urgent need to explore other ways to expand the donor pool.

To me, this observation also highlights the need for a national transplant registry, which is not present in many countries including India. If we don’t have the data, we will not realize our problems, leave aside solving them.

5 A Novel Method for Rapid Bedside Measurement of GFR

‘One accurate measurement is infinitely superior to thousand expert opinions’ -Grace Brewster Murray Hopper.

During my daughter’s summer vacation, I learned many amazing games she and her friends innovate. I  must share one of them with the nephrologists. They would arbitrarily divide the entire sky into 4 parts and 4 teams will start counting the number of stars in their quarter share of the space. The team that gets to count the highest number wins. They have no doubt in their mind that the number estimated is the right one. When I said, it’s not a true number, they replied ‘we are well aware of the fact and this is just a game. So please shut up.’

Now, doesn’t that sound similar to estimating GFR by various equations and assume that it reflects the true kidney function? Forget about clinical practice, even research trials continue to rely on eGFR and even manage to get FDA approvals for the studied drug.

This interesting phase 2b study in JASN is a step ahead towards having mGFR (measured GFR) in practice. Authors developed a novel marker, VFI (Visible Fluorescence Injectate) which after administration can be easily measured in the plasma (rapid readout unlike iohexol where time-consuming HPLC or mass spectroscopy is needed). mGFR by VFI showed almost perfect correlation with the gold standard – mGFR by iohexol (coefficient correlation value of 0.996). This performed similarly well in patients with normal and abnormal kidney function (CKD 3 and 4).

This is exciting, promising and much needed ‘precision’ in the measurement of kidney function that can be potentially put into clinical practice. I am waiting to read more about this.

6 Burosumab Therapy in Children with X-Linked Hypophosphatemia 

Before it is stopped after correct diagnosis, repeated massive doses of vitamin D have already calcified kidneys of many patients with X-Linked Hypophosphatemia (XLH). Diagnosis and treatment of this disease are one of those ‘ah!’ moments in medicine, when a crippled child starts ambulating and growing after phosphate replacement. Whether you use traditional Joulies solution or newer phosphate preparation, GI intolerance is a major limiting factor and also a common reason for noncompliance. Also, hyperparathyroidism resulting from phosphate administration can worsen the bone disease and needs active vitamin D to control, which in turn further worsen hypercalciuria and nephrocalcinosis. Vicious cycle of disease—>therapy—> disease—->therapy.

Burosumab -a monoclonal antibody that targets FGF-23- precisely acts at the site of the defect in this disease and has shown promising results in this open-label, phase 2 trial, of 52 children with XLH. Burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets (assessed by Thacher rickets severity total score). Given the similar pathogenesis, this may also work for other hypophosphatemic diseases like autosomal recessive hypophosphatemic rickets and tumor-induced osteomalacia. If the cost of this agent permits, this is a great news for patients with these rare disorders.

7 Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery

In this pragmatic trial of 3000 patients undergoing major abdominal surgery, restrictive versus liberal fluid administration in the first 24 hrs didn’t result in significant difference in the primary endpoint of disability-free survival at 1 year (you can debate about the impact of fluid therapy in first 24 hours on an outcome at 1 year). However restrictive fluid group suffered more episodes of AKI (8.6% vs 5%) and needed renal replacement therapy (RRT) more often (0.9% vs 0.3%) which were secondary endpoints.

I can only hope that this doesn’t encourage our surgery colleagues to pump in fluids indiscriminately. AKI and RRT need were secondary outcomes and can’t be considered definitive as very few patients developed severe AKI. While we are not sure whether blood urea or creatinine by themselves kill patients with AKI, evidence suggests that water can. Note the number of events for benefit and harm of these two approaches: 13 vs 4 (P=0.04) for RRT need (NNT=166) and 20 vs 32 (P=0.1) for pulmonary edema (NNH=125) in restrictive vs liberal strategy respectively. Case for statistical versus clinical significance!

8 Base excess, antiphospholipid antibody syndrome 

Two nice reviews: base excess and antiphospholipid antibody syndromes in NEJM.

sBE is reported in all the ABGs, however many don’t routinely use this value for assessment of acid-base disturbances. For those like me who hate mathematics, BE is a much easier method for interpretation of ABG, with two important caveats: first, you interpret it along with anion gap, second, your blood gas devices should standardize the standard base excess equation and use only the standard base excess calculation recommended by the National Committee for Clinical Laboratory Standards. Interesting recap of the history of acid-base assessment starting from Copenhagen polio epidemic, through transatlantic debate to the current standard of care is a nice read.

Another ‘don’t miss’ review is on APLA syndrome. Renal involvement in this disease can come rarely as AKI due to catastrophic APLA, or a chronic vaso-occlusive disease. 30% of the SLE patient will have these antibodies. Recap of latest definitions, clinical syndromes, laboratory test interpretation and management is worth your time.

 

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.

Kidney-paired donation to increase living donor kidney transplantation in India: Guidelines of Indian Society of Organ Transplantation – 2017

This month’s guest blog post is written by Dr. Vishwanath Billa, a Nephrologist and Transplant Physician at the Bombay Hospital Institute of Medical Sciences, Mumbai and a Professor of Nephrology at the Maharashtra University of Health Sciences.  Dr. Billa is one of the authors of the Kidney Paired Donation Guidelines of Indian Society of Organ Transplantation – 2017, published in January 2018.

viswanath-billa

 

 

The release of the Kidney Paired Donation (KPD) guidelines by the Indian Society of Nephrology early this year is a significant step forward by the Society to formalize an activity that has been occurring in a limited and localized fashion across the country. These guidelines encourage this activity to become a comprehensive and coordinated national effort. The ability of paired kidney exchanges to provide quick transplant opportunities to easy to match pairs, as well as an alternate option for difficult to match kidneys has already been recognized.

While the guidelines have laid down the ground rules for this activity, understanding the concept and its implementation needs more than just ground rules. A paired kidney exchange program can be most successful when it functions as a single large database. The more the number of pairs in the registry, more are the opportunities for the pairs. This would mean that the multiple small such registries across the country need to merge into a single national database. From this centralized structure, there can be regional pairing as defined by patient geographies.

When the registry functions in this fashion and generates compatible pairs, my personal view is that donors should travel rather than the kidneys whenever a paired exchange takes place. Any step that can protect the function of the transplanted kidney in such an activity has to be adopted and adding the element of cold ischemia to a precious transplant does not add appeal.

The working of such a national registry has to reassure the Nephrology community that each of their registered pairs, when matched, would be transplanted by the registering Nephrologist alone. Involvement of the Nephrologists to register their incompatible donor- recipient pairs into the national registry would be effective only when they are convinced that by doing so they retain the opportunity to perform the transplant on their respective patients whenever matched.

The process of approval of paired kidney exchange transplants involves screening at the local hospitals followed by an interview by the Authorization committee. The process could get complicated when there is a long chain domino exchange planned or when the two pairs are registered at two distant centers. The insistence of the Authorization committee to individually interview each of the members of such an exchange poses huge logistic challenges. There is a need to evolve a procedure to address this challenge.

While manual allocation works when the size of the registry is small, it is imperative that a single national database needs to run on a computerized algorithm. Elimination of bias, assuring the best match to the patient, and quick matching are the tangible benefits of this approach. While the science of matching is standardized across the world, the philosophy of matching would vary from country to country based upon local laws, local culture, local economy and size of the country. There is a need to develop a local algorithm incorporating all these elements for a specific country.

For Nephrologists, there needs to be regulation (self or external) into choosing kidney paired donation over ABO incompatible transplants, especially for easy to match blood groups.

 

Dr. Vishwanath Billa,

Bombay Hospital and Medical Research Centre, Mumbai.

April 2018

1. Antihypertensive efficacy of clonidine

In ‘difficult CKD hypertensives’, many nephrologists here use clonidine as a preferred 3rd or 4th add-on (with the guilt in mind- ‘what is the evidence?’). After seeing that on one of his patient’s prescription, I was called back by a very senior GP asking my age and then thanking me for making him nostalgic about his early days of practice 40yrs ago in addition to controlling his patients BP.

Spironolactone is preferred 4th drug to add based on the results of PATHWAY 2 trial. Clonidine is probably the “nephrologist’s spironolactone”- the 4th  drug to add in patients whose BP remains uncontrolled with RAS blockade, CCBs, and thiazides. Unfortunately, clonidine has almost become an orphan drug (you will find a passing mention at the bottom of the UpToDate chapter on resistant HTN with no accompanying reference), and today is only talked about its role in de-addiction, hot flushes etc. A KOL in the field of hypertension was clueless when asked about the role of Arkamin (clonidine) in the treatment of resistant HTN in a nephrology conference. He just said,”no data… I don’t know”

Results of  ReHOT randomized Study will reduce this guilt to some extent. Patients with resistant hypertension (defined as no office and ambulatory BP monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID). Compared to the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary endpoint- BP control by office BP and ABPM- (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55–1.88]; P=1.00). Secondary endpoint relating to the absolute decrease in BP favored spironolactone leading authors to conclude that spironolactone is preferable for the fourth-drug therapy.

Other important findings of the study were prevalence and predictors of resistant HTN among this population (n=1597). 12% of their patients had resistant HTN. A history of stroke, diabetes mellitus, or BP ≥180/100 mm Hg at study entry was independently associated with it.

 

2. BP control with the help of barbers

My childhood memories of barbershop are painful: our grandfather taking six of us to his barber friend where they use to relentlessly chat while barber literally plucking out (and not cut) hairs- yes, we all used to be teased by schoolmates as ‘bald ghosts’. This left a permanent impression and I continue to think that ‘one hour a month, with your neck tied to a chair, some nonsensical music at the background, and to make the things worse a barber who won’t just stop talking’ is too much to bear in life. So, I go there with a clear intention of postponing next visit as further as possible.

But, if I were a hypertensive non-Hispanic black (uniquely disadvantaged due to genetics and environment, multiplying their risk of hypertension, kidney failure, and CVD), I must visit a barbershop at least 2 times a month, if I am to get my BP controlled. That’s what this interesting cluster-randomized trial of BP Reduction Black Barbershops published in NEJM shows.

Black-owned Barbershops are not just the places for the haircut but are the cultural institutions that draw a large and loyal male clientele and provide an open forum for discussion of numerous topics, including health, with influential peers. Pharmacist (who were specially trained in BP treatment) led intervention at the barbershop in which barbers encouraged meetings in barbershops with specially-trained pharmacists who prescribed drug therapy under a ‘collaborative practice agreement with the participants’ doctors’ OR active control approach in which barbers encouraged lifestyle modification and doctor appointments only. A phenomenal mean 21.6 mm Hg greater reduction in BP was achieved with the intervention (95% confidence interval, 14.7 to 28.4; P<0.001). A blood pressure level of less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% of the participants in the control group (P<0.001).

For those obsessed with ‘intensive control’, this is an excellent example of the much needed novel ways to achieve ‘extensive BP control’. It would be interesting to see the sustainability and replication of this approach and its impact one hard clinical outcomes. Notwithstanding limitations, comments questioning the place of this research in NEJM are really unfortunate. For those who are at unique health disadvantage, solutions outside the framework of conventional healthcare settings are urgently needed and this is one such way out. This is “Universal health coverage: everyone, everywhere” in action. Barefoot doctors in China, CKD prevention programme in India and home-based neonatal care are other similar examples of this approach decentralizing health care. Excellent blog post by @RogueRad here.

 

3. The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT)

 

Divya VA TAKE IT

 

Visual abstract by Dr. Divya Baipai (@divyaa24), Assistant Professor, Dept. of Nephrology, Seth G.S.M.C & K.E.M.Hospital, Mumbai and an NSMC intern.

 

‘I just took it at a different time’….this generally means ‘missing the dose’ or  ‘I missed one dose’ -most likely means ‘discontinued for a couple of days’. Nonadherence is common and often under-recognized. This is a leading cause of acute rejections and graft loss;  especially so for children in whom 44% of all graft losses and 23% of late acute rejection episodes are due to nonadherence.  Improving adherence, unlike newer drugs, is one of those few interventions in this area which doesn’t carry the cost of side effects and something that every center should seriously work upon. TAKE-IT  randomized kidney transplant recipients between 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States. The multicomponent intervention included electronic monitoring of adherence, messages, emails for dose reminders, and 3 monthly meeting with a coach who used “Action-Focused Problem Solving”  to address adherence barriers selected as important by the participant.

Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15- 2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls. The trial was small (n=169) and wasn’t powered to assess clinical outcomes of interest like rejections, graft loss etc.

TAKE-IT TOO will look at effectively integrating the TAKE-IT intervention into clinical practice.

 

4. Antibiotics for asymptomatic bacteriuria in kidney transplant recipients

Asymptomatic bacteriuria develops in almost half of the renal transplant recipients and there is uncertainty about the treatment. Transplant physicians face this dilemma regularly- whether to treat (and possibly reassure yourself and the patient) or to wait and watch.  There are at least two reports (here and here) which demonstrated that treating asymptomatic bacteriuria in general populations and also in kidney transplant recipients was not only unnecessary but also possibly counterproductive-leading to a higher incidence of symptomatic pyelonephritis. Moreover, selecting ‘MDR bugs’ and ‘exotic fungi’ remain other dangers of antibiotic treatment. Given the lack of good quality evidence, KDIGO and IDSA (2005) decided not to issue a recommendation on this topic. AST – Infectious Diseases Community of Practice advised avoiding treating asymptomatic bacteriuria that occurs beyond 3 months post-transplant unless there is an associated rise in creatinine.

A recent Cochrane review Antibiotics for asymptomatic bacteriuria in kidney transplant recipients also doesn’t take you any further and highlights the lack of evidence for treatment. Preventing symptomatic UTI (2 studies, 200 participants: RR 0.86, 95% CI 0.51 to 1.45), all-cause mortality (1 study, 112 participants: RR 2.23, 95% CI 0.21 to 23.86), graft loss (1 study, 112 participants: RR 1.11, 95% CI 0.07 to 17.36), acute rejection (1 study, 112 participants: RR 0.93, 95% CI 0.44 to 1.97), hospitalisation for UTI (1 study, 112 participants: RR 0.74, 95% CI 0.13 to 4.27), graft function (2 studies, 200 participants, MD in serum creatinine concentration -0.06 mg/dL, 95% CI -0.19 to 0.08) and adverse reactions (1 study, 112 participants: no severe adverse event attributable to the antibiotic treatment).

The situation may change soon- at least three RCTs are underway examining this issue. In practice, however, most of us can select patients for treatment: past history of pyelonephritis, significant bladder issues, pyuria, SIRS, unexplained graft dysfunction etc. Also, it may be more effective to work on several modifiable factors (urologist being the first and not always easy) preventing its development: early Foley’s catheter and stent removal, avoiding stent placement altogether, avoiding DGF are among a few.

 

5. Cisplatin-associated Acute Kidney Injury (C-AKI): who is at risk?

Cisplatin-a potent and important anticancer agent-is associated with nephrotoxicity in approximately 30 percent of patients at some point during their treatment. Observational studies have highlighted various risk factors for AKI following its use, however, their application is limited by small sample size and restriction to a particular cancer type. In the largest study evaluating this risk, Motwani et al developed and validated a score-based model to predict the risk of AKI after the first course of cisplatin.  C-AKI occurred in 13.6% of 2,118 patients in the DC and in 11.6% of 2,363 patients in the VC. Older age, higher cisplatin dose, hypoalbuminemia and a history of hypertension were associated with C-AKI. An interesting finding was no association of baseline eGFR with the risk of C-AKI (within the range of study-all the participants had baseline creatinine ≤1.5 mg/dL).

A risk prediction score was generated based on the presence of four identified risk factors (age, cisplatin dose, history of hypertension, and hypoalbuminemia).

Variable Score
Age ≤ 60 0
Age 61-70 1.5
Age 71-90 2.5
Albumin >3.5 g/dL 0
Albumin 1.3- 3.5 g/dL 2
Dose ≤ 100 mg 0
Dose 101- 150 1
Dose > 150 mg 3
No hypertension 0
Hypertension 2

The probability of cisplatin-induced AKI was 10, 24, and 51 percent for scores of 3, 5.5, and 8.5, respectively. The c- statistic showed that the model was a good if not strong, model. [The c-statistics in the DC and the VC were 0.72 (95% CI, 0.69 to 0.75) and 0.70 (95% CI, 0.67 to 0.73), respectively.] Additional studies will be required to determine the utility of this model in clinical practice.

In authors’ words, ‘this model will empower providers and patients with more accurate, patient-specific information regarding the risk of kidney injury.’

 

6.Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

Hyperuricemia and gout are associated with higher cardiovascular risk, the causative role of uric acid here, however, remains controversial. Although febuxostat is more effective uric acid lowering agent compared to allopurinol, it was associated with a modestly higher rate of cardiovascular events resulting in an FDA alert. 

In a multicenter, randomized, double-blind noninferiority trial, 6190 patients with gout and a history of major cardiovascular disease were randomized to receive febuxostat 40 to 80 mg/d or allopurinol dosed according to estimated creatinine clearance. Febuxostat scored over allopurinol with regards to urate-lowering (higher proportions of patients in the febuxostat group had maintenance of serum urate levels at less than 6.0 mg per deciliter at most time points); however, the rates of gout flares were similar in the two treatment groups (0.68 and 0.63 flares per patient-year in the febuxostat group and allopurinol group, respectively).

Primary end-point event (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina) occurred at similar rates in the febuxostat group and the allopurinol group (10.8% and 10.4% of patients, respectively, at a median period of 32 months; hazard ratio, 1.03; upper bound of the one-sided 98.5% confidence interval [CI], 1.23; P = 0.002 for noninferiority). However, the risk of death from any cause and the risk of cardiovascular death were higher in the febuxostat group than in the allopurinol group. (7.8%  vs 6.4%; HR 1.22 (1.01–1.47), p 0.04). The reason for higher mortality with febuxostat is unclear. Preclinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism.

A major limitation of this trial is a large number of participants who discontinued the trial treatment and did not complete the follow-up. 56.6% of patients discontinued trial treatment prematurely, rates of discontinuation being similar in both the groups.

So until we have more data, allopurinol seems to be a safer option for uric acid lowering in patients with gout and high CV risk.  Also, this should curb the enthusiasm wider use of urate-lowering (so commonly seen here) with febuxostat outside current recommendation.

 

7. Cardiac Rhythm Disturbances in Hemodialysis Patients

The primary cause of death in patients on hemodialysis is cardiovascular, with sudden death (SD) constituting a significant proportion. In a multicenter, interventional-observational, prospective cohort study Sacher et al sought to monitor the mechanisms leading to sudden death.

71 patients were implanted subcutaneously with implantable loop recorders (ILRs) with remote monitoring capabilities. During a mean follow-up period of 21.3 ± 6.9 months, 16 patients died, the cause of death being cardiac in 5.

The actual incidence rates of patients with significant conduction disorders, ventricular arrhythmias, and atrial fibrillation were, respectively, 14 (IQR: 7 to 21), 9 (IQR: 4 to 14), and 18 (IQR: 1 to 26) per 100 patient-years in HD patients implanted with ILRs.

In the multivariate analysis, pre-dialysis serum concentrations of K >5 mmol/l, bicarbonate <22 mmol/l, hemoglobin >11.5 g/dl, high-risk period (±24 h around the first HD session of the week after the long interdialytic period), history of coronary artery disease, occurrence of other cardiac arrhythmia during follow-up, and diabetes were associated with a higher risk for significant conduction disorders. Systolic blood pressure ≤ 140 mm Hg after HD was associated with a lower risk for significant conduction disorder. Serum K <4 mmol/l and the occurrence of other cardiac arrhythmias (conduction disorders or AF) during follow-up were associated with a higher risk for ventricular arrhythmias.

Male sex, serum K <4 mmol/l and serum phosphate >1.45 mmol/l (> 4.5 mg/dL) were associated with an increased risk for atrial fibrillation.

 

8. Urgent: Stop Preventable Infections Now

23% of the deaths in HEMO trial were attributed to infections (this probably is an underestimate if we consider non-research settings)- arguably is the leading cause of morbidity and mortality in patients on dialysis. Last month, CJASN published a timely series of papers discussing the challenge of infections in hemodialysis facilities. The articles systematically review the extent of the problem and discuss the ways to prevent the infections.

Addressing the Problem of Multidrug-Resistant Organisms in Dialysis: This article gives an overview of the transmission dynamics of multidrug-resistant (MDR) organisms and reviews infection prevention strategies in hemodialysis units. Soon we are going to face resistant bacteria with no antibiotic active against them. To avoid this disaster, prevention of transmission of infection is essential, as is antimicrobial stewardship. The author discusses the CDC recommendations to prevent the spread of MDR organisms.

(1) wearing gloves and performing hand hygiene in between patients and stations

(2) following published guidelines for judicious antimicrobial use and appropriate de-escalation

(3) avoiding multiuse medication vials and common medication carts

(4) disinfection and cleaning of equipment, non-disposable items, and the surrounding environment,

(5) separate clean/ contaminated areas and medication preparation in a dedicated room or a clean area away from treatment stations.

(6) using separate gowns for patients colonized/ infected with MDR organisms and have the high risk of transmission, for example, diarrhea, fecal incontinence or draining, uncovered wounds.

Now, all this appear ridiculously simple but ensuring 100% compliance with these recommendations may not be as easy and needs systematic assessment, training, audits, and retraining.

What We Learned from Ebola- Preparing Dialysis Units for the Next Outbreak: In this paper, the authors discuss the Ebola virus disease epidemic that occurred in West Africa in 2014-2015 to highlight the unique issues faced by out-patient hemodialysis units. They discuss how a unit should prepare itself to face such an epidemic. “Ebola Virus Disease outbreak should serve as a stimulus to establish the situations in which patients with highly transmissible infections might be dialyzed in outpatient settings, review emergency preparedness policies and infrastructure needs, and improve access to infection control expertise in outpatient hemodialysis units.”

 

100% Use of Infection Control Procedures in Hemodialysis Facilities- Call to Action:

In this paper, authors discuss the role of all the stakeholders in adherence to recommended infection control practices and highlight the important leadership role of nephrologists, especially medical directors, in preventing infections in HD facilities. Infection control procedures, immunization and screening for viral infections, and strategies to improve adherence are discussed.

March 2018

Before you read this months post, do have a look at the beautiful infographic of our last month’s post by Omar Taco (@Errantnephron) of Nephrology Social Media Collective (NSMC)

lastmonth_feb18

 

Coming back to this month’s post:

1 Balanced Crystalloids versus Saline in Critically Ill Adults

If you want 9 reasons not to use normal saline, you can find them here. In addition, non-believers have two large RCTs published in NEJM that compared normal saline with balanced solutions.

The SMART trial investigators conducted a pragmatic, single-center, unblinded, cluster randomized, multiple-crossover trial in which the use of balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) was compared with saline for intravenous fluid administration among 15,802 critically ill adults admitted to five ICUs at Vanderbilt University Medical Center between June 1, 2015, and April 30, 2017. The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction defined as an elevation of the creatinine level to ≥200% of baseline.

Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P = 0.04). The number needed to treat, if you calculate that here, would be 90.9. Is this 1.1% difference clinically significant? Or large sample size has made it possible for the difference to be statistically significant? If true, this effect would be important at the population level.

Individual components of the primary endpoint were not different between the groups.

Fewer patients in the balanced-crystalloids group had high plasma chloride or low plasma bicarbonate.

Should we stop using NS after these results? Probably not. Though the study is robust, the results may not be enough to seal the fate of NS. (See a good post about caveats.)

Another lesson here for nephrology research community-pragmatic trials may answer many questions in clinical practice, where traditional randomized controlled trials are difficult, expensive or simply impractical to conduct. They may be easier to conduct. They are highly generalizable. However, Certain methodological issues are already being discussed.  There was a concern that consent was not obtained from the patients.

Look at this twitter thread. The scientific community has probably never had an opportunity to interact the way they are doing now on social media. With all its limitations and challenges, social media is proving a useful tool in the learning process.

2 History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease

See the NephJC summary by Michelle Rheault here. Visual abstract created by Michelle Lim (@whatsthegfr)

childhood_kidney_disease_va_v3

In a nationwide, population-based, historical cohort study in Israel, investigators reviewed baseline examination records of 1,521,501 adolescents before compulsory military service between 1967 and 1997. Inclusion in the cohort required normal kidney function, no proteinuria, and normal blood pressure irrespective of a history of childhood kidney disease categorized as CAKUT (congenital anomalies of the kidney and urinary tract), pyelonephritis and glomerular disease. The adolescent cohort data was linked to the Israeli ESRD registry and hazards ratios for ESRD associated with childhood kidney disease were estimated. Persons with diabetes mellitus, systemic lupus erythematosus, vasculitis or any rheumatic disease, cancer, hypertension, or evidence of impaired renal function from any cause at the time of pre-conscription assessment were excluded.

Over 30 years of follow up, 2490 (0.2%) persons developed ESRD. Multivariable-adjusted analysis showed a history of any childhood kidney disease was associated with a hazard ratio of 4.19 for adult ESRD with HR of 5.19 for CAKUT, 4.03 for pyelonephritis, and 3.85 for glomerular diseases. A history of childhood kidney disease was associated with an earlier age of onset of ESRD (41.6 years vs 48.6 years).

What is not captured in the dataset is whether there were any risk factors developed between the pre-conscription assessment in adolescence and identification of ESRD in adulthood.

A history of childhood kidney disease, even when renal function was normal in adolescence, was associated with a four-fold risk of ESRD in adulthood. These findings suggest the need for early identification and interventions to prevent the progression of CKD.

Even with several limitations, this study is an important piece of information. Similar to the development of renal insufficiency in living donors or in people with low nephron endowment, patients with past history of kidney disease, even when current GFR is normal and there is no hypertension or proteinuria, could develop ESRD.

To sum up, don’t ever discharge the patients from your clinic if they have a history of childhood kidney disease.

3 Risk of ESRD in Prior Living Kidney Donors

“Doctor, will my mom need dialysis just because she donated me her kidney?”, an anxious 20-year-old man on dialysis asked me. What should I tell this young man?

Various cohort studies have tried to answer this question. Typically, as the follow-up duration increases, the studies find that there is a small increase in the risk of End Stage Renal Disease (ESRD) in renal donors. Quantifying this risk is important. The risk of ESRD after kidney donation does not exceed ESRD risk in the general population; however, it is higher than healthy matched donors.

Wainright et al analyzed the Organ Procurement and Transplantation Network and Centers for Medicare and Medicaid Services data to study ESRD in 123,526 living kidney donors who donated in the US between 1994 and 2016. 218 donors developed ESRD, with a median duration of 11.1 years after kidney donation, giving 20 years overall cumulative post-donation ESRD incidence of 49 per 10,000 donors. Hypertension, glomerulonephritis, and diabetes were the leading causes.

The risk was low but was highly variable. A 20-year-old white female donor had a predicted 20-year ESRD risk of 8 per 10,000, compared to 111 per 10,000 for a 20-year-old black male donor.

Male gender, higher BMI, being African-American, living in a neighborhood with low income, being a first degree relative of the recipient and having a low GFR at donation were associated with a higher risk. Older age at donation for white donors and younger age at donation for black donors conferred a higher risk.

While informing the prospective donors the risks of donation, these real-world figures are important. The pre-transplant clinic visits are always emotionally charged. In the authors’ words- “Relative risks among donors are useful to clinicians, but potential donors must also understand their absolute risk when making the decision to donate. Potential donors should receive the best available information – including limitations of existing research – about their own personal risk of ESRD after donation.”  

4 Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis

A group of nephropathologists proposed modifications to the ISN/ RPS classification of lupus nephritis to improve problematic definitions that form the basis of the lupus nephritis classification and thereby increase the interobserver agreement between nephropathologists worldwide.

Apart from clarification of various definitions, the group proposes two important alterations- Elimination of segmental versus global designation in class IV and replacing ambiguous III/IV-A/C with III/IV-modified activity and chronicity score.

Below is the summary of these changes.

Class Modification Suggested
Class II Definition for mesangial hypercellularity adjusted: Four or more nuclei fully surrounded by the matrix in the mesangial area not including the hilar region.
Class III and IV The term endocapillary proliferation is replaced by endocapillary hypercellularity
The term crescent is used for a lesion consisting of extracapillary hypercellularity, composed of a variable mixture of cells. Fibrin and the fibrous matrix may be present; 10% or more of the circumference of Bowman’s capsule should be involved.
Cellular crescent: more than 75% cells and fibrin and less than 25% fibrous matrix
Fibrous crescent: more than 75% fibrous matrix and less than 25% cells and fibrin.
Fibrocellular crescent: 25%–75% cells and fibrin and the remainder fibrous matrix.
Adhesion: an area of isolated continuity of extracellular matrix material between the tuft and capsule even when the underlying segment does not have overt sclerosis
Fibrinoid necrosis: fibrin associated with glomerular basement membrane disruption and/or lysis of the mesangial matrix; this lesion does not require the presence of karyorrhexis
Elimination of segmental and global subdivisions of class IV
Modification of the NIH lupus nephritis activity and chronicity scoring system to be used instead of the currently used A, C, and A/C parameters
Tubulointerstitial lesions Indicate whether interstitial inflammation occurs in presence or absence of interstitial fibrosis

I am curious to see how the efforts to define the disease better improve the way we treat our patients better.

5 Outcomes after ICD implantation in patients with CKD

CVD is the most common cause of death in a 73-year-old man who has poor LV function (due to ischemic and non-ischemic aetiologies), hypertension and other comorbidities. If a nephrologist sees him, he also gets an additional disease called as ‘CKD stage 3a/3b’ that has reached epidemic proportions in some parts of the world. 1556 such individuals who happened to need  ICD implantation, were compared with 4321 matched controls with heart failure, and similar CKD in a retrospective cohort study at 4 Kaiser Permanente health care delivery systems. At the end of 3.1 year of follow up, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization.

This research is a significant addition to the evidence which is scarce to guide practice here. Several limitations should be noted: confounding by indication (those with lower EF and severe heart failure are more likely to be selected for ICD), doubtful validity of CKD definition based on eGFR without albuminuria in elderly, lack of information on precise causes of increased hospitalisation (may or may not be related to ICD use), high competing risks of death and predominantly non-ischemic LV dysfunction are significant limiting generalisability of these findings to all CKD population.

I don’t think this data is enough to exclude patients with community-dwelling CKD needing ICD insertion as per current ACC/AHA guidelines 2012, after a shared decision making.

6 Worsening Renal Function (WRF) in Acute Heart Failure Patients Undergoing Aggressive Diuresis

“Stop/decrease diuretics, avoid contrast, hold RASi for now”-after seeing this renal consult, my cardiology colleague finding hard to keep his eyes open after a busy night shift, used to ask,”why don’t briefly summarise it as -cardiologists to go to sleep for now?”

As a nephrology registrar early in my residency, it was a tough task completing all consults in a given 24 hrs duty time. I recall developing a triage mechanism, where some of these consults can be assigned -“attend last”-cardiology was one of them. ‘Cardio-renal’ wasn’t born until then. By the time I used to reach cardiac floors, more than half the patients have already normalized their ‘hypercreatininemia’ and no longer required my help. After we had a uniform and sensitive diagnostic criteria for AKI in 2004, small increases in the serum creatinine levels were found to be associated with adverse outcomes-causality of which is still today is largely hypothetical. However, this led to growing concern among cardiologist using aggressive diuretic therapies for treating heart failure -‘cardiorenal syndrome’ was born. This study in Circulation is a post hoc analysis on 283 of 360 patients participated in ROSE AHF trial may alleviate this anxiety to some extent. Authors noted no difference in kidney tubular injury biomarkers (urinary NAG, NGAL, KIM1) in 60 patients who developed WRF (>20% decline in GFR estimated by cystatin C) when compared to 233 without WRF. Those who actually developed kidney injury i.e. had WRF and increase in injury biomarkers, survived better than those who didn’t-probably indicating that diuresis worked. These provocative findings are not conclusive but hypothesis generating, also, this analysis was underpowered to conclude definitively on survival. However WRF in such settings was not associated with adverse outcomes (here, here, and DOSE trial) in previous reports. Save them from drowning in their secretions, before you start bothering about creatinine or biomarkers.

7 Trimethoprim, UTI, and adverse events 

In this large UK cohort study of 1,78, 238 older patients in the general population,  treatment with trimethoprim for a urinary tract infection (UTI) was associated with a 72% increase Higher odds of acute kidney injury were seen with TM (OR 1.72, 95% CI 1.31 to 2.24) and  to a lesser extent with ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. TM was also associated with a greater than doubling of the odds of hyperkalemia compared with amoxicillin. Findings remained consistent across various subgroups and sensitivity analyses. 

Adverse effects of TMP-SMX and ciprofloxacin, when used in combination with RASi or spironolactone, were highlighted previously, however, this is the first time that a large, general practice based evaluation trimethoprim is linked to adverse events. While one can argue about the relevance of serum creatinine elevation alone (that can occur due to inhibition of tubular secretion due to TMP), hyperkalemia is a potentially serious concern. Safety issues with TMP-SMX in patients receiving RASi or spironolactone have been documented previously, however, this study raises suspicion on the role TMP over SMX in mediating these effects. Unlike many other countries, TMP use is common in the UK (as per guidelines)- I see TMP here as a favorite choice of some urologists for chronic prostatitis. 

In patients who are 65+, already challenged by homeostenosis, it takes little to tip the balance and TMP can be one of these reasons. If compelled to use, monitor carefully. 

 

Authors’ view: Renal Replacement Therapy initiation strategies in septic shock and ARDS patients -Stéphane Gaudry, MD, Ph D and Didier Dreyfuss, MD

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Stéphane Gaudry (@StephaneG05) and Didier Dreyfuss are physicians in the Critical Care Department at Louis Mourier hospital, Colombes, France (Assistance Publique – Hôpitaux de Paris). They are the authors of AKIKI trial.

 

 

Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory Distress Syndrome

The timing of RRT initiation during sepsis-associated acute kidney injury (AKI) is highly debated but the lack of data from large RCTs preclude definitive conclusions. Similarly, the question of RRT initiation during ARDS and severe AKI is crucial regarding the hypothetical better fluid balance management with ultrafiltration.
The recent study published in the AJRCCM  was a post-hoc analysis of the AKIKI trial focused on predefined subgroups including ARDS and Septic shock. None of these subgroups derived any significant survival benefit from an early RRT initiation strategy but renal function recovery occurred faster with a delayed strategy. Delayed strategy lead to respectively avoid 45% and 46% of RRT initiation for septic shock and ARDS patients with severe AKI. Moreover, duration of mechanical ventilation for ARDS patients was not influenced by RRT initiation strategy.
The relationships between RRT strategies on one hand and diuresis in the very first days after randomization and renal function recovery on the other were also examined. Starting RRT early was associated with a considerable and highly significant reduction in two-day cumulative urine output and this initial reduction of urine output was associated with delayed renal function recovery. In addition, this study shows that it is wiser to try to control fluid balance with diuretics than with ultrafiltration during RRT in unstable patients, as underlined in the accompanying editorial. Indeed, one can imagine that patients with hemodynamic instability will not respond to diuretics but will suffer from ultrafiltration. On the opposite once stabilized, patients may have an adequate response to diuretic administration making RRT useless if the goal is only the control of fluid balance.
To summarize, initiation of RRT when a patient is not stabilized might further compromise renal function and lead to “Artificial Kidney-Induced Kidney Injury” (AKIKI). A strategy of “permissive hyperuremia” as suggested in the paper 1 may allow for a reduction of iatrogenic injury and lead to considerable savings by limiting the number of undue RRT sessions.
Stéphane Gaudry, MD, Ph D and Didier Dreyfuss, MD
Louis Mourier hospital, Colombes, France