Örebro University Programme in Medicine Independent Project, 15.0 HP June 2020
Major Complications After Percutaneous Renal Biopsy at Örebro
A retrospective observational study
Author: Joel Bringman Supervisor: Nektarios Karefyllakis, Consultant of Medicine, Helsingborg Hospital
BACKGROUND: The most accurate method to diagnose many renal diseases is by performing an ultrasound guided percutaneous kidney biopsy. While being an invasive procedure it is generally considered to be safe and major complications, such as large hematomas requiring blood transfusion, are rare but occur.
AIM: To investigate whether the histological diagnosis following the percutaneous renal biopsy was correlated to the potential major complications after the procedure. We also studied if there were any predictive factors for the incidence of major complications.
MATERIALS AND METHODS: Data from the Swedish Renal Registry were collected for this retrospective observational study. Biopsy records from 2015 – 2019 were added, which included the patient’s clinical status, histological diagnosis and possible major complications. RESULTS: 146 subjects, 58 females and 88 males aged 18-87 were included. Major
complications were experienced in 8.9% of the cases, where crescentic glomerulonephritis and thrombotic microangiopathy were the most common histological diagnoses affected. A low hemoglobin level was the only significant predictor for the outcome.
CONCLUSIONS: Patients being diagnosed with crescentic glomerulonephritis or thrombotic microangiopathy seem to be at higher risk for major complications. Our data also suggest that a low level of hemoglobin before the percutaneous renal biopsy is increasing the probability.
PRB – Percutaneous Renal Biopsy LM – Light Microscopy
IM – Immunofluorescence EM - Electron microscopy MC – Major Complication NC – No Complications
RBx – Real-time ultrasound guided percutaneous renal biopsy BBx – Blind percutaneous renal biopsy
eGFR – Estimated Glomerular Filtration Rate SCr – Serum Creatinine
Hb – Hemoglobin BP – Blood Pressure
SBP – Systolic Blood Pressure DBP – Diastolic Blood Pressure SRR – Swedish Renal Registry
NSAID – Nonsteroidal Anti-Inflammatory Drug aPTT - activated Partial Thromboplastin Time CrGN – Crescentic Glomerulonephritis TMA - Thrombotic Microangiopathy vWF - von Willebrand factor
GPIb - Glycoprotein Ib TXA2 – Thromboxane A2 ADP - Adenosine Diphosphate
TTP – Thrombotic Thrombocytopenic Purpura HUS – Hemolytic Uremic Syndrome
Table of Contents
Introduction ... 5
Indications and contraindications for biopsy procedure ... 5
History of the PRB ... 5
Major complications ... 7
Risk factors for PRB complications ... 7
Aim ... 7
Objective ... 7
Hypothesis ... 7
Material and Methods ... 8
Study design and population ... 8
Biopsy procedure ... 8 Statistical analysis ... 9 Ethical considerations ... 9 Results ... 10 Baseline demographic ... 10 Histological diagnoses ... 11 Major complications ... 11
Predictive factors for major complications ... 14
Discussion ... 14
Conclusion ... 16
The diagnosis of many renal diseases is most accurately made by performing an ultrasound guided percutaneous kidney biopsy (PRB). Even though different blood tests and clinical presentations can tell us a lot about a patient’s status, the gold standard for diagnosis of renal disease is the PRB .
Three different methods are used to analyze the biopsy samples: Light microscopy (LM), Immunofluorescence (IM), and Electron microscopy (EM) [1,2]. When analyzing the samples, the examiner inspects the three different histological compartments to verify the location of the damage: glomerular, vascular or tubulointerstitial compartment. Based on these histological findings, together with the patient’s clinical history and status, the physician can make the diagnosis.
While being an invasive procedure the PRB is generally considered to be safe and major complications (MCs), such as severe bleeding that requires transfusion, are rare. Minor complications such as hematuria, small hematomas and pain are more frequent, but do not usually require intervention [3–7].
Indications and contraindications for biopsy procedure
Indications for PRB includes non-nephrotic proteinuria with or without hematuria, nephrotic syndrome, acute nephritic syndrome, and unexplained acute renal failure. In Sweden, isolated hematuria is usually not an indication for PRB, since it rarely alters the therapy for the
According to the local guidelines of Region Örebro Län, contraindications for PRB includes renal tumors, multiple renal cysts, ongoing septic infection, uncontrolled high blood pressure (BP), single kidney, a platelet count less than 100 x 109/L or the use of antiplatelet
drugs/anticoagulants within one week of the procedure.
History of the PRB
In 1951, the Danish physicians Iversen and Brun  published an article describing the use of a radiographically lead aspiration biopsy technique for sampling of renal tissue. Until that point the percutaneous aspiration procedure had only been used for biopsies of tumorous tissue and, to a lesser extent, for examination of liver and spleen parenchyma.
6 The technique was proven to be safe and only mild complications were reported by the
authors. However, the yield of representative biopsies was low (about 50-70%) [9,10]. According to Kark and Muehrcke  (1954), this was related to the upright position of the patient, which due to the mobility of the kidney made it more difficult to locate anatomically. In an attempt to address the issue and increase the diagnostic yield from the biopsies, Kark and Muehrcke introduced a new biopsy technique where the patient was instead placed in a prone position. This would put the kidneys more fixed against the tissues of the back, making them more immobilized and accessible for the physicians, leading up to 96% of representative biopsies.
Instead of the aspiration needle used by Iversen and Brun , Kark and Muehrcke utilized a version of the Silverman-Vim cutting needle (called the Franklin-Vim-Silverman needle ), modified to trap the sampled tissue without having to twist the instrument. They also used a long exploring needle before the actual biopsy needle to verify the location of the kidney [11,12]. Later, the Tru-Cut needle (1968) became the popular choice .
In the early 1970s the use of ultrasound was described in the literature as a simple and safe addition to the percutaneous kidney biopsy procedures [14,15]. Then, in 1982, Lindgren  presented the use of an improved, automated version of the Tru-Cut needle, which was spring-loaded and could fire the obturator and cannula from the same device, thus eliminating the need for the clinician to use both hands for the procedure.
Comparative studies have shown the benefit of the real-time ultrasound guided PRB (RBx) vs the blind approach (BBx) [17–20]. In the BBx the ultrasound was used only to initially locate the kidney and to mark the entry point for the needle. The needle was then inserted blindly based on the markings made beforehand. To verify the correct location, the needle was monitored for movement influenced by the patient’s respiration. If no respiratory movements of the needle occurred, the procedure was repeated. In a study by Maya et al.  (2007) the number of glomeruli obtained with the RBx technique was 18 ± 9, and with the BBx
technique 11± 9.
However, looking at the major bleeding complications needing transfusion, the results differs between studies. Maya et al.  reported a statistically significant result of 0% (RBx) vs 11% (BBx), whereas Pongsittisak et al.  showed no difference between the groups: 7.7% (RBx) vs 7.0% (BBx). In a similar study by Cozen et al.  from 1992, no significant discordance was found between the techniques (1% vs 4%), but it was postulated that the
7 results could be affected by factors such as higher age and more comorbidities in the RBx group.
In the recent years multiple studies at different centers around the world have evaluated the incidence of complications related to the PRB procedure [3–7,21–26]. Although the definition of major vs minor complications differs somewhat, most authors agree that an MC is an incident following the biopsy procedure that requires intervention, such as a blood transfusion or surgery [6,24]. Minor complications on the other hand are defined as less severe and spontaneously resolving without intervention (e.g. flank pain or gross hematuria) [5,26]. According to literature [3,4,6,7,24], death following PRB is extremely rare. In a meta-analysis from 2012  a total of 8,971 biopsies from 29 different studies were analyzed. The death rate was only 0.02%.
Risk factors for PRB complications
The risk factors for developing complications after PRB include older age, female gender, hypertension, low estimated Glomerular Filtration Rate (eGFR), low hemoglobin (Hb) and high serum creatinine (SCr). However, the evidence for most of these predictors is disputed and differs from study to study. The strongest risk factor seems to be a low Hb [4,6,24,25,28].
The main objective of this study is to determine if the diagnosis established following the percutaneous kidney biopsy has any correlation to the potential MCs ensuing the procedure. We are also analyzing whether the patients’ clinical data (e.g. BP or Hb) has any connection to the incidence of MCs.
Material and Methods
Study design and population
In this retrospective observational study, we obtained data from the Swedish Renal Registry (SRR) which contained data of kidney biopsies from native kidneys performed at Örebro University Hospital between January 2015 and December 2019. There were 146 patients included whereof 58 female and 88 male, between 18-87 years old. The exclusion criterium was a non-representative biopsy where too few, or no glomeruli were obtained. All subjects gave their informed consent to having their data anonymized and used for statistical purposes by health care personnel.
The information collected included: age, gender, date of biopsy, diagnosis, MCs (if
applicable), pre-biopsy systolic and diastolic BP, pre/post-biopsy Hb, SCr, and eGFR. MCs were defined as severe hematomas and bleeding that required blood transfusion, infections, hydronephrosis, nephrectomy and death. Minor complications were categorized as post-procedural events that did not require intervention such as pain, hematuria, and minor hematomas. Minor complications were not included in this study.
The percutaneous kidney biopsies were performed according to the local guidelines of Region Örebro Län. All biopsies were performed by radiologists at Örebro University hospital. Medications such as antiplatelet drugs, NSAID and Omega 3 were discontinued seven days prior, whereas anticoagulants (e.g. Warfarin) were stopped five days before the intervention. Within one week before the procedure, laboratory tests were performed to ensure no
contraindications for the biopsy. The tests included: BP, Hb, platelet count, prothrombin complex, activated partial thromboplastin time (aPTT), SCr, blood typing and antibody screening. A BP above 160/90 was contraindicated and had to be adjusted, preferably using calcium antagonists. If the patients’ SCr levels exceeded 150 µmol/L, 0.3 µg/kg OctostimⓇ (desmopressin) was administered subcutaneously one hour before the biopsy to reduce bleeding time and the risk of related complications . The patients were required to be fasting four hours prior but were administrated a glucose buffer during the biopsy.
Medications with anxiolytic action, such as 5-10 mg StesolidⓇ (diazepam), were given orally leading up to the procedure.
9 The patients were put in a prone position with a pillow under the abdomen in order to
decrease lumbar lordosis. Local anesthesia was applied subcutaneously. With real-time ultrasound guidance, an automated spring-loaded biopsy device with 16G biopsy needles (1.66 mm diameter, 10 mm2) was used to retrieve two renal biopsies. The lower pole of the left kidney was the preferred target, but due to anatomical variance and organ orientation this was not always achieved.
The first biopsy was added to a test tube containing a 4% paraformaldehyde buffer and was later used for electron microscopy. The second one was applied on a saline moisturized compress, put in a closed jar, and sent to the laboratory for analysis. If the second biopsy were to be transported to another facility, it was instead added to a Zeus solution (tissue fixative)  which increased the sample viability up to five days. If only one representative biopsy was obtained it was prioritized for the Zeus solution. A representative biopsy was defined as containing 12-15 glomeruli.
After the procedure the patients were closely monitored at timed intervals with regards to BP, heart rate, and needle puncture location. The patients’ urine was also checked for blood or clots which could indicate a more severe complication. One day after the procedure the patients’ Hb and SCr levels were assessed again.
The data collected from SRR was processed using Microsoft Excel for Mac 16 and
subsequently analyzed using JASP (version 0.11.1). Variables were ordered and mean/median values obtained using descriptive statistics. The Shapiro-Wilks test was used to determine whether data was normally distributed, followed by the Mann-Whitney U test to compare nonparametric, continuous data. The chi-square test was chosen for categorical data. To determine potential predictive factors for MCs, uni- and multivariate logistic regression analyses were performed. A p-value of < 0.05 was considered statistically significant.
This study is reviewed and approved by the SRR. All subjects in the study population have given their informed consent, allowing their data to be used for statistical purposes by health care personnel. Any data that could potentially be used to identify a specific individual have been removed.
10 However, since some of the histological diagnoses presented in the study only have one or two subjects, and there are relatively few subjects in total, there is a potential possibility that the patients, or their relatives, may be able to identify themselves.
Between January 2015 and December 2019, 146 patients who underwent PRB at Örebro University Hospital were included in the study (table 1). Mean biopsies per year was 29.2, with 2019 having the highest number of procedures (n=33). Of the subjects, 39.7% were female and 60.3% male with a median age of 46 and 52 respectively.
In the population, 47% (F=43%, M=49%) had an SBP of >140 mmHg and were considered hypertensive. Diastolic hypertension (DBP >90 mmHg) were seen in 22% (F=14%, M=27%). Before the PRB, 58% of the population were considered anemic (Hb <120 g/L female, <130 g/L male), and after the procedure, 67%.
Table 1. Baseline demographic and clinical data
Mean ± SD or n Median (min, max)
Patients, n 146 Female 58 (39.7%) Male 88 (60.3%) Age, years 51.6 ± 18.3 50.5 (18, 87) Systolic BP, mmHg 133.6 ± 15.8 135 (100, 160) Diastolic BP, mmHg 78.7 ± 9.6 80 (50, 105) Pre-biopsy Hb, g/L 123 ± 21.6 121 (79, 183) Post-biopsy Hb, g/L 114.9 ± 22.7 115 (62, 176) SCr, µmol/L 259.7 ± 283.7 159 (49, 2214) eGFR, mL/min/1.73m2 45.6 ± 35.3 35.6 (1.4, 134)
SD = Standard Deviation, BP = Blood Pressure, Hb = Hemoglobin, SCr = Serum Creatinine, eGFR = estimated Glomerular Filtration Rate
21 different histological diagnoses (and one normal kidney) were yielded from the 146 biopsies (figure 1). The most common diagnosis was IgA nephropathy (n=24, 16.4%) followed by crescentic glomerulonephritis (CrGN) (n=16, 11.0%).
Figure 1. Number of histological diagnoses (green) and associated complications (red) following the
percutaneous renal biopsy.
Of the 146 biopsies performed, 13 (8.9%) had MCs. Per year the mean MC rate was 2.6 (± 2.51), where in 2015 and 2017 there were 0, 2018-2019 had 5 each, and 2016 had 3. Both genders were affected equally (F=8.6%, M=9.1%, p=0.922). The age of the patient did not influence the outcome (p=0.650). However, the age range with the highest frequency of MCs was 71-80-year olds, with an incidence of 17.4% (n=4/23). There were no complications (NC) in the oldest age group 81-90 (n=0/4).
The most common MC was a hematoma requiring 2 units of blood transfusion (6.8%, n=10) (table 2). The histological diagnosis most associated with MC was CrGN (2.7%, n=4) followed by thrombotic microangiopathy (TMA) (2.1%, n=3) (figure 1, 2).
0 5 10 15 20 25
Table 2. Major complications after percutaneous renal biopsy
n Female Male
Patients 146 58 88
Major complication 13 (8.9%) 5 8
Hematoma requiring blood transfusion, 1 unit 2 (1.4%) 1 1 Hematoma requiring blood transfusion, 2 units 10 (6.8%) 4 6
Hematoma, infection 1 (0.7%) 0 1
Figure 2. Rate of major complications in relation to no complications with regards to histological
diagnosis following the percutaneous renal biopsy. The diagnosis with the highest relative complication rate is to the left.
All patients with MC were anemic both before and after the biopsy procedure (p=0.001 vs p=0.008) (table 3). In fact, all patients who were later diagnosed with TMA (n=5) and 14 out of 16 patients with CrGN (p=0.003) had a Hb level <120 (female) or <130 (male), both before and after the procedure. The MC group had a median Hb loss of -20 g/L, whereas the NC had a loss of median -7 g/L. This group even had 18 subjects gaining Hb after the procedure (median=2, range 1-8 g/L). 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Complications No Complications
13 The SBP did not show any discrepancy between the patients with MC and those with NC (median 140 vs 135 mmHg, p=0.906). The patients with MC were as likely to have hypertension as not having it (n=7 vs n=6, p=0.582).
SCr differed significantly between the NC group as compared to MC (median 144 vs 393 µmol/L, p < 0.001). No patient with a SCr < 104 µmol/L had MC (n=45). However, the ranges were large in both (NC: 49-2214 vs MC: 104-1086 µmol/L), and the largest outlier (2214µmol/L) was found in the NC group.
The median eGFR was significantly higher in the NC group (39.7 vs 11.7 mL/min/1.73m2, p < 0.001), but the ranges were large here as well (1.4-134 vs 4.0-65.8 mL/min/1.73m2).
Table 3. Baseline clinical data and complications
No complications median (min, max)
median (min, max) p-value
Patients, n 133 13 Female 53 5 Male 80 8 Age, years 51 (18, 87) 50 (22, 80) 0.650 Systolic BP, mmHg 135 (100, 160) 140 (110, 160) 0.906 Diastolic BP, mmHg 80 (50, 105) 80 (68, 90) 0.484 Pre-biopsy Hb, g/L 124 (90, 183) 91 (79, 128) < 0.001 Female 118 (94, 163) 88 (83, 111) 0.010 Male 127.5 (90, 183) 94.5 (79, 128) < 0.001 Post-biopsy Hb, g/L 116 (81, 176) 75 (62, 119) < 0.001 Female 112 (81, 149) 73 (66, 85) < 0.001 Male 121.5 (82, 176) 76 (62, 119) < 0.001 Hb Change g/L -7.0 (-27, 8) -20.0 (-31, -6) < 0.001 SCr, µmol/L 144 (49, 2214) 393 (104, 1086) < 0.001 eGFR, mL/min/1.73m2 39.7 (1.4, 134) 11.7 (4.0, 65.8) < 0.001
BP = Blood Pressure, Hb = Hemoglobin, SCr = Serum Creatinine, eGFR = estimated Glomerular Filtration Rate Values are given in median (min, max). The Mann-Whitney U test was used to obtain p-values. Statistically significant values in bold.
Predictive factors for major complications
Both univariate (table 4) and multivariate (table 5) logistic regression analyses were performed in order to identify any predictors for major complications. When considered alone, a lower Hb, eGFR and a higher SCr were predictive of major complications following the PRB. However, when analyzed using a multivariate, forward method, only pre-biopsy Hb (OR=0.848) and Hb change (OR=0.732) came out significant predicting that a lower pre-biopsy Hb and a greater Hb reduction (i.e. more bleeding) increased the risk for major complications.
Table 4. Baseline clinical data predictive of major complications (univariate)
Risk factor OR 95% CI p-value
Age 1.007 0.976-1.039 0.659 Pre-biopsy Hb 0.893 0.844-0.946 < 0.001 Post-biopsy Hb 0.829 0.756-0.909 < 0.001 Hb Change 0.817 0.744-0.897 < 0.001 SCr 1.002 1.001-100.4 0.008 eGFR 0.951 0.916-0.988 0.009 SBP 1.001 0.966-1.038 0.948 DBP 0.985 0.929-1.045 0.615
BP = Blood Pressure, Hb = Hemoglobin, SCr = Serum Creatinine, eGFR = estimated Glomerular Filtration Rate, OR = Odds Ratio, CI = Confidence Interval. A univariate logistic regression test was performed to obtain p-values. Statistically significant values in bold.
Table 5. Baseline clinical data predictive of major complication (multivariate)
Risk factor OR 95% CI p-value
Pre-biopsy Hb 0.848 0.772-0.933 < 0.001
Hb Change 0.732 0.615-0.870 < 0.001
Hb = Hemoglobin, OR = Odds Ratio, CI = Confidence Interval. A multivariate logistic regression test was performed to obtain p-values. Statistically significant values in bold.
In this study we found that patients being diagnosed with either TMA or CrGN have an increased risk of MCs following a PRB.
15 The bleeding tendency in TMA could be explained by the molecular pathologies behind the disease (e.g. TTP/HUS), in which a thrombocytopenic state develops due to abnormal platelet aggregation [31,32]. With CrGN, the predisposition to bleed may be explained by the loss of integrity to the small vessels and glomeruli that is due to the different vasculitides or anti-GBM antibodies in the disease .
Why the most common histological diagnosis, IgA Nephropathy, did not result in any MC may have to do with the slightly younger age of patients in that group (mean=37.8,
median=33) vs the TMA group (mean=39.6, median=44) or the CrGN group (mean=63.5, median=69). It can also be explained by the underlying pathology and histological changes, that may not be as severe as with TMA or CrGN .
Considering the predictive factors, our results show that a low Hb increased the risk for MC. A low Hb, and potential anemia, can increase the bleeding tendency by virtue of a low erythrocyte count. In anemia, the platelets tend to travel further away from the lining
endothelium and more towards the center of the vessel, resulting in less chance of adhesion to the vessel wall in the event of tissue damage . Additionally, the pathophysiology behind TMA could also explain the increased risk for bleeding as the thrombi tend to destroy the erythrocytes as they pass by in the microvasculature . Thus, our finding that low Hb is a predictive factor for MC supports this, as is also evident in other studies [3,6,7,21,27]. Many studies state hypertension as a risk factor for complications following the PRB, although this is disputed [4,6,24,25]. In our study, we did not see any correlation between having a high SBP and MC. Since the cut off criterium for PRB in our center was SBP >160 mmHg, we can speculate that many patients assumably received antihypertensive drugs prior to the procedure in order to normalize their BP. However, this information is not included in the data extracted from the SRR.
The mechanism behind a higher SCr and the potentially increasing risk of transfusion-needing hematoma (uremic bleeding), is according to literature multifactorial . Nonetheless, it includes a defect relationship between von Willebrand factor (vWF) and glycoprotein Ib (GPIb). Either the expression of GPIb is lower on circulating platelets or the affinity for it to bind to vWF is decreased. This phenomenon may lead to less activation for breakdown of arachidonic acid and thus less production of the platelet aggregating substances thromboxane A2 (TXA2) and adenosine diphosphate (ADP), which may progress to a greater bleeding tendency [35,36].
16 When comparing the MC incidence in our study (8.9%) with similar studies done previously, we can see that our center has higher level. In a large German study from 1998 by Hergesell et al. , 1,090 PRBs were included with an MC rate of 0.36% (4/1090). A similar article was published in 2014 by Korbet et al.  where they had MCs in 6.6% of the cases, with a population of 1,055 subjects. One of the larger retrospective studies was done by Lees et al.  in 2017. In the study they looked at renal biopsy data from 2000 – 2014 where 2,563 subjects were included. The MCs reported there were 2.2%. Azmat et al.  had a slightly higher frequency of 7.4% MCs, although this was a smaller study with only 220 subjects. The rate of MC in our center varied greatly over the five years that are included in our study. If we were to only include the years 2015 and 2017, we would present a ratio of 0% MC. On the other hand, our MC rate was as high as 17.9% in 2018 and 15.2% in 2019 (n=5 both years). Why the discrepancy is this large, we cannot be certain. One hypothesis is considering a low Hb as a predictive factor leading up to the PRB. The rate of MC per year seems to be correlated to the prevalence of anemic patients. During the years with NC, the prevalence of patients with anemia were lower (2015=41.7%, 2017=48.3%) compared to the years with MCs (2016=53.1%, 2018=71.4% and 2019=72.7%).
There could be many limitations to this study. One is the fact that there may be other
variables, not included in the data, that could be predictive of major complications. We have, for example, no information regarding the specific biopsy indication for each patient.
Considering the variance of complications between the different years in our center, we don’t know of any confounding comorbidities that may be of interest, other than the clinical data included in the study. Another example is that the data from the SRR did not include the information about platelet count, which means we cannot study that potentially predictive factor for MC. All we know is that the platelet count for every patient is greater than 100 x 109/L, since the PRB is otherwise contraindicated. Perhaps the human factor could play a part as well, such as the skill of the radiologist, which could have varied between procedures.
In our material, patients with the histological diagnosis of TMA or CrGN were especially susceptible for MCs following the PRB. We also found that having a low Hb before the procedure was a predictive factor. The correlation may be explained by the fact that patients with TMA and CrGN most often suffer from anemia.
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