|Year : 2019 | Volume
| Issue : 2 | Page : 325-333
|Acute cortical necrosis in pregnancy still an important cause for end-stage renal disease in developing countries
Anupma Kaul1, Hiral Lal2, Prabhakar Mishra3, Manoj Jain4, Narayan Prasad1, Mandakini Pradhan5, Manas Ranjan Patel1, Amit Gupta1, Raj Kumar Sharma1
1 Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Radio Diagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Biostatistics and Health Informatics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
4 Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
5 Department of Maternal and Reproductive Health, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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|Date of Submission||20-Jan-2018|
|Date of Decision||03-Mar-2018|
|Date of Acceptance||06-Mar-2018|
|Date of Web Publication||23-Apr-2019|
| Abstract|| |
Renal cortical necrosis (RCN) is a serious complication of acute kidney injury (AKI) and pregnancy is a clinical state closely associated with it with poor renal outcomes. The incidence is much higher in obstetrical AKI compared to other causes of RCN. Despite better medical care facilities available, this continues to be an important cause of morbidity and mortality in developing countries. This is a retrospective analysis among all pregnant females presenting with AKI from January 1999 to December 2014 at a tertiary care center in the northern part of India. We looked for the incidence of obstetrical-related RCN in our renal biopsies performed in the last 15 years and to evaluate precipitating factors responsible for RCN. RCN constituted 8.3% of pregnancy-related AKI cases in our institution. The overall incidence has been declining which was 9.09% from 1999 to 2008 to 7.8% from 2009 to 2014. The patient’s median age was 29.3 ± 5.2 years. The average time to presentation from the day of delivery was 8.7 ±2.1 days. The mortality was observed in 11.7% of them with sepsis and multiorgan dysfunction present in all of them. The most common etiology for RCN was found to be septic abortion and puerperal sepsis accounting for - 15.3% each. Postpartum hemorrhage was a cause in 9.09% of patients. The most important cause of RCN was postpartum thrombotic microangiopathy which was observed in 48.7% of patients. Kidney biopsy was helpful in diagnosis in 31 patients while computed tomography scan abdomen alone helped in diagnosis in five patients. Patchy cortical necrosis in histology was seen in 35.4% of patients and morbidity in terms of prolonged hospitalization was seen in 22.7% while dialysis dependency in 61.5% of the study population. In conclusion, strategies need to be implemented in reducing the preventable causes for RCN which is not only catastrophic in terms of renal outcomes but also for social and psychological perspectives as well.
|How to cite this article:|
Kaul A, Lal H, Mishra P, Jain M, Prasad N, Pradhan M, Patel MR, Gupta A, Sharma RK. Acute cortical necrosis in pregnancy still an important cause for end-stage renal disease in developing countries. Saudi J Kidney Dis Transpl 2019;30:325-33
|How to cite this URL:|
Kaul A, Lal H, Mishra P, Jain M, Prasad N, Pradhan M, Patel MR, Gupta A, Sharma RK. Acute cortical necrosis in pregnancy still an important cause for end-stage renal disease in developing countries. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 May 24];30:325-33. Available from: http://www.sjkdt.org/text.asp?2019/30/2/325/256839
FNx01Both authors contributed equally to this manuscript
| Introduction|| |
Renal cortical necrosis (RCN) is a serious complication of acute kidney injury (AKI) and pregnancy is a clinical state closely associated with it with poor renal outcomes. It is characterized by patchy or diffuse ischemic destruction of renal cortex with significantly diminished renal arterial perfusion resulting from vascular spasm, micro vascular injury or intravascular coagulation.
Its occurrence in developed countries has gone down to 1.5%–2%, yet it is found in 5%–7% among developing countries., These high incidences among developing countries are due to serious obstetrical complications such as septic abortion, puerperal sepsis, abruptio placentae, postpartum hemorrhage (PPH), and eclampsia. The incidence of RCN is much higher in obstetrical AKI (10%–30%) as compared to other causes of this condition (5%). In the Indian subcontinent, its incidences varies from 18% and 42.8%.,
Despite improved medical care facilities available, this continues to be an important cause of morbidity and mortality in developing countries. Diagnosis is confirmed by kidney biopsy which helps in differentiating from acute tubular necrosis, which holds a better prognosis. This is an invasive diagnostic tool with possibly serious post-biopsy complication. Computed tomography (CT) scan is a useful, noninvasive investigative modality for an early diagnosis of RCN. This modality can obviate the need for performing an invasive procedure like kidney biopsy and is useful in certain situations, wherein kidney biopsy is not possible. We share our experience about the incidence of obstetric-related RCN among all patients who presented with pregnancy-related AKI from January 1999 to December 2014 and to evaluate precipitating factors responsible for RCN.
| Materials and Methods|| |
This hospital-based retrospective study was conducted in the Department of nephrology with collaboration to Department of radio-diagnosis and pathology at a tertiary care referral center of north India from January 1999 to December 2014 on patients with RCN due to pregnancy-related complications. All those who fulfilled the inclusion criteria have been included in the study.
Hospital records were analyzed for demographic characteristics, obstetric history, and clinical profile on admission. Obstetric history included parity, history of antenatal follow-up, location, nature of delivery, pregnancy, maternal, and fetal outcomes were looked into. The etiology, time of renal failure with respect to gestational age, need of renal replacement therapy (RRT), and outcome in terms of fetal and maternal mortality, and number of women reaching end-stage renal disease (ESRD) were noted individually.
Specific investigations were carried out to exclude uncommon and/or rare cause of AKI. They included ANA, anti-dsDNA antibody testing, C3, C4, and antiphospholipid antibody. Platelet count, PT-INR, activated partial thromboplastin time, blood smear for schistocytes, serum lactate dehydrogenase, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminases level were estimated. Kidney biopsies were done in patients with:
- Anuria and/or oligoanuria following delivery of >4 weeks duration
- Patients with pregnancy-related AKI, needing dialysis and not recovering within four weeks
- Partial recovery of renal function >4 weeks duration after the AKI episode following pregnancy.
The renal histopathology was looked for evidences of ischemic necrosis of renal cortex, which could be patchy or diffuse in distribution The biopsies were analyzed for light microscopy (H and E stain) and immunofluorescence to stain for immunoglobulin, A and M as well complement factors C3 and C1q as well as kappa and lambda light chains.
In a situation where kidney biopsy was not possible (coagulation abnormalities) or when the patients were not willing, a non contrast CT was done to look for cortical calcification.
However, contrast-enhanced computed tomography (CECT) scan was done wherever it was possible to look for hypoattenuated subcapsular rim of cortex which was taken as diagnostic of cortical necrosis.
Pregnancy outcomes (preterm, term, miscarriages, abortions, and mortality) and fetal outcomes (birth weight and mortality) were noted as well.
All female patients presenting with pregnancy-induced AKI (PAKI) with clinical evidence of cortical necrosis along with histological and or radiological evidence of cortical necrosis were included in the study.
Patients with preexisting diabetes mellitus, hypertension, chronic kidney disease defined as serum creatinine >1.5 mg/dL or the presence of proteinuria >1+ on dipstick or renal transplant recipients, contracted kidneys on ultrasound were excluded from the analysis.
AKI in pregnancy: The diagnosis of AKI in pregnancy based on any one of the three criteria: (a) serum creatinine >1 mg/dL, (b) oliguria/anuria >12 h duration, and (c) need for dialysis.
Postpartum AKI: AKI diagnosed from the time of childbirth to six weeks post delivery
Preeclampsia: Blood pressure reading >140/90 mm Hg diagnosed for the first time after 20 weeks of gestation with 2+ proteinuria on dipstick.
Severe preeclampsia: Association of severe arterial hypertension (systolic arterial pressure exceeding 160 mm Hg and diastolic arterial pressure exceeding 110 mm Hg) or proteinuria ≥5 g/L or ≥3 + or signs of visceral involvement (headaches, visual disturbances, epigastric, or right upper-quadrant pain).
Eclampsia: Presence of new-onset grand mal seizures in a woman with pre-eclampsia.
HELLP syndrome: Combination of thrombocytopenia (<100 g/L), elevated liver enzymes (AST >70 UI/L), and hemolysis.
Puerperal sepsis: As per the World Health Organization definition – Any bacterial infection of the genital tract that occurs after the birth of a baby. It is usually more than 24 h after delivery before the symptoms and signs appear.
PPH: A blood loss of ≥500 mL after vaginal delivery or ≥1000 mL after cesarean delivery or as noted in the medical record by a care provider.
Postpartum thrombotic microangiopathy (TMA): Presence of autoimmune hemolytic syndrome (characterized by the presence of schistocytes, increased reticulocyte count, and raised lactate dehydrogenase), thrombocytopenia, and renal failure or evidence of TMA on a renal biopsy following pregnancy.
RCN: Clinical evidence of nonresolving AKI beyond four weeks with dialysis dependency along with histological/CT evidences of RCN i.e., the total ischemic necrosis of the entire elements (glomeruli, blood vessel, and tubule) of the affected area of renal cortex is a typical histological feature of RCN, while CT non contrast revealing cortical calcification and (contrast) revealing hypo attenuated subcapsular rim of renal cortex.
Renal histology of RCN: Light microscopy: There is coagulative necrosis involving all tubular segments and glomeruli. Nuclei appear pale and pyknotic or may no longer be apparent.
Renal histology of RCN secondary to TMA: Both tubules and glomeruli are necrotic with fibrin filling glomeruli and inter-lobular vessel, with early signs of injury with intimal fibrosis and fibrin occluding the lumen.
Immunofluorescence microscopy: No specific staining will be seen.
Complete cortical necrosis: Confluent global cortical destruction extending into the columns of Bertin. The thin rim of subcapsular and juxtamedullary tissue may be preserved. Irreversibility of renal function is the rule in complete cortical necrosis.
Patchy cortical necrosis: Contiguous areas of cortical necrosis involving one-third to half of the entire cortical tissue. This form has the potential for partial recovery of renal function to dialysis independency.
Early pregnancy AKI: Those causes of AKI presenting before 20 weeks of gestation
Late pregnancy AKI: Those causes of AKI presenting beyond 20 weeks of gestation.
Outcomes: Patient outcomes were evaluated for mortality and renal outcomes.
Complete recovery: Decline in serum creatinine to ≤1.0 mg/dL and the presence of 24-h urine protein of <150 mg within six weeks of diagnosis of AKI.
Partial recovery: Recovery of the patient to dialysis independent state regardless of serum creatinine levels.
No recovery: Patient who had anuria and/or oligoanuria of >4 weeks.
A total of 44 female patients of renal cortex necrosis associated with pregnancy-related complications were included in the study. However, five patients were lost to follow up, so were excluded from the analysis.
| Statistical Analysis|| |
Normality of the continuous data was tested using Shapiro–Wilk test. Continuous data were presented in mean ± standard deviation, but in case nonnormal data, median (interquartile range) was used. To compare the means among three groups, one-way ANOVA test was used, in case data were skewed, Kruskal–Wallis H-test was used to compare the distributions. Fisher’s exact test was used to test the association between the variables/compare the proportions as expected frequency in any cell was <5. A value of P <0.05 considered as statistically significant. Data were analyzed using Statistical Package for Social Sciences, version 23.0 (IBM Corp., Armonk, NY, USA).
| Results|| |
A total of 8382 patients were diagnosed to have AKI during this period and those with PAKI were 529 (6.3%). Among those who developed PAKI, a total of 44 female patients, i.e., 8.3% had RCN who were included in the study. The incidence remained around 9.09% between 1999 to 2008 whereas it was around 7.8% between 2009 and 2014. Eighteen females (40.09%) were primigravidas. Nearly 61.3% reported to have received ante-natal care with all patients underwent institutional deliveries. Nineteen (43.1%) patients had vaginal delivery, whereas seven patients underwent dilatation and curettage [Table 1].
Out of these patients, five (11.4%) died, five (11.4%) were lost to follow up, 10 (22.7%) patients showed partial recovery and were dialysis non-dependent, whereas 24 (54.5%) patients became dialysis dependent. The five cases who were lost to follow up were excluded from further analysis.
The average time to presentation from the day of delivery was 8.7 days. All patients required RRT (AKI-RRT). The chief modality of RRT was intermittent hemodialysis or slow low-efficiency dialysis. Continuous RRT was done in two patients.
The etiology of RCN was found to be multifactorial. Sepsis was noted in 16 patients (41.02%) and disseminated intravascular coagulation (DIC) in 11 patients (68.2%). Majority of sepsis was related to puerperal sepsis and septic abortions (n = 6) ie 15.3% in each group whereas 14 patients (31.8%) had retained products of conception. Majority of them were culture-negative sepsis with profound use of wide-spectrum antibiotics before the arrival at our institute. RCN was attributed to PPH in four patients (9.09%). Seventeen patients (43.5%) required packed red blood cell transfusion. Other important cause of RCN was postpartum TMA which was observed in 19 i.e., 48.7%of patients [Table 1].
The maternal mortality was observed in 11.7% with sepsis and multiorgan failure contributing to deaths (n = 5). Puerperal sepsis accounted for four deaths (80%). One death was attributed to septic abortion leading to DIC. Mortality in AKI-RRT group was 100% (n = 5). In terms of fetal outcomes, abortions happened in four pregnancies, 23 pregnancies had good outcome in terms of live birth whereas fetal mortality was noted in 16 neonates (41.02%) who either were premature (<37 weeks of gestation)/had intrauterine death.
Kidney biopsy was performed among pregnancy induced AKI beyond four weeks with no signs of clinical recovery, i.e., oliguria and dialysis dependency. Histology was contributory in 31 patients while CT scan (non contrast/ contrast) alone was contributory in five patients (12.8%) where kidney biopsy was not possible due to coagulopathy. Three patients had undergone kidney biopsy as well as CT scan which showed cortical calcification and/ or hypoattenuated subcapsular rim of renal cortex following contrast injection. CT alone contributed to the diagnosis in five patients (12.8%).
Out of the 39 patients, mean age of the patients was 29.3 ± 5.2 years with a range of 21–40 years [Table 1].
Similarly number of days admitted in the hospital, serum creatinine, number of weeks of pregnancy, time to renal failure from delivery, renal failure to referral days was computed for the three types of the outcomes (dialysis dependent, partial recovery, died). Result indicated that mean value was statistically equal (P >0.05). Similarly, values of the total leukocyte count (TLC), platelet count, reticulocyte count, serum lactic dehydrogenase, bilirubin, serum glutamic pyruvic transaminase, and serum glutamic oxaloacetic transaminase was compared among the outcomes which were statistically equal (P >0.05) [Table 2].
Similarly, out of 39 patients, all patients were dialysis dependent at presentation however 24 patients continued to be dialysis dependent while 10 showed partial recovery. Among 24 patients who were dialysis dependent, 41.7% patients also received plasmapheresis. Among the partial recovery group, 60% patients received plasmapheresis, whereas in the five patients who died 20% received plasmapheresis. Fisher’s exact test revealed that proportions of the patients received plasmapheresis among the groups was not statistically significant (P >0.05). Other factors such as non contrast/CECT, bad obstetrical history, history of renal failure prenatal care access, hypertension, edematous illness, neurologic manifestations, liver involvement, history of preeclampsia, PPH, type of pregnancy outcomes, were not statistically associated with patients outcomes (P >0.05), whereas etiology (TMA/sepsis) was statistically associated with patients outcomes (P <0.05) [Table 3].
| Discussion|| |
Cortical necrosis following pregnancy is not only a dreadful cause for ESRD in young women but also a serious complication in terms of morbidity and mortality. Even with the advancement in the field of medical facilities, antenatal care, a large proportion still land up with this castasrophic result of AKI. Septic abortion, PPH, abruptio placentae, puerperal sepsis, and intrauterine death (IUD) are the major causes (50%–70%) of RCN in developing countries which has become extremely rare in the western world with an incidence of <2% of all cases of acute renal failure. Cortical necrosis can be partial where there is chance of reversibility to a stage of dialysis independency, however complete cortical necrosis has a grave prognosis resulting in dialysis dependency.
Over the years, its incidence even in the developing countries is coming down from 17% to 2.4% which was the observation in our study also. We observed the incidence to be 9.09% between 1999 and 2008 and 7.8% between 2009 and 2014. The trend toward a decline in incidence could be due to regular antenatal checkups with regular monitoring and management of complications such as preeclampsia. Awareness among the pregnant females and decreasing incidences of postabortal sepsis and PPH are also important factors for its decline.
We observed that among the 31 patients who underwent kidney biopsy 35.4% showed evidence of patchy cortical necrosis, whereas 64.5% showed diffuse cortical necrosis. The injury largely depends on the initial insult. Sometimes, juxtamedullary glomeruli (15%–20% of total) may escape destruction, even in the complete cortical necrosis and the early functional return is due to the recovery of this nephron segment. This was observed in two our patient who regained some dialysis independency after 3.4 months after the initial injury. Although RCN in obstetrical AKI may be a dreadful yet some of these glomeruli may undergo hypertrophy with the passage of time, leading to partial renal functional recovery.
It was observed that diffuse cortical necrosis was seen in (72%) cases, whereas patchy cortical necrosis was noted in 28% of patients among patients with RCN (n = 57). It was the cause for 77.1% of cortical necrosis among all cause of RCN (n = 57). Obstetric causes for renal cortical necrosis accounted for 56% and 65.2% of patients in two Indian studies., Other studies have reported an incidence ranging from 10% to 30% of all cases of obstetric AKI compared with only 5% of nongravid patients.
In this study, RCN occurred in 10.2% of early pregnancy AKI and 89.7% of late pregnancy AKI. However, in another study, the incidence was observed to be 18.6% of early pregnancy AKI and 37.8% of late pregnancy AKI.
Etiology for cortical necrosis varies among developed versus developing nations, concealed hemorrhage and placental abruption among developed and sepsis (postabortal and puerperal sepsis) in the latter. Despite better healthcare facilities available in India currently, yet the incidence of sepsis as the cause for RCN is still prevalent, partly because of untrained personals conducting deliveries in the unhygienic environment along with unscrupulous cesarean sections being done with no proper postoperative management.
Diagnosis is made based on clinical presentation with failure to recovery beyond four weeks with histological evidence of cortical necrosis as observed in 79.4% of our population. Biopsy is the gold standard for diagnosis and to differentiate from acute tubular necrosis which has a reversible renal outcome besides helping us differentiate from other causes like TMA, wherein early plasmapheresis may be beneficial. Therefore, a careful history and at times in doubt despite having evidence of hemolysis with suspicion of TMA early plasmapheresis may help with better renal and maternal outcome. In the study population, TMA was a prominent cause 48.7% for RCN which at early stage could have been treatable and reversible.
At times, kidney biopsy may not be possible due to DIC or coagulopathy due to other causes or patient not consenting, non contrast CT/CECT scan has emerged as a good noninvasive modality of early diagnosis of RCN with the characteristic finding of the presence of cortical calcification/hypoattenuated subcapsular rim of renal cortex following contrast injection. Since contrast can further worsen renal injury, it can be avoided, and at times, a noncontrast CT scan can serve as a more sensitive modality in picking up cortical calcification, though it may not be always there. In the study population, histology helped in diagnosis in 79.4% while CT and histology contributed in diagnosis in three patients ie (7.6% while CT (noncontrast/contrast CT) alone helped in clinching the diagnosis in five ie 12.8% patients. Recently, contrast enhanced ultrasound has been proposed as a useful modality for the early diagnosis of cortical necrosis and this modality has a high chance in picking up such patients.
The most important cause for RCN in our study population seemed to be postpartum TMA. This is a less recognized problem in developing countries which may be triggered by infections and needs to be evaluated and managed appropriately. This observation may be because of a referral bias or maybe because a large number of patients presenting with RCN may have been having the inherent problem superimposed by sepsis. Other reasons for RCN in our subcontinent may be hypovolemia due to excessive blood loss or an endothelial injury either directly (eclampsia, placental abruption) or through release of various circulating factors such as endotoxin in patients with sepsis (septic abortion and puerperal sepsis).
These causes are avoidable and prevention can really put an end to such a disastrous outcome of a venerable state like motherhood. Strict implementation of measures for pregnancy monitoring including complications and delivery by trained personnel under hygienic environment can be of great benefit in reducing its incidence as has been achieved in developed countries.
A healthy mother stands for a healthy family. However there occurs increasing incidence of maternal mortality 11.7% and morbidity, i.e., infections contributing in prolonged stay in 22.7% while dialysis dependency in 61.5% secondary to RCN in our study which shows a grim prognosis. Literature suggested a high incidence of mortality (86%) in RCN among earlier studies with a decline over time with better management of obstetrical care in terms of sepsis, other complications of pregnancy and early initiation of dialysis. It seems essential to improve our pregnancy related care in order to achieve better maternal and fetal outcomes.
| Conclusion|| |
Strategies need to be implemented in reducing the preventable causes for RCN which is not only catastrophic in terms of renal outcomes but also for social and psychological perspectives as well. Prevention is always better than cure and hence improvement in health-care facilities in terms of healthy conduction of delivery undertrained personnel and better management of pregnancy-related complications can have good maternal as well as fetal outcomes
Conflict of interest: None declared.
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Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
[Table 1], [Table 2], [Table 3]
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