Hyperechogenic renal parenchyma in potential live related kidney donors: Does it justify exclusion?

OBJECTIVES: To assess the predictive importance of ultrasonic grade 1 hyperechogenicity in potential live related kidney donors in the absence of urinary abnormalities and with perfect renal function. SUBJECTS AND METHODS: The study included 34 potential living related kidney donors with this abnormality; their mean (SD, range) age was 32.7 (8.45, 23-48) years. Ten matched healthy donors with normal ultrasonographic appearance of the kidneys were studied as controls. All cases were thoroughly investigated, including measuring glomerular filtration rate by isotopic scintigraphy. The renal reserve was estimated by dopamine and amino-acid infusion in all subjects (study and control groups). A percutaneous renal biopsy was taken from 17 subjects in the abnormal echogenicity group and open renal biopsy was taken from eight of the control subjects.
RESULTS: The renal reserve was comparable in both groups. Abnormal histopathological changes were found in seven subjects (41%) of the abnormal echogenicity group, i.e. partial glomerulosclerosis in one, mesangial thickening in two, interstitial fibrosis in one, focal tubular atrophy in one, immunoglobulin (Ig M) immune deposits in three and IgA in one. Only one subject in the control group showed mild mesangial thickening.
CONCLUSION: Grade 1 echogenicity might be a sign of unrecognized kidney disease. Renal biopsy is mandatory when such related donors are the only available ones. Abnormal histopathology contraindicates donation.

Introduction

Ultrasonography (US) is usually the first imaging procedure used to evaluate the kidneys in patients with renal diseases. For many years the relative reflectivity of the renal cortex compared to that of the adjacent right lobe of the liver and the spleen was used to indicate normality of the kidney and to diagnose diffuse renal disease [1]. This was based on the assumption that normal renal cortex has a reflectivity less than that of adjacent organs. This concept remained current in several reports [2,3]. Others reported that these views have been challenged, by suggesting that grade 1 renal cortical echogenicity can occur in normal kidneys and might be absent in a large proportion of those patients with active renal disease [4].

In a previous study comparing US and pathological findings in 201 patients with different forms of renal diseases with various stages of chronic kidney disease, there was a significant correlation between cortical echogenicity and glomerular sclerosis or tubular atrophy [5]. Surprisingly, there was no correlation between echogenicity and interstitial fibrosis. Another study reported that renal cortical echogenicity was correlated with the severity of histological changes in renal parenchymal diseases, such as overall sclerosis and tubular atrophy [6].

Although different parenchymatous renal diseases should have an effect on the US variables, there are no reports studying the expected parenchymatous disorders in healthy potential kidney donors having grade 1 hyperechogenic renal parenchyma. The presence of histopathological findings will contraindicate donation even if they are the only available or highly motivated donors.

In the present study we correlated histological findings with the US findings of grade 1 echogenicity in several potential apparently healthy live related kidney donors.

Subjects and methods

Over 3 years of our routine practice evaluating renal transplant preparation, 34 of 700 potential apparently healthy live related kidney donors were found to have grade 1 renal parenchymal echogenicity during routine US evaluation. These 34 potential donors, together with 10 age- and sex-matched controls comprising healthy kidney donors with normal US appearance of kidneys, were included in the study. The study protocol was approved by the institutional ethical committee.

These donors had a history taken, a thorough clinical examination and laboratory assessment, including repeated urine analysis at least three times on different days, and renal profile (serum creatinine, endogenous chemical creatinine clearance, sodium, potassium, calcium, phosphorus and uric acid determination). The US evaluation was carried out and interpreted by two senior experienced radiologists.

All US variables were evaluated and echogenicity was quantified as previously described [6]. The GFR was measured by MAG3 scans. The renal functional reserve was then estimated by simultaneous infusion of dopamine (2.5 μg/kg/min) and 10% of the multi-amino-acids preparation Vamin N (80 mL/h). During the procedure, a diuresis of at least 100 mL/h was maintained with oral fluids. After 6 h of combined dopamine and amino-acids infusion, when the GFR reached its maximum, isotope clearance was measured by MAG3 scans. The renal functional reserve was calculated as the difference between the isotope clearance values on isotope scan before and after the infusion of dopamine and amino acids [7].

Percutaneous kidney biopsies were taken from those who were considered the only available related donors (17 of 34) among the study group. Donors who showed any histopathological abnormality were excluded from donation. In addition, open kidney biopsies were taken ex vivo just before transplanting the allograft in eight of the 10 controls.

For the study group, all specimens were examined by light microscopy (LM), and immunofluorescence (IF) was used in 12 subjects. The eight subjects of the control group were examined by LM only. Tissue for LM examination was prepared in the conventional manner. Each biopsy contained at least eight glomeruli. Biopsies were evaluated in terms of glomerular sclerosis, mesangial thickening, tubular atrophy, vascular wall thickening and interstitial fibrosis. Each variable was measured in every biopsy using a semi-quantitative grading scale of 0–5, where the percentage of biopsy affected was: 0, ⩽5%; 1, 6–20%; 2, 21–40%; 3, 41–60%; 4, 61–80%; and 5, >80% [5].

Snap-frozen tissue was used for glomerular localisation of immunoglobulins and complement; reagents included antibodies specific for IgG, IgA, IgM, C3, and C1q, κ light chains, λ light chains and fibrinogen. The staining was assessed using direct IF. All the antibodies used were labelled with fluorescence-isothiocyanate, then tissues were examined by IF microscopy. All cases were scored by one senior experienced nephropathologist. For quality assurance, random cases were reviewed by another nephropathologist, with excellent agreement.

The groups were compared using Chi-square, Fisher’s exact and Student’s t-test, as appropriate, with P < 0.05 taken to indicate statistical significance.

Results

Of 700 healthy potential living related kidney donors, 34 (4.8%) were found to have grade 1 renal parenchymal echogenicity despite repeated normal urine analysis and perfect renal function. The characteristics of these donors and those of the 10 age- and sex-matched controls with normal US appearance of kidneys are summarised in Table 1.

Table 1

Characteristics of donors and radioisotope variables before and after infusion of dopamine and amino acids, in the study and control groups; none of the studied variables had statistically significant differences between the groups.

Variable	Study	Control
No.	34	10
Mean (SD, range)
Age, years	32.65 (8.45, 23–48)	31.35 (9.17, 22–50)
Sex (male/female)	27/7	8/2
Consanguinity, n
Parents	3	3
Siblings	1	–
Brother	21	4
Sisters	6	2
Husband	1	–
Wife	1	1
Cousin	1	–
Mean (SD)
Serum creatinine (mg/dL)	0.91 (0.15)	0.93 (0.17)
Creatinine clearance (mL/min)	114.6 (1.92)	116.1 (9.71)
GFR (mL/min)
Basal condition	118.2 (14.3)	127.0 (11.2)
After infusion	133.7 (13.0)	137.6 (12.1)
Renal functional reserve (%)	18.1 (5.3)	15.1 (7.7)

The GFR was estimated by isotope clearance before and after maximal vasodilating stimuli, induced by infusion of dopamine and amino acids. The functional renal reserve for both groups was calculated as the increase in GFR above the basal values, and it was comparable in both groups (Table 1).

Seven subjects in the study group and only one in the control group had histopathological findings with various degrees of glomerular injury. This ranged from mild mesangial thickening to glomerular sclerosis, as well as tubular atrophy and interstitial fibrosis. These changes are listed in Table 2; four representative cases (three from the study group, 1, 2 and 4; and one of the control group that had glomerular pathology, no. 8) are described below.

Table 2

Histopathological abnormalities in the study and control groups.

Subject	Glomerular	Tubular atrophy	Interstitial fibrosis	IF
1	Sclerosis (1)	N	N	–
2	MT (1)	N	N	IgA+++
3	N	(1)	N	–
4	MT (1)	N	N	−ve
5	N	N	(1)	IgM +ve
6	N	N	N	IgM +ve
7	N	N	N	IgM +ve
8 (control)	MT (1)	N	N	Mild focal mesangial IgM deposits

(n), score; MT, mesangial thickening; N, normal findings.

Case 1: A 21-year-old man was strongly motivated to donate a kidney to his brother. The biopsy specimen showed a score 1 glomerular sclerosis, while tubules, interstitium and blood vessels were normal (Fig. 1).

Figure 1

Segmental patch of sclerosis, periodic acid-Schiff ×200.

Case 2: A 27-year-old man, a potential kidney donor for his sister, had a biopsy showing mesangial thickening, score 1 (Fig. 2) and IF microscopy showed heavy mesangial IgA deposits.

Figure 2

Mild segmental mesangial thickening, periodic acid-Schiff ×400.

Case 4: A 30-year-old woman was eager to donate a kidney for her sister; the histopathology showed only focal tubular atrophy of ≈10% of the biopsy specimen (Fig. 3).

Figure 3

Mild focal tubular atrophy, periodic acid-Schiff ×200.

Case 8 (control): A 45-year-old woman was donating a kidney to her son; the biopsy showed mild focal interstitial fibrosis affecting ≈15% of biopsy tissue (score 1; Fig. 4), and IF showed mild mesangial IgM deposits. No specific pathology was identified in her recipient, as his kidney was shrunken and fibrotic.

Figure 4

Mild focal interstitial fibrosis, Masson trichrome ×200.

Discussion

The lack of cadaveric donors has led to a dependence on living kidney donors. At the same time, indications for living kidney donation have been expanding in terms of donor medical status, e.g. those with mild diabetes and slight proteinuria, as well as human leukocyte antigen matching and ABO compatibility [8].

In Egypt, the absence of a cadaveric programme and the insistence of strongly motivated donors to donate their kidneys have prompted us to study the significance of US findings of grade 1 echogenicity in apparently healthy live related kidney donors. To the best of our knowledge, there are no reports discussing this issue in such a way among this particular group of potential healthy kidney donors.

Previously we reported the problem of asymptomatic microscopic haematuria in potential live related kidney donors. A renal biopsy was taken from 30 donors and we found that hereditary nephritis (with or without nerve deafness) was the most common cause of microscopic haematuria, followed by isolated C3 deposit disease, IgA nephropathy and IgM nephropathy. We concluded that relatives of uraemic patients with asymptomatic microscopic haematuria should not be considered for kidney donation, even if they are strongly motivated [9].

Recently, international standards for candidates for live kidney donors, including conditions such as hypertension, obesity, dyslipidaemia, diabetes and renal function, were published in the Amsterdam Forum & Guidelines [10]. However, we often encounter cases in which the propriety of living kidney donation is difficult to decide because the situation is very marginal or unusual, and the donor candidate might be very eager to donate. The finding of renal parenchymal echogenicity in a potential live related kidney donor is an example of such situations.

Our results showed comparable GFR levels, as estimated by isotope clearance, in the group with grade 1 echogenicity and in controls. Moreover, the response of the kidneys to infusions of dopamine and amino acids was similar in the two groups; both groups had a similar increase in GFR. The estimated mean functional reserve was 18.6% for the echogenicity group and 15.5% for controls. These results are similar to that of Bosch et al. [11] and greater than that of Tapson et al. [7], indicating that grade 1 echogenicity does not adversely affect renal functional reserve.

Although safe and noninvasive procedures are recommended in preparation for live kidney donation, kidney biopsies might be mandatory for evaluating the condition of the prospective donor kidney. The biopsy specimens showed minor degrees of changes in seven subjects in the echogenicity group and in only one in the controls. These changes were partial glomerular sclerosis, mild mesangial thickening, mild focal tubular atrophy and mild focal interstitial fibrosis. IF microscopy showed IgA deposits in one subject and IgM deposits in three in the echogenicity group.

Subjects with grade 1 hyperechogenicity and positive histopathological data (although minor) were not used in our series as donors. This might be due to the presence of other highly motivated family members with no single abnormality and who were ready for donation. The second cause is that (in our country) we are dealing only with living donation, and we seek better graft survival and function, and avoid kidney donors who might have progressive kidney disease or can cause problems for the recipient. Based on these findings, we considered all cases with grade 1 echogenicity to be inappropriate for donation.

Several studies were designed to address the correlation between US findings of a kidney with histological lesions and clinical findings of patients with different renal diseases, including glomerular, tubulointerstitial or systemic diseases affecting the kidneys [5,6,12]. They reported that renal cortical echogenicity is correlated with the severity of histological changes in renal parenchymal diseases such as overall sclerosis, focal tubular atrophy and hyaline casts per glomerulus.

The present study has at least shown that living kidney donation should be managed carefully and every effort should be made to be sure that donors must be free from any renal disease.

In conclusion, grade 1 echogenicity might be of value in donor selection, as it can be a sign of unrecognized kidney disease. When these donors are the only ones available for donation, renal biopsy must be considered. Follow-up of these donors, especially those with abnormal histopathology, is crucial in verifying and confirming the importance of grade 1 echogenicity in donor selection. The presence of positive radiological and histopathological data in a given donor should be considered with extreme caution and might even contraindicate donation, irrespective of minor lesions or the extent of motivation, as this might compromise graft function in the future; however, there should be a trial to obtain grafts from these donors and record their development. A protocol for future study is now being devised.

Conflict of Interest

The authors have no conflict of interest to declare.