May 2024

Impact of clinical practice guidelines on hospital admissions and mortality in people living with kidney disease

The goal of clinical practice guidelines (CPG) is to lessen the burden of disease on the community and the individuals by reducing hospitalization, morbidity, and mortality. Whether the CPGs in chronic kidney disease are achieving this goal or not is an important question. Whether guidelines are getting translated into better outcomes for patients is the question answered by a cluster RCT by ICD-Pieces Study Group.

In this open-label, cluster-randomized trial, the investigators assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year. Secondary outcomes included emergency department visits, readmissions, cardiovascular events, dialysis, and death.

If you have not read the trial earlier, we want you to pause a bit and think before reading further. What do you think would have been the results of the trial? If you are like us, you would be thinking that CPGs would have made a SIGNIFICANT difference in the outcomes. Well, only one of us-Dr Tukaram- was skeptical regarding the effect of CPGs.

The results were alarming! The hospitalization rate at 1 year was 20.7% (95% confidence interval [CI], 19.7 to 21.8) in the intervention group and 21.1% (95% CI, 20.1 to 22.2) in the usual-care group (between group difference, 0.4 percentage points; P=0.58). The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death from any cause were similar in the two groups. The risk of adverse events was also similar in the trial groups, except for acute kidney injury, which was observed in more patients in the intervention group (12.7% vs. 11.3%).

Let that sink in! CPGs did not make any difference in outcomes. In fact, adverse events like AKI increased in the intervention group.

The trial has several strengths. It has a pragmatic study design with a large patient number. The intervention used a personalized algorithm (based on the patient’s electronic health record) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions

One may argue that this may not be the correct way to deliver evidence based interventions. But to refute the results of this study, there is a need for another pragmatic trial which has more efficient delivery of CPGs.  Until then, we must make do with the fact that CPGs may not be a panacea. The tapestry of combined wisdom gleaned from the trials, scripted by experts, and etched in gold may not deliver what we hope for.

Sparsentan reduces proteinuria in FSGS and IgAN, but is that enough? 

Glomerular diseases are the leading cause of ESRD in the developing world where diabetes is fast catching up or it would be more apt to say that diabetes has already caught up and GN hasn’t loosened its grip a bit. After a long period of quiescence, the field of GN management is finally witnessing long awaited controlled trials, testing various treatments strategies to prevent or delay kidney failure in this population. 

About 50% of patients with primary FSGS don’t attain remission with available options and have high risk of ESRD. Modulation of the common downstream injury pathways involving hypertension, glomerular hyperfiltration, vasoconstriction, and fibrosis, has been the cornerstone of the treatment. SGLT2i and MRAs were important additions to the RAS inhibition in recent years. 

 A dual endothelin–angiotensin receptor antagonist, sparsentan, has shown promising reduction in the proteinuria in a phase 2 study, and was evaluated in the phase 3, DUPLEX clinical trial involving  371 patients across 240 centers (mainly USA). At the median follow-up of 2 years, primary efficacy endpoint -the eGFR slope at the time of the final analysis at 108 weeks- was similar in two groups: the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute (95% CI −1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute (95% CI, −1.3 to 3.0). The mean change in eGFR from baseline to week 112 was −10.4 ml per minute with sparsentan and −12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per min, 95% CI, −1.4 to 4.9). Proteinuria reduction at prespecified interim analysis conducted at 36wks was more with sparsentan than irbesartan: partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P=0.009). 

Trial failed to show the impact of the drug on the primary endpoint of kidney function but demonstrated a reduction in proteinuria. Limited representation of blacks, reliance on surrogate endpoints of eGFR change and proteinuria reduction, limited duration of follow up, high discontinuation rate in both the arms are significant limitations. Very few patients had features or nephrosis (edema, hypoalbuminemia) and unfortunately, almost ⅓ of the patients enrolled didn’t have electron microscopy available, implying that this was a heterogeneous population inadvertently including many patients with secondary and genetic FSGS.

FSGS as a cause of ESRD has increased tenfold in the United States (0.2% in 1980s to 2.3% in 2000), unlike the rest of the world where such increases are not observed. This is likely to do with the misclassification of histological lesions of FSGS (which can be practically observed in kidney disease affecting almost any of the glomerular, tubulointerstitial or vascular compartments of the kidney) as primary FSGS. Other background information on the disease like severity of associated HTN, response to the prior immunosuppressive treatments, trajectory of eGFR before enrolment, important histological characteristics like glomerular, tubulointerstitial and vascular chronicity changes- which would significantly affect the natural history of the disease irrespective of the intervention -is not available. Authors hope that longer follow up may discover more substantial benefit on eGFR but it is equally likely to reveal side effects of sparsentan.

Sparsetan was also studied in IgA nephropathy (with proteinuria >1gm and eGFR 30-90ml), in a phase 3, PROTECT trial, randomizing over 400 patients to sparsetan or irbesartan. The primary endpoint was proteinuria change between treatment groups at 36 weeks favored sparsentan :change from baseline in UPCR was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group: eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per year versus −3·8 mL/min per year (difference 1·1 mL/min 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per year versus −3·9 mL/min per year (difference 1·0 mL/min per year, 95% CI −0·03 to 1·94; p=0·058).

While DUPLEX investigators remain equivocal about the benefits of sparsentan as an option to renoprotection, those of PROTECT trial seem to be convinced. The least important part of the research paper is ‘discussion’, especially when written by medical writers appointed by sponsors. But it can sometimes reveal important biases. Authors of the PROTECT trial express their disappointment twice in this section by stating “P value for total eGFR slope narrowly missed statistical significance” rather than simply stating that there was no significant difference in eGFR. While both trials are important and welcome addition to the scarce evidence base to manage common GNs, conclusions should be viewed alongside the important limitations. Interestingly, more than half of the IgAN patients in the PROTECT trial were normotensive; this is unlike most patients with IgAN especially when other features like significant proteinuria, decreased GFR, and hematuria were present. High discontinuation (23% in irbesartan and 14% in irbesartan), higher use of rescue treatment in the irbesartan group (did they have higher disease activity/severity?) are other bothersome observations. Similar to DUPLEX, detailed reporting of the histological severity (MEST-C) or International IgA nephropathy score, information on treatment and responses prior to randomization are missing. Higher incidence of dizziness and hypotension were reported in the sparsentan arm of the PROTECT trial. Side effects attributed to fluid retention: edema, hypertension and heart failure were not observed in the trial. This might be related to the specific safety of sparsentan (unlike other endothelin receptor blockers where these are reported in >15% patients). However, high discontinuation rate in both the arms of the trial make this hypothesis less than convincing. One needs to be watchful about hepatotoxicity although no such signal was observed in the PROTECT or DUPLEX trial. Of note, pivotal trials of ERAs also failed to pick up this safety signal which emerged only during post marketing surveillance. Finally, the perpetual question that bothers me is this: why can’t trials spending so much money measure BP and GFR by gold standards-24hr ABPM and measured GFR respectively? Larger studies with longer follow up are needed to better clarify efficacy and safety of this drug in FSGS and IgAN. 

Beginning of a new era in GN management?

An interesting development in the therapeutics of IgA is here with the publication of the APRIL trial. This is arguably the first example of the immunosuppressive agent specifically developed for a GN (IgAN) which until now were borrowed/ repurposed from rheumatology or oncology. APRIL-a proliferation-inducing ligand- is a member of the TNF α superfamily, regulates  IgA production by B-cells and is implicated in the pathogenesis of IgAN. Sibeprenlimab (VIS649) is a humanized IgG2 monoclonal antibody that binds to APRIL and produce reversible and dose dependent decrease in the serum levels of IgA, galactose-deficient IgA1, IgG, IgM, and APRIL. 

In this phase 2 study involving 155 patients with IgAN (proteinuria >1gm in 24 hour urine and eGFR >30ml/min on standard of care) safety and efficacy of sibeprenlimab at various doses (2, 4, or 8 mg per kilogram of body weight) was compared to placebo with regards to primary endpoint of change in proteinuria at 12 months. A significant reduction in proteinuria was noted: geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. Similarly eGFR was better presented with drug: the least-squares mean (±SE) change from baseline in eGFR was −2.7±1.8, 0.2±1.7, −1.5±1.8, and −7.4±1.8 ml per minute in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. Higher incidence of nasopharyngitis and upper respiratory tract infection was noted but major infections were not observed. 

Proteinuria reduction at 12 months was maintained at 16 months (4months after treatment discontinuation) in 4mg and 8mg groups but started to increase to baseline in the 2mg group. APRIL, IgA and Gal deficient IgA levels showed significant decline and APRIL levels returned to pretreatment levels by 16 months, indicating need for further repeated administration of the drug. Lack of detailed histological assessment at baseline is a notable limitation of the study, nevertheless, initial results are highly encouraging and phase 3 evaluation of this drug is eagerly awaited. 

Inaxaplin for APOL1 associated FSGS

About 13% of black individuals have high risk APOL1 genotype, with biallelic G1 and/or G2 haplotype and contributes to 70 % excess ESRD risk in them. Inaxaplin, is a small molecule inhibitor of APOL1 channel function, and has shown activity in an APOL1 transgenic mouse model of proteinuric kidney disease. In 13 participants with two APOL1 variants and biopsy-proven FSGS, this molecule showed remarkable decrease in the proteinuria: the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was −47.6% (95% confidence interval, −60.0 to −31.3). 

Small sample size, short duration of follow up and lack of placebo-are important limitations. FSGS in patients who are homozygous (or compound heterozygous) for two APOL1 variants is rare, and progresses fast with a very low likelihood of spontaneous remission of proteinuria. Results are preliminary but exciting and further evaluation of this therapy is ongoing in phase 3 trial.  

Risk of hair straightening products 

About 60 percent of the world population has curly or wavy hair (and among South Asians, it’s nearly 85 percent). Many desire to have straight and long hairs. Skin straightening traditionally involved use of formalin (Brazilian blow out) which was declared a health hazard for both the person treated and treatment provider. This led to the emergence of alternatives like glycolic acid for this purpose. A recent report from Israel highlighted the havoc this hair straightening chemical can create in the kidney. 26 cases of AKI (2 cases had recurrent AKI) were reported, over 3 year (2019-2022), from 14 centres. All were female in their 20s. Dialysis was needed in 3 two patients had recurrent AKI. Kidney biopsy was performed in 7 cases: all 7 had acute tubular injury, 6/7 had calcium oxalate deposition. A recent NEJM report described a case of AKI following use of glyoxylic acid for hair straightening. Investigators went on to elegantly demonstrate the underlying mechanism of AKI by a case control (5 mice in each group) experiment in mice. Secondary oxalosis was induced by glyoxylic acid application- demonstrated by 4D computerized tomography and histopathology. Possible predictor might be local burning/itching sensation or ulcers after the treatment. Given the wide popularity of such treatments, problem may be a tip of iceberg and we need to maintain high degree of suspicion in appropriate settings. Typically, hairs go back to their curly style after 3 months of such treatment, same can’t be said about elevated serum creatinine and then AKI becomes CKD.

False positive urine ethanol test 

In the small village where I was born, a certain tribe had exceptional skills of cheap ethanol production that could cater to the needs of half a dozen villages surrounding our’s. I vividly remember those women carrying bright white bricks of ammonium chloride (navsagar) which is supposed to activate yeasts for fermentation and subsequent country liquor production. The British categorised these tribes as “criminal” which was repealed after independence. But, this had made little difference, and any robbery or major crime in the district would automatically lead to arrest of the several men from these tribes. Police would drag their sniffer dogs (even when they were pointing in opposite directions) to the village outskirts where these people lived. Things have significantly changed now and several young men from these tribes hold reputable positions in police and administration now. 

The reason I went back in the memory lane is a recent case report of a gentleman in 60s who was being investigated by the city probation office and was about to be sent to jail for illegal alcohol use. He claimed to be sober for at least the last 10 months, but a positive urine toxicology screen for ethanol proved him a blatant liar. Primary care physician requested another test at his clinic, that turned out to be negative and investigation into this disparity revealed something that all of us should be aware about. Urine was sent outside for testing after 24 hours of storage without refrigeration at the probation office. During this time ‘glucose’ in the urine was fermented to ethanol by the ‘microbes’, -two ingredients needed for ethanol production. Who put them in urine? Man was on SGLT2i.

That’s why patients love their primary care physicians, they treat and can sometimes prevent you from going to jail.

May 2023

Hydrochlorthiazide: the turtle of the race?
“Adalphane Acedrex (a Novartis made combo of Reserpine+Dihydralazine+Hydrochlorothiazide)- was available in the hospital formulary and ‘uncontrolled hypertension’ was a rare condition”, Prof Hase would get nostalgic and remark on his grand rounds discussing evolution of pharmacotherapy for hypertension.

One of the earliest classes of antihypertensives, thiazide diuretics, are also one of the most effective drugs, with latest trial evaluating chlorthalidone showing a BP decline of almost 10mmHg. However, whether chlortalidone should altogether replace hydrochlorothiazide is still a matter of debate. This is an attractive proposition given the higher potency and some pleotropic benefits attributed to chlorthalidone (the term ‘pleotropic effect’ awakens sleeping skeptic in us, as this term is typically invoked to defend something that can’t stand scientific rigor alone). Large observational studies and meta-analyses have differing conclusions waiting for a randomized trial to settle the debate. (see here, here and here)

In a pragmatic randomized controlled trial involving 13,523 patients over 65 years of age, getting treated at Veterans Affairs health system, a switch to chlorthalidone (hydrochlorothiazide was the default thiazide at baseline), 12.5 or 25 mg did not improve the primary composite outcome of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non–cancer-related death. Primary outcome occurred in 702 patients [10.4%] in chlorthalidone and 675 patients [10.0%] in the hydrochlorothiazide group (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P=0.45). The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001).

This trial is long-awaited evidence to understand the difference between two commonly used thiazide diuretics for the treatment of hypertension and reassures those physicians who haven’t yet switched to chlorthalidone. The superior efficacy of chlorthalidone to reduce blood pressure doesn’t translate into effectiveness. This trial is an example of low cost, operational research in the setting of structured heath care systems like VA. Such pragmatic trials are feasible, can be completed quickly (phenomenal recruitment rate of 100 patients per week!), and are possible at a substantially lesser cost.

Many hypertension clinics have already switched to chlorthalidone given the higher potency and 24-hour action of chlorthalidone. Both of these reasons are not good enough to inform practice. First, potency may not necessarily translate into efficacy (which current trial confirms). For example, immediate release nifedipine or hydralazine are potent antihypertensives but not necessarily effective at the ultimate goal of BP control-CV protection. Duration of action as well may not be valid argument as the mechanism of BP reduction with thiazides is unclear and both volume depletion and fall in systemic vascular resistance play a role. Modest vasodilatation observed with these drugs is more pronounced with chlorthalidone but contribution of this to the long-term BP reduction may not be substantial to change hard clinical endpoints.

Baxdrostat: new drug to treat hypertension

Hypertension is ‘the disease of kidney’, hypothesis that is supported by the fact that one of the most effective antihypertensives exert their effect via kidneys. Here is a welcome addition to the antihypertensive armamentarium —baxdrostat-a highly selective aldosterone synthase inhibitor. Prior efforts to inhibit this key enzyme in aldosterone synthesis were thwarted by concomitant and undesirable inhibition of cortisol synthesis catalyzed by 11 beta-hydroxylase (which share 93% sequence similarity with aldosterone synthase).

In this phase 2 trial-BrigHTN, 248 patients with treatment resistant hypertension were randomized to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo.

Treatment resistant HTN was defined as: stable doses of at least three antihypertensive medications (one of which was a diuretic) and had a mean blood pressure of at least 130/80 mm Hg (the average of three measurements obtained with the use of an automated in-office blood-pressure monitor).

Trial was stopped early as criteria for overwhelming efficacy were met-a substantial decrease in blood pressure was noted with treatment: difference between the 1mg group and the placebo group, −8.1 mm Hg, and difference between the 2mg group and the placebo group, −11.0 mmHg, but the difference between the 0.5mg group and placebo was not significant.

Resistant hypertension is associated with high morbidity and mortality; baxdrostat is a welcome addition to our armamentarium to manage this condition. Some caution is needed before we consider it as a breakthrough. First, office BP measurements (primary endpoint) were used to assess the efficacy-why on the earth a Pharma who is able to pioneer a drug development can’t afford to use gold standard 24-hour ABPM to assess efficacy, when it is already used widely in practice? Second, there unexpectedly large placebo effect (9-10mmHg). The reasons for this may be multiple and given the office BP measurements used white coat effect is possible. For the same reason, patients with pseudo resistant HTN might have got enrolled. Factors like adherence to salt restriction, drug adherence, optimization of other antihypertensives might have decreased blood pressure in placebo arm as well as the drug (Hawthorne effect). More elderly patients got randomized to placebo; did it put control arm at disadvantage? This difference will be more relevant in long term, when CV outcomes of these patients will be compared. Phase 3 trials, involving larger sample size, longer follow up, and hard CV outcomes will clarify the pace of this agent in hypertension treatment.

Rise and fall of the sympathetic denervation in the treatment of hypertension

Last few months are of sympathetic overactivity: RADIANCE HTN TRIO trial, with its longer term (6 month) follow up and follow up efficacy data of SIMPLICITY HTN 3 were published back-to-back in JAMA and Lancet.

In patient on triple drug combination of CCB, ARB and thiazide, additional reduction in the BP after renal denervation was modest at 2 months. 136 patients with resistant HTN were randomized to ultrasound guided renal denervation-uRDN-(n=69) or a sham procedure (n=67). Primary outcome of reduction in daytime ambulatory systolic blood pressure was more with intervention than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0]vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022). This difference persisted at six months as documented in this prespecified follow up analysis; however was diminished as compared to that noted at 2 months: mean daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of -2.4 [16.6]vs -7.0 [16.7]mm Hg from month 2, respectively).

Authors, nonetheless, are happy about fewer medication usages (although this difference wasn’t statistically significant at 6 months), and lesser need of aldosterone antagonists in intervention arm (hardly a reason to celebrate).

Renal denervation trials are classic example of the “big bang effect ” of scientific innovations. SIMPLICITY 1 and SIMPLICITY 2 reported a phenomenal reduction in BP over 30mmHg (for a moment elevating blood pressure of hypertension pharma). This was a massive overestimate, confirmed by SIMPLICITY 3 that addressed the key flaw of not having a sham control group in previous studies. We thought of waving a goodbye to renal denervation after these results.

But authors of the simplicity 3 want us to walk back in time and believe that the large reductions in BP reported by previous studies are supported by their 36 months follow up data of simplicity 3 trial published by lancet. The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). 

There are more than one reasons not believe this tall claim: first, after unmasking at 6 months study didn’t remain a blinded trial and all the patient and physician related biases can cloud the conclusions. As highlighted by the editorial and a letter, Hawthorne effect- change in the behaviour of physicians (better monitoring, frequent reassessments) and patient (better compliance to dietary restrictions and medications) in the intervention arm can explain the apparent difference. Second, despite having uncontrolled hypertension, control arm didn’t receive additional medications to optimize control (did they punish participants refusing to cross over?). Several important questions are raised by this interesting letter as well.

Another confusing feature of this post trial follow up data was the choice of the comparator group, and the way BP measurements were done for this group. After 6 months, a large majority (101 of 171) of the patient crossed over to intervention, however as one might have expected, authors didn’t compare those who received denervation with those who didn’t. Instead, they considered cross over patients (along with those not crossed over) with their BP at 6month considered for final assessment (last observation carried forward). This further adds to difficulty in interpreting the effect of intervention versus placebo and makes assessment of true effect size difficult.

Lost and found theme has created a large number of Bollywood blockbusters, where lost brother or sister is brought back by the director after plot starts getting dull to add life to the story. Producer/director of SIMPLICITY 3 (Medtronic) tries this, but this is hardly enough to bring back this intervention in hypertension practice. There is no easy way to know the contribution of sympathetic over activity in an individual patient with hypertension and if such measures become available, we may be able to better define the role of this treatment. Until then, results of 36 months follow up can be taken with a pinch of NaCl.

Na restriction works to lower BP , may take potassium’s help

BP control doesn’t always need more drugs or interventions like denervation, sometimes smart and simple interventions can yield significant benefits. Two recent studies highlight this point clearly. Salt restriction can prevent age associated increase in blood pressure (age is no more a non-modifiable risk factor), controls BP in those who are already hypertensive and has huge potential to save lives. Salt restriction is the default advice that most hypertensive patients in our clinic receive but it easier said than done. With rapidly changing food environments, adhering to salt restriction is more and more challenging, controlling salt intake in clinical trial can be difficult. These group of investigators from China in their DECIDE-Salt trial played a smart trick.

48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted salt intake (You can fool your taste buds and slow reduction in the salt intake can go unnoticed) versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (–7.1 mmHg, 95% confidence interval (CI) –10.5 to –3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure.

This degree of reduction in BP is clinically relevant and is equivalent to adding one antihypertensive. Fewer cardiovascular events were noted in salt substitute group (hazard ratio (HR) 0.60, 95% CI 0.38–0.96), but this had no effect on mortality (HR 0.84, 95% CI 0.63–1.13). As expected, salt substitute increased biochemical hyperkalemia, but this was not associated with adverse clinical outcomes. Results confirm the findings of a previous large SSaSS trial which evaluated effect of this intervention in hypertensive rural Chinese population with past history of stroke. Greater reduction in BP (than SSaSS trial) is attributed to “better modulation” of diet in collective living setting where residents have limited control over the composition of the food they eat.

Important finding of the study was no effect of ‘progressively restricted salt intake’ strategy, which authors attribute to reliance on facility manager and cooks to deliver this (whom residents could influence), and the possibility that residents might have identified the food with restricted salt (buds used to a very high salt intake) and resorted to usual salt intake. Whatever may be the reason, this highlights the difficulty of implementing salt restriction at community level.

Predominantly men and Chinese population, lack of complete follow up data from one particular site, lack of 24-hour urine collection to ascertain the delivery of the intervention are the notable limitations. However, this study is a welcome and important addition to the efficacy and feasibility of sodium restriction as an intervention in hypertension.

STOPACE trial

Medical reversal -where in an established practice/treatment is proved either useless or, sometimes, harmful when subjected to rigorous testing by an RCT- is a regular occurrence in medicine. One classic example of this in nephrology was targeting higher hemoglobin in dialysis patients. This practice was proved harmful after many years when subjected to rigorous scrutiny by well designed RCTs. Stopping ACEi with advancing CKD may be another. This practice was based on hunch of the physicians and observational data . Even clinical practice guidelines are silent on what to do with RASi in advanced CKD. With no guidance and data, it was left to whims and fancies of treating physicians to decide regarding use of RASi in advanced CKD. We now have better evidence that stopping RASI may not be the right thing to do in advanced CKD.

STOP ACEi trial randomized 411 patients with advanced and progressive CKD (GFR<30ml/min) either to discontinue or to continue therapy with RAS inhibitors. The primary end point was the eGFR at 3 years. The difference in eGFR at 3 years was not different in the two groups (difference, −0.7ml/min; 95% CI, −2.5 to 1.0; P=0.42). Other important outcomes like ESKD, initiation of dialysis and CV events were no different in both groups.

The trial results are important in many aspects. It breaks the strongly held dogma that RASi must be withheld in advanced CKD. The trial enrolled real world advanced CKD: median age- 63 years, median serum creatinine-3.4mg/dl, median GFR-18ml/min, 29% patients had GFR<15ml/min, and 37% were diabetics.

The findings of the trial do not support the practice of STOPPING RASi in advanced CKD to improve kidney function. But what about effect of RASi on CV outcomes in advanced CKD? Well, there are no data in advanced CKD patients. Observational data suggests an association between increased CV events after discontinuing RASi.

With this study, it is prudent to continue RASi in advanced CKD and it’s time to move from “hunch” based medicine to evidence-based medicine!

EMPA-CKD trial

After iron and iodine, a day is not far when Flozins will be added to the list of food fortifications. That might be an exaggeration. But after securing a star status in management of DKD and heart failure, flozins are all set to stamp their authority in management of CKD patients.

EMPA CKD randomized 6609 CKD patients to empagliflozin or placebo. Enrolled patients had an eGFR 20 to 45 ml/min/ 1.73 m², or who had an eGFR of 45 – 90 ml/min/ 1.73 m² with a urinary ACR >200(mg/gm). After median 2 years of follow up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001).

Of the patients enrolled mean age was 63.8 years, non-diabetics were 54% and 35% had eGFR<3oml/min. Serious adverse events were not different in the groups. The patient population is more like what we see in CKD clinics. EMPA CKD trial in addition to DAPA CKD trial defines the role of flozins in CKD. Benefits were not significant in those without albuminuria (was it due to premature termination of the trial?) and in this patient subgroup further evaluation of these agents is needed.

Heterogeneity of response to treatment of hypertensive

One of my patients with CKD is a tailor and his chief complaint in the last clinic visit was his shrinking business in the era of ‘readymade’. Now a days, it is far more convenient to order online or buy readymade trousers from showrooms. I was wearing such a ‘readymade trouser’ in my cousin’s wedding, and everyone was staring at me instead of the newlyweds on the dais. I had just started feeling elated at my youthfulness, when my smarter half (wife) revealed to me that I was appearing a clown. ‘One size fits all’ approach is disastrous whether its clothing or medicine.

Everyone has experienced this phenomenon in our patients with hypertension; some people respond better to some medication than other. In this interesting and intelligently designed study, authors explored this question in a randomized double blind multiple cross over trial.

280 patients (median age 64 yrs, grade 1 hypertension) were randomized: Each participant was scheduled for treatment in random order with 4 different drugs (from 4 different classes): lisinopril, candesartan, hydrochlorothiazide, and amlodipine with repeated treatments for 2 classes. Each treatment period consisted of one week placebo washout, 2 weeks of dose escalation period, and at least 4 weeks of target dose period. 1468 completed treatment periods were evaluated and significant difference in BP responses were observed: Specifically for choices of lisinopril versus HCTZ, lisinopril versus amlodipine, candesartan versus HCTZ and candesartan versus amlodipine. Personalized approach can achieve BP reduction equivalent to half of that expected from single agent in monotherapy, and half of that expected after adding second agent. While some clinical characteristics are often used practically to decide which drug to start with, they are crude at the best. Laragh has proposed individualization based on plasma renin activity and classified drugs acting on renin axis – R drugs (RAS blockers, beta blockers, sympatholytics) or volume axis of hypertension V drugs (duiretics, CCBs, alfa blockers) and proposed to use drug from two difference classes in combination. This study shows that such approach is not only pathophysiologically appropriate but also produce clinically meaningful effect in BP management.

Since that embarrassing incident at my cousin’s marriage, I get all my trousers from my tailor friend, and he is just amazing. Hypertension, makes one of the good cases for personalized medicine-tailoring.