Game changers in Nephrology for 2020: Dr. NK Hase
M3 India Newsdesk Jan 13, 2020
Dr. NK Hase picks major trials and updates in Nephrology from the previous year, that will have significant influence on practice and treatment decisions in 2020.
Game changer in Diabetic Kidney Disease: CREDENCE Trial
India is the new 'world capital' of diabetes. Half of these diabetics develop diabetic kidney disease (DKD), which is becoming the most common cause of end-stage kidney disease (ESKD). Cardiovascular events are one of the most common causes of death in diabetes and ESKD. Almost 20 years ago, ACE inhibitors/Angiotensin receptor blockers (ARBs) were compared with placebo and found to retard progression and development of ESKD by nearly 20% mostly independent of hypertensive control.
Since then, there have been numerous interventions in the last two decades, like dual-agent renin-angiotensin system blockers, Bardoxolone, protein kinase C beta inhibitors, antifibrotics and anti-inflammatories that have been tested in DKD without much benefit. The recent data from a large randomised controlled trial (RCT) of SGLT2 inhibitors for the treatment of individuals with relatively preserved kidney function (EMPA-REG outcome, CANVAS and DECLARE TIMI58) have shown cardiovascular protection and suggested potential kidney benefit.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial  results are 'game changers' in diabetic kidney disease. The CREDENCE trial was the first to evaluate SGLT2 inhibitors for efficacy and safety in participants with type 2 diabetes with CKD and albuminuria. It was a double-blind randomised controlled trial in which 4401 patients with type 2 diabetes with eGFR 30 to 90 ml/min per 1.73 m2 of body surface area (mean baseline 56) and severely-elevated albuminuria (urine albumin to creatinine ratio >300 mg/g) received 100 mg of Canagliflozin or placebo added to RAS blockade and baseline diabetic therapy after a 2-week run in period.
Outcome & key findings:
- Canagliflozin reduced the primary outcome of ESKD, serum creatinine doubling, or death from kidney disease or cardiovascular causes by 30%.
- These risks were meaningfully diminished such that the number needed to treat or prevent ESKD, serum creatinine doubling or kidney disease death was 28 and ESKD alone was 43.
- Secondary outcome of three-point MACE and hospitalisation for heart failure were also significantly decreased.
- The progression of diabetic nephropathy was slower in the Canagliflozin group than in the placebo group.
- The Hba1c levels, blood pressure, and weight were reduced more by Canagliflozin than placebo.
- The adverse events- fractures and lower limb amputations were similar in both groups.
- Diabetic ketoacidosis was more frequent in the Canagliflozin group than in the placebo group.
The CREDENCE trial demonstrated remarkable kidney and heart protection in patients with diabetic kidney disease on top of ACE/ARB and standard care.
What is the mechanism of action of SGLT2 inhibitors resulting in renal and cardiovascular protection?
The mechanism of action of SGLT2 inhibitors are both renal and extra-renal. SGLT2 inhibition in the proximal tubule of kidney results in glycosuria leading to the loss of approximately 70 to 80 g of glucose per day and decreases HbA1c by 0.5 to 0.8%.
As a result of glucose loss and net caloric loss SGLT2 inhibitors lead to weight loss of 2 to 3 kg. Along with glycosuria SGLT2 inhibitors also lead to natriuresis resulting in decreased plasma volume, blood pressure, increased haematocrit and restoration of tubule-glomerular feedback.
It is assumed that there is increased SGLT2 expression in type 2 DM resulting in glucose and sodium reabsorption leading to decreased distal delivery of sodium. This results in suppression of tubule-glomerular feedback and afferent arteriolar vasodilatation, increased renal blood and hyperfiltration. SGLT2 inhibitors increase delivery of sodium to macula densa. Sodium reabsorption in macula densa results in adenosine release which binds adenosine receptors in afferent arterioles causing vasoconstriction, and decreased hyperfiltration and intra-glomerular pressure.
Kidney protection is mainly attributed to restoration of tubule-glomerular feedback. Other mechanisms of renal protection include improving renal proximal tubule oxygenation, suppressing anti-inflammatory and antifibrotic pathways, improving endothelial function, decreasing arterial stiffness and improving renal perfusion, due improved cardiac function.
To sum up, SGLT2 inhibitors are potentially ideal anti-diabetic agents- with the least chance of hypoglycaemia, weight and blood pressure reduction, preserved beta cell function, improved insulin sensitivity, decreased albuminuria with additional benefit of cardiac and renal protection. Accumulated evidence of >40,000 patients who have participated in the EMPA-REG outcome, CANVAS, DECLAR TIMI 58 and CREDENCE trails convinces us to use SGLT2 inhibitors in DKD with GFR >30 ml/min/1.73 m2 and albuminuria (ACR >300 mg/g).
The American Diabetes Association in 2019 updated the standard of medical care in diabetes and recommends the use of SGLT2 inhibitors according to inclusion criteria from CREDENCE, to reduce the risk of CKD progression, cardiovascular events or both (CLASS A).
Treating Anaemia in CKD beyond Erythropoietin- Roxadustat (HIF/PHI)
Anaemia is a common feature of CKD. Erythropoetin (EPO) deficiency remains the major cause and introduction of recombinant EPO in 1989 dramatically changed the management and outcome in patients with CKD. Administration of erythropoietin stimulating agent (ESA) and iron has since changed the standard of care. However, our current therapy has significant shortfalls in safety and effectiveness.
The normal haematocrit trial showed, full correction of haematocrit to 42% was associated with a greater risk of mortality from thrombotic events and cardiovascular events. Various trials CREAT, CHOIR and TREAT confirm these events with high-dose ESA and iron to maintain near normal haemoglobin. There was a great need for alternative ESA to EPO which is effective and safe. Roxadustat may fulfil this need.
Roxadustat is an oral hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) that stimulates transcription of EPO gene in the kidney and liver leading to an increased level of endogenous EPO. This is more physiological than replacing endogenous EPO with ESA. Astra Zenica presented detailed results from phase 3 OLYMPUS and ROCKIES trial showing that Roxadustat significantly increased haemoglobin in both patients on dialysis and pre-dialysis CKD patients at ASN Kidney Week 2019.
- N Chen et al.  reported safety and efficacy of Roxadustat in Chinese CKD dialysis patients and patients not on dialysis. 154 patients with CKD not on dialysis having haemoglobin level of 7 to 10 gm/l were randomly assigned in 2:1 ratio to receive Roxadustat or placebo three times per week for 8 weeks in double blind manner. The randomised phase trial was followed by an 18-week open label period in which all patients received Roxadustat. Parenteral iron was withheld. The primary end point was the change in mean from baseline in the haemoglobin level at 8 weeks.
- Similarly 305 patients of CKD undergoing dialysis (204 in Roxadustat group and 101 in epoetin alpha group) underwent randomisation . The oral Roxadustat was more effective than placebo in patients not on dialysis and non-inferior to parenteral epoetin alpha.
As compared to epoetin alpha, Roxadustat increased transferrin levels, maintained serum iron levels and attenuated decrease in transferrin saturation and reduced hepcidin. Roxadustat decreased total cholesterol and LDL levels better than epoetin alpha.
Adverse reactions reported where hyperkalaemia, metabolic acidosis, and upper respiratory tract infection. Prima facie, Roxadustat appears as a novel, oral ESA that may change the way we treat anaemia of CKD. But, word of caution, since HIF pathway regulates or interacts with many biologic processes, there is concern about non-erythropoiesis adverse effects including risk of cancer, thrombosis, cardiovascular disease, progression of CKD, and diabetic retinopathy. Long-term follow up is eagerly awaited.
Proactive IV Iron Therapy in Haemodialysis Patients: PIVOTAL Trial
In patients undergoing haemodialysis, the treatment of choice is erythropoietin. The most common cause of sub-optimal response to erythropoietin (EPO) is iron deficiency. Intravenous administration of iron is the standard of care in the management of anaemia. The most appropriate intravenous iron replacement regime in adults undergoing dialysis is unknown.
The PIVOTAL trial  was a randomised controlled trial consisting of two strategies for iron therapy. A total of 2141 patients underwent randomisation (1093 patients to high-dose group and 1048 to low-dose group). The experimental arm, high-dose group received 400 mg monthly unless the ferritin concentration went over 700 mcg/l or TSAT went over 40%, while the control arm was administered iron sucrose IV in response to low TAST or ferritin <200 mcg/l in reactive fashion.
- The primary outcome was a composite of non-fatal myocardial infarcts, non-fatal stroke, hospitalisation for heart failure or death.
- Secondary end points included death, infection rate and dose of erythropoiesis-stimulating agents.
- The median follow up was 2.1 years.
Proactive use of iron meant that the patient got a lot more iron and high TSAT and ferritin. The study met its non-inferiority primary outcome. It did reveal a number of intriguing secondary outcomes:
- Reduced ESA dose by 19.4%
- Reduced transfusion rate- 21%
- No increase risk of infection or hospitalisation
- Reduced risk of hospitalisation for heart failure
- Reduced risk of recurrent events
Though primary outcome was negative, secondary outcomes showed benefits from more iron. Though more iron is better, monitoring is important to avoid iron overload.
KDIGO guidelines recommend a serum ferritin level of 500 mcg/L and TSAT of >30% to stop iron supplementation in HD patients. The UK-based National Institute of Health and Care Excellence guidelines suggest serum ferritin level should not exceed 800 mcg/L and review of iron overload must be done when ferritin reaches 500 mcg/L. The results of the PIVOTAL trial suggest ferritin of 700 mcg/L is likely to become the upper safety target of serum ferritin in the absence of infection and inflammation.
Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: The UBI Study
One of the important kidney functions is to maintain normal acid-base balance by eliminating non-volatile acids, primarily as ammonium and reabsorbing and generating bicarbonate. Metabolic acidosis is a common complication of CKD. Metabolic acidosis is associated with several serious consequences including risk of CKD progression, skeletal muscle catabolism, insulin resistance, bone demineralisation and increased mortality.
The Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study  was a multicentre, randomised, unblended, pragmatic controlled trial. The study population consisted of CKD stage 3-5 with metabolic acidosis with serum bicarbonate more than 18 and less than 24. A total of 795 individuals enrolled in the UBI study (398 in sodium bicarbonate (SB) and 397 in standard (SC).
- The primary outcome was time to doubling of serum creatinine. All cause mortality and time to renal replacement were secondary endpoints. SB was administered twice daily to achieve target bicarbonate concentration 24 to 28 mmol/lit in the experimental group.
- A total of 87 participants reached the primary end points 62 (17%) in SC and 25 (6.6%) in SB (p<0.001).
- Similarly 71 participants [45(12.3%) in SC and 26(6.9%) in SB (p = 0.0016)] started dialysis, while 37 participants- 25 (6.8%) in SC and 12 (3.1%) in SB, (p=0.004) died.
- There was no significant effect of SB on blood pressure, total weight, or hospitalisation.
This is the largest randomised controlled trial to confirm that the treatment of metabolic acidosis with sodium bicarbonate in patients with CKD stage 3-5 is safe, delay progression of CKD, improve nutritional status and reduce mortality in CKD. This study is likely to make KDIGO guidelines suggesting alkaline therapy sodium bicarbonate in a daily dose of 0.5-1 meq/kg/day to maintain serum bicarbonate concentration in the normal range 23-24 mEq/l from grade 2b to 1b evidence.
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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The writer, Dr. Niwrutti Hase is a Director Clinical Nephrology & Kidney transplant working in Jupiter Hospital, Thane.
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