Concept Map- Immune checkpoint inhibitors and AKI- biomarkers

 

As of 2023, this is the most updated bio-markers that have been studied at single centers around the world for AKI associated with ICI therapy. 

References:

Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

AKI in patients with immune check point inhibitors

Biomarkers, Clinical Features and rechallenge for ICI related renal immune related adverse events

Cytokines and immune cell phenotypes in AKI associated with ICI

Differentiating acute interstitial nephritis from ICI from other causes

Concept Map: Endothelin-1 and the Kidney

Emerging concept of use of endothelin antagonists in the field of Nephrology. This concept figure is on data up to May 2023

Figure created using biorender.com and adapted from this review. 

Topic Discussion: Mastocytosis and the Kidney

 

A recent review by us in NDT discusses the kidney involvement in systemic mastocytosis.

Systemic mastocytosis(SM) is a clonal mast cell disorder due to a somatic gain-of-function mutation in the KIT gene resulting in mast cell accumulation in tissues. SM manifests as symptoms related to mast cell mediator release (flushing, pruritus, cramps, diarrhea, bronchospasm, angioedema) and organ damage. Skin involvement is frequent, esp. in indolent SM, red-brown macules and papules, fine telangiectasias, urticate on stroking

Kidney involvement: 1)Paraprotein-related kidney disease like light chain amyloidosis and MIDD, common association between plasma cell dyscrasia and SM 2)Immune-mediated GN like mesangial proliferative GN, membranous GN, and diffuse proliferative GN. Hypothesis- Increased circulating immune complexes and vasodilatory mediators released by mast cells increase glomerular permeability. 3)nephrotoxicity of drugs to treat SM: IFN-alpha, bisphosphonates, tyrosine kinase inhibitors

4)nephro-urolithiasis: increased prevalence in SM. Be careful of mast cell mediator release from treatment used for stones. Avoid radiocontrast agents, use pre-operative steroids, use selective COX-2 inhibitors

5)bladder mast cell infiltration causing interstitial cystitis

Treatment of SM-directed therapy includes agents to control mediator release, and mast cell clone directed therapy, interstitial nephritis is typically treated with glucocorticoids in addition.

Although rare, kidney involvement is increasingly described, either direct or indirect

Topic Discussion: Atypical anti GBM disease

 

We are aware that circulating anti-GBM antibodies are directly pathogenic in anti-GBM disease. However, about 10% of patients with anti-GBM disease do not have circulating anti- GBM antibodies.

Atypical anti-GBM disease is considered when patients have linear IgG deposition along the glomerular basement membrane without anti-GBM antibodies in the circulation.

Atypical anti-GBM disease comprises 8% to 12% of all anti-GBM disease cases. About 2% to 8% of patients with anti-GBM disease have negative serology despite rigorous testing.

Pathogenesis:

(1)different composition of antigen/epitope: a)Antibodies against the NC1 domain of other alpha chains like alpha1, alpha4, or alpha5 chains of type IV collagen or to the NC1 domain of alpha345 hexamers, b)Linear epitopes of the collagenous domain, or C)entactin

(2)different affinity of antibodies: a) high-affinity autoantibodies trapped in the kidneys and present with low titer in circulation, or (b)Autoantibodies could also have a low affinity for the substrate in the assay

(3) different types of antibody: a). the dominance of different IgG subclass such as IgG4 or IgG1 and frequent presence of IgG2, b) presence of IgA or IgM dominance which is not exactly atypical anti-GBM diseases in terms of clinical/pathological presentation

Pathology: (i) Lack diffuse crescentic and necrotizing glomerulonephritis, (ii). Light microscopy heterogenous: mesangial and/or endocapillary proliferative GN, MPGN, FSGS, mesangial sclerosis; and glomerular endothelial changes resembling TMA are common

Monotypic atypical anti-GBM disease: Monotypic Ig deposits along the GBM are increasingly observed to cause a disease pattern similar to atypical anti-GBM. Needs further study to confirm if it is a form of MGRS?

Prognosis: Kidney dysfunction is usually milder and evolves slower than classic anti-GBM disease; however, presentation as RPGN has also been reported. Proteinuria and nephrotic syndrome are more frequent than classic anti-GBM disease.

Treatment: is individualized and typically consists of immunosuppressive agents used to treat classic anti-GBM disease or monotherapy with renin-angiotensin-aldosterone blockers

Check out this review

Topic Discussion: Calcium and Pre-eclampsia- using AI

 I now am re-doing the post on using calcium to prevent pre-eclampsia using artificial intelligence website- https://chat.openai.com/chat 

Prompt: Can calcium prevent PEC?

Response: 

Calcium supplementation has been shown to reduce the risk of pre-eclampsia in pregnant women who have low dietary calcium intake or are at high risk for pre-eclampsia. However, it is important to note that calcium supplementation is not a guaranteed prevention method for pre-eclampsia and should only be taken under the guidance of a healthcare professional.

The World Health Organization (WHO) recommends that pregnant women receive at least 1,500 mg of calcium per day, either through diet or supplementation, to reduce the risk of pre-eclampsia. In cases where dietary calcium intake is insufficient, calcium supplements may be recommended.

It is important to note that pre-eclampsia is a complex condition that can have various causes, and calcium supplementation alone may not prevent it in all cases. Other preventative measures such as maintaining a healthy lifestyle, attending regular prenatal checkups, and managing pre-existing health conditions can also help reduce the risk of pre-eclampsia.

Several studies have investigated the effectiveness of calcium supplementation in preventing pre-eclampsia. Here are some key findings:

1. A Cochrane review of 13 randomized controlled trials involving over 15,000 women found that calcium supplementation reduced the risk of pre-eclampsia by 55% in women with low calcium intake and by 24% in women at high risk for pre-eclampsia.

2. A meta-analysis of 21 trials involving over 23,000 women found that calcium supplementation reduced the risk of pre-eclampsia by 24%, with a greater effect seen in women with low dietary calcium intake.

3. A study published in the British Medical Journal found that calcium supplementation reduced the risk of pre-eclampsia by 66% in women with a history of pre-eclampsia.

Overall, the data suggests that calcium supplementation can be an effective preventative measure against pre-eclampsia, especially in women with low dietary calcium intake or a history of pre-eclampsia. However, it is important to note that calcium supplementation should only be taken under the guidance of a healthcare professional, as excessive calcium intake can have adverse effects.

When I asked to provide references:

Sure, here are some references for the information I provided:

1. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2018;10(10):CD001059. doi:10.1002/14651858.CD001059.pub5

2. Hofmeyr GJ, Manyame S, Medley N, Williams MJ, Kramer MS, Duley L. Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy. Cochrane Database Syst Rev. 2019;10(10):CD011192. doi:10.1002/14651858.CD011192.pub2

3. Villar J, Abdel-Aleem H, Merialdi M, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006;194(3):639-649. doi:10.1016/j.ajog.2005.10.831

4. Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C, Laopaiboon M. Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. Cochrane Database Syst Rev. 2015;(2):CD007079. doi:10.1002/14651858.CD007079.pub3

5. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337(2):69-76. doi:10.1056/NEJM199707103370201

Topic Discussion: Calcium and Pre-eclampsia

Interesting data is emerging that calcium supplementation may help prevent pre-eclampsia(PEC). There are in vitro studies that have demonstrated that calcium has an anti-inflammatory effect and reduces the endothelial activation and dysfunction resulting from trophoblastic debris in pre-eclampsia. This may be mediated through the effect of calcium on the nitric oxide synthetase pathway, and the subsequent increased production of nitric oxide. 

At a population level, there is some evidence that dietary calcium intake and incidence of PEC is inverse. This cochrane based review back in 2017 showed that High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of PEC and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers. The limited evidence on low-dose calcium supplementation suggests a reduction in PEC, hypertension and admission to neonatal high care. 

A recent review in JACC does put calcium in the benefit category for prevention of PEC.

Then came the CAP study published in Lancet. The CAP study was a double-blind RCT, which aimed to assess whether 500 mg of calcium supplementation before pregnancy and in early pregnancy prevents pre-eclampsia in a population group of women at a high-risk for PEC and with a generally low dietary calcium intake. In this study of 1,355 women with a history of PEC, there was no difference in the incidence of PEC between the treatment or placebo group (RR 0.80, 95% CI 0.61–1.06). However, the compliance rates were low (only 50% of the population took at least 80% of the expected tablets), which may limit the validity of these results. Interestingly, in a subgroup analysis of participants with adequate compliance (defined as >80%), the rate of PEC was significantly lower in the calcium group in comparison to the placebo controls (RR 0.66, 95% CI 0.44–0.98). Another limitation of this study was the dosage of calcium used, which at 500 mg appeared to be lower than the doses prescribed in previous trials.

(Image from https://pre-empt.obgyn.ubc.ca/home-page/past-projects/cap/) 

Finally, a more recent meta-analysis published is adding some mixed data. The meta-analysis included 30 trials (N = 20 445 women), and the network meta-analysis to evaluate calcium dosage included 25 trials (N = 15 038). Calcium supplementation prevented PEC similarly with a high dose (RR 0.49, 95% CI 0.36–0.66) or a low dose (RR 0.49, 95% CI 0.36–0.65). By network meta-analysis, high-dose (vs low-dose) calcium did not differ in effect (RR 0.79, 95% CI 0.43–1.40). Calcium was similarly effective regardless of baseline PEC risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake.

The authors conclude that by using direct and indirect trial evidence in meta-analysis and network meta-analysis, calcium supplementation (vs placebo/no therapy) decreases the incidence of PEC, defined traditionally as gestational hypertension and new proteinuria. This effect is similar with high- or low-dose calcium, regardless of baseline PEC risk, timing of calcium initiation. But, the effectiveness of calcium is restricted to populations with low average baseline calcium intake. The small increase (of an absolute 0.2%) in HELLP syndrome with calcium was more than balanced by a reduced incidence of death or severe maternal morbidity (by 1.0%). 

In summary, very fascinating science here and perhaps something that needs a closer look. At this point, based on data, perhaps women with low calcium intake maybe the best that benefit from this preventive strategy. The International Federation of Gynecology and Obstetrics (FIGO), women with low calcium intake (<80 mg/day) calcium replacement (<1 g/day) or supplementation (1.5–2 g/day) is recommended. In populations where baseline dietary calcium intake is low, the World Health Organization recommends for 1500 to 2000 mg elemental calcium supplementation per day for pregnant individuals to reduce the risk of PEC, particularly among those at higher risk of developing hypertension. The WHO recommendation is based on positive results from systematic reviews as discussed above.

Golden Era in therapeutics for IgA Nephropathy

Just in the last 1 year, we have two new drugs being approved for IgA Nephropathy. In addition, we have seen an emergence in using SGLT2i perhaps in IgAN and other GNs. The DAPA-CKD trial IgAN patients were evaluated and the use of dapagliflozin was superior than placebo. The EMPA-Kidney had close to 800 IgAN patients, we shall await those results soon.

MMF has just made a come back with a recent Chinese study showing some promise in a RCT. 

Finally, a targeted release steroid called budesonide has been FDA approved. This was developed to deliver the active drug in the distal ileum, where the Peyer's patches are -- the likely culprit where a large amount of galactose deficient IgA is made. The data was just published in KI.

And finally, the first single molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA) approved for use in patients with IgAN. The data is not published yet in a journal.

There are still ongoing trials of other DEARAs, and complement inhibitors, APRIL inhibitors for IgAN. In my opinion, the future of treatment of IgAN can be perhaps summarized in the below figure: ( created using biorender.com)