The spectrum of renal cysts in adulthood—discussion of eight cases*

Hartmut P. H. Neumann

Department of Nephrology, Albert-Ludwigs-University, Freiburg i. B., Germany

Correspondence and offprint requests to: Prof. Dr med. Hartmut P. H. Neumann, Department of Nephrology, Albert-Ludwigs-University, Hugstetter Strasse 55, D-79106 Freiburg i. B., Germany.

Keywords: autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; nephronophthisis; autosomal dominant medullary cystic kidney disease; echinococcosis of the kidney; medullary sponge kidney; tuberous sclerosis complex; Von Hippel-Lindau disease

Introduction

The diagnosis of cystic renal disease in adults can be challenging. In this paper, the spectrum of cystic renal disease will be illustrated by focusing on the key radiological findings in eight patients (Figure 1Go). The reader may first wish to consider the differential diagnosis based on the radiographic images, before reading the associated text. Important points in the clinical or family history that contribute to the correct diagnosis will be emphasized, and the current molecular understanding of the disease will be summarized.




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Fig. 1. Radiological findings in eight patients (see over).

 
The six crucial pieces of information and questions which can help to find the diagnosis of cystic renal disease are given in Table 1Go.


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Table 1. Evaluation of adults with renal cysts
 
The majority of cystic renal diseases are inherited and associated with predisposing mutations of susceptibility genes. The nomenclature of localization of the genes is based on chromosomal bands obtained by Giemsa staining. Figure 2Go shows chromosome 7 with short (p) and long (q) arms and numbers of bands with more precise subbands (middle and left). Typical mutation types of intra-exonic mutations (missense, nonsense, frame shift) are shown below the chromosome.



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Fig. 2. Chromosome 7 and examples of intraexonic mutations.

 
Case 1

Figure 3Go shows the contrast-enhanced computed tomography (CT) scan of a 36-year-old male with normal serum creatinine. Both kidneys are enlarged, contain abundant cysts, have irregular surface and seem to have reduced functioning parenchyma indicated by contrast-enhanced tissue. In addition, the liver shows several cysts. It is important to know whether there is a positive family history of polycystic kidney disease, consistent with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD) (Figure 4Go). In ADPKD, extrarenal lesions can include cysts in the liver, pancreas or spleen, CNS aneurysms, heart valve insufficiency, hernia and diverticula of the colon (Figure 5Go) [1]. There are at least three susceptibility genes for ADPKD. The PKD1 gene is localized on the short arm of chromosome 16 (16p13) with 46 exons encoding a protein of 4304 AA named polycystin 1. PKD1 is mutated in about 85% of ADPKD. The PKD2 gene is localized on the long arm of chromosome 4 (4q13-23) with 15 exons encoding a protein of 968 AA called polycystin 2. Additional PKD genes have not yet been identified [2,3].



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Fig. 3. CT scan of case 1.

 


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Fig. 4. Family tree of case 1.

 


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Fig. 5. Extrarenal lesions in the Freiburg ADPKD-register (n=298) and angiography of a cerebral aneurysm in ADPKD.

 
There are four important consequences of knowing the underlying PKD1 or PKD2 mutation in a patient with ADPKD:
  1. to make the diagnosis if family history and screening investigations are negative,
  2. to differentiate ADPKD 1 and ADPKD 2 since ESRF occurs roughly 15 years later in type 2,
  3. to exclude a carrier status in a relative who is willing to serve as a donor for kidney transplantation and
  4. for prenatal diagnosis.

Due to the gene structure, however, mutation analysis is still time intensive and not available for clinical practice. Linkage analysis which provides only the results of likelihood have been used (Figure 4Go demonstrating linkage of allele C with the disease; bold symbols) [4]. Mutations reported from limited series of PKD1 and PKD2 patients have shown mutations of different types in both genes.

Molecular biological and biochemical research has yielded interesting aspects for understanding the macro- and micro-pathological features of proliferation, fluid accumulation and matrix alteration, but currently no proposals for prevention have emerged from such pathophysiological analysis [1].

Case 2

This CT showed abundant cysts scattered all over the renal parenchyma, and the 18-year-old patient with CRF was considered to have ADPKD (Figure 6Go). The young age of the patient, and the family history (only a sister had PKD) were atypical, leading to the possible diagnosis of ARPKD (Figure 7Go). In such a situation further investigations should be performed including renal sonography of the parents, paternity test and liver biopsy of the patient (Figure 8Go). Liver fibrosis is a classical feature of ARPKD [5]. The gene has been mapped on chromosome 6p21-cen, but is not identified [6]. The diagnosis has important implications, since offspring have a very low risk of developing the disease. Interestingly, this patient subsequently required surgery for multiple cerebral aneurysms (Figure 9Go), lesions usually associated with ADPKD [7]. ARPKD is most frequently diagnosed in very young children based on clinical findings.



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Fig. 6. CT scan of case 2.

 


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Fig. 7. Family tree of case 2.

 


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Fig. 8. Liver biopsy of case 2.

 


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Fig. 9. Cerebral aneurysm in ADPKD (case 2).

 
Case 3

This CT of a 17-year-old male patient showed bilateral renal cysts which were localized in the cortico-medullary boundary area, consistent with juvenile nephronophthisis (NPH) (Figure 10Go). Patients develop symptoms of renal failure in the first and second decade (serum creatinine 2.4 mg/dl in the given case). Family information, particularly renal ultrasound findings of the parents, are important. The family history in this disease can be consistent with either autosomal recessive (Figure 11Go) or autosomal dominant (see later) inheritance.



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Fig. 10. CT scan of case 3.

 


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Fig. 11. Family tree of case 3.

 
Both histological findings and molecular genetic testing can be crucial for establishing the diagnosis. Classical findings are low number of nephrons, shrunken parenchyma, corticomedullary cysts, signs of inflammation and fibrosis in the interstitium (Figure 12a and bGo). High power magnification shows alterations of the tubular basement membrane with splitting and peritubular sclerosis. Based on such findings and in absence of ocular changes, the diagnosis juvenile NPH can be established [8].



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Fig. 12. Renal biopsy results of case 3.

 
Mutations predisposing for NPH have been identified in the NPHP1 gene which is localized on the short arm of chromosome 2 (2p13) [9]. An example is shown in Figure 13Go. The father has hemizygous deletion of a gene, the mother a T->A mutation causing a stop codon, and both affected chromosomes (alleles) have been inherited by the child. The autosomal recessive form of this disease is important, since the offspring of affected individuals are unlikely to develop nephronophthisis. The protein encoded by the NPHP1 gene is called nephrocystin.



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Fig. 13. Analysis of the NPHP 1 gene (20 exons) on 2p13 (taken from ref. 9).

 
Every patient in whom the diagnosis of NPH is suspected should undergo ophthalmological investigation (Figure 14Go) [10,11]. Retinitis pigmentosa associated with NPH constitutes the Senior Loken syndrome (SLS). Retinoscopy reveals pigmented spots (Figure 14aGo). Visual fields can be bilaterally reduced to the central area and a sickle-like region in the periphery (Figure 14bGo). Night blindness may be caused by reduced rod function. The susceptibility gene for SLS remains still unknown.



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Fig. 14. Ophthalmological investigation of case 3.

 
NPH and SLS can occur as isolated and thus seemingly sporadic cases, possibly explained by the small size of the family. Increasing availability of genetic laboratories and research progress are expected to permit classification of most patients within the near future.

All findings including histology (Figure 15Go) of NPH can be present also in patients whose family pedigree is consistent with autosomal dominant inheritance of the disease, as shown in Figure 16Go. Such a patient become mostly symptomatic at the end of the 3rd decade and can in fact not be distinguished from NPH except by pedigree analysis. This entity is autosomal dominant medullary cystic kidney disease (ADMCKD) [12]. The susceptibility gene has not been mapped or identified yet.



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Fig. 15. Histology of NPH/ADMCKD.

 


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Fig. 16. Family tree of ADMCKD (see discussion of case 3).

 
Case 4

This CT of a 27-year-old female patient shows a single cyst of 10–15 cm in diameter (Figure 17Go). Other renal findings were normal—as can be expected in unilateral renal disease. Most of such cysts are assumed to be simple cysts and do not require therapy. Hypertension was present in this patient. Blood pressure values may return to the normal range once the cyst has been removed by puncture (or other means). In cases of unilateral cystic disease, echinococcosis should be considered as the underlying disease, as was present in this patient. Echinococcal cysts often exhibit calcifications in the membrane and inhomogeneous internal structures, although these were not present in this case. It is necessary to evaluate the cyst fluid (Figure 18a and bGo) by microscopy immediately after it has been obtained [13].



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Fig. 17.

CT scans of case 4.

 


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Fig. 18. Microscopy of cyst fluid.

 
Case 5

These CT findings of a 33-year-old male patient had initially been interpreted as polycystic kidney disease (Figure 19Go). The patient was admitted with impaired renal function (serum creatinine 2.2 mg/dl). Renal tubular acidosis and the disseminated microcalcification are consistent with the diagnosis of medullary sponge kidney. This disease causes deceleration of urine flow in i.v. pyelography or magnetic resonance angiography. The etiology remains to be clarified. The family history was negative [14].



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Fig. 19. CT scan of case 5.

 
Case 6

The numerous bilateral spheroid lesions in the CT of a 36-year-old female patient are not cysts (Figure 20Go). Radiological density reveals negative Hounsfield units which is consistent with fat tissue. These lesions are multiple angiomyolipomas (AML) [15]. Patients with AML, however, can have in addition renal cysts as shown in Figure 21Go. Such lesions are highly suggestive of the tuberous sclerosis complex (TSC), whereas isolated AML mainly occur as sporadic lesions [16]. Renal manifestations are essential for the diagnosis of TSC. The spectrum of involved organs is broad and variable. Classical features are facial angiofibroma, subependymal calcifications, retinophacoma (Mulberry tumour), and periungual fibromas (Figure 22Go) [17,18].



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Fig. 20. CT scan of case 6.

 


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Fig. 21. CT scan showing bilateral renal cysts and angiomyolipoma in a TSC patient.

 


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Fig. 22. Classic extrarenal features of TSC.

 
Mutations in two genes, the TSC1 gene, localized on chromosome 9 (9q34) [19], and the TSC2 gene on chromosome 16 (16p13) [20] can independently lead to the syndrome without phenotypic differences. Both TSC genes are very large (TSC1 1164 amino acids encoding the protein hamartin, the TSC2 gene 1784 amino acids encoding the protein tuberin). A limited series of TSC2 patients showed mutations of different types scattered over many of the 41 exons of the TSC2 gene [21]. Possibly because of a high spontaneous mutation rate, the TSC patients, family history is frequently negative in TSC patients.

Case 7

This MRI with i.v. Gadolinium contrast of a 38-year-old male patient showed bilateral renal cysts (C) and bilateral tumours (T). Together with TSC, the second important cystic and tumorous disease of the kidneys is Von Hippel-Lindau syndrome (VHL) (Figures 23 and 24GoGo) [22]. Similarly to TSC, cysts of different size occur, and renal function is not impaired. Again similarly to TSC, multiple solid lesions are typically seen. In contrast to TSC, there is no fatty tissue component in VHL, and the tumours are renal clear cell carcinomas (RCC). Most of the VHL-associated RCCs have a marked fibrous `capsula', and a cystic growth pattern (Figure 25Go) which can in some cases be recognized based on their radiologic pattern [23].



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Fig. 23. MRI scan of case 7 with bilateral VHL-associated renal cell carcinomas (T) and cysts (C).

 


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Fig. 24. Features of Von Hippel-hindau syndrome. Note the various expressions of the disease with symptomatic (solid) and asymptomatic (hatched symbols); lesions of the eye (upper left), CNS (upper right), kidney (lower left), and pancreas (central).

 


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Fig. 25. Cystic growth pattern of VHL-associated renal clear cell carcinoma.

 
VHL is an autosomal dominant disorder, and VHL-associated lesions occur in many organs. Most can be treated effectively, if the patients are recognized in time. The VHL gene, localized on the short arm of chromosome 3 (3p25-26), was identified through positional cloning and subsequently identified [24]. The VHL gene contains three exons, and more than 200 distinct mutations spread all over the three exons have been reported [2527]. Analysis for germline mutations should be performed in all subjects with candidate lesions of the kidney. This includes multiple and bilateral RCC with or without uni- or bilateral renal cysts in predominantly younger patients (<50 years) with or without extrarenal VHL-associated lesions with or without family history.

Case 8

This MRI of a 63-year-old male patient was primarily suggestive of Von Hippel-Lindau disease because of bilateral renal cysts and tumors (Figure 26Go). Nephron-sparing surgery revealed 20 tumours of the left, and 9 tumours of the right kidney, all oncocytomas (Figure 27Go) [28]. Thus, some patients with cystic and tumorous renal lesions may be difficult to classify. Such patients may lead to the identification of new syndromes and the identification of novel tumour predisposition genes [29].



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Fig. 26. MRI scan of case 8.

 


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Fig. 27. Oncocytoma from Histological typing of kidney tumours, Mostofi FK, Davis CJ Jr (eds), WHO/Springer, 1998.

 

Acknowledgments

The author appreciates the editorial assistance of Elizabeth Petoi Henske, MD, Philadelphia.

Notes

* Invited Guest Lecture at the ERA-EDTA Congress, Rimini, 1998. Back

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