May 2019

The Nephrology Social Media Collective (NSMC) internship was established in 2015 with the goal of training doctors to effectively harness social media in order to be leaders in medicine. NSMC mentors and interns have contributed to our blog from time to time. This month, NSMC interns Vicki Sandys from Dublin City, Ireland and Charlie Hall from London have written some of the summaries for our blog. Divya Bajpai  has created a beautiful visual abstract and has written a part of the post.

1 Preterm birth and CKD

More than 60% of the fetal nephrogenesis occurs in the third trimester of the pregnancy, and preterm birth leads to low nephron endowment. Low nephron number is associated with hypertension and progressive CKD in later life.

Here is a large, nationwide cohort study involving 4 186 615 singleton live births from Sweden, evaluating relation between preterm birth (gestational age <37 weeks) and risk of CKD from childhood into mid-adulthood. Preterm (<37 weeks) and very preterm(<28 weeks) were significantly associated with development of CKD in childhood and mid-adulthood (adjusted HR for preterm 1.94, 95% CI 1.74 to 2.16; P<0.001; HR for very preterm 3.01, 1.67 to 5.45; P<0.001). Even early term birth (37-38 weeks) carried a similar although lesser risk (1.30, 1.20 to 1.40; P<0.001).

This massive study underscores the importance of preterm birth as a risk factor for CKD, which carries practical significance with regards to management of other risk factors (like nephrotoxins, diabetes, smoking, obesity, UTIs) and counselling prior to acceptance as kidney donors. Birth history becomes the vital information in the evaluation. Thirteen percent of all the newborns in India are preterm (10% in US and 5-6% in Europe). This implies a huge non-modifiable CKD risk.

2 Octreotide LAR in ADPKD

ALADIN trial evaluating use of octreotide LAR in early stage CKD showed that, octreotide LAR use, as compared to placebo, was associated with statistically significant decrease in the rate of total kidney volume (TKV) increase. Difference persisted even at 3 year follow up, however, wasn’t statistically significant.

ALADIN 2, evaluating the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD, in a parallel-group, double blind phase 3 clinical trial, is published in PLOS One.

Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Fewer patients treated with octreotide LAR experienced the composite end point: a doubling of serum creatinine or ESRD (HR 0.127 to 0.742], p = 0.009). A strange observation was no difference in the rate of mGFR by iohexol clearance decline in the two groups. (Why should mGFR by iohexol clearance not be a mandatory measurement in all CKD progression trials?) Is GFR a sensitive and reliable indicator of progression in kidney diseases that predominantly affect tubulointerstitium?

Tubular disruption in ADPKD can cause iohexol accumulation or back-leakage, further compromising accuracy of GFR assessment. Also, tubular disruption may affect creatinine tubular handling. Is it the reason that in ALADIN 2, serum creatinine levels are disproportionately low in patients progressing to ESKD and treatment effect is largely driven by protection against progression to ESKD rather than against serum creatinine doubling over time? This is an issue that needs further investigation, probably in experimental models of the disease (Personal communication, Giuseppe Remuzzi).

3 Drinking water salinity and risk of hypertension

Ground water salinity is found high in some geographic regions (especially the coastal areas where sea water intrusion is common). While high sodium content in drinking water is likely to contribute to increased dietary sodium intake and thus hypertension, it is unclear how high calcium and magnesium content interact, as both have been associated with a salutary effect on blood pressure and CV risk. Exploring this issue, here is a study led by International Centre for Diarrhoeal Disease Research, Bangladesh, evaluating drinking water salinity, urinary macro‐mineral excretions, and BP across three seawater intrusion affected districts in southwest coast of this country.

Compared with fresh water drinkers, mild-salinity water drinkers had lower mean systolic BP (-1.55 [95% CI: -3.22–0.12] mm Hg) and lower mean diastolic BP (-1.26 [95% CI: -2.21–0.32] mm Hg). The adjusted odds ratio among mild-salinity water drinkers for stage 1 hypertension was 0.60 (95% CI: 0.43–0.84) and for stage 2 hypertension was 0.56 (95% CI: 0.46–0.89). Mild-salinity water drinkers had high urinary Ca2+, and Mg2+, and both urinary Ca2+ and Mg2+ were associated with lower BP.

Several limitations should be noted: EC (Electrical conductivity) was used as a surrogate of cation content (and not the actual mineral levels), lack of data on mineral intake through other foods, bias by over or under-collection of 24 hr urinary measurements, and residual confounding by other risk factors for hypertension.

Water hardness and CV risk is an area of debate, although not conclusive, this study is an important addition to the previous epidemiological data showing similar association of higher calcium and magnesium content in the drinking water with better CV risk profiles. With widespread use of drinking water treated by reverse osmosis (this is undertaken as a policy in areas of endemic CKDu in some parts of Maharashtra, India) this definitely merits further research.

4 Exostosin 1/2 in the diagnosis of secondary membranous GN

Visual abstarct by Divya Bajpai  

Discovery of PLA2R as a target antigen in primary Membranous nephropathy was a major breakthrough in the field of biomarkers in nephrology and brought a paradigm shift in the diagnosis and classification of the disease. There is increasing interest in the use of this biomarker in order to obviate the need of kidney biopsy. While PLA2R and THSD7A are identified as target antigens in 70%–80% and 1%–5% cases of primary MN respectively, the antigen for secondary MN was not known until this study in JASN by Sethi et al

They studied 224 cases of biopsy-proven PLA2R negative MN and 102 controls (47 PLA2R positive MN, 13 Proliferative Gn, 42 others) to identify new antigens using laser microdissection and mass spectroscopy. Accumulation of Exostosin 1/Exostosin 2 (EXT1/EXT2) in the GBM was found in 26/224 cases but in none of the controls. 80.7% of these 26 EXT1/EXT2 positive cases had clinical evidence of autoimmune features. The association with autoimmunity was further confirmed in the ‘Validation cohort’ where 8 out of 18 pure class V LN cases were positive for  EXT1/EXT2 while only one of the 14 cases of mixed class LN was positive. Also, 3 out of 16 cases with PLA2R negative primary MN were positive and all had autoimmune features. It is interesting to note that 2 of these EXT1/EXT2 positive patients were initially diagnosed as primary MN but later developed full-blown MN.

Small sample size and failure to demonstrate circulating anti-exostosin antibodies in patients with EXT1/EXT2 associated MN, are the major limitations to note. Absence of antibodies can also mean that exostosin proteins may not actually be target antigens for MN but just a biomarker protein. Can the demonstration of exostosin antibodies diagnose class V LN in patients with appropriate secondary features without a biopsy?

While we need to wait for further studies to answer these questions, this is surely an exciting development in the world MN biomarkers!

5 Pre-Eclampsia and risk of later kidney disease

In a previous meta-analysis, the relative risk of developing ESRD was higher in women with history of pre-eclampsia [Relative risk 4.7, 6.7 and 6.4 for women who had preeclampsia during the 1st, 2nd, and both pregnancies respectively] . Women with a history of pre-eclampsia have an increased risk of microalbuminuria-risk similar to patients with type 1 diabetes mellitus. 

Here is another massive (of course Danish!) nationwide cohort study in the BMJ examining the association between pre-eclampsia and incident postpartum CKD, in 1,072,330 women followed up for average 18.6 years between 1978-2015. Overall, 14,816 women developed kidney disease, higher risk of chronic renal conditions (mainly, hypertensive kidney disease, and glomerular/proteinuric disease.) was noted in women with history of pre-eclampsia: HR 3.93 [95% CI 2.90 to 5.33, for early preterm pre-eclampsia (delivery <34 weeks); 2.81 (2.13 to 3.71) for late preterm pre-eclampsia (delivery 34-36 weeks); 2.27 (2.02 to 2.55) for term pre-eclampsia (delivery ≥37 weeks)]. 

The association of preeclampsia with CKD and glomerular/ proteinuric diseases was much stronger within five years of the latest pregnancy (HR 6.11, and 4.77, respectively). However, even > 5 years after the pregnancy, the risks remained 100% and 50% higher than the risks observed in women with no history of preeclampsia (HR 2.06 and 1.50, respectively).

6 CREDENCE of SGLT 2 inhibitors in nephrology

Presentation of the results of CREDENCE trial was one of the most remarkable events at WCN 2019 for the obvious reason. Dramatic benefits of a pharmacotherapy in CKD came as the much awaited showers after a ‘drought of 18 years (back to back publication of RENAAL and IDNT trials in 2001). We have been criticized as being hypercritical of SGLT2 inhibitors in our previous blog posts and hereby we must congratulate the patients, investigators and sponsors for the successful completion of CREDENCE.

Trial was stopped early due to overwhelming benefit: primary outcome ESRD, doubling of serum creatinine, renal or cardiovascular (CV) death, for canagliflozin vs. placebo, was 43.2 vs. 61.2 per 1,000 patient-years (p = 0.00001). Importantly, there was no increased risk of amputations or fractures. Dramatic benefits indeed!

Two caveats: One, trials terminated early-truncated trials- overestimate the benefit. Overall smaller the number of endpoints, higher the chance of overestimation. Important overestimates occurred with 200 to 500 events (CREDENCE is here); large overestimate for those with events <200 and trials with over 500 events showed small overestimates. Second, the crucial issue of safety. Serious genitourinary infections and lower extremity amputations continue to be reported in the post-marketing data, and so, in real world, vigilance is needed to identify and address these risks.

7 Oral protein supplementation and exercise training on physical function in hemodialysis patients

The effect of exercise on the health of our haemodialysis (HD) patients has been extensively reviewed in the latest Nephmadness playoffs.

Protein malnutrition increases the risk of death in patients on hemodialysis. Oral nutrient supplements during dialysis can offer some benefit, although evidence supporting this treatment is very poor.

Theoretically, protein supplements given during HD may result in increased skeletal muscle amino acid uptake and this effect is potentiated by exercise. IHOPE trial evaluated the effect of 30gm whey protein supplementation with or without intradialytic exercise (30 -45 min cycling) on physical function and the quality of life (QOL) in 120 patients from 5 dialysis clinics is Illinois.

Over the 12 months of study period, primary outcome (change in physical function as assessed by ‘shuttle walk test‘) did not differ between the groups. Improvement in some secondary measures was noted but did not reach statistical significance.

A large number of variables affect wellbeing of dialysis patients and it is very difficult to tease out effects of protein supplementation and exercise in such a small group over a period of one year. Or maybe these interventions are simply not enough to overcome the overwhelming burden of comorbidities that a typical dialysis patient has. Also note the dropout rate of 41% at the end of 12 months in the exercise group indicating the practical difficulties of implementing exercise programmes in these patients.

March-April 2019

1) Plazomicin for complicated UTIs

Given the reputation of being birthplace of some of the superbugs of global concern, India needs to have an ‘antibiotic stewardship’ policy, even better, a law! Crisis is no less urgent than global climate change and melting glaciers. Developing new antibiotics with novel mechanisms of actions is another important although very difficult way out.

Aminoglycosides are effective against many ESBL producing organisms and are often used as an alternative to carbapenems in the treatment of urosepsis. Carbapenem resistance is rising and about 80% of such organisms are also producing ‘amino glycoside modifying enzymes’ limiting our treatment options further. Plazomicin is an aminoglycoside that is engineered to evade modification by aminoglycoside- modifying enzymes, and it maintains activity in the presence of most mechanisms that lead to resistance in Enterobacteriaceae, including mutations in sites targeted by fluoroquinolones and the production of aminoglycoside-modifying enzymes, extended-spectrum β-lactamases, and carbapenemases.

Here is the EPIC study in NEJM reporting efficacy of once daily plazomicin vs meropenem, for complicated urinary tract infections (UTIs): composite cure (clinical cure and microbiologic eradication) at day 5 [88.0% (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (–3.4 95% CI –10.0 to 3.1)], and at the test-of-cure visit-15 to 19 days after initiation of therapy-[81.7% (156 of 191 patients) and 70.1% (138 of 197 patients) respectively (11.6 ; 95% CI, 2.7 to 20.3). 

Plazomicin performed better in UTIs by ESBL producers, aminoglycoside resistant organisms and also had higher microbiological cure rates and lower relase rates: these finding can only be hypothesis generating given the “noninferiority”design of the trial. Renal dysfucntion, as expected, was more common with Plazomicin (11 vs 4 patients). As with all antibiotic therapies, local susceptibility patterns and selection pressures make it important to see data in other geographic areas. 

Welcome Plazomicin! 

2) Genetic basis for CKD in adult

While children with CKD are often evaluated with genetic testing, adults typically are not. You may consider expanding genetic evaluation even in adults after reading this clinical investigation in Kidney International. Whole exome sequencing (WES) was performed in a multi- centre cohort of 114 families including 138 affected individuals with CKD, across nephrology services in Ireland. Pathogenic mutation in known monogenic CKD genes was detected in more than one-third of families. The yield was highest in those with extrarenal features (69%), followed by those with positive family history (36%) and least (15%) in those without either of these. 

Authors hypothesize that later-onset disease is due to allelic heterogeneity, with “milder” phenotypes likely attributable to “milder” missense mutations. 

This exercise is likely to be further more fruitful in populations (like the one we encounter) where aetiology of CKD is uncertain in large majority of young and middle aged adults. Screening for extra renal disease, and potential avoidance of kidney biopsies and donor risk stratification are other proposed advantages of this testing. 

Irish population, higher than usual prevalence of familial CKD and possibility of missing deletion–insertion, copy-number variants, or mutations residing within a promotor or other intronic region (WES doesn’t capture these) are the limitations. Another important issue is the uncerainty about how to deal with the other genetic information that is typically unmasked by WES and this can potentially create anxiety and initiate additional diagnostic workup. Don’t miss this accompanying editorial.

CKDu researcher community can consider incorporating WES along with other evaluations. 

3) Rate of correction of hypernatremia and health outcomes in critically il

Rapid correction of hyponatremia is associated with definite harm. What should be the rate of correction for hypernatremia? We don’t know. “Go-slow- strategy” is extrapolated from the principles of hyponatremia management . Here is a retrospective observational study in CJASN, reporting the association of the rate of hyponatremia correction and outcomes (in hospital mortality and length of hospital stay).

In hospital 30-day mortality in rapid (>0.5 mmol/L per hour) and slower (<0.5 mmol/L per hour) correction rate groups was not significant either in patients with hypernatremia at admission (25% versus 28%; P=0.80) or in patients with hospital acquired hypernatremia (44% vs 40%;P=0.50). There was no difference in aOR of mortality for rapid vs slow correction in either admission (aOR, 1.3; 95% CI, 0.5 to 3.7) or hospital-acquired hypernatremia (aOR, 1.3; 95% CI, 0.8 to 2.3). 

This is now the largest cohort study addressing the issue of rate of hypernatremia correction, and can reassure us to correct dehydration in these patients (there were no cases of cerebral edema in the 78 patients who had serum sodium correction of 12 mmol/L per day). 

Several important limitations should be noted though: inability to identify exact timing of onset of hyponatremia, exclusion of patients with milder hypernatremia limiting generalisability to patients with serum Na 145-155 (>155 was inclusion criteria), lack of information about etiology, types of fluids used for treatment, reliance on ICD coding and patient chart. 30-40% patients were DNR-highlighting the type of patient population that generally develop severe hyponatremia and outcomes here will be principally driven by underlying illness, with hypernatremia being just a marker of its severity. 

4) Contribution of non-HLA incompatibility to kidney allograft survival: genome-wide analysis study 

Why do half of the renal allografts fail by 15 years post transplant? Chronic antibody mediated graft injury underlies many of the graft losses after initial few years, even in HLA matched individuals, highlighting the importance of non HLA alloimmunity. 
In this prospective genome wide association study involving 477 pairs of deceased donors and recipients, genome wide mismatches in non-synonymous single nucleotide polymorphism (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. In 25 patients with biopsy-confirmed chronic antibody-mediated rejection, customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes. 
The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch. Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17–2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). 

In the absence of effective therapy, chronic ABMR is almost the point of no return for recipients. Whether immunological risk stratification using non HLA mismatches help prevent this process will be interesting to see. 

5) Low dose daily versus alternate day prednisolone in frequently relapsing nephrotic syndrome

Initial strategy for children with frequently relapsing nephrotic syndrome is to use long term alternate day prednisolone. However, many children do relapse on this regimen.

In a single-centre open-label randomised controlled trial, Yadav et al tested efficacy and safety of 12-month therapy with prednisolone administered daily low-dose versus on alternate days (standard therapy) in 61 patients with FRNS.

Children receiving daily prednisolone had significantly fewer relapses than those on alternate day therapy (0.55 relapses/person-year VS 1.94). Daily therapy was associated with higher rates of sustained remission at six months and lower rates of treatment failure (defined as frequent relapses, steroid toxicity or infections) at six months and one year. The cumulative prednisolone dose was similar in both the groups. Adverse effects were not different in the two groups.
If an adequately powered study confirms this observation, it will strengthen the KDIGO suggestion of using daily prednisolone at the lowest dose where alternate day prednisolone therapy is not effective. 

6) SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease

Fellows preparing for their final theory exam, here is a theory long question stuff for you: “Unmet need of Renoprotection addressed by newer antidiabetic drugs”. EUropean REnal and CArdiovascular Medicine (EURECA-m) and Diabesity workgroup of ERA-EDTA summarise the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists. You will have to squint to find the limitations of the trials though (reviewed in depth here and here by us before).

Here is a quote from this review: “Although EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 were not studies with primary renal endpoints, an objective (!) reader cannot overlook that a 40–50% reduction in the composite outcome is much larger than relevant reductions in seminal trials in DKD.” Curiously missing mentions about FDA warnings- DKA, foot amputations, genital infections, fractures. Everyone is smitten with SGLT2 inhibitors! 
Let’s wait for CREDENCE.

7) Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD

Alternative RRT techniques like HDF are looked upon as a hope to improve the dismal long term survival of dialysis patients. RCTs do not show clear survival benefit, however, jury isn’t out yet and HDF is increasingly used (18% of ESRD cases in Europe) for many of its possible benefits.

There is little data on efficacy of HDF in children and this observational study is a important first step. In this prospective cohort study of 190 children from 28 centers, Shroff et al noted that the children on HDF grew better: annualized change in height SD score remained static in HD, but showed a small but statistically significant increase in HDF (Δ=20.16; P=0.02), so that patients on HDF were taller than patients on HD at 12 months (P=0.04).

Carotid intima media thickness (cIMT) is a non-invasive surrogate marker for atherosclerotic changes in the artery. HDF group fared better in terms of cMIT SD score. At 1-year follow-up, the cIMT SD score increased by median 0.41 in the HD group and decreased by 0.07 in the HDF group (P=0.02).

Patient-reported outcomes like post-dialysis recovery time, headaches, dizziness, and cramps favoured HDF group. There was no difference in sleep disturbances, pruritus, or restless leg syndrome between groups. If transplant isn’t an option, children are expected to have maximum dialysis vintage, so may benefit by alternative dialysis therapies. Lets hope to see more data from randomised controlled trials.


January 2019

1 Diuretic use in incident ESRD

Hospitalizations in patients initiated on dialysis are common-especially in the first year- and are associated increased risk of death. What if a drug can address this burning issue?

According to this retrospective, database analysis of a large dialysis organization, the continuation of loop diuretics after hemodialysis initiation was associated with lower rates of hospitalization (adjusted incidence rate ratio, 0.93; 95% CI 0.89 to 0.98) and intradialytic hypotension (adjusted incidence rate ratio, 0.95; 95% CI 0.92 to 0.99) as well as lower interdialytic weight gain (P=0.03). No difference in the 1 yr mortality was observed (adjusted hazard ratio, 0.92; 95% CI, 0.84 to 1.01)! Oh dear confidence interval, couldn’t you limit yourself to <1 here, like you did it for hospitalizations and hypotension? You just prevented a breakthrough in dialysis medicine that kidney doctors are longing for!

Confounding by indication (which can still exist even after sophisticated analysis you do for adjusting) is the major issue with data like this, where patients who are more likely to receive drug (diuretic here) are also the ones who are less likely to experience the adverse outcome that one plans to evaluate (hospitalizations, hypotension, and interdialytic weight gain) because they are inherently different. Why upon the earth one would put someone on diuretic when the last hyperfiltrating nephron has stopped making urine?

It won’t be a surprise if another such large database analysis shows the mortality benefit of diuretic; based upon the results, we need not start or stop prescribing diuretics to HD starters. One ml by the kidney is worth liters by machine!

 

2 Total versus subtotal parathyroidectomy for secondary hyperparathyroidism

Compared with parathyroidectomy (PTX) for primary hyperparathyroidism, the mortality and morbidity rates are higher in secondary hyperparathyroidism. Reviewed here by us before.

In a retrospective study of 824 patients in the Swedish Renal Registry, the outcome of the cardiovascular event (a composite outcome of acute myocardial infarction, transitory ischaemic attack, ischaemic or hemorrhagic stroke, ruptured aortic aneurysm, and acute limb ischemia) was a lower after subtotal parathyroidectomy (436 patients) compared with total parathyroidectomy (388 patients): adjusted HR of 0.43 (95% CI 0.25–0.72). The 90-day mortality was 2% both after subtotal parathyroidectomy and total parathyroidectomy.

The risk of re-PTX was higher after subtotal PTX compared with total PTX, with an adjusted HR (95 % CI) of 3.33 (1.33–8.32). There were no differences in the adjusted risk of hip fracture.

The paper does not describe the indications for which total v/s subtotal parathyroidectomy was done. We could assume that all these patients were refractory to medical management and the decision of subtotal v/s total PTX was based on the clinical or biochemical severity. Confounding by indication is the elephant in the room here. Clinical practices and surgical expertise vary widely making it difficult to extrapolate these results to day-to-day practice.

The only thing we know for sure in CKD-MBD literature is that we don’t know enough about CKD-MBD. While we can go on finding the optimum PTH target, the lower PTH level achieved by parathyroidectomy does not appear to help reduce cardiovascular mortality.


3 Zoledronic Acid to Prevent Bone Loss in the First Year after Kidney Transplantation

If you are one of those whose prescription of the post KTR patient is incomplete without a bisphosphonate, then here is a news for you. In an open-label, a single center trial evaluating the safety (risk of adynamic bone disease) and efficacy of zoledronic acid (effect on bone histomorphometry, DXA, HR-pQCT-this stands for high resolution peripheral quantitative CT, and bone biochemical measures like sclerostin, bone-specific ALP, tartarate resistant ALP -quite a list!). This probably will be the first RCT in this area and also first in CKD-MBD actually using bone biopsy.

Zoledronate didn’t increase the risk of ABD, and KTR itself decreased the bone turnover questioning the routine use of bisphosphonates in the contemporary immunosuppression era where steroids aren’t used in high doses and calcium+vitamin D use is a routine.

The study is limited by the small sample size and short follow up. Whether the promising effect of zoledronate on some surrogate bone markers and BMD at the peripheral skeleton (like radius, tibia where fractures after KTR are more likely than central skeleton) will become relevant after longer follow up remains to be seen.

If one is seriously considering bisphosphonate in KTR recipient with high fracture risk, zolendronate obviously scores over others in terms of cost and compliance.

4 APOL1 in non-African Americans

APOL1 risk allele is implicated in a higher prevalence of HTN, CKD, faster GFR decline and earlier onset ESRD among African-Americans. According to this NEJM letter reporting global frequencies of APOL1 risk variants among 111 populations in two large studies [the Population Architecture using Genomics and Epidemiology Study (https://pagestudy.org) and the Consortium on Asthma among African-ancestry Populations in the Americas (www.caapa-project .org)], this risk may not be restricted to the African -Americans as traditionally believed.

Authors found other populations with elevated frequencies, including Jamaican, Barbadian, Grenadian, and Brazilian from Salvador (>10 to 22%); Trinidadian, Panamanian, Honduran, Haitian, Garifunan, and Palenque (>5 to 10%); and Guyanese, Dominican, Peruvian, Belizean, and Native American (1 to 5%). These findings show that the risk alleles are present in populations of persons who are not typically screened, which may result in the underdiagnosis and undertreatment of kidney disease and related coexisting conditions.

5 Tweaking Nephrogenesis to Boost Nephron Number

What can be offered to patients with such elevated risk of kidney disease apart from a genetic diagnosis? This ‘Clinical Implications of Basic Research’ series article  “Tackling Tsc1 to Promote Nephrogenesis” (I just love their graphic!), discusses exciting findings of basic research by Volovelsky et al.

Nephron number at birth is variable (200,000 to more than 2.5 million per kidney) and ‘lower nephron endowment’ is believed to be a nonmodifiable risk. 14 different cell types at ‘ureteric bud-mesenchymal niche interface’ regulated by various genes and growth factors make modulating the complex process of nephrogenesis difficult. Volovelsky et al in an interesting experiment in mice showed that it’s not impossible though.

They noted that deletion of both copies of Tsc gene  (Tsc1 encodes for a protein hemartin which prolonged nephrogenesis in vitro), led to a lethal phenotype with markedly aberrant kidneys while deleting only one Tsc1 allele, they observed slightly prolonged nephrogenesis, which involved an increase in nephron progenitor cells within the niche and resulted in an increase of 25% in nephron endowment. Hamartin (and its downstream effectors) is a candidate target for experimental approaches to protecting at-risk infants and perhaps to treat- ing kidney disease in children and adults. Bravo! Waiting to see more.

 

6 SGLT2 inhibition repairs pumps, pipes, and filter! 

Ibsen’s play An Enemy of the People was elegantly transported to India in his last movie Ganshatru (although not among the best of Satyajit Ray.) The film depicts Dr. Ashoke Gupta (Soumitra Chatterji) as an idealistic doctor working in a town near Calcutta who discovers that the water at a popular temple is the source of an outbreak of typhoid and hepatitis. In order to save lives, he risks his career by voicing the issue. His efforts are thwarted by a local group of building contractors. Here is an adaptation of Ganshatru for our readers:

The city engineer Intmed was in charge of the water supply and drainage. He was the master of his job and citizens were happy with his services. Occasionally, he used to call plumbing agency Corona, pumping company Cardio, and filter supplier Kidnee. Water was clean, citizens responsible, everything going fine. 

For some strange reason, the city got afflicted with a curious habit: the habit of flushing greasy food into the drain water leading to blockade of the pipes and repeated breakdowns. Intmed warned citizens of this potential problem but his words fell on the dumb ears. Services of plumber Corona and pump Cardio were needed with increasing frequency, which led them to separate from Intmed’s City Engineering department and formation of separate agencies of their own-now no more in control of Intmed. Sometimes chronic stagnation of the contaminated water also started affecting filtration and clogging of filters was reported. Albus was a protein that used to start leaking as filters started getting damaged. Interruption of water supply due to filter clogging was actually a rare event, however as soon as Albus appeared in the water (filter suppliers educated citizens to check Albus in the water regularly to detect filter clogging early, however, neither citizens, not agencies were aware of how best to treat the clogged filters and which filters will ultimately need to be replaced). Intmed questioned this strategy of Albus testing and its relation with actual filter clogging but by now everyone including regulators had accepted Albus testing as a valid method to predict filter failures. 

With a close watch on disruption in the city, 3 industrialist Jansyn, Astrazi, and Boingel claimed that they can address this burning issue without routinely requiring plumbing, pumping and filter agencies. They invented a bullet- Flozina that required to be fired into the water at the supply and claimed to address pipe blockades, pump failures, and clogged filters all at once-last one being most effectively addressed.

To convince authorities, they just needed to show that Albus level in the water has gone down and the flow rates past the filters are marginally better. Whether this would actually translate into prevention of filter failures is yet to be proven however this news that a bullet can save the city became viral after getting publicity in the leading newspapers Fancet, LEJM and others. Volumes are already been written (find the latest here) and many more are in making-praising the role of Flozina in restoring city’s messed up water supply system to order. Will Flozina be effective and safe? Will plumbers, and filter agencies go out of the job? Stay tuned for more to come.