Sickle Cell and Kidneys- Guilty of Not Going With the Flow

Written by Priti Meena,MD; Rima Zahr, MD.

Infographics by Priti Meena, MD; Salar Bani Hani, MD

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Sickle cell disease (SCD) is one of the most commonly encountered hereditary haematologic diseases worldwide. Sickle cell anemia (SCA) is the most severe and common form. Every year about 300,000 babies are born with SCA.SCD is caused by a homozygous (more common) or compound heterozygote inheritance of a mutation in the β-globin gene. A single base-pair point mutation (GAG to GTG) leads to the substitution of the amino acid glutamic acid (hydrophilic) to valine (hydrophobic) in the 6th position of the β-chain of hemoglobin. SCD is a multi-system disorder that results in both acute and chronic complications presenting when fetal hemoglobin (HbF) drops towards the adult level by five to six months of age. Unfortunately, in poor resource countries, more than 90 percent of children with SCD do not survive to see adulthood. Chronic anemia, asplenia/hyposplenia, sepsis, stroke, pulmonary hypertension, priapism, avascular necrosis of the hip, hemolysis, and recurrent acute vaso-occlusive crises are the frequently observed manifestations (figure 1).

Figure 1. Overview of sickle cell disease

Kidney disease in SCD remains an important cause of increased mortality and contributes to substantial morbidity. Here, we discuss kidney involvement in SCD with underlying pathogenetic mechanisms, manifestations, and potential therapeutic options.

Renal involvement in SCD

SCD gives rise to diverse renal manifestations (figure 2) with varying severity starting from impaired urinary concentrating ability to those that are rare and fatal such as renal medullary carcinoma. Sickle cell nephropathy (SCN) is more likely to be observed with more severe genotypes (homozygous HbSS and sickle-beta thalassemia) rather than with milder genotypes (HbSC disease or sickle-beta thalassemia).

Figure 2. Kidney manifestations of sickle cell disease

Pathogenesis of sickle cell nephropathy

The inner medulla environment is ideal for Hb S polymerization and subsequent RBC sickling and intravascular hemolysis, which is related to some inherent properties of the inner medulla such as lower blood flow and oxygen tension, acidosis, hyperosmolarity, and low blood flow. Sickled RBCs consequently cause microvascular occlusion of the vasa recta, which is the sole supply for renal papillae.

Furthermore, depletion of nitric oxide (NO), facilitated by intravascular hemolysis, vasoconstriction, and increased reactive oxygen species (due to elevated endothelin-1 concentration) causes disseminated vascular injury. This entire process sets up a vicious cycle for the development of chronic medullary ischemia. The injury from viscosity-vaso-occlusive damage leads to hemolysis-endothelial dysfunction which further contributes to systemic damage in SCD. Heme has a pro-inflammatory action and induces vasculopathic chemokines, such as monocyte chemoattractant protein-1 adding further to vascular injury. In addition, heme is nephrotoxic, specifically leading to tubular injury. Hemolysis alongside NO deficiency contributes to the occurrence of glomerulopathy in SCD.

Glomerular injury: Hemolysis and endothelial dysfunction mainly affect the renal cortex, causing hyperfiltration and glomerular injury. In SCD patients, the size of the glomerulus tends to expand with age, with glomerular congestion starting to appear at beyond the age of 2 years. Histopathology shows hypertrophy of the glomeruli and hemosiderin deposits in the tubular cells predominantly. The most common renal pathologies seen are focal segmental glomerulosclerosis (FSGS) followed by membranoproliferative glomerulonephritis (MPGN), and thrombotic microangiopathy (less common). The typical age for glomerular diseases is 7-18 months.

Figure 3. Manifestations of sickle cell nephropathy by age

Proteinuria: Loss of size and charge selectivity as sickled RBC induce endothelial activation and inflammation, leading to albuminuria. Some degree of tubular proteinuria could be due to tubular injury caused by hemolysis. The age of 7 years old is widely considered the typical age of onset of albuminuria. A higher level of albuminuria has a direct correlation with progression to ESRD in adulthood.

Renal tubular disorders: Damage to the vasa recta caused by sickled RBCs, leads to a loss of countercurrent multiplication and exchange system, produces hyposthenic urine. The patient often complains of nocturia and polyuria. Hypoxia and disturbance in the medullary blood flow lead to reduced hydrogen ions and electrochemical gradients along the collecting ducts. Impaired distal hydrogen and potassium secretion can result in a partial distal renal tubular acidosis as well.

Hematuria: Microscopic hematúria can be present in up to 30% of patients with SCD. The reason could be due to nutcracker syndrome, renal infarction, renal papillary necrosis. Macroscòpic hematuria can be present due to papillary necrosis as a consequence of vascular occlusion.

Electrolyte imbalance: Hyperuricemia and hyperkalemia are often observed.

AKI: AKI in SCN is mostly caused by the vaso-occlusive crisis and is common between the ages of 8-18 years. Other contributing factors to AKI could be dehydration, infection, rhabdomyolysis, concurrent use of nephrotoxic medications, renal vein thrombosis, or obstruction in the urinary tract.

Chronic kidney disease: Published studies revealed a high prevalence of CKD (in up to one-fourth to one-third of adults) amongst patients with sickle cell disease. Even the presence of sickle cell trait has been found to be associated with an increased risk of CKD, declining eGFR, and albuminuria.

Renal infarction and papillary necrosis are frequent in SCN and can be observed in as many as 23 to 40% of patients. Contributing factors are interstitial nephritis, acute pyelonephritis, diabetes mellitus, or analgesic use. Urinary tract obstruction and infection can further add to complications. Renal infarcts could present with nausea, vomiting, flank pain, fever, and rarely hypertension.

Renal medullary carcinoma (RMC): Though very rare, RMC is a very fatal complication of SCN with the typical age of onset being early adulthood. It is a non-clear-cell kidney cancer. RMC is predominantly found in individuals with sickle cell trait. It commonly presents with flank pain and hematuria or a palpable abdominal mass. RMC is characterized as highly aggressive, and often metastatic at presentation.

Patients with SCN often suffer from other comorbidities such as pulmonary hypertension, systemic hypertension, and central nervous system (CNS) injuries including stroke.

In SCD patients it can be challenging to correctly estimate GFR due to glomerular hyperfiltration, supranormal proximal tubule function, and hydroxyurea (causing interference in measurement platforms like i-stat Creatinine). The use of cystatin C might give a better correlation with eGFR in this population, however, this has not been validated.

Management Strategies

There is no one specific treatment for the management of SCN and treatment often requires multi-drug therapy. It is important to first address the primary disease, SCD, and work in concert with hematologists. Nephrologists can then focus on the development of novel therapies to address albuminuria, to slow the progress of kidney disease.

Hydroxyurea is the mainstay of therapy for SCD. Hydroxyurea increases HbF levels and inhibits the polymerization of HbS. Hydroxyurea prevents the onset and progression of albuminuria in children with sickle cell anemia. It is important to note that hydroxyurea is metabolized via kidneys and also removed by hemodialysis; thus dose adjustments may be required in individuals with impaired kidney function. A very rare adverse event is myelotoxicity. Furthermore, treating physicians must be aware of the possibility of waning effectiveness over time, and work with hematologist to monitor therapy.

Adequate hydration to maintain a urine output of 1.2 mL/kg/h is an essential part that reduces the chances of recurrent AKI in SCD (supported by a low grade of evidence). Concurrent use of nephrotoxic medications should be avoided. Recurrent blood transfusions can cause high panel reactivity, due to a high level of circulating induced plasma antibodies from foreign antigens, and can complicate finding a matching donor for renal transplantation. Usually, kidney damage occurs during the early part of childhood; thus early identification and treatment to limit damage is crucial.

ACEi and ARBs

As supported by a few trials, the initiation of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) for renal complications, regardless of blood pressure, has been suggested by current guidelines with very low certainty in the evidence about effects. Though RAAS inhibition had shown a decline in albuminuria with the greatest benefits seen in patients with macroalbuminuria, no significant reduction in the progression of CKD could be observed in published trials.

Endothelin receptor antagonists (Crizanlizumab) have shown potent reno-protective effects in mice studies, but human studies are currently ongoing.

Other disease-modifying drugs and therapies Voxelotor, an HbS polymerization inhibitor, is currently being used in patients with SCD. In a phase 3 randomized, placebo-controlled trial in SCD patients, Voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. Another, new agent is Crizanlizumab, a P-selectin inhibitor. It has been shown to decrease vaso-occlusive pain crises in individuals 16 years and older. Results from another multicenter study, assessing the effect of this drug on CKD, are pending.

Gene therapy with the use of LentiGlobin in SCD patients showed promising results in a recently published analysis. It led to reduced hemolysis and complete resolution of severe vaso-occlusive events.

Dialysis and transplantation As in non-SCD patients, the choice of dialysis modality between hemodialysis and peritoneal dialysis depends on clinical factors and patient preferences. Experience of transplantation in SCD patients is limited because they are less likely to be placed on a kidney transplant waiting list. In a recent analysis, kidney transplantation was found to be associated with a substantial decrease in mortality in the sickle cell group with a decrease in 10-year mortality of 20.3 percentage points when compared with their matched waitlisted candidates. (PMID: 33632759)

Take Home Message:

• Renal Involvement begins early in the first decade of life and is commonly manifested as hyposthenuria

• Albuminuria occurs in ~ 20% of children, and is a harbinger of kidney disease progression

• Mean survival in patients with SCN is significantly decreased when a diagnosis of ESKD is made

• Treatment of SCN should focus on the treatment of albuminuria, the use of ACEI and ARBs have been used in these patients

• Screening for SCN should being in childhood with a yearly urinalysis (UACR and UPCR)

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Big MAC attack: Outcomes in membranous nephropathy & membrane attack complex on biopsy

Written by: Brian Rifkin, MD, Ana Cecilia Farfan Ruiz, MD MSc & Miquel Blasco Pelicanom MD, PhD

Inforgraphics by: Brian Rifkin, MD & Corina Teodosiu, MD

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Membranous nephropathy (MN) is responsible for nearly 30% of nephrotic syndrome presentations and remains one of the most common causes of nephrotic syndrome among non-diabetic adults, with an estimated incidence of 8-10 cases per 1 million in Western countries. Most patients present with the triad of nephrotic range proteinuria, edema and low serum albumin (with or without kidney failure). High blood pressure, elevated cholesterol, and the potential risk for thrombosis are also often present in patients with membranous nephropathy.

70-85% of MN cases are classified as primary membranous glomerulonephritis— previously known as idiopathic. Secondary MN accounts for roughly 30% of patients with MN and typically occurs in the setting of autoimmune diseases, infections, malignancies, or with certain medication exposures. (FIGURE 1)

Figure 1.

Much of what we know of the pathogenesis of MN comes from the classic Heymann Nephritis (HN) model from 1959, where the glycoprotein 330 (megalin) was identified as the antigen involved in the autoimmune process observed in rat models. Megalin provoked podocyte injury by forming immune complexes that activated complement.

In humans, autoantibodies against the M-type phospholipase A2 receptor on podocytes were eventually discovered, and were present in 70-80% of patients with MN without a concomitant secondary disease. The additional discovery of other podocyte antigens causing MN, and their respective antibodies, have been shown to be associated with malignant tumors: thrombospondin 1 domain- containing 7 A (THSD7A) discovered in 2014 and NELL-1 (neural epidermal growth factor- like 1). The list of MN associated antibodies continues to grow in recent years with the identification of EXT1/EXT2 in 2019, Semaphorin 3B and Protocadherin 7 (PCDH7) in 2020, and serine protease HTRA1 in 2021.

Subepithelial immune deposits occur in situ when circulating antibodies bind to intrinsic, fixed antigens forming dense “spike” antigen-antibody complexes visible on electron microscopy. (FIGURE 2)

Figure 2.

The immune complexes serve as activators that trigger the formation of C5b-C9 complexes (FIGURE 3) or membrane attack complexes (MAC), that insert on the glomerular epithelial cells membrane resulting in damage. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". On light microscopy, there is glomerular basement thickening as evidenced by epimembranous spikes on silver stain. IgG1 and IgG3 deposits are seen with immunofluorescence earlier in the course of the disease. Later IgG4 deposits can be demonstrated along the capillary loop, in addition to the deposition of C3.

Figure 3.

In terms of prognosis, it is generally understood that about a third of untreated patients have spontaneous remission, another third progress to require dialysis and the last third continue to have proteinuria, without worsening kidney function. Features that have classically been taught to be indicative of progressive disease on kidney biopsy include the presence of segmental sclerosis including the extent of interstitial fibrosis and tubular atrophy. In addition, in order to define the initial approach to treatment in these patients, there are clinical and laboratory risk factors for disease progression that have been determined. These include PLA2R levels, the amount of proteinuria, baseline kidney function and life-threatening nephrotic syndrome. (FIGURE 4) Given that spontaneous remission occurs in 1/3 of patients with 32% occurring during the first 14 months after presentation (including spontaneous remission in patients with proteinuria of up to 12 g/day), we need better tools to decide which patients to treat early and aggressively with immunosuppressive therapy.

Figure 4. KDIGO 2021 Guidelines Chapter 3, Membranous Nephropathy

PLA2R antibodies levels have been found to correlate to the amount of proteinuria and the likelihood of remission. However, a single level of PLA2R antibodies matched to a single quantity of proteinuria is of limited value, as this may only reflect a phase of the disease. As explained in the review byLerner et Al, primary membranous nephropathy can be divided into 5 phases (FIGURE 5) that include PLA2R antibodies (deposits in the kidney and ultimately appearing in the serum) and proteinuria (as a marker of podocyte injury that takes time to resolve even after suppression of autoimmune activity) as immunological and clinical parameters. Complement activation, which is a key component in this process, could potentially help with stratification of treatment and prognosis.

Figure 5. Five phases of membranous nephropathy

In the study by Teysseyre et al, they theorize that components of the complement system seen on biopsy could be used as markers of disease in MN. As a reminder, C3 is involved in the membranous lesion. The intensity of its deposition is associated with the severity of the level of eGFR at the time of the biopsy in the glomeruli of patients with MN, and also seemed to be correlated with the level of proteinuria. The formation of MAC is central to the pathogenesis of glomerular damage and back in 1992 Brenchley et al, described an association between high urinary C5b-9 levels and unstable clinical courses in MN. The use of urinary MAC excretion as a prognostic marker has also been studied. However, it is not specific for MN and can be present in diabetic nephropathy and FSGS with nephrotic range proteinuria. Also complement markers of activation (like C3dg) can be derived from the renal tubules and not from the glomeruli, as in tubulointerstitial nephritis, reminding us that C3 synthesis occurs in proximal tubular cells, hence the expression of MAC.

The authors retrospectively reviewed a database from the Department of Pathology of Montpellier University Hospital, France. To be included, patients had to have undergone a kidney biopsy confirming MN from December 2004 to December 2015. Exclusion criteria included: age < 18 years, kidney transplant, patients lost to follow-up, insufficient biopsy (< 2 glomeruli), MN associated with another nephropathy, and patients with an uncertain diagnosis. Historical samples were stained for PLA2R, anti-human C4d, and anti-human C9 neoepitope (which is highly specific to C5b-9 fixation in the membrane). Two renal pathologists, who were blinded to the clinical data, graded the intensity of staining from negative to strong (0-3+). There was no discordance between the two pathologists regarding positivity of the staining in the given set of samples.

The primary endpoint was renal survival from the date of the biopsy until the date of renal failure, as defined by an estimated GFR <30 ml/min/1.73m2 calculated by the CKD-EPI formula. Secondary endpoints were clinical remission of the nephrotic syndrome (partial or complete) as defined by the 2012 KDIGO guidelines at 6 months, 12 months and the end of follow-up.

64 patients’ biopsies were included for study, including 45 with primary MN and 19 with secondary MN (FIGURE 6) with a median follow-up of 94.5 months. Patients were primarily male (59.4%) with a median age of 54 years. 65.6% had nephrotic syndrome at the time of biopsy. All but one patient received renin-angiotensin-aldosterone system (RAAS) inhibitors. Forty-five (70.3%) received at least one immunosuppressive therapy during follow-up (corticosteroids, mycophenolate mofetil, alkylating agents and/or rituximab).

Figure 6.

C5b-9 glomerular staining was positive in 29 patients (45.3%). The deposits were granular and diffuse and located in the subepithelial space (FIGURE 7). C5b-9 staining was weak (1+) in 17 patients, moderate (2+) in 9 patients and strong (3+) in 3 patients. There was no C5b-9 staining positivity in the control kidney biopsy. C5b-9 positive patients had higher proteinuria and lower eGFRs compared with C5b-9 negative patients. There were no other significant differences in patient characteristics or administered treatments. More importantly, there were no differences in classical histologic grading characteristics including vascular lesions, interstitial fibrosis and tubular atrophy between groups. This showed that classical markers of severe disease on kidney biopsy really did not help in differentiating outcomes.

Figure 7.

C5b-9 positive patients did have significantly decreased remission rates (as defined by level of proteinuria) at 6 months, 12 months and at the end of follow-up (FIGURE 8). In addition, analysis showed a faster time to remission in patients without C5b-9 glomerular deposition, a difference of about 9 months on average. Of the 45 patients receiving immunosuppression, 26 achieved remission, including 38.5% with C5b-9 deposits versus 61.5% without deposits. Overall, glomerular deposition of C5b-9 was associated with a lower remission rate even after corrections for eGFR and proteinuria at baseline. C5b-9 deposits were also strongly associated with renal failure. 51.7% (15/29) of the patients with deposits versus 11.4% (4/35) progressed to an eGFR < 30 ml/min/1.73 m2 (p= 0.0004). Baseline eGFR and glomerular deposition of C5b-9 were most strongly associated with renal failure.

Figure 8.

The complement system is being increasingly recognized as having a significant role in patients with glomerulonephritis. In this study, C5b-9 positive patients had more severe nephrotic syndrome at diagnosis, more treatment failures and lower renal survival rates than patients without glomerular deposition of C5b-9. Furthermore, in this study of MN nearly 95% of patients had staining with C3 and C4d, suggesting that complement activation is almost universal, even though only 45.3% of MN patients demonstrated C5b-9 deposits on biopsy. “Complete” activation of the complement cascade and MAC may carry a more devastating prognosis. Complement is regulated at both the systemic and glomerular levels. Podocytes express complement regulatory proteins that may incompletely activate the complement cascade. Similarly, glomerular lesions may be secondary to complement activation in addition to antibody mediated mechanisms.

As more therapeutics are developed to interrupt complement activation, it is possible that C5b-9 positivity identified on biopsies may help guide which subset of MN patients could benefit from such interventions. Eculizumab, a C5 binding agent that blocks the terminal formation of MAC, previously did not show benefits in patients with MN, however the doses regimens used in the trial were lower than the usual for complement mediated disease (C3 glomerulopathy or atypical HUS). It is alsopossible that treating only the subpopulation of patients with C5b-9 positive biopsies might give more significant results, and warrants further study. In addition, we currently have two new C5 blockers (ravulizumab, cemdisiran), as well as new molecules with action at different complement levels. Among them, there are three phase II clinical trials for MN (pegcetacoplan, BCX9930, Narsoplimab). (FIGURE9) As previously described inKI reportscommunity blog, iptacopan, a new potent oral and highly selective factor B inhibitor of the alternative complement pathway is being evaluated for C3GN but could eventually have broader use in other glomerular diseases. The authors note several limitations of the current study including: retrospective nature, single center, number of patients lost to follow-up, historical treatments (low rituximab use), inclusion of secondary MN (mostly SLE), serum PLA2R not evaluated (no serum bank), and use of a single kidney biopsy as a control. The authors intend to replicate this study with a more modern cohort. If this study can be reproduced, the addition of C5b-9 glomerular staining on MN biopsies could be a revolutionary prognostic, and hopefully, therapeutic indicator.

Figure 9.

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Primary Glomerulonephritis and Pregnancy

Written by : Priyadarshini John DM

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The incidence of primary glomerulonephritis ranges between 0.2/100,000/year and 2.5/100,000/year. Pregnancy can take a toll on the kidney or vice versa. There is sparse literature about pregnancy counseling and managing primary glomerulonephritis during pregnancy.

Disease activity is the most important factor that affects maternal and fetal outcomes, and therefore control of the active disease should be undertaken prior to conception. This study which studied outcome of pregnancy in chronic kidney disease including chronic glomerulonephritis reported stable renal function in 79% of pregnant women, out of which 20% of the women had a 25% decline in renal function postpartum and 10% progressed to end-stage renal disease by six months postpartum, which probably undermines the importance of contributing factors like presence of HTN, amount of proteinuria and etiology of renal dysfunction at the time of conception. Fetal outcomes in terms of birth weight and gestational period were better in women with renal dysfunction without proteinuria than in women with proteinuria.

Control of proteinuria prior to embarking on pregnancy is of utmost priority, and evidence stems from outcomes of pregnancies in lupus. It is recommended to achieve complete remission of proteinuria for at least 3 to 6 months prior to pregnancy.

For glomerular diseases that mandate treatment with RAS inhibitors, these drugs can safely be used before pregnancy and are not considered teratogenic in the first trimester. Nevertheless, the best practice is to stop RAS inhibitors prior to conception.

Cyclophosphamide and Mycophenolate mofetil should be discontinued six weeks prior to planning pregnancy and it is recommended to wait for at least a year after rituximab.

Chronic hypertension is also common in patients with CKD and GN.The strict control of blood pressure is critical in pregnant women with glomerulonephritis, as severe hypertension in the first trimester is associated with adverse pregnancy outcomes. Methyldopa, extended-release dihydropyridine calcium channel blockers, and hydralazine are preferred antihypertensive drugs during pregnancy.Beta blockers labetalol are also first line. Labetalol crosses the placenta and can cause neonatal bradycardia and hypoglycemia. RAS inhibitors cause congenital cardiac abnormalities like atrial and ventricular septal defects, patent ductus arteriosus, pulmonary hypoplasia in the fetus, and oligohydramnios. For a comprehensive review about hypertension in pregnancy check here.

However, patients with glomerulonephritis may also experience difficulty getting pregnant or difficulties during their pregnancy.

Infertility in glomerulonephritis is secondary to disease processes of advanced chronic kidney disease, which causes hypothalamic pituitary dysfunction and impaired ovulation. In chronic kidney disease, there is defective pulsatile release of Gonadotropin releasing hormone(GnRH) and hence decreased release of Follicular stimulating hormone(FSH) and luteinizing hormone(LH) from pituitary.(Figure 1)

Figure 1 Hypothalamic-Pituitary axis in Normal Vs ESKD

Pharmacological therapy like cyclophosphamide can sometimes put women at risk for infertility. Oral cyclophosphamide and older age put women at risk for gonadal failure. It is emphasized that intense hemodialysis or transplantation might improve fertility.

Superimposed preeclampsia can develop on chronic hypertension, and patients with CKD are at particularly higher risk of preeclampsia compared to the general population. Worsening proteinuria and blood pressure after 20 weeks of gestational age should prompt evaluation for preeclampsia. Diagnosis of preeclampsia can be ruled out if sFlt1/PlGF ratio<38, but again the utility of these markers in underlying chronic kidney disease or glomerulonephritis is unclear. Kate et al studied the utility of markers of preeclampsia like serum sFLT1, PIGF in a spectrum of chronic kidney disease patients and inferred that cut off of these markers are similar to those who do not have chronic kidney disease population.Until these assays are validated in CKD for commercial purpose, high resistance patterns and low-velocity waveforms in uterine and umbilical arteries can differentiate chronic kidney disease (normal flow waves) from preeclampsia (high resistance flows with a pulsatility index >1.4) as suggested by Piccoli et al.

Despite best efforts, some patients may develop worsening renal function or proteinuria or de novo AKI or proteinuria that may necessitate renal biopsy.Indications for renal biopsy in pregnancy include rapid deterioration of renal function and de novo nephrotic syndrome. Renal biopsy should be considered, especially when diagnosing the underlying pathology will change the management of the patient and cannot wait until the delivery time.Complications of Kidney biopsy like the need for renal artery embolization, blood transfusion, preterm delivery, or fetal death occur in around 2% of pregnant women and were more common after 23 weeks of gestational age and during the postpartum period.

Medications:Prenatal supplementation of folic acid 5 mg, oral/IV iron, Vit D, and calcium are recommended.Calcium and low-dose aspirin (75-100mg/day) are known to reduce the risk of preeclampsia in high-risk women.Erythropoietin stimulating agents are safe to be used in pregnancy and help reduce the need for blood transfusion. Anticoagulation and thromboprophylaxis should be considered in women with albumin less than 2.5mg/dl. Treatment with low molecular weight heparin is deemed safe during pregnancy. Warfarin crosses the placenta and causes fetal loss and skeletal and central nervous system defects. Thromboprophylaxis is usually held before delivery and reinitiated at the earliest and continued until six weeks postpartum as the risk of thrombosis increases during the postpartum period.

Immunosuppression:Corticosteroids are the mainstay of therapy in many glomerular diseases and are considered safe to use in pregnancy. The placenta acts as a barrier and inactivates maternal cortisol by 11-beta-hydroxysteroid dehydrogenase type 2 on syncytiotrophoblasts, and low-doses do not cause thymic hyperplasia and adrenal suppression. Betamethasone and dexamethasone bypass this step, and fetal levels will be around 30% of maternal levels and hence used to accelerate fetal lung maturation. Adrenal suppression should be considered and treated during labor and delivery if a woman is on more than 20mg of steroids for greater than three weeks within six months prior to delivery.

Azathioprine in doses <2 mg/kg/day is safe to use in pregnancy as the fetal liver lacks inosinate pyrophosphorylase, essential in conversion to the active metabolite. Increased risk of congenital malformations, prematurity, and perinatal mortality is seen with azathioprine. Still, these adverse effects were not confirmed by the National Transplantation Pregnancy Registry.

Evidence regarding the safety of calcineurin inhibitors comes from their use in transplantation. These drugs can aggravate maternal hypertension. Dosages of CNI should be regularly monitored and adjusted due to the increased volume of distribution.

Rituximab safety is not well documented. Though there is some reassuring data about the usage of rituximab during pregnancy, it is recommended to delay pregnancy for at least 6-12 months after exposure to rituximab.

Cyclophosphamide and Mycophenolate are potential teratogens. Mycophenolate, a purine biosynthesis inhibitor, causes cleft lip and palate microtia with atresia of the external auditory canals, micrognathia, and hypertelorism. Cyclophosphamide causes calvarial defects, abnormalities of the ear, craniofacial structure, limb, and visceral organs, and developmental delay.

Table 1. Summary of immunosuppression in pregnancy

Glomerular disease-specific outcomes in pregnancy:There is meager data about pregnancy outcomes in minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Few of the oldest studies by Jungers et al and Barcelo et al reported fair maternal and fetal outcomes if hypertension and proteinuria are well controlled. Proteinuria in the first trimester of idiopathic membranous nephropathy is associated with worsening nephrotic syndrome, gestational hypertension, renal dysfunction, fetal loss, and prematurity.

Pregnancy has minimal effect on IgA nephropathy as long as the renal function is preserved, and pregnancy did not have a significant impact on disease progression over a period of 4 years when compared to the non-pregnant population. Proteinuria at the time of conception is an independent risk factor for the postnatal decline in renal function. Shimizu et al in study concluded that renal function at the time of conception has a significant impact over a period of five years or thereafter. They observed that women who had eGFR <45 ml/min/m2 had progressed to CKD stage 4 during pregnancy and reached stage 5 within five years postpartum. Perinatal death in 3%, premature delivery in 10%, HTN in 21%, and 8.5% had superimposed preeclampsia are some of the Maternal and fetal outcomes in IgA nephropathy

Literature regarding pregnancy in Anti GBM disease is sparse. Significant maternal morbidity in the form of infections, preeclampsia, and need for renal replacement therapy are seen, and IUGR, prematurity, fetal demise, and congenital malformations contribute to fetal morbidity. Anti-GBM antibodies cross the placenta, which is detectable in the blood of neonates without renal or pulmonary disease.

Pregnancy in ANCA vasculitis is rare, unlike SLE. Active vasculitis at the time of conception might result in spontaneous abortions and deterioration of renal function. Relapse during pregnancy is seen in 18% and postnatal flare in 21.3% of patients. Vasculitis Clinical Research Consortium Patient Contact Registry looked into the pregnancies before and after vasculitis and concluded that there is an increased risk of fetal demise and preterm delivery in women who conceived after vasculitis. Case reports of neonatal vasculitis are secondary to transplacental passage of anti-MPO and anti-PR3 antibodies.

Conclusions:

• Women with glomerulonephritis can plan conception after discussing it with a multidisciplinary team of obstetricians, nephrologists, and pediatricians.

• Safe maternal and fetal outcomes depend on renal function, which includes control of HTN and proteinuria

• Timely maternal and fetal monitoring is the key to optimal outcomes.

Figure 2. Holistic approach to women with glomerulonephritis who wish to get pregnant.

Reviewed by : Amy Yau MD, Sophia Ambruso MD, Silvi Shah MD

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