Nephro- hospitalists?- should we consider this

Not much has been written regarding the role of a nephro-hospitalists in the Nephrology literature. There is one perspective back in 2019, before the pandemic that discusses the evolution of nephrology as a medical specialty and addresses the challenges it faces, particularly the declining interest among medical trainees in pursuing careers in nephrology. The authors emphasize the importance of adapting to these challenges and propose a solution in the form of a nephrology hospitalist model.

The field of nephrology has evolved significantly from its early focus on kidney physiology to becoming an independent clinical specialty, particularly with the introduction of dialysis in the 1960s. While patient care was initially delivered primarily in hospitals, the growing population of individuals with kidney disease led to a shift in care to outpatient settings, with a recent emphasis on subspecialized training in transplantation, interventional, and critical care nephrology.

The decline in interest among medical trainees in nephrology careers is attributed to various factors, including a lack of mentorship, the complexity of kidney physiology, busy workloads, perceived lower compensation, and a perceived lack of innovation in therapies and dialysis.

To address these challenges, the authors introduce the concept of a nephro-hospitalist model, exemplified by the experience at Washington University in St. Louis. The model involves a dedicated nephrology hospitalist service comprising attending physicians focusing on inpatient care and medical education. Medical students and rotating internal medicine residents are preferentially placed on this service, and the model includes a flexible schedule of alternating periods of service.

The benefits of this model include improved teaching and mentorship for trainees, increased elective time for fellows, and the opportunity for attending physicians to foster specific interests. The authors highlight the positive impact on education and mentorship, which is crucial for attracting trainees to nephrology.

However, the authors also acknowledge the downsides to the model, including the need for an every-other-month schedule to prevent burnout and potential limitations in attracting new trainees. Financially, the model is described as roughly break-even, and the authors note that financial considerations should be weighed against the educational benefits.

The paper discusses other institutions that have adopted similar models with varying success and mentions the potential role of nephrology hospitalists in private practices, particularly to mitigate issues related to "windshield time" and electronic health record systems.

What have other fields done

Check out this regarding the role of onco-hospitalists and cancer hospitals.
Other fields such as GI and Neurology as well have adopted this model. 

It is possible that a full-time hospital-based nephrology model can be a valuable addition to nephrology education, providing increased attending contact and mentorship for residents and medical students. We should consider further exploration of innovative models to expose trainees to the unique aspects and satisfactions of nephrology, ultimately aiming to address workforce challenges and recruit future nephrologists.

CMML and the Kidney

 

This figure summarizes the various glomerular, reno-vascular and tubulointerstital disorders seen with Chronic Myelomonocytic leukelmia ( recent review in Kidney Medicine by us)

Detective Nephron: Next Venture

 

Here is the next venture with a new cast- Graft Guardian

Topic Discussion: Hyponatremia with Spironolactone

Hyponatremia from MRAs is a rare phenomenon but we have encountered it clinically. There are times, when we check labs after starting spironolactone for HTN, 3-4 weeks later, the Potassium is slightly up and the Na comes back 130 or 131 mmol/L.  What is the data and the mechanism for hyponatremia following spironolactone use? Is this even related.

In an abstract presented at AHA few years ago, small amount of patients were noted in an EHR to have hyponatremia following starting of spironolactone but most were following on after being started on a thiazide.

In another paper, high doses of furosemide and spironolactone, or concomitant use of these diuretics, seem to be an important cause of hyponatremia in HF patients, particularly in combination with advanced age, diabetes, and alcohol consumption. Diuretic dose reduction may help avoid hyponatremia and improve clinical status and prognosis in such patients.

Is it possible that a combination of a thiazide and a K⁺-sparing diuretic such as amiloride and spironolactone can increase the risk of hyponatremia because of the enhanced urinary loss of sodium in the cortical distal tubule? Perhaps not the main mechanism.

What about the concept of vasopressin escape? During hyponatremia, the body limits the degree to which serum sodium concentration falls through a mechanism called "vasopressin escape". Vasopressin escape is a process that prevents the continuous decrease in serum sodium concentration even under conditions of sustained high plasma vasopressin levels. In a recent basic science study, the abilities of aldosterone synthase (Cyp11b2) knockout and wild-type mice to escape from vasopressin were compared. Wild-type mice escaped while the aldosterone synthase knockout mice did not. Both the water channel aquaporin 2 (AQP2) and the urea transporter UT-A1 protein abundances were higher in aldosterone synthase knockout than in wild-type mice at the end of the escape period. Vasopressin escape was also blunted in rats given spironolactone, a mineralocorticoid receptor blocker. The authors results indicate that aldosterone regulates vasopressin escape through calcineurin-mediated protein changes in UT-A1 and AQP2.

    So is it possible that we are blunting the natural vasopressin escape when we combine thiazides with MRAs? Do all MRAs do this?- this is still unclear. Hyponatremia related to MRAs is an understudied area worth exploring.

Concept Map: AKI in ECMO

 

Concept Map of pathophysiology related to AKI in a patient on ECMO- created by Dr. Purva Sharma using biorender.com 

Consult Rounds: BK in non renal solid organ transplantation

What is the incidence of BK viremia, and BK Nephropathy in non renal solid organ transplants?

Not much that I could find in the literature.

In this retrospective study from 2021, the authors investigated the clinical characteristics, pathological findings, and outcomes of BK viremia and nephropathy in non-renal solid organ transplant patients (NRSOT) who sought nephrology consultation over a five-year period. Among liver, heart, and lung transplant recipients referred to Nephrology, 14% were diagnosed with BK viremia, with a median peak serum BK viral load of 35,500 copies/ml (ranging from 250 to 21,100,000 copies/ml). Notably, BK viremia resolved in six out of seventeen patients (35%), but four out of five biopsied patients exhibited BK virus (BKV) nephropathy. Furthermore, eleven out of the seventeen patients with BK viremia progressed to advanced stages (stage 4 or 5) of chronic kidney disease. Additionally, four patients experienced rejection of their solid organ transplant within the first year following the detection of BK viremia after reducing immunosuppressive treatments. This may be a sign of just net immunosuppression.

Another study back in 2019 had looked at literature systematically on report of BK disease in native kidneys. In their review at that time, in heart transplant recipients, 13 cases of BKV nephropathy had been reported, with most occurring in males (10 out of 13), and the mean age being 36.6 years. In lung transplant patients, six cases of BKV nephropathy were identified, with a mean diagnosis age of 47.3 years. Only one case of BKV nephropathy was reported in a liver transplant recipient, and one in a pancreas transplant recipient. More have been reported since their report. The average time from transplant to BKV nephropathy diagnosis in the solid organ transplant population was 2.88 years. For patients who had undergone hematopoietic cell transplantation (HSCT), 19 cases of BKV nephropathy were found, with a mean diagnosis age of 30.6 years. In cases with demographic information, 58% were males, and half of these patients required renal replacement therapy, with a mortality rate of 63.2%. Ten cases of BKV nephropathy were reported in the context of hematologic malignancies, with an average time from malignancy diagnosis to BKV nephropathy diagnosis of 3.06 years. Ten cases of BKV nephropathy were reported in HIV-infected patients, all in males, with a mean age of 34.5 years. Three of these patients required renal replacement therapy, and mortality at the time of publication was 30%. Additionally, individual cases of BKV nephropathy were described in various other clinical settings, such as rheumatoid arthritis, Hyper IgM immunodeficiency syndrome, pulmonary tuberculosis, diabetes mellitus, prostate cancer, and an immunocompromised patient with an unclear medical history. This is fascinating to note that this entity has been ignored in the recent non renal transplant literature. 

In a meta-analysis evaluating the frequency and risk factors for BK viruria and viremia in NRSOT patients, Viswesh et al found a relatively high rate of viruria (8%-52%) but infrequent progression to viremia (3%-7%) and BKV nephropathy (1 biopsy-proven case in an heart transplant recipient). Among those NRSOT patients who did have progression to viremia and BKV nephropathy, heart transplants patients represented the majority of cases. This finding might be due to the proposed “double-hit” hypothesis, which suggests that the cumulative insult of immunosuppression and renal hypoperfusion secondary to cardiac allograft dysfunction causes clinical progression to BKV nephropathy.  

Should implementing a systematic BK screening program could effectively identify and manage this issue in the NRSOT population and or HCT patients?

In the News: Is it prime for Xenotransplantation

A seminal paper in Lancet published in 2023 focuses on the immune response after pig-to-human kidney xenotransplantation. The study uses a comprehensive approach to characterize this response in detail. 

Two pig kidney xenografts transplanted into deceased human recipients were thoroughly analyzed using various methods including morphological evaluation, immunophenotyping, gene expression profiling, digital spatial profiling, and cell deconvolution. The findings indicate early signs of antibody-mediated rejection, with evidence of microvascular inflammation, immune deposits, endothelial cell activation, and positive xeno-reactive crossmatches. The inflammation primarily consists of innate immune cells like CD68+, CD15+, and NKp46+ cells. Gene expression analysis reveals increased activation of various immune-related pathways, such as monocyte and macrophage activation, natural killer cell response, endothelial activation, complement activation, and T-cell development. 

The injury associated with antibody-mediated rejection is concentrated in the glomeruli of the xenografts, with transcripts related to monocytes, macrophages, neutrophils, and natural killer cells being significantly enriched. This rejection pattern is distinct from control autografts and ischemia-reperfusion models. The study suggests that despite initial positive outcomes, antibody-mediated rejection might still be occurring in pig-to-human kidney xenografts. The findings highlight potential therapeutic targets to address the humoral aspect of rejection and improve the success of xenotransplantation.

Interestingly, in JAMA surgery, a case report is published at the same time. The paper presents a case involving a male individual in his 50s who was declared brain dead and had acute kidney injury on top of a history of chronic kidney disease (CKD) and hypertension. After all other organ donation options were exhausted, the individual received bilateral native nephrectomy and cessation of dialysis. Crossmatch-compatible xenotransplantation was performed using 10-gene-edited pig kidneys (UKidney). The pig kidneys were modified with 10 gene changes, including knockdowns, knockouts, and human transgene insertions. The recipient was treated with a complement inhibitor (anti-C5; eculizumab) prior to xenotransplantation, followed by standard induction therapy and maintenance immunosuppression. The pig kidneys were transplanted en bloc with their vasculature anastomosed to the recipient's arteries and veins, and the ureters connected to the recipient's bladder. The pig kidneys exhibited rapid function, producing significant amounts of urine within minutes of reperfusion, and urine concentration improved over time. Serum creatinine levels dropped significantly after xenotransplantation, and creatinine clearance improved as well.

Biopsies of the xenografts showed normal histology without evidence of thrombotic microangiopathy. The authors discuss that while this case series demonstrates the success of pig-to-human xenotransplantation in providing kidney function to a deceased individual with CKD, more research with living human recipients is needed to determine the long-term function of xenograft kidneys and their potential use as a solution for the organ shortage crisis. Although single case, it highlights the potential of xenotransplantation as a viable solution for addressing the shortage of organs, which results in preventable deaths annually.

In the News: Urine Na as a marker for diuresis success

A recent editorial in JAHA discusses the use of urinary sodium (UNa) as a biomarker for monitoring and guiding diuretic therapy in patients with acute heart failure (AHF). Activation of the renin-angiotensin system in heart failure leads to sodium retention, hyperaldosteronism, and increased sympathetic activity, contributing to fluid overload. The authors highlight that assessing diuretic response through traditional methods, such as weight loss and urine volume output, can be inaccurate and logistically challenging. Instead, they propose using UNa measurements from spot urine samples taken 2 hours after diuretic administration as a more dynamic and early indicator of diuretic response.

The European Society of Cardiology (ESC) guidelines recommend using spot UNa analysis to evaluate diuretic treatment response in AHF patients. A low UNa (<50-70 mEq/L) at 2 hours post-diuretic administration is associated with inadequate diuretic response and suggests the need for more intensive diuretic therapy. The paper discusses observational studies and expert opinions that support this approach. However, it also points out limitations, such as the influence of kidney function, concurrent conditions like chronic kidney disease (CKD) and cirrhosis, and the potential loss of UNa's predictive strength after the first day of treatment due to changes in sodium excretion patterns.

The authors present data from studies that endorse the feasibility and efficacy of UNa-guided diuretic therapy in AHF. They discuss the ENACT HF trial, which showed improved natriuresis, diuresis, and shorter hospitalization duration with UNa-guided diuretic treatment. Another ongoing study, PUSH-AHF, aims to provide more definitive results on natriuresis-guided therapy using a stepwise diuretic approach.

The authors acknowledge that UNa assessment alone may not fully capture diuretic response and recommend combining UNa measurements with other indicators of decongestion, such as urine output. They also emphasize the importance of accounting for different patient factors like fluid overload status, kidney function, and the type of diuretics used.

In conclusion, while UNa-guided diuretic therapy appears promising for AHF management.. interesting and simple to do.

Love this figure from the paper

In the NEWs- New Myeloma Working Group Update-- Myeloma related renal disease management

 An important guideline/recommendation was published in Lancet thismonth. This is an evidence based summary by the International Myeloma Working Group on myeloma related kidney disease. A must read!

Here is a summary of the findings

1.      Diagnosis is important- the serum free light chain becomes the corner stone of diagnosis. An algorithm below summarizes the novel way of looking at it. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and FLCs measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed.

2.      How high is the involved FLC—can tell you if this is cast nephropathy vs looking for a glomerular process. In addition – the urine protein being selective vs non selective can aid in overflow proteinuria vs a true glomerular process.

3.      Kidney biopsy is NOT required but may be recommended if suspicious of cast nephropathy is high. Although recent studieshave shown that the IFTA and number of casts presents on renal bx can predictrenal outcomes.

4.      The IMWG criteria for renal response was recommended( change in eGFR)- see table below. This is used for many studies and validated.

5.      Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment( fluids, correction of hypercalcemia, avoiding NSAIDS)

6.      Mechanical approaches do not increase overall survival( plasma exchange- data is in the non bortezomib era, and HCO dialyzer- two RCTs showed no benefit).

7.      Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. The panel suggested to Start Daratumumab + Bortezomib + Dex early and then add IMiD starting cycle two once renal function has stabilized.

8.      Carfilzomib should not be first line in patients with CKD as risk of TMA( first time someone mentioning this)- glad the toxicities are being considered.. But then again- is the incidence of TMA from carfilzomib that high- I don’t think so.

9.      Dose adjustments are discussed for all anti Myeloma agents and their potential nephrotoxicities- mainly the TMA from carfilzomib. There are other renal toxicities of other agents as well not mentioned here.

10.    Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment

11.   Finally, with improved survival in myeloma, when should we consider kidney transplantation in pts. with ESKD? Should we use sustained MRD-negativity to select transplant candidates? What about the MGRS patients?—the consensus was 2 years of disease free state. But low level evidence.. I have seen sooner in most cases. Overall their outcomes are not great when compared to non myeloma ESKD. 

In the NEWS: Biomarkers-- Hype or Hope for AIN

A new study in JCI sheds light into a potential biomarker for Acute Interstitial Nephritis. This entity has been the bane of Nephrologists' existence. Its a hard diagnosis to make and treatment is the usual- steroids. 

First came the urine eosinophils-- then they were found to be useless.  Apparently, despite several studies showing no clear benefit in diagnosing AIN, several folks love to order this useless test. 

A slew of biomarkers came and went but none were real superhits for AIN. TNF-alpha and IL-9 were two potential candidates over the last few years.  The authors of a recent study published in JCI performed urine proteomics to identify a potential candidate that maybe best and top contender for AIN- chemokine C-X-C motif ligand 9( CXCL9).  This was then externally validated and then confirmed in kidney tissue of AIN patients compared to control groups.  They also showed that urinary CXCL9 together with TNF-α and IL-9 is the optimal combination of biomarkers for AIN diagnosis.

Here is the visual abstract from the paper

What is this CXCL-9? Apparently, it is a monokine induced by IFN-γ, is a chemokine that binds to its receptor, CXCR-3, and promotes lymphocyte recruitment at sites of inflammation.

It has been shown to be associated with

acute cellular rejection( makes sense- similar to AIN)
predict future risk of rejection
AIN associated with immunotherapy ( inviting T cells and monokine)
Predicting any immune mediated events when using ICI therapy

Drawbacks-- may not tell you specifically what is the cause of the T cell invitation but can clearly tell you a clue. Urinary tests are usually challenging in oligo-anuric AIN. 

It seems that the combination of TNF-alpha, CXCL-9 and IL-9 may hold promise for AIN. 

Despite amazing advances in urinary markers in transplant rejection since last 15 years, we are not using it in clinical practice. 

Lets hope that it is the troponin for AIN else we are still doing renal bx to confirm these tough diagnosis. 

Consult rounds: Hyperammonemic encephalopathy in the setting of myeloma

Can paraproteinemia cause an elevated ammonia level?

While liver disease and certain medications are known to cause hyperammonemia, myeloma is a rare cause of hyperammonemia. One of the first cases published on this topic was back in 2002 in NEJM.

Here are some cases published in the literature.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891795/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891795/

https://www.amjmed.com/article/S0002-9343(03)00630-2/fulltext

https://diagnosticpathology.biomedcentral.com/articles/10.1186/s13000-022-01285-6

https://pubmed.ncbi.nlm.nih.gov/35871579/

 

 A retrospective study shed more light. In this study of individual patients diagnosed with ammonia related disease from myeloma was evaluated( 27 patients), interesting findings were noted. The mean age was 76 years with a 5:1 male-to-female ratio. All had stage III based on the International Staging Scale (ISS). Bone marrow biopsies demonstrated 54–98% (mean 69%) plasma cell infiltration. IgA subtype was the most common. The mean ammonia level was 113 umol/L. No intracranial processes were detected on imaging. Three patients had improvement in mental status and decreased ammonia levels after chemotherapy; the other three patients declined further interventions. Inpatient mortality was over 66%. 

    The authors also did a MEDLINE search revealing 20 articles originating from the United States and Japan detailing a total of 32 patients who were diagnosed with myeloma induced hyperammonemic encephalopathy. The mean age was 52 years  with an equal distribution between men and women. The average ammonia level amongst these patients was 121 umol/L with as high as 299umol/L.  All these patients had stage III disease by the ISS or the Durie-Salmon system. IgG was the most common subtype at 44% (n=12), followed by IgA with 37% (n=10), light chain multiple myeloma with 11% (n=3), and IgD with 7% (n=2). Of the 25 patients that received chemotherapy, 15 (60%) survived until discharge. The inpatient mortality was 40% (n=10). Those patients who did not receive chemotherapy had a lower rate of survival at 25%.

Some studies report beneficial effects in using hemodialysis to remove excess ammonia. Several others suggest that the initiation of aggressive chemotherapy is the most effective measure to achieve normal ammonia levels and clinical improvement.  Mechanism of this association is still unclear. 

It is important to consider myeloma as a cause of hyperammonemia.

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)