1. Effect of intensive glucose control on renal and patient survival
In this Cochrane review of 11 RCTs involving 29141 diabetics, intensive control of sugars (HbA1c < 7% or FBS <120) made little or no difference in the renal and patient survival endpoints: doubling of serum creatinine, ESRD or death as compared to the usual control (HbA1c >7 or FBS >120). Intensive control was shown to improve some surrogate endpoints like albuminuria or non-fatal myocardial infarction. Findings were consistent in various subgroups and sensitivity analyses. Similar findings were also noted in a 2012 meta-analysis.
Some of my physician friends were disappointed by this ‘negative study’-a term I fail to understand, when, in fact, such studies further our understanding and thereby improve care. These results, therefore, should be considered as an important ‘positive’ input to guide care.
Moderate heterogeneity, underrepresentation of type 1 diabetes and fewer clinically important events like doubling of creatinine could have led to the less precise effect estimates. However, RCT on this issue, addressing these limitations, seems to be a fantasy, and this data is an important addition to the evidence guiding glucose control. While benefits of intensive control remain controversial, such attempts are associated with definite harm (often underreported)-hypoglycemia-which is the most common endocrine emergency associated with morbidly and mortality. While I was discussing these results with my endocrine colleagues, they say, they will continue to practice ‘good (and never practiced ‘intensive’) control’ which means individualizing targets, HbA1c between 7-8 and as close to 7 as possible without risking hypoglycemia.
2. ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes (AdDIT trial)
443 type 1 diabetics with UACR values in the upper third of the albumin-to-creatinine ratios (below <30 mg/gm) were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design, to evaluate its effects on change in the urine albumin/ creatinine ratio (primary outcome), and development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk assessed by carotid intima-media thickness, hsCRP, ADMA (secondary outcomes). It was a commendable job to successfully maintain this population in the trial. While the value of albuminuria as a sign of nephropathy is much more certain in type 1 than type 2 diabetes, authors proposed that even below the traditional thresholds of 30 mg/gm, rise in albumin excretion implies heightened risk based on their previous experience of Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) group.
Treatment of risk factor to prevent disease is called as primordial prevention; what do we call it when we treat risk markers? I don’t know, but, here is what authors of this study found: while statin did their job (of lowering lipids) ACE inhibitors didn’t perform as expected-there was no change in albuminuria assessed every 6 months over 2 to 4 years, and expressed as the area under the curve. Such attempts in type 2 diabetics were successful in achieving surrogate endpoint of reducing albuminuria but were associated with harm. In AdDIT trial, therapy was tolerated well and authors are hopeful that they might expect some ‘legacy effect’ of these interventions in future.
Hope, yes, that’s what keeps us going—to the next research article.
3. Multitarget therapy for maintenance treatment of lupus nephritis
This open-label, multicenter study for 18 months (as an extension of the prior induction therapy trial) in 19 renal centers in China aimed to assess the efficacy and safety of multitarget (MT) maintenance therapy in patients who had responded at 24 weeks during the induction phase. Multitarget (doesn’t that sound opposite of precision?) maintenance therapy with Tac+MMF+Predni compared with AZA+Predni was associated with similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74). Serum creatinine levels and eGFR remained stable in both the groups. Authors conclude that MT therapy is an effective and safe maintenance treatment for patients with lupus nephritis. Significant dropout, the inclusion of patient only in remission (complete or partial), all Chinese participants , surrogate endpoint (proteinuria) which can be easily altered by CNI by their nonimmune effects producing ‘pseudo-remission’ and limited follow up are important concerns that make me wait to see safety and efficacy of MT strategy to be replicated in some more trials.
Another interesting finding of the study is almost similar response rate in the ‘cyclophosphamide–>AZA’ arm at 1.5 yrs indicating the fact that some patients will remain proteinuric at the end of induction treatment and they continued to respond slowly to match those treated with MT therapy. The distinction of induction and maintenance here may, therefore, be not very relevant.
4. UK/UK+UNa as an indicator of hypovolemia in nephrotic syndrome
‘Overfill’ or ‘underfill’? Don’t worry fellows, this question about the genesis of edema bothers you only until you start actually treating nephrotic edema, where it’s ‘underfill’ if diuretics produce azotemia and overfill if they work. In those ‘difficult nephrotics,’ we often resort to albumin+frusemide infusion especially if they already have elevated BUN and creatinine.
Here is an interesting report, telling us how to identify these patients who will be benefited by the use albumin ( costly and not always the safe option). They studied UK/UK+UNa as an indicator of hypovolemia (and therefore elevated aldosterone) in a prospective study involving 44 children and 36 controls. Subjects were grouped into low, normal, and high GFR [assessed by continuous inulin and para-aminohippurate (PAH) perfusion]. In the low GFR group, significantly lower renal plasma flow (p = 0.01), filtration fraction (p = 0.01), and higher UK/UK+UNa (p = 0.03) ratio were noted. Authors conclude that a urinary potassium to potassium plus sodium ratio > 0.5–0.6 identifies patients with nephrotic syndrome who are hypovolemic suggesting benefit of albumin infusion in this subgroup.
Although small, this study involved detailed and objective assessment of GFR, renal plasma flow, and vasoactive hormone and I’m eager to check how this simple urine lytes measurement works at the bedside.
5. Levamisole in Children with Frequently Relapsing Nephrotic Syndrome
Levamisole (Dicaris) is less toxic and relatively inexpensive alternative steroid-sparing agent commonly used in childhood in nephrotic syndrome. While its use is common, evidence supporting its use till date was weak at the best. Here is an RCT that now seems to bridge this evidence gap. In an international (significant contribution from India), multicenter, placebo-controlled, double-blind, randomized clinical trial, Gruppen et al randomized 99 children with frequently relapsing nephrotic syndrome with or without steroid dependence to receive levamisole or placebo after inducing remission with prednisone. Time to first relapse (primary endpoint) was not different between the two groups in first 100 days; however, later, levamisole group had lower hazard for developing a relapse needing prednisone. Fewer children had relapse requiring prednisone over 1 year in levamisole group compared to the placebo group. More children in the levamisole group had adverse reactions (mainly neutropenia in 16%).
One child developed arthritis and antineutrophil cytoplasmic antibodies. Disseminated vasculitis has been described with levamisole use for nephrotic syndrome. Recently, there have been several reports describing ANCA positive vasculitis in association with the use of cocaine contaminated with levamisole. A close follow-up is warranted if levamisole is used for a prolonged period.
6. Global Kidney Health and Country-specific CKD characteristics
Articles starting with ‘global kidney health’ scares me as this generally means in brief: ‘CKD epidemic’, ‘population screening’, ‘cohesive plans’, ‘implementation of this integrated comprehensive plan’ and stuff like that with minor differences of the details. This Lancet article is a report from ‘CKD summit’ of more than 85 experts around the globe, convened by the International Society of Nephrology, aimed to identify and prioritize key activities for the next 5–10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on 10 themes …..(interested ones can refer to the article). Identifying CKD as ‘one disease’ is something like diagnosing someone with serious abdominal pathology as ‘chronic abdomen’, and reflects the fact that we as a specialty are probably farthest from the talk of the town -precision medicine’.
One of the 10 themes that caught my attention was “Reduce acute kidney injury—a special risk factor for CKD”. While there is no doubt that CKD is one of the most important risk factors for AKI, and AKI episodes can hasten CKD progression, considering AKI as a risk factor for de-novo CKD (barring specific scenarios like HUS, cortical necrosis, allogeneic BMT) that too of public health significance is too simplistic understanding of CKDu.
Here is a BMJ article reporting population-based data in six countries assessing if attributes of persons with CKD differ in low-income and middle-income countries compared with high-income countries. In the USA, urban India and Moldova, 79.0%–83.9%; in China and Nepal, 62.4%–66.7% and in Nigeria, 51.6% persons with CKD fit
one of three established risk profiles (Profile 1-Diabetes, Profile 2 CVD, Profile 3 Obesity, HTN, low HDL, high TG, and Profile 4 CKD without established risk factors). So except, Nigeria, authors propose, that most other countries should be focussing on traditional risk factors for prevention of CKD. The study also highlights the need to further evaluate CKD without established risk factors in low-income and middle-income countries.
Data from India comes from two of its largest metros -Delhi and Chennai, and therefore I suspect that Profile 4 CKD might be underrepresented. Also in 3/6 countries, for the purpose of assessment, the healthy general population was invited to the center-something like a health camp where people with a known medical condition are more likely to turn up-and, therefore, might not represent actual population characteristics.
CKDu is big and it’s good that we are admitting it as an issue, better late than never.
7. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock
Patients who have a multivessel disease and present with cardiogenic shock after acute myocardial infarction, it is unclear if PCI of all the stenotic lesions found there works better in comparison to the PCI of culprit lesion alone. In an open-label, multicentre RCT, Thiele et al randomly assigned 706 such patients to one of two initial revascularization strategies: either PCI of the culprit lesion only-with the option of staged revascularization of nonculprit lesions or immediate multivessel PCI. The primary endpoint (a composite of death or severe renal failure leading to renal-replacement therapy) occurred in fewer patients in the PCI of the culprit lesion only group (45.9% vs 55.4%; relative risk, 0.83; 95% confidence interval, 0.71 to 0.96; P=0.01). This was mainly driven by the number of deaths in multivessel PCI group; the number of episodes of AKI requiring renal replacement therapy was similar (11.6% in culprit vessel PCI group and 16.4% in multivessel PCI group; relative risk, 0.71; 95% CI, 0.49 to 1.03; P = 0.07). About one-third of the patients in either group received renal replacement therapy for uremia, defined as blood urea >50 mg/dl. The article does not mention the number of less severe episodes of AKI that are known to be associated with mortality.
Authors, strangely, attribute poor outcome in multivessel PCI group to “contrast cardiomyopathy” (if not the kidney, contrast can be of consequence to the heart!)-higher dose of contrast material that was used in the multivessel PCI group may have led to acute left ventricular volume overload and a subsequent negative effect on myocardial function and recovery. However, more logical explanation of these findings may be the prolonged duration of the multivessel PCI procedure (classical wisdom says not to treat chronic total occlusion in nonculprit vessels in this setting) may be hazardous at a time when the patient is hemodynamically compromised.
8. Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment
There is limited data on the safety of sofosbuvir-based DAA regimens in patients with CKD-this drug is almost entirely cleared renally and there is a concern of acute GFR decline during the therapy. Here is a multicenter, open-label, single-group (without a control group), phase 3 trial published in NEJM, Gane et al studied 104 patients with HCV infection and advanced CKD (stage 4 or 5), 82% on hemodialysis. They could have any genotype of HCV. Combination of glecaprevir and pibrentasvir was given for 12 weeks. Twelve weeks after the end of this treatment, sustained virologic response (SVR) was seen in 98% of the patients (102 of 104 patients; 95% confidence interval, 95 to 100). PK studies showed no significant clearance of these drugs during dialysis. Pruritus, fatigue, and nausea were the common adverse events. None of the 24 serious adverse events occurring during the study period were considered to be drug-related. So here we have a pan-genomic therapy that can be used safely in our patients with advanced CKD and on dialysis. Looking forward to having this drug combo available and accessible for our patients most of whom pay out of pocket for their treatment.
|Interferon-free regimens for patients with eGFR < 30 ml/min per 1.73 m2|
|Genotype 1||Elbasvir- grazoprevir ± ribavirin
Ombitasvir- paritaprevir- ritonavir plus dasabuvir ± ribavirin
|Genotype 2||Glecaprevir- pibrentasvir|
|Genotype 3||Glecaprevir- pibrentasvir|
|Genotype 4||Elbasvir- grazoprevir ± ribavirin
Ombitasvir- paritaprevir- ritonavir