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.